r/EPA
United States
Environmental Protection
Agency
Office of Research and
Development
Washington DC 20460
JEPA/600/AP-95/001 b
April 1995
External Review Draft
d.l
Air Quality
Criteria for
Paniculate
Matter
Volume II of III
Review
Draft
(Do Not
Cite or
Quote)
Notice
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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DRAFT-DO NOT QUOTE OR CITE EPA/eoo/AP-95/ooib
April 1995
External Review Draft
Air Quality Criteria for
Particulate Matter
Volume II of
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Printed on Recycled Paper
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DISCLAIMER
This document is an external draft for review purposes only and does not constitute
U.S. Environmental Protection Agency policy. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
April 1995 H-ii DRAFT-DO NOT QUOTE OR CITE
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Air Quality Criteria for Particulate Matter
TABLE OF CONTENTS
Volume I
1. EXECUTIVE SUMMARY 1-1
2. INTRODUCTION 2-1
3. PHYSICS AND CHEMISTRY OF PARTICULATE MATTER 3-1
4. SAMPLING AND ANALYSIS OF PARTICULATE MATTER AND
ACID DEPOSITION 4-1
5. SOURCES AND EMISSIONS OF SUSPENDED PARTICLES 5-1
6. ENVIRONMENTAL CONCENTRATIONS 6-1
Appendix 6A: Tables of Chemical Composition of PM 6A-1
7. EXPOSURE: AMBIENT AND INDOOR 7-1
Volume II
8. EFFECTS ON VISIBILITY AND CLIMATE 8-1
9. EFFECTS ON MATERIALS 9-1
10. DOSIMETRY OF INHALED PARTICLES IN THE
RESPIRATORY TRACT 10-1
11. TOXICOLOGY OF PARTICULATE MATTER CONSTITUENTS 11-1
Volume III
12. EPIDEMIOLOGY STUDIES OF HEALTH EFFECTS ASSOCIATED
WITH EXPOSURE TO AIRBORNE PARTICLES/ACID
AEROSOLS 12-1
Appendix 12A: Effects of Weather and Climate on Human Mortality and
Their Roles as Confounding Factors for Air Pollution 12A-1
13. INTEGRATIVE HEALTH SYNTHESIS 13-1
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TABLE OF CONTENTS
LIST OF TABLES II-xiv
LIST OF FIGURES II-xxiii
AUTHORS, CONTRIBUTORS, AND REVIEWERS II-xxx
8.EFFECTS ON VISIBILITY AND CLIMATE 8-1
8.1 INTRODUCTION 8-1
8.2 FUNDAMENTALS OF ATMOSPHERIC VISIBILITY 8-2
8.2.1 Physics of Light Extinction 8-2
8.2.2 Measurement Methods 8-3
8.2.2.1 Total Extinction 8-3
8.2.2.2 Light Scattering 8-5
8.2.2.3 Light Absorption Coefficient 8-6
8.2.3 Role of Paniculate Matter in Visibility Impairment 8-7
8.2.3.1 Rayleigh Scattering 8-7
8.2.3.2 Nitrogen Dioxide Absorption 8-7
8.2.3.3 Particle Scattering 8-7
8.2.3.4 Particle Absorption 8-10
8.2.4 Chemical Composition of Atmospheric Particles 8-12
8.2.4.1 Role of Water in Visibility Impairment 8-14
8.2.4.2 Light Extinction Budgets 8-16
8.3 VISIBILITY AND PERCEPTION 8-16
8.4 SOURCES OF VISIBILITY IMPAIRMENT 8-19
8.4.1 Natural Sources 8-19
8.4.2 Anthropogenic Sources 8-20
8.5 ECONOMIC VALUATION OF EFFECTS OF PARTICULATE
MATTER ON VISIBILITY 8-28
8.5.1 Basic Concepts of Economic Valuation 8-28
8.5.2 Economic Valuation Methods for Visibility 8-29
8.5.2.1 Contingent Valuation Method 8-30
8.5.2.2 Hedonic Property Value Method 8-31
8.5.3 Studies of Economic Valuation of Visibility 8-32
8.5.3.1 Economic Valuation Studies for Ah* Pollution
Plumes 8-32
8.5.3.2 Economic Valuation Studies for Urban Haze 8-34
8.6 CLIMATIC EFFECTS 8-39
8.6.1 Introduction 8-39
8.6.2 Radiative Forcing 8-40
8.6.3 Solar Radiative Forcing by Aerosols 8-43
8.6.3.1 Modeling Aerosol Direct Solar Radiative Forcing 8-46
8.6.3.2 Global Annual Mean Radiative Forcing 8-49
8.6.4 Climate Response 8-51
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TABLE OF CONTENTS (cont'd)
Page
8.6.4.1 Early Studies 8-51
8.6.4.2 Recent Regional Studies 8-53
8.6.4.3 Integrated Global Studies 8-55
8.6.5 AEROSOL EFFECTS ON CLOUDS AND
PRECIPITATION 8-61
8.6.5.1 Indirect Solar Radiative Forcing 8-61
8.6.5.2 Observational Evidence 8-65
8.6.5.3 Modeling Indirect Aerosol Forcing 8-66
8.7 SUMMARY 8-68
REFERENCES 8-72
9. EFFECTS ON MATERIALS 9-1
9.1 CORROSION AND EROSION 9-1
9.1.1 Metals 9-1
9.1.2 Paints 9-3
9.1.3 Stone 9-4
9.1.4 Electronics 9-5
9.2 SOILING AND DISCOLORATION 9-6
9.2.1 Building Materials 9-7
9.2.1.1 Fabrics 9-9
9.2.1.2 Household and Industrial Paints 9-9
9.2.1.3 Soiling of Works of Art 9-12
9.3 ECONOMIC ESTIMATES 9-12
9.3.1 Economic Loss Associated with Materials Damage and Soiling .. 9-15
9.3.1.1 Metals and Other Material Damage 9-15
9.3.1.2 Soiling of Paint and Other Materials 9-16
9.4 SUMMARY OF ECONOMIC DAMAGE OF PARTICULATE
MATTER TO MATERIALS 9-22
REFERENCES 9-24
10. DOSIMETRY OF INHALED PARTICLES IN THE RESPIRATORY
TRACT 10-1
10.1 INTRODUCTION 10-1
10.1.1 General Considerations for Extrapolation Modeling 10-3
10.1.1.1 Model Structure and Parameterization 10-4
10.1.1.2 Intraspecies Variability 10-6
10.1.1.3 Extrapolation of Laboratory Animal Data to
Humans 10-7
10.2 CHARACTERISTICS OF INHALED PARTICLES 10-7
10.3 ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY TRACT . . 10-14
10.4 FACTORS CONTROLLING COMPARATIVE INHALED DOSE 10-28
10.4.1 Deposition Mechanisms 10-34
10.4.1.1 Gravitational Settling or Sedimentation 10-35
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TABLE OF CONTENTS (cont'd)
Page
10.4.1.2 Inertial Impaction 10-36
10.4.1.3 Brownian Diffusion 10-38
10.4.1.4 Interception 10-39
10.4.1.5 Electrostatic Precipitation 10-41
10.4.1.6 Comparative Aspects of Deposition 10-41
10.4.1.7 Additional Factors Modifying Deposition 10-46
10.4.2 Clearance and Translocation Mechanisms 10-53
10.4.2.1 Extrathoracic Region 10-55
10.4.2.2 Tracheobronchial Region 10-56
10.4.2.3 Alveolar Region 10-58
10.4.2.4 Clearance Kinetics 10-61
10.4.2.5 Factors Modifying Clearance 10-68
10.4.2.6 Comparative Aspects of Clearance 10-72
10.4.2.7 Lung Overload 10-73
10.4.3 Acidic Aerosols 10-75
10.4.3.1 Hygroscopicity of Acidic Aerosols 10-75
10.4.3.2 Neutralization and Buffering of Acidic Particles 10-81
10.5 DEPOSITION DATA AND MODELS 10-85
10.5.1 Humans 10-85
10.5.1.1 Total Deposition 10-85
10.5.1.2 Extrathoracic Deposition 10-88
10.5.1.3 Tracheobronchial (TB) Deposition 10-94
10.5.1.4 Alveolar Deposition 10-97
10.5.1.5 Nonuniform Distribution of Deposition and Local
Deposition Hot Spots 10-100
10.5.1.6 Summary 10-101
10.5.2 Laboratory Animals 10-104
10.5.3 Acidic Aerosols 10-116
10.6 CLEARANCE DATA AND MODELS 10-119
10.6.1 Humans 10-120
10.6.2 Laboratory Animals 10-126
10.6.3 Species Similarities and Differences 10-127
10.6.4 Models to Estimate Retained Dose 10-132
10.6.4.1 Extrathoracic and Conducting Airways 10-135
10.6.4.2 Alveolar Region 10-138
10.7 APPLICATION OF DOSIMETRY MODELS TO DOSE-RESPONSE
ASSESSMENT 10-139
10.7.1 Dosimetry Model Selection 10-140
Human Model 10-140
Laboratory Animal Model 10-141
10.7.2 Choice of Dose Metrics 10-142
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TABLE OF CONTENTS (cont'd)
Page
10.7.3 Choice of Exposure Metrics 10-150
Human Exposure Data 10-150
Laboratory Animal Data 10-155
10.7.4 Deposited Dose Estimations 10-155
Human Deposition Estimates 10-164
Laboratory Animal Deposition Estimates 10-172
10.7.5 Retained Dose Estimations 10-183
10.7.6 Summary 10-201
REFERENCES 10-203
11. TOXICOLOGICAL STUDIES OF PARTICULATE MATTER 11-1
11.1 INTRODUCTION 11-1
11.2 ACIDIC SULFATE PARTICLES 11-3
11.2.1 Controlled Human Exposure Studies of Acid Aerosols 11-3
11.2.1.1 Introduction 11-3
11.2.1.2 Pulmonary Function Effects Of H2SO4 In
Healthy Subjects 11-13
11.2.1.3 Pulmonary Function Effects Of H2SO4 In
Asthmatic Subjects 11-16
11.2.1.4 Effects Of Acid Aerosols On Airway
Responsiveness 11-31
11.2.1.5 Effects Of Acid Aerosols On Lung
Clearance Mechanisms 11-34
11.2.1.6 Effects Of Acid Aerosols Studied By
Bronchoscopy And Airway Lavage 11-35
11.2.1.7 Acid Aerosols And Other Pollutants 11-36
11.2.1.8 Particulate Matter Other Than Acid Aerosols 11-41
11.2.1.9 Summary and Conclusions 11-43
11.2.2 Laboratory Animal Studies 11-45
11.2.2.1 Introduction 11-45
11.2.2.2 Mortality 11-45
11.2.2.3 Pulmonary Mechanical Function 11-46
11.2.2.4 Pulmonary Morphology and Biochemistry 11-52
11.2.2.5 Pulmonary Defenses 11-58
11.3 SIMPLE BINARY MIXTURES 11-73
11.3.1 Mixtures Containing Acidic Sulfate Particles 11-78
11.3.2 Nitrates 11-82
11.3.2.1 Human Studies 11-82
11.3.2.2 Animal Studies 11-84
11.4 COMPLEX MIXTURES 11-86
11.4.1 Introduction 11-86
11.4.2 Mixtures Containing Other PM 11-86
11.4.3 Atmospheric Particulate Matter 11-87
11.4.3.1 Introduction 11-87
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TABLE OF CONTENTS (cont'd)
Page
11.4.3.2 Particulate Matter and Cancer in Animals 11-88
11.4.3.3 Genotoxicity of Particulate Matter 11-97
11.4.3.4 Testing of Emission Sources Contributing
to Particulate Matter 11-100
11.4.3.5 Discussion of Evidence for Genotoxicity
and Carcinogenicity in Animals 11-106
11.4.3.6 Particulate Matter and Cancer in Humans 11-107
11.4.3.7 Biomarkers of Genetic Damage 11-111
11.4.4 Diesel Exhaust Emissions 11-113
11.4.4.1 Noncancer Health Effects 11-114
11.4.4.2 Mutagenicity 11-129
11.4.4.3 Diesel Carcinogenicity Studies 11-129
11.5 ULTRAFINE PARTICLES 11-144
11.6 METALS 11-148
11.6.1 Introduction 11-148
11.6.2 Aluminum 11-149
11.6.2.1 Chemical and Physical Properties 11-149
11.6.2.2 Pharmacokinetics 11-149
11.6.2.3 Health Effects 11-152
11.6.2.4 Factors Affecting Susceptibility 11-159
11.6.3 Antimony 11-160
11.6.3.1 Chemical and Physical Properties 11-160
11.6.3.2 Pharmocokinetics 11-161
11.6.3.3 Health Effects 11-163
11.6.3.4 Factors Affecting Susceptibility 11-173
11.6.4 Arsenic 11-173
11.6.4.1 Physical/Chemical Properties 11-173
11.6.4.2 Pharmacokinetics 11-174
11.6.4.3 Health Effects 11-177
11.6.4.4 Factors Affecting Susceptibility 11-182
11.6.5 Barium 11-182
11.6.5.1 Chemical and Physical Properties 11-182
11.6.5.2 Pharmacokinetics 11-182
11.6.5.3 Health Effects 11-184
11.6.5.4 Factors Affecting Susceptibility 11-186
11.6.6 Cadmium 11-188
11.6.6.1 Chemical and Physical Properties 11-188
11.6.6.2 Pharmacokinetics 11-189
11.6.6.3 Health Effects 11-192
11.6.6.4 Factors Affecting Susceptibility 11-219
11.6.7 Chromium 11-220
11.6.7.1 Chemical and Physical Properties 11-220 *
11.6.7.2 Pharmacokinetics 11-221
11.6.7.3 Health Effects 11-223
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TABLE OF CONTENTS (cont'd)
Pas
11.6.7.4 Factors Affecting Susceptibility 11-239
11.6.8 Cobalt 11-239
11.6.8.1 Chemical and Physical Properties 11-239
11.6.8.2 Pharmacokinetics 11-240
11.6.8.3 Health Effects 11-242
11.6.8.4 Factors Affecting Susceptibility 11-256
11.6.9 Copper 11-257
11.6.9.1 Chemical and Physical Properties 11-257
11.6.9.2 Pharmacokinetics 11-258
11.6.9.3 Health Effects 11-259
11.6.9.4 Factors Affecting Susceptibility 11-266
11.6.10 Iron 11-267
11.6.10.1 Chemical and Physical Properties 11-267
11.6.10.2 Pharmacokinetics 11-268
11.6.10.3 Health Effects 11-268
11.6.10.4 Factors Affecting Susceptibility 11-274
11.6.11 Mercury 11-274
11.6.11.1 Physical/Chemical Properties 11-274
11.6.11.2 Pharmacokinetics 11-274
11.6.11.3 Health Effects 11-279
11.6.11.4 Factors Affecting Susceptibility 11-296
11.6.12 Manganese 11-298
11.6.12.1 Physical and Chemical Properties 11-298
11.6.12.2 Pharmacokinetics 11-299
11.6.12.3 Health Effects 11-301
11.6.12.4 Comparative Toxicity 11-305
11.6.12.5 Factors Affecting Susceptibility 11-307
11.6.13 Magnesium 11-307
11.6.13.1 Chemical and Physical Properties 11-307
11.6.13.2 Pharmacokinetics 11-308
11.6.13.3 Health Effects 11-308
11.6.13.4 Factors Affecting Susceptibility 11-313
11.6.14 Molybdenum 11-314
11.6.14.1 Chemical and Physical Properties 11-314
11.6.14.2 Pharmacokinetics 11-314
11.6.14.3 Health Effects 11-315
11.6.14.4 Factors Affecting Susceptibility 11-323
11.6.15 Nickel 11-323
11.6.15.1 Physical/Chemical Properties 11-323
11.6.15.2 Pharmacokinetics 11-324
11.6.15.3 Health Effects 11-327
11.6.15.4 Factors Affecting Susceptibility 11-346
11.6.16 Potassium 11-347
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TABLE OF CONTENTS (cont'd)
11.6.16.1 Chemical and Physical Properties 11-347
11.6.17.2 Pharmacokinetics 11-348
11.6.16.3 Health Effects 11-348
11.6.16.4 Factors Affecting Susceptibility 11-351
11.6.17 Selenium 11-351
11.6.17.1 Chemical and Physical Properties 11-351
11.6.17.2 Pharmacokinetics 11-352
11.6.17.3 Health Effects 11-355
11.6.17.4 Factors Affecting Susceptibility 11-362
11.6.18 Tin 11-362
11.6.18.1 Chemical and Physical Properties 11-362
11.6.18.2 Pharmacokinetics 11-363
11.6.18.3 Health Effects 11-364
11.6.18.4 Factors Affecting Susceptibility 11-374
11.6.19 Titanium 11-374
11.6.19.1 Chemical and Physical Properties 11-374
11.6.19.2 Pharmacokinetics 11-375
11.6.19.3 Health Effects 11-377
11.6.19.4 Factors Affecting Susceptibility 11-387
11.6.20 Vanadium 11-387
11.6.20.1 Chemical and Physical Properties 11-387
11.6.20.2 Pharmacokinetics 11-388
11.6.20.3 Health Effects 11-391
11.6.20.4 Factors Affecting Susceptibility 11-400
11.6.21 Zinc 11-400
11.6.21.1 Chemical and Physical Properties 11-400
11.6.21.2 Pharmacokinetics 11-401
11.6.21.3 Health Effects 11-403
11.6.21.4 Factors Affecting Susceptibility 11-414
11.7 SILICA 11-414
11.7.1 Physical and Chemical Properties 11-415
11.7.2 Health Effects 11-416
11.7.2.1 Differences Between Chemical Forms of Silica 11-417
11.7.2.2 Species Differences 11-418
11.7.3 Recent Concepts in the Mechanisms of Silica-related
Lung Disease 11-421
11.8 ASBESTOS 11-423
11.8.1 General Characteristics 11-423
11.8.1.1 Types of Asbestos 11-424
11.8.2 Biophysical Factors and their Roles in the Development
of Fiber Toxicity 11-425
11.8.2.1 Studies on the Mechanisms of Asbestos-Induced
Lung Injury 11-427
11.8.2.2 Fiber-Induced Inflammation 11-429
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TABLE OF CONTENTS (cont'd)
Page
11.8.2.3 Growth Factors 11-429
11.9 TOXICOLOGY OF OTHER PARTICULATE MATTER 11-430
11.9.1 Introduction 11-430
11.9.2 Mortality 11-431
11.9.3 Pulmonary Mechanical Function 11-431
11.9.4 Pulmonary Morphology and Biochemistry 11-435
11.9.5 Pulmonary Defenses 11-445
11.9.5.1 Clearance Function 11-445
11.9.5.2 Resistance to Infectious Disease 11-448
11.9.5.3 Immunologic Defense 11-452
11.9.6 Systemic Effects 11-452
11.10 MECHANISMS OF TOXICOLOGICAL INTERACTIONS 11-454
11.11 TOXICOLOGY OF PM IN COMPROMISED HOST ANIMAL
MODELS 11-455
11.12 FACTORS INFLUENCING PM TOXICITY 11-457
11.12.1 Particle Acidity 11-458
11.12.2 Particle Surface Coatings 11-458
11.12.3 Particle Size 11-460
11.12.4 Particle Number Concentration 11-463
11.14 SUMMARY 11-464
11.14.1 Summary of Acid Aerosols 11-464
11.14.2 Summary of Complex Mixtures 11-467
11.14.2.1 Summary of Carcinogenicity of Atmospheric
Paniculate Matter 11-467
11.14.2.2 Summary of Diesel Emissions 11-468
Noncancer effects of diesel emissions 11-468
Carcinogenic effects of diesel emissions 11-469
11.14.3 Summary of Metals 11-470
11.14.3.1 Aluminum 11-470
11.14.3.2 Antimony 11-471
11.14.3.3 Arsenic 11-472
11.14.3.4 Barium 11-472
11.14.3.5 Cadmium 11-473
11.14.3.6 Chromium 11-474
11.14.3.7 Cobalt 11-475
11.14.3.8 Copper 11-477
11.14.3.9 Iron 11-478
11.14.3.10 Mercury 11-478
11.14.3.11 Manganese 11-479
11.14.3.12 Magnesium 11-481
11.14.3.13 Molybdenum 11-482
11.14.3.14 Nickel 11-483
11.14.3.15 Potassium 11-484
11.14.3.16 Selenium 11-485
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TABLE OF CONTENTS (cont'd)
11.14.3.17 Tin 11-486
11.14.3.18 Titanium 11-486
11.14.3.19 Vanadium 11-487
11.14.3.20 Zinc 11-488
11.14.4 Silica 11-489
11.4.5 Asbestos 11-491
REFERENCES 11-492
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LIST OF TABLES
Number
8-1 Average Natural Background Levels of Aerosols and Light Extinction .... 8-13
8-2 Long-Term Visibility and Aerosol Databases 8-21
8-3 Short-Term Intensive Visibility and Aerosol Studies 8-24
8-4 Economic Valuation Studies for Air Pollution Plumes 8-33
8-5 Economic Valuation Studies on Urban Haze 8-35
8-6 Radiative Forcing and Climate Statistics 8-60
10-1 Hierarchy of Model Structures for Dosimetry and Extrapolation 10-5
10-2 Respiratory Tract Regions 10-16
10-3 Architecture of the Human Lung According to Weibel's (1963) Model A,
With Regularized Dichotomy 10-25
10-4 Morphology, Cytology, Histology, Function, and Structure of the
Respiratory Tract and Regions Used in the ICRP (1994) Human
Dosimetry Model 10-29
10-5 Interspecies Comparison of Nasal Cavity Characteristics 10-43
10-6 Comparative Lower Airway Anatomy as Revealed on Casts 10-44
10-7 Acinar Morphometry 10-45
10-8 Deposition Data for Men and Women 10-47
10-9 Overview of Respiratory Tract Particle Clearance and Translocation
Mechanisms 10-55
10-10 Long-Term Retention of Insoluble Particles From the Alveolar Region
in Non-Smoking Humans 10-65
10-11 Fraction of "Normal" Ventilatory Airflow Passing Through the Nose in
Human Augmenter" and "Mouth Breather" 10-99
10-12 Regional Fractional Deposition 10-109
10-13 Deposition Efficiency Equation Estimated Parameters 10-111
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LIST OF TABLES (cont'd)
Number Page
10-14 Comparative Pulmonary Retention Parameters for Poorly Soluble
Particles Inhaled by Laboratory Animals and Humans 10-129
10-15 Average Pulmonary Retention Parameters for Poorly Soluble Particles
Inhaled by Selected Laboratory Animal Species and Humans 10-132
10-16 Physical Clearance Rates 10-133
10-17 Physical Clearance Rates3 for Modeling Alveolar Clearance of Particles
Inhaled by Humans and Selected Mammalian Species 10-139
10-18 Species Comparisons by Miller et al. (1995) of Various Dose Metrics as
a Function of Particle Size for 24 h Exposures to 150 /xg/m3 10-143
10-19a Body Weight and Respiratory Tract Region Surface Areas 10-145
10-19b Human Activity Patterns and Associated Respiratory Minute
Ventilation 10-145
10-20 Body Weights, Lung Weights, Respiratory Minute Ventilation and
Respiratory Tract Region Surface Area for Selected Laboratory Animal
Species 10-146
10-21 Distribution of Particle Sizes in a Trimodal Polydisperse Aerosol 10-152
10-22 Distribution of Particle Mass in a Trimodal Polydisperse Aerosol 10-153
10-23 Distribution of Particle Sizes in a Trimodal Polydisperse Aerosol for
Philadelphia 10-156
10-24 Distribution of Particle Mass in a Trimodal Polydisperse Aerosol for
Philadelphia 10-157
10-25 Distribution of Particle Sizes in a Trimodal Polydisperse Aerosol for
Phoenix 10-159
10-26 Distribution of Particle Mass in a Trimodal Polydisperse Aerosol
for Phoenix 10-160
10-27 Distribution of Particle Sizes in a Polydisperse Aerosol for
Los Angeles 10-163
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LIST OF TABLES
Number
10-28 Distribution of Particle Mass in a Polydisperse Aerosol for
Los Angeles 10-164
10-29 Daily Mass Deposition of Particles from Aerosol in the Respiratory
Tract of "Normal Augmenter" Adult Male Humans Exposed at 50 tig
Particles/m3 10-165
10-30 Daily Mass Deposition of Particles From Aerosol in the Respiratory
Tract of "Mouth Breather" Adult Male Humans Exposed at 50 fig
Particles/m3 10-166
10-31 Daily Mass Deposition of Particles From Philadelphia Aerosol in
the Respiratory Tract of "Normal Augmenter" Adult Male Humans
Exposed at 50 fig Particles/m3 10-167
10-32 Daily Mass Deposition of Particles From Philadelphia Aerosol in
the Respiratory Tract of "Mouth Breather" Adult Male Humans
Exposed at 50 fig Particles/m3 10-168
10-33 Daily Mass Deposition of Particles From Phoenix Aerosol in
the Respiratory Tract of "Normal Augmenter" Adult Male Humans
Exposed at 50 fig Particles/m3 10-169
10-34 Daily Mass Deposition of Particles From Phoenix Aerosol in
the Respiratory Tract of "Mouth Breather" Adult Male Humans
Exposed at 50 iig Particles/m3 10-170
10-35 Daily Mass Deposition of Particles From Los Angeles Aerosol in
the Respiratory Tract of "Normal Augmenter" and "Mouth Breather"
Adult Male Humans Exposed at 50 fig Particles/m3 10-171
10-36 Daily Mass Deposition of Aerosol Particles in the Respiratory Tracts
of "Normal Augmenter" and "Mouth Breather" Adult Male Humans
Exposed to 50 fig Particles/m3 10-173
10-37 Extrathoracic Deposition Fractions of Inhaled Monodisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" 10-174
10-38 Extrathoracic Deposition Fractions of Inhaled Polydisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" 10-175
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LIST OF TABLES (cont'd)
Number Page
10-39 Tracheobronchial Deposition Fractions of Inhaled Monodisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" ................................ 10-176
10-40 Tracheobronchial Deposition Fractions of Inhaled Polydisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" ................................ 10-177
10-41 Alveolar Deposition Fractions of Inhaled Monodisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" ................................ 10-178
10-42 Alveolar Deposition Fractions of Inhaled Polydisperse Aerosols
in Various Laboratory Species and Human "Normal Augmenter"
and "Mouth Breather" ................................ 10-179
10-43 Fraction of Inhaled Particles Deposited in the Alveolar Interstitial
Region of the Respiratory Tract for Selected Mammalian Species and
Adult Male Humans ................................. 10-185
10-44 Summary of Common and Specific Inhalation Exposure Parameters
Used for Predicting Alveolar Burdens of Particles Inhaled by Mice,
Rats, Syrian Hamsters, Guinea Pigs, Monkeys, Dogs, and Humans .... 10-186
10-45 Alveolar Particle Burdens (/^g) of 0.5 /*m MMAD Aerosol Assuming
Particle Dissolution— Absorption Half-Time of 10 Days ........... 10-187
10-46 Alveolar Particle Burdens (ug) of 0.5 jiim MMAD Aerosol Assuming
Particle Dissolution-Absorption Half-Time of 100 Days ........... 10-188
10-47 Alveolar Particle Burdens (ug) of 0.5 /xm MMAD Aerosol Assuming
Particle Dissolution— Absorption Half— Time of 1,000 Days ........ 10-189
10-48 Alveolar Particle Burdens (ug) of 2.55 /*m MMAD Aerosol Assuming
Particle Dissolution— Absorption Half— Time of 10 Days .......... 10-190
10-49 Alveolar Particle Burdens (ug) of 2.55 pun MMAD Aerosol Assuming
Particle Dissolution-Absorption Half— Time of 100 Days .......... 10-191
10-50 Alveolar Particle Burdens (/xg) 2.55 ^m MMAD Aerosol Assuming Particle
Dissolution- Absorption Half-Time of 1,000 Days ............... 10-192
11-1 Controlled Human Exposures to Acid Aerosols and Other Particles ...... 11-7
April 1995 H-xvii DRAFT-DO NOT QUOTE OR CITE
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LIST OF TABLES (cont'd)
Number
11-2 Asthma Severity in Studies of Acid Aerosols and Other Particle 11-17
11-3 Pulmonary Function Responses After Aerosol and Ozone Exposures
in Subjects with Asthma 11-39
11-4 Effects of Acidic Sulfate Particles on Pulmonary Mechanical Function ... 11-47
11-5 Effects of Acidic Sulfate Particles on Respiratory Tract Morphology .... 11-53
11-6 Effects of Acidic Sulfate Particles on Respiratory Tract Clearance 11-60
11-7 Effects of Acid Sulfates on Bacterial Infectivity in Vivo 11-71
11-8 Toxicologic Interactions to Binary Mixtures Containing PM 11-74
11-9 Exposure Conditions and Responses in Subjects Exposed to Nitrates .... 11-83
11-10 Carcinogenicity Tests of Samples of Ambient Air Particulate
Matter in Animals 11-89
11-11 Human Studies of Diesel Exhaust Exposure 11-115
11-12 Short-term Effects of Diesel Exhaust on Laboratory Animals 11-120
11-13 Effects of Chronic Exposures to Diesel Exhaust on Survival and
Growth of Laboratory Animals 11-121
11-14 Effects of Diesel Exhaust on Pulmonary Function of Laboratory Animals 11-122
11-15 Histopathological Effects of Diesel Exhaust in the Lungs of
Laboratory Animals 11-124
11-16 Effects of Exposure to Diesel Exhaust on the Pulmonary Defense
Mechanisms of Laboratory Animals 11-126
11-17 Summary of Animal Carcinogenicity Studies 11-132
11-18 Numbers and Surface Areas of Monodisperse Particles of Unit Density of
Different Sizes at a Mass Concentration of 10 /ug/m3 11-145
11-19 Human Exposure Conditions and Effects for Aluminum Compounds ... 11-153
11-20 Laboratory Animals Exposure Conditions and Effects for Aluminum
Compounds 11-157
April 1995 II-xviii DRAFT-DO NOT QUOTE OR CITE
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LIST OF TABLES (cont'd)
Number Page
11-21 Human Exposure Conditions and Effects for Antimony and
Compounds 11-164
11-22 Laboratory Animal Exposure Conditions and Effects for Antimony and
Compounds 11-167
11-23 Laboratory Animal Exposure Conditions and Effects for Arsenic and
Compounds 11-179
11-24 Human Exposure Conditions and Effects for Barium and Compounds ... 11-185
11-25 Laboratory Animal Exposure Conditions and Effects for Barium and
Compounds 11-187
11-26 Human Exposure Conditions and Effects for Cadmium and Compounds . 11-193
11-27 Laboratory Animal Exposure Conditions and Effects for Cadmium and
Compounds 11-207
11-28 Human Exposure Conditions and Effects for Chromium and
Compounds 11-225
11-29 Laboratory Animal Exposure Conditions and Effects for Chromium and
Compound 11-232
11-30 Human Exposure Conditions and Effects for Cobalt and Compounds ... 11-243
11-31 Laboratory Animal Exposure Conditions and Effects for Cobalt and
Compounds 11-252
11-32 Human Exposure Conditions and Effects for Copper and Compounds . . . 11-260
11-33 Laboratory Animal Exposure Conditions and Effects for Copper and
Compounds 11-263
11-34 Human Exposure Conditions and Effects for Iron and Compounds 11-270
11-35 Laboratory Animal Exposure Conditions and Effects for Iron and
Compounds 11-273
11-36 Human Exposure Conditions and Effects for Mercury and
Compounds 11-281
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LIST OF TABLES (cont'd)
Number Page
11-37 Laboratory Animal Expsoure Conditions and Effects for Mercury
Vapor and Compounds 11-291
11-38 Human Exposure Conditions and Effects for Magnesium and
Compounds 11-310
11-39 Laboratory Animal Exposure Conditions and Effects for Magnesium and
Compounds 11-312
11-40 Human Exposure Conditions and Effects for Molybdenum and
Compounds 11-316
11-41 Laboratory Animal Exposure Conditions and Effects for Molybdenum
and Compounds 11-319
11-42 Exposure Conditions and Effects for Nickel
and Compounds 11-328
11-43 Laboratory Animal Exposure Conditions and Effects for Nickel and
Compounds 11-331
11-44 Human Exposure Conditions and Effects for Potassium and
Compounds 11-349
11-45 Human Exposure Conditions and Effects for Selenium and
Compounds 11-357
11-46 Laboratory Animal Exposure Conditions and Effects for Selenium and
Compounds 11-359
11-47 Human exposure conditions and effects for tin and compounds 11-365
11-48 Laboratory Animal Exposure Conditions and Effects for Tin and
Compounds 11-372
11-49 Human Exposure Conditions and Effects for Titanium and Titanium
Compounds 11-378
11-50 Laboratory Animal Exposure Conditions and Effects for Titanium
and Titanium Compounds 11-380
11-51 Human Exposure Conditions and Effects for Vanadium Compounds .... 11-393
April 1995 H-xx DRAFT-DO NOT QUOTE OR CITE
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LIST OF TABLES (cont'd)
Number Page
11-52 Laboratory Animal Exposure Conditions and Effects for Vanadium
Compounds 11-396
11-53 Human Exposure Conditions and Effects for Zinc and Compounds .... 11-405
11-54 Laboratory Animal Exposure Conditions and Effects for Zinc and
Compounds 11-410
11-55 Summary of Occupational Studies of Silicosis Risk 11-420
11-56 Effects of PM (>1 jtm) on Mortality 11-432
11-57 Effects of Inhaled PM on Pulmonary Mechanical Function 11-434
11-58 Effects of PM on Respiratory Tract Morphology 11-438
11-59 Effects of PM on Markers in Lavage Fluid 11-442
11-60 Effects of PM on Lung Biochemistry 11-444
11-61 Effects of PM on Alveolar Macrophage Function 11-446
11-62 Effects of PM on Microbial Infectivity 11-449
April 1995 n.xxi DRAFT-DO NOT QUOTE OR CITE
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LIST OF FIGURES
Number Page
8-1 Calculated scattering coefficient per unit mass concentration at
a wavelength of 0.55 /mi for absorbing and nonabsorbing materials is
shown as a function of diameter for single-sized particles 8-9
8-2 For a light-scattering and absorbing particle, the scattering per volume
concentration has a strong peak at particle diameter of 0.5 fjim 8-10
8-3 For a typical aerosol volume (mass) distribution, the calculated
light-scattering coefficient is contributed almost entirely by the size
range 0.1 to 1.0 /mi 8-11
8-4 Relative size growth is shown as a function of RH for an ammonium
sulfate particle at 25° C 8-15
8-5 Changes in radiative forcing due to increases in greenhouse
gas concentrations between 1765 and 1990 8-42
8-6 A schematic diagram showing the relationship between the radiative
forcing of sulfate aerosols and climate response 8-43
8-7 Extinction of direct solar radiation by aerosols showing the diffusely
transmitted and reflected, as well as the absorbed components 8-44
8-8 Global, direct, and diffuse spectral solar irradiance on a horizontal
surface for a solar zenith angle of 60° and ground reflectance of 0.2 8-46
8-9 Surface measurements of direct, diffuse, and global solar radiation
expressed as illuminance, at Albany, NY, on August 23, 1992, and
August 26, 1993 8-47
8-10 Single scattering albedo of monodispersed spherical aerosols of varying
radius and three different refractive indices at a wavelength of 0.63 /xm . . . 8-50
8-1 la Annual mean direct radiative forcing resulting from anthropogenic
sulfate aerosols 8-57
8-1 Ib Annual mean direct radiative forcing resulting from anthropogenic
and natural sulfate aerosols 8-57
8-12a Annual averaged greenhouse gas radiative forcing from increases
in CO2, CH4, N2O, CFC-11, and CFC-12 from preindustrial time to the
present 8-59
April 1995 II_xxiii DRAFT-DO NOT QUOTE OR CITE
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LIST OF FIGURES
Number Page
8-12b Annual averaged greenhouse gas forcing plus anthropogenic sulfate
aerosol forcing 8-59
8-13 Schematic illustration of the difference between response times of climate
forcing due to CO2 (heating) and sulfate (cooling) during different patterns
of global fossil fuel consumption 8-62
9-1 Geographic distribution of paint soiling costs 9-21
10-1 Schematic characterization of comprehensive exposure-dose-response
continuum and the evolution of protective to predictive dose-response
estimates 10-2
10-2 Lognormal particle size distribution for a hypothetical aerosol 10-10
10-3 These normalized plots of number, surface and volume (mass)
distributions from Whitby (1975) show a bimodal mass distribution
in a smog aerosol 10-12
10-4 Diagrammatic representation of respiratory tract regions in humans 10-17
10-5 Schematic representation of five major mechanisms causing particle
deposition where airflow is signified by the arrows and particle
trajectories by the dashed line 10-18
10-6 Lung volumes and capacities 10-23
10-7 Estimated TB deposition in the rat lung, via the trachea, with no
interceptional deposition, Graph A, is shown in relation to total TB
deposition, via the trachea, Graph B, for the same fibrous aerosol
under identical respiratory conditions 10-40
10-8 Total deposition data in children with/during spontaneous breathing
as a function of particle diameter 10-48
10-9 Deposition increment data versus particle electronic charge q for
three particle diameters at 0.3, 0.6, and 1.0 /mi 10-51
10-10 Calculated mass deposition from polydisperse aerosols of unit density
with various geometric standard deviations as a function of MMD
for quiet breathing (tidal volume = 750 mL, breathing frequency =
15 mitf1) 10-52
April 1995 H-xxiv DRAFT-DO NOT QUOTE OR CITE
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LIST OF FIGURES (cont'd)
Number Page
10-11 Calculated regional deposition fraction of unit-density fibers in
humans at quiet mouth breathing .......................... 10-54
10-12 Major clearance pathways from the extrathoracic region and
tracheobronchial tree ................................. 10-56
10-13 Diagram of known and suspected clearance pathways for insoluble
particles depositing in the alveolar region ..................... 10-57
10-14 Theoretical growth curves for sodium chloride, sulfuric acid,
ammonium bisulfate and ammonium sulfate aerosols in terms of the
initial (d0) and final (d) size of the particle .................... 10-76
10-15 Distinctions in growth (r/r0) of aqueous (NH4)2SO4 droplets of
0.1 and 1.0 fim initial size are depicted as a function of their
initial solute concentrations (X0) .......................... 10-78
10-16 The initial diameter of dry NAC1 particles (d0) and equilibrium
diameter achieved (d) are shown for three relative humidity
assumptions ....................................... 10-79
10-17 The initial dry diameter (dae s) of three different salts is assumed
to be 1.0 /im ........ '. ............................. 10-80
10-18 Total deposition data (percentage deposition of amount inhaled) in
humans as a function of particle size ........................ 10-87
10-19 Total deposition as a function of the diameter of unit density spheres
in humans for variable tidal volume and breathing frequency ......... 10-88
10-20 Inspiratory deposition A of the human nose as a function of d^Q ....... 10-90
10-21 Inspiratory extrathoracic deposition data in humans during mouth
breathing as a function of dfe Q2/3VT1/4 ...................... 10-91
10-22 Inspiratory deposition efficiency data and fitted curve for human
nasal casts plotted versus Q/1/8D1/2 (Lmin"1)'1/8(cm2s'1)1/2 ........... 10-93
10-23 Inspiratory deposition efficiency data in human oral casts plotted
versus Q-1/8D1/2 (Lmin V^CcmY1)1'2 ....................... 10-94
10-24 TB deposition data in humans at mouth breathing as a function of dae . . . . 10-96
April 1995 n.xxv DRAFT-DO NOT QUOTE OR CITE
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LIST OF FIGURES (cont'd)
Number Page
10-25 Slow-cleared or alveolar deposition data in humans as a function of dae . . . 10-97
10-26 Percentage of total ventilatory airflow passing through the nasal route
in human "normal augmenter" (solid curve) and in habitual "mouth
breather" (broken curve) 10-99
10-27 Local deposition pattern in a bifurcating tube for inhalation (top panel)
and exhalation (bottom panel) 10-101
10-28 Regional deposition efficiency in experimental animals as a function of
particle size 10-106
10-29 Comparison of regional deposition efficiencies and fractions for the
mouse 10-113
10-30 Range of particles for lognormal distributions with same MM AD but
differing geometric standard deviations 10-115
10-31 Regional deposition data in rats versus particle size for sulfuric acid
mists and dry particles 10-117
10-32 Regional deposition of hygroscopic H2SO4 and control Fe2O3 particles
at quiet breathing in the human lung as a function of subject age 10-118
10-33 Schematic of the International Commission on Radiological Protection
(ICRP66, 1994) model 10-124
10-34 An example of histogram display and fitting to log-normal functions
for particle-counting size distribution data 10-151
10-35 Impactor size distribution measurement generated by Lundgren et al.
with the Wide Range Aerosol Classifier: (a) Philadelphia and
(b) Phoenix 10-155
10-36 Data from the South Coast Air Quality Study (John et al., 1990).
Plots show (a) frequency of sulfate modes of various sizes as a function
of mode mass mean diameter (MMD) and (b) average sulfate mode
concentration as a function of mode MMD 10-162
10-37 Predicted extrathoracic deposition fractions versus MMAD of
inhaled monodisperse aerosols shown in top panel or
polydisperse aerosols shown in bottom panel 10-180
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LIST OF FIGURES (cont'd)
Number
Page
10-38 Predicted tracheobronchial deposition fractions versus MMAD of
inhaled monodisperse aerosols shown in top panel or
polydisperse aerosols shown in bottom panel 10-181
10-39 Predicted alveolar deposition fractions versus MMAD of inhaled
monodisperse aerosols shown in top panel or polydisperse
aerosols shown in bottom panel 10-182
10-40 Predicted retained alveolar dose (ug/g lung) for 0.5 (j.%m MMAD
monodisperse aerosol assuming a dissolution-absorption
half-time of 10 day 10-194
10-41 Predicted retained alveolar dose (ug/g lung) for 0.5 /i%m MMAD
monodisperse aerosol assuming a dissolution-absorption
half-time of 100 day 10-194
10-42 Predicted retained alveolar dose (ug/g lung) for 0.5 /*%m MMAD
monodisperse aerosol assuming a dissolution-absorption
half-time of 1,000 day 10-195
10-43 Predicted retained alveolar dose (ug/g lung) for 2.55 /i%m MMAD
polydisperse aerosol assuming a dissolution-absorption
half-time of 10 day 10-195
10-44 Predicted retained alveolar dose (ug/g lung) for 2.55 /*%m MMAD
polydisperse aerosol assuming a dissolution-absorption
half-time of 100 day 10-196
10-45 Predicted retained alveolar dose (ug/g lung) for 2.55 /n%m MMAD
polydisperse aerosol assuming a dissolution-absorption
half-time of 1,000 day 10-196
10-46 Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 /xm MMAD monodisperse and
2.55 fim MMAD polydisperse aerosols assuming a
dissolution-absorption half-time of 10 days 10-198
10-47 Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 /im MMAD monodisperse and
2.55 jiim MMAD polydisperse aerosols assuming a
dissolution-absorption half-time of 100 days 10-199
April 1995
II-xxvii DRAFT-DO NOT QUOTE OR CITE
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LIST OF FIGURES (cont'd)
Number Page
10-48 Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 /zm MM AD monodisperse and
2.55 ftm MM AD poly disperse aerosols assuming a
dissolution-absorption half-time of 1,000 days 10-200
11-1 Mean ± SEM Specific Airway Resistance (SRaw) Before and After a
16-min Exposure for (A) Nine Subjects Who Inhaled Low Relative-humidity
NaCl, Low-RH H2SO4, and High-RH H2SO4 Aerosols at Rest, and (B) Six
Subjects Who Inhaled Low-RH NaCl and Low-RH H2SO4 Aerosols During
Exercise 11-29
11-2 Decrements in FEVj (± SE) Following 6.5-h Exposures on 2
Successive Days 11-38
11-3 Asthmatic Subjects 11-40
11-4 Comparative Potency of a Series of Complex Mixtures and
Benzo[a]pyrene in the Sencar Mouse Skin Tumor Initiation
Assay 11-98
11-5 Cumulative Exposure Data for Rats Exposed to Whole Diesel
Exhaust 11-138
April 1995 II-xxviii DRAFT-DO NOT QUOTE OR CITE
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II-xxix
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHAPTER 8. EFFECTS ON VISIBILITY
Principal Authors
Ms. Beverly Comfort-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Harshvardhan-Purdue University, Department of Earth and Atmospheric Sciences,
W. Lafayette, IN 47907-1397
Contributors and Reviewers
Dr. Adarsh Deepak-Science and Technology, 101 Research Drive, Hampton, VA 23666
Dr. Peter Hobbs-University of Washington, Atmospheric Sciences AK40, Seattle, WA
98195
Dr. Derrick Montaque-University of Wyoming, Department of Atmospheric Sciences,
P.O. Box 3038, University Station, Laramie, WY 82071
Dr. Joseph Sickles-Atmospheric Research and Exposure Assessment Laboratory (MD-80A),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
CHAPTER 9. EFFECTS ON MATERIALS
Principal Author
Mr. Fred Haynie-300 Oak Ridge Road, Gary, NC 27511
Contributors and Reviewers
Ms. Beverly Comfort-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Edward Edney-Atmospheric Research and Exposure Assessment Laboratory (MD-84),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Douglas Murray-TRC Environmental Corporation, 5 Waterside Crossing, Windsor,
CT 06095
April 1995 H-XXX DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
Contributors and Reviewers (cont'd)
Dr. John Spence-Atmospheric Research and Exposure Assessment Laboratory (MD-75),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. John Yocom-Environmental Consultant, 12 Fox Den Road, West Simsbury, CT 06092
CHAPTER 10. DOSIMETRY OF INHALED PARTICLES IN
THE RESPIRATORY TRACT
Principal Authors
Ms. Annie M. Jarabek-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Paul E. Morrow-University of Rochester Medical Center, School of Medicine and
Dentistry, Rochester, NY 14614
Dr. Richard B. Schlesinger-New York University, Department of Environmental Medicine,
550 First Avenue, New York, NY 10016
Dr. Morris Burton Snipes-Inhalation Toxicology Research Institute, Lovelace Biomedical and
Environmental Research Institute, Albuquerque, NM 87185-5890
Dr. C.P. Yu-State University of New York, Department of Mechanical and Aerospace
Engineering, Buffalo, NY 14260-4400
Contributors and Reviewers
Dr. William J. Bair-Battelle, Pacific Northwest Laboratories, Kl-50, P.O. Box 999,
Richland, WA 99352
Dr. Timothy R. Gerrity-Veterans Administration, Acting Deputy Director, Medical
Research, 810 Vermont Avenue, NW, Washington, DC 20420
Dr. Judith A. Graham-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Raymond A. Guilmette-Inhalation Toxicology Research Institute, Lovelace Biomedical
and Environmental Research Institute, Inc., P.O. Box 5890, Albuquerque, NM 87185
April 1995 H-xxxi DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
Contributors and Reviewers (cont'd)
Dr. F. Charles Killer-University of Arkansas for Medical Science, 4301 W. Markham,
Little Rock, AR 72212
Dr. Wolfgang G. Kreyling-GSF, Institute for Inhalation Biology, Ganghferstr,
40 Unterschleissheit, Germany D-85716
Dr. Ted Martonen-Health Effects Research Laboratory (MD-74), U.S. Environmental
Protectiona Agency, Research Triangle Park, NC 27711
Ms. Margaret G. Menache-Duke University Medical Center, Center for Extrapolation
Modeling, P.O. Box 3210, First Union Plaza/Suite B-200, Durham, NC 27710
Dr. Gunter Oberdorster-University of Rochester, Department of Environmental Medicine,
575 Elmwood Avenue, Rochester, NY 14642
Dr. Robert F. Phalen-University of California - Irvine, Department of Community and
Environmental Medicine, Air Pollution Health Effects Laboratory, Irvine, CA 92717-1825
Dr. Otto G. Raabe-University of California-Davis, Institute of Toxicology and Environmental
Health, Old Davis Road, Davis, CA 95616
Dr. Sid Soderholm-National Institute for Occupational Safety and Health, 1095 Willowdale
Road, Morgantown, WV 26505
Dr. Magnus Svartengren-Karolinska Institute of Huddinge University Hospital, Department
of Occupational Medicine, S-141 86 Hugginge, Sweden
Dr. William Wilson-Atmospheric Research and Exposure Assessment Laboratory (MD-75),
Research Triangle Park, NC 27711
CHAPTER 11. TOXICOLOGICAL STUDIES OF PARTICULATE MATTER
Principal Authors
Dr. Mark Frampton-University of Rochester Medical Center, Pulmonary Disease Unit,
601 Elmwood Avenue, Rochester, NY 14642-8692
Ms. Karen Gan-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
April 1995 II-xxxii DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Principal Authors (cont'd)
Dr. Lynne Haber-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
Dr. Rogene Henderson-Lovelace Biomedical and Environmental Research Institute,
Inhalation Toxicology Research Institute, Albuquerque, NM 87105
Ms. Annie M. Jarabek-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Peter McClure-Syracuse Research Corporation, Merrill Lance, Syracuse,
NY 13210-4080
Dr. James McGrath-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Guenter Oberdorster, University of Rochester, Department of Environmental Medicine,
575 Elmwood Avenue, Rochester, NY 14642
Ms. Kimberly Osborne-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway,
Fairfax, VA 22031-1207
Ms. Katherine Rantz-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
Mr. Paul Raskin-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
Dr. Richard B. Schlesinger-New York University, Department of Environmental Medicine,
550 First Avenue, New York, NY 10016
Dr. Brenda Tondi-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
Ms. Roberta Wedge-ICF Consulting Group, ICF Incorporated, 9300 Lee Highway, Fairfax,
VA 22031-1207
Contributors and Reviewers
Dr. Daniel L. Costa-Health Effects Research Laboratory (MD-82), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
April 1995 II-xxxiii DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Contributors and Reviewers (cont'd)
Dr. Kevin E. Driscoll-The Miami Valley Laboratories, Procter & Gamble Company,
P.O. Box 538707, Cincinnati, OH 45253-8707
Dr. Don Dungworth-6260 Cape George Road, Port Townsend, WA 98368
Dr. Gary Foureman-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Donald Gardner-P.O. Box 97605, Raleigh, NC 27624-7605
Dr. Andy Ghio-Duke University Medical Center, Division of Pulmonary Medicine and
Critical Care Medicine, P.O. Box 3177, Durham, NC 27710
Dr. Jeff Gift-Environmental Criteria and Assessment Office (MD-52), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Judith A. Graham-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Lester D. Grant-Environmental Criteria and Assessment Office (MD-52), U.S.
Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Daniel Guth-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Jack Harkema-Michigan State University, Department of Pathology, College of
Veterinary Medicine, Veterinary Medical Center, East Lansing, MI 48824
Dr. Gary Hatch-Health Effects Research Laboratory (MD-82), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Michael T. Kleinman-University of California - Irvine, Department of Community &
Environmental Medicine, Irvine, CA 92717-1825
Dr. Dennis Kotchmar-Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Gunter Oberdorster-University of Rochester, Department of Environmental Medicine
575 Elmwood Avenue, Rochester, NY 14642
Dr. Mary Jane Selgrade-Health Effects Research Laboratory (MD-92), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
April 1995 Il-xxxiv DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Contributors and Reviewers (cont'd)
Dr. Jeff Tepper-Genetech, Inc., Pulmonary Research, 460 Point San Bruno Boulevard,
South San Francisco, CA 94080-4990
Dr. David B. Warheit-Haskell Laboratory, E.I. Du Pont de Nemours, P.O. Box 50, Elkton
Road, Newark, DE 19714
Dr. Hanspeter Witschi-University of California-Davis, Laboratory for Energy-Related Health
Research, Davis, CA 95616
April 1995 II-xxxv DRAFT-DO NOT QUOTE OR CITE
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1
8. EFFECTS ON VISIBILITY AND CLIMATE
2
3
4 8.1 INTRODUCTION
5 Visibility is defined as the relative ability to see objects under different conditions of
6 distance, light, and atmosphere. It takes into account not only how far one can see but, also
7 how well one can see nearby objects. The legislative mandate for visibility protection began
8 with the Clean Air Act (CAA) of 1970. Additional protection for pristine areas - mainly
9 Class I areas in National Parks and Wilderness areas, primarily in the western portion of the
10 United States (U.S.), were mandated in the CAA Amendments of 1977 (Baedecker, 1991).
11 There are may complex physical (rain, dust, and snow) and chemical atmospheric
12 processes that affect our ability to see distant objects or to distinguish nearby objects clearly.
13 There are also atmospheric constituents that interfere with our visual range. These
14 atmospheric constituents include fine paniculate matter which individually have no effect on
15 the visual range; however, collectively can significantly impair the visual range. Airborne
16 particles can reduce visibility through both light scattering and absorption. Some questions
17 about the relationship between paniculate matter and visibility are still unanswered, but many
18 have been resolved. Scientists have made progress in evaluating the optical changes and
19 perceptual consequences from increased paniculate matter, but it is more difficult to
20 determine the effect of increased paniculate pollution on the aesthetic appeal. It is, however,
21 known that reduced aesthetic appeal carries significant social and economic costs.
22 The effects of particle induced light scattering and absorption may effect climate by
23 reducing solar radiation at ground level, making less energy available for photosynthesis.
24 Reduced solar radiation may alter local or regional temperatures. Also, increased cloud
25 formation may alter precipitation patterns.
26 This chapter briefly discusses factors affecting visibility, ways to measure it, historical
27 trends, and methods to determine its value. Paniculate matter effects on climate will also be
28 discussed. Much of the information contained in the section on visibility is a summarization
29 of information from the previous criteria document on paniculate matter and sulfur oxides.
30 For a more detailed discussion of the information on visibility, see Air Quality Criteria for
31 Paniculate Matter and Sulfur Oxides (U. S. Environmental Protection Agency, 1982), Air
April 1995 8-1 DRAFT-DO NOT QUOTE OR CITE
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1 Quality Criteria for Oxides of Nitrogen (U. S. Environmental Protection Agency, 1993), and
2 the National Acid Precipitation Assessment Program (Baedecker, 1991).
3
4
5 8.2 FUNDAMENTALS OF ATMOSPHERIC VISIBILITY
6 8.2.1 Physics of Light Extinction
7 Light, electromagnetic radiation, is altered by the interaction of its electric and
8 magnetic fields with all matter through which and near which it passes. The altering may be
9 by scattering (redirection) or by absorption. There are two theories that address the physics
10 of light extinction in the atmosphere. The first theory was proposed by Lord Rayleigh in the
11 late 1800's. The Raleigh theory (Raleigh scattering) refers to the scattering of light by the
12 gaseous molecules comprising the atmosphere (Middleton, 1952; Kerker, 1969). Rayleigh
13 scattering is directly proportional to the molecular number density and decreases as elevation
14 increases. Rayleigh scattering represents the cleanest possible condition of the atmosphere
15 and almost all cases of visibility impairment are caused by the presence of particles, the sole
16 exception being discoloration caused by the pollutant gas NO2.
17 The second theory, commonly referred to as the Mie theory, is the attenuation of light
18 in the atmosphere by scattering due to particles of a size comparable to the wavelength of the
19 incident light. It is this phenomenon that is largely responsible for the reduction of
20 atmospheric visibility. The Mie theory allows the computation of light scattering in any or
21 all directions and the absorption of light by a single spherical particle. For visible light, the
22 size range requiring use of Mie theory extends from 0.05 to 10 ;um (and larger if the
23 particles are spherical), the sizes at which most long-lived atmospheric particles accumulate.
24 Visible solar radiation falls into the range form 0.4 to 0.8 /xm, with a maximum intensity of
25 around 0.52 /mi (U.S. National Acid Precipitation Assessment Program (Baedecker, 1991).
26 The wavelength of light, particle size, and complex refractive index must be specified. For
27 absorbing particles, the imaginary part of the refractive index is nonzero. For a
28 monodisperse aerosol of number concentration N, the extinction coefficient (the
29 proportionality constant determined by the scattering and absorption of light by particles and
30 gases) becomes:
31
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"ext = N Qext Trr2 (8-1)
1
2 where r is the particle radius and Qext is the extinction efficiency factor calculated from Mie
3 theory. If the particles are of differing composition (and thus differing complex refractive
4 index), the number size distribution of each species must be known. Extinction coefficients
5 for the various species are then summed. The precise calculation of extinction by spherical
6 particles allowed by Mie theory requires detailed knowledge of the composition and size
7 distribution of the particles.
8 Mie theory is strictly applicable only to spherical particles. Fortunately, a majority of
9 scattering particles in the optically important size range of 0.1- to 2-jrni diameter are
10 spherical (many being droplets), or nearly spherical (Allen et al., 1979; Pueschel and
11 Wollman, 1978; Pueschel and Alice, 1980). Electromagnetic solutions have been achieved
12 for several nonspherical shapes, such as spheroids (Latimer, 1980); disks (Weil and Chu,
13 1980); cylinders; and for the important case of layered or coated spheres (Kerker, 1969;
14 Schuerman, 1980; Pinnick et al., 1976; Fowler and Sung, 1979; Mugnai and Wiscombe,
15 1980). These exact solutions can be applied if circumstances warrant. Absorbing particles
16 are usually distinctly nonspherical. Many are chain-aggregates such as flame soot. Janzen
17 (1980) empirically showed that Mie theory predicts measured absorption quite well for
18 carbon black particles by assuming the aggregates to be spheres of equal volume.
19
20 8.2.2 Measurement Methods
21 8.2.2.1 Total Extinction
22 Human Observer
23 Human observation has by far been the most often used measure for determining visual
24 range (Middleton, 1952). In practice, a set of targets at known distances is selected and an
25 observer then records whether or not they are able see each target. The "prevailing
26 visibility" is then defined as the greatest distance attained or surpassed around at least half of
27 the horizon circle, but not necessarily in continuous sectors (National Weather Service,
28 1979). The human observer also can make qualitative statements about overall visual air
29 quality, unusual coloration, and the presence of plumes. However, different days or studies
April 1995 8-3 DRAFT-DO NOT QUOTE OR CITE
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1 are difficult to compare because even minute changes of scenes from day to day may affect
2 human perception. This limitation may be partially remedied by the use of photography.
3 Visual range is affected not only by the optical properties of the atmosphere, but also by
4 target characteristics, illumination conditions, and the observer (Duntley, 1964).
5
6 Photography
1 Photographs are typically used to document scenes for later qualitative analysis by
8 humans or for later analysis of a target's apparent contrast by film densitometry (Steffans,
9 1949; Veress, 1972). Photographs provide a more accurate long-term retention of a scene
10 than does the human mind and enables large numbers of people to evaluate a given scene for
11 perception studies. Significant errors are possible, however, with the use of photography
12 because of varying film characteristics, the use of filters, exposure and processing, aging,
13 storage conditions, and reproducibility of the image. If the reproduced image of a scene is to
14 accurately portray what a human eye sees, it is necessary that the overall response of the
15 photographic process be photopic (i.e., match the wavelength response of the human eye);
16 otherwise, the rendition may not be true, and both densitometry and qualitative applications
17 may be seriously affected.
18
19 Telephotometry
20 A telephotometer, a photometer designed to measure the radiant energy arriving for a
21 scene weighted in accordance with the response of the human eye brain system to spectral
22 light, can measure the apparent brightness of a faraway object (Middleton, 1952; Ellestad
23 and Speer, 1981). By measuring the brightness of an object at a predetermined distance,
24 distance x, and the horizon sky around it, the object's apparent contrast can be computed.
25
-1 C
"ext - — Oge -£-
26
27 Telephotometry is useful for several reasons. It is a path measurement; thus, atmospheric
28 nonuniformities are averaged. The instrument's absolute calibration is unimportant; only its
29 linearity and short-term stability matter. It requires no sample aspiration, and therefore,
April 1995 8-4 DRAFT-DO NOT QUOTE OR CITE
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1 avoids large particle losses and sample heating or cooling. Finally, it is perhaps the closest
2 instrumental approximation to human observation. The method is, however, limited when
3 the target's intrinsic contrast is unknown or assumed, when measuring dark objects at close
4 range (due to internal stray light errors), and when clouds cause uneven illumination.
5
6 Long-path Extinction
1 Long-path extinction measures aext by measuring the decrease in intensity of a light
8 beam over a known distance x,
T
10
9
10 where I and I0 are the final and initial intensities, respectively. This method does not require
11 the use of assumptions, it measures average extinction over the path, and it requires no
12 sample aspiration. The method is limited because for values of
-------
1 nephelometer when significant large particle concentrations occur. The first of these
2 potential errors is angular truncation, resulting in underestimation of scattering (Ensor and
3 Waggoner, 1970; Rabinoff and Herman, 1973), and secondly, sample aspiration
4 (Heintzenberg and Quenzel, 1973), resulting in the loss of large particles through impaction
5 on the ductwork. These inherent errors may result in depressed correlations between
6 scattering and total mass concentration when significant large particle concentrations occur.
7 Despite these limitations, nephelometry remains one of the most widely used visibility
8 measurement methods.
9
10 8.2.2.3 Light Absorption Coefficient
11 Elemental carbon (soot, graphitic C, free C) is a prominent species in cities and
12 industrial regions. Even a few percent of the submicrometer mass as soot produces a
13 significant effect on aap or aext. No single method for evaluating aap is widely accepted;
14 however, the following particle absorption methods are commonly used:
15
16 1. Determining the difference between aext and asp by using long-path transmissometry
17 and nephelometry (Weiss et al., 1979);
18
19 2. Determining change of transmission of Nuclepore ® filters with scattered light
20 collected by an integrating plate of opal glass (Lin et al, 1973; Weiss et al., 1979);
21
22 3. Determining change of transmission of Millipore ® filters (Rosen et al., 1980);
23
24 4. Determining the reflectivity of a white powder with aerosol mixed into it, called the
25 Kubelka-Monk method (Lindberg and Laude, 1974);
26
27 5. Determining absorption of light by a sample of particles inside a white sphere (in-
28 tegrating sphere) (Elterman, 1970);
29
30 6. Estimating an imaginary refractive index from regular scattering or polarization and
31 size distribution (Eiden, 1971; Grams et al., 1974);
32
33 7. Measuring the amount of graphitic C and its size distribution and then calculating
34
-------
1 8.2.3 Role of Participate Matter in Visibility Impairment
2 As noted earlier, the extinction coefficient comprises contributions from gas and
3 particle scattering and absorption:
4
5 This section discusses the relative magnitudes of these contributions.
6
7 8.2.3.1 Rayleigh Scattering
8 Rayleigh scattering is a definable and measurable background level of extinction with
9 which other extinction components can be compared. Rayleigh scattering decreases with the
10 fourth power of wavelength, and contributes a strongly wavelength-dependent component to
11 extinction. When Rayleigh scattering dominates, dark objects viewed at distances over
12 several kilometers appear behind a blue haze of scattered light, and bright objects on the
13 horizon (such as snow, clouds, or the sun) appear reddened at distances greater than about 30
14 km. Scattering by gaseous pollutant molecules is negligible because of their low
15 concentrations compared to N2 and O2; thus, variations in pollutant gas concentrations have
16 no effect on Rayleigh scattering.
17
18 8.2.3.2 Nitrogen Dioxide Absorption
19 Of all common gaseous air pollutants, only NO2 has a significant absorption band in the
20 visible spectrum. Nitrogen dioxide strongly absorbs blue light and can color plumes or
21 urban atmospheres red, brown, or yellow if significant concentrations and path lengths are
22 involved. The effects of NO2 on visibility are generally minor and are discussed more fully
23 in the document Air Quality Criteria for Oxides of Nitrogen (U.S. Environmental Protection
24 Agency, 1993).
25
26 8.2.3.3 Particle Scattering
27 In general, scattering by particles accounts for 50 to 95% of extinction, depending on
28 location, with urban sites in the 50- to 80% range and nonurban sites in the 80- to 95%
29 range (Waggoner et al., 1981; Weiss et al., 1979; Wolff et al., 1980).
April 1995 8-7 DRAFT-DO NOT QUOTE OR CITE
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1 Fine particles (i.e., those particles of diameter less than 1 to 3 /xm) usually dominate
2 light scattering. Particles smaller than 0.1 /mi, though sometimes present in high numbers,
3 are individually very inefficient at scattering light and thus contribute very little to visibility
4 loss; particles larger than about 1 to 3 /mi, though individually efficient at scattering light,
5 usually exist in relatively small numbers and contribute only a small fraction of visibility
6 loss.
7 In areas where fine-particle concentrations are low, coarse particles may contribute
8 significantly to light extinction. However, coarse dust particles are much less efficient
9 scatterers per unit mass (Figure 8-1), so that much higher mass concentrations are required
10 to produce a given optical effect. In windblown dust, for example, Patterson and Gillette
11 (1977) reported values of the ratio of light scattering to mass concentration that were more
12 than an order of magnitude lower than those noted above for fine particles.
13 Atmospheric particles are made up of a number of chemical compounds (see Chapter
14 3). All these compounds exhibit a peak scattering efficiency in the same diameter range (0.1
15 to 1.0 /mi) calculated to be optically important (Figure 8-2). Because of differences in
16 refractive index, however, the values of the peak efficiency and the exact particle size at
17 which it occurs vary considerably among the compounds (Figure 8-1; Faxvog, 1975).
18 Figure 8-1 demonstrates the high extinction efficiencies of carbon and water. As
19 discussed later in chapter, these compounds are often significant fine mass components and
20 are therefore, often responsible for significant amounts of extinction. Figure 8-1 should not,
21 however, be taken to present invariable, precise extinction efficiencies of the various species.
22 It was produced with best estimates of the refractive indexes and for monodisperse particles.
23 In reality, the species do not exist as monodispersions or in equal concentrations and their
24 relative roles in causing extinction may vary considerably.
25 Measured particle size distributions can be used in conjunction with Mie theory calcula-
26 tions to determine the contribution of different size classes to extinction. The results of this
27 kind of calculation are shown in Figure 8-3. The peak in scattering per unit volume
28 concentration is at 0.3 /mi, so that the fine particles dominate extinction in most cases.
April 1995 8-8 DRAFT-DO NOT QUOTE OR CITE
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o>
«"*
f
A - 0.55 \nn\
•S?
™E
^ 4
0.01
0.01
- Water
Carbon
,. Silica
0.01
0.1 1.0
Diameter, \im
10.0
B
Carbon
0.1 1.0
Diameter, nm
10.0
A. - 0.55 urn
Carbon
Water
0.1 1.0
Diameter, urn
10.0
Figure 8-1. (A) Calculated scattering coefficient per unit mass concentration at a
wavelength of 0.55 /tin for absorbing and non-absorbing materials is shown
as a function of diameter for single-sized particles. The following refractive
indices and densities (g/cm3) were used: carbon (m = 1.96-0.66i, d = 2.0),
iron (m = 3.51-3.95i, d = 7.86), silica (m = 1.55, d = 2.66), and water
(m = 1.33, d = 1.0). (B) Calculated absorption coefficient per unit mass
concentration at 0.55 jim for single-sized particles of carbon and iron.
(C) Calculated extinction coefficient per unit mass concentration at 0.55 /on
for single-sized particles of carbon, iron, silica, and water.
Source: (a) Faxvog (1975); (b and c) Faxvog and Roessier (1978).
April 1995
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10
CO
E
E E
to
-------
0=5
CO
CC
Volume
0.01
0.1
1.0
Particle Diameter, urn
10
li
11
(0
£
O
Figure 8-3. For a typical aerosol volume (mass) distribution, the calculated
light-scattering coefficient is contributed almost entirely by the size range
0.1 to 1.0 nm. The total and total aerosol volume concentration are
proportional to the area under the respective curves.
Source: Charlson et al. (1978a).
1
2
3
4
5
6
7
8
9
10
11
12
13
the extinction efficiency factor in this region, predicted a linear and size distribution-
independent relation between extinction coefficient and mass concentration of carbon
particles, with a ratio of 9.5 m2/g at 0.55 /urn. Laboratory studies by Roessler and Faxvog
(1980) showed values of 9.8 m2/g for acetylene smoke and 10.8 m2/g for diesel exhaust.
They also summarized results from other investigators on various aerosols that showed values
of 6.1 to 9.5 m2/g. In developing a spectrophone, Truex and Anderson (1979) measured an
absorption of mass concentration ratio 17 m2/g (at 0.417 /xm wavelength) for aerosol from a
propane-oxygen flame. As methods for measuring elemental carbon have improved,
Groblicki et al. (1981) have performed atmospheric measurements of fine absorption/fine
elemental carbon mass concentration in Denver and found an average of 11.8 m2/g. While
the amount of absorption per unit mass concentration depends on chemical composition and
particle size distribution (Waggoner et al., 1973; Bergstrom 1973), the pattern emerging
from these empirical and theoretical studies is that absorbing particles have a more significant
April 1995
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1 visibility impact than their mass would indicate, probably by a factor of 3 to 4, compared to
2 scattering-only particles.
3 Weiss and Waggoner (1981) calculated that, for constant mass concentration, changing
4 20% of each particle of a nonabsorbing aerosol to an equal volume of absorbing soot reduces
5 visual range (or increases aext) by about 35 %. They pointed out the importance of this
6 concept as fuel conservation practices (e.g., use of diesel engines, wood burning) lead to
7 greater emissions of light-absorbing aerosol.
8
9 8.2.4 Chemical Composition of Atmospheric Particles
10 This section briefly discusses the most commonly observed paniculate species in the
11 context of visibility impairment. For actual concentrations and a more detailed evaluation of
12 the aerosol components see Chapters 4 and 6 of this document.
13 Current knowledge indicates that fine aerosol is composed of varying amounts of
14 sulfate, ammonium, and nitrate ions; elemental carbon and organic carbon compounds;
15 water; and smaller amounts of soil dust, lead compounds, and trace species. The
16 components may also coexist within the same particle. Table 8-1 gives the average natural
17 background levels of aerosols and light extinction.
18 Sulfate occurs predominantly in the fine mass (Stevens et al., 1978; Tanner et al.,
19 1979; Lewis and Macias, 1980; Ellestad, 1980). The sulfate ion has been reported to
20 compose 30 to 50% of the fine mass at a wide variety of sites (Stevens et al., 1978; Pierson
21 et al., 1980; Stevens et al., 1980; Lewis and Macias, 1980; Ellestad, 1980; Macias et al.,
22 1981), although some urban sites have values of 10 to 20% (Countess et al., 1980b; Cooper
23 and Watson, 1979). Sulfate usually occurs in combination with hydrogen and ammonium
24 ions (Stevens, 1978; Pierson et al., 1980; Charlson et al., 1978b; Stevens et al., 1980;
25 Tanner et al., 1979) and to a lesser extent calcium and magnesium. Ammonium ion is
26 typically found to account for 5 to 15% of the fine mass (Lewis and Macias, 1980; Patterson
27 and Wagman, 1977; Countess et al., 1980b) and often correlates well with sulfate levels
28 (Tanner et al., 1979). Because of the possible reaction of ammonia with previously collected
29 acidic particles, reported ammonium ion values may be higher than those actually existing in
30 the atmosphere.
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TABLE 8-1. AVERAGE NATURAL BACKGROUND LEVELS OF AEROSOLS AND
LIGHT EXTINCTION
Average
Concentration
East
West
/xg/m3
Extinction
Error Efficiencies
Factor m2/g
Extinction
Contributions
" East
Mm'1
West
Mm'1
Fine Particles (<2.5 /tin)
Sulfates (as NH4 HSO4)
Organics
Elemental Carbon
Ammonium Nitrate
Soil Dust
Water
0.2
1.5
0.02
0.1
0.5
1.0
0.1
0.5
0.02
0.1
0.5
0.25
2
2
2-3
2
1.5-2
2
2.5
3.75
10.5
2.5
1.25
5
0.5
5.6
0.2
0.2
0.6
5.0
0.2
1.9
0.2
0.2
0.6
1.2
Coarse Particles (2.5-10 /tm)
3.0
3.0
1.5-2
Rayleigh
0.6
Scatter
Total
1.8
12
26+7
1.8
11
17+2.5
aThe extinction efficiencies are based on the literature review by Trijonis et al. (1986, 1988). All the extinction
efficiencies represent particle scattering, except for elemental carbon where the 10.5 m2/g value is assumed to
consist of 9 m2/g absorption and 1.5 m2/g scattering. Note that the 0.6 m2/g value for coarse particles is a
"pseudo-coarse scattering efficiency" representing the total scattering by all ambient coarse particles (<2.5
divided by the coarse particle mass between 2.5 and 10 fim.
Source: Baedecker (1991).
1 Earlier particulate nitrate measurements had significant positive or negative biases.
2 More recent measurement techniques provide a more accurate representation of ambient
3 particulate nitrate concentrations.
4 Appel el al. (1983, 1985) reported that mean nitrate concentrations represented 17 to
5 37% of the total fine particle mass in 3 California cities. Watson et al. (1991) reported that
6 ammonium nitrate represented 19% of the fine particle mass in the morning in Phoenix, AZ
7 and 31% of the fine particle mass in the afternoon. Ammonium nitrate represented 6.4 to
8 10.4% of the fine particle mass at 3 locations in the Grand Canyon during January through
9 March 1990 (Richards et al., 1991).
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1 Several investigators have concluded that elemental carbon is the only significant light-
2 absorbing species. Figure 8-l(c) shows the extinction mass concentration for carbon to be
3 higher than for any other species.
4 Soil particles significantly impair visibility mostly in arid or semiarid areas (Patterson,
5 1977) (in the United States, the Southwestern states). This is likely due to the relatively low
6 fine-particle concentrations there, than to high concentrations of soil particles. What fraction
7 of coarse particles is derived from natural sources has not been established. However, it is
8 likely that more dust is entrained over anthropogenically disturbed soil surfaces (e.g.,
9 unpaved roads, off-road-vehicle trails) than over undisturbed soils. Minor contributions to
10 fine mass also are made by soil-related elements, lead compounds (especially in urban areas),
11 and trace species (Stevens et al., 1978).
12
13 8.2.4.1 Role of Water in Visibility Impairment
14 Water affects visibility only when in the liquid or solid phase. Direct measurement of
15 liquid water's contribution to mass is difficult due to its rapid phase change and the fact that,
16 except in fogs, typically less than 0.01% of all water in a given volume exists in the liquid
17 phase.
18 Relative humidities (RHs) above about 70% will often greatly reduce visibility due to
19 the size growth of common aerosol species such as ammonium sulfate and sea salt (Orr et
20 al., 1958). Natural fluctuations of RH can greatly influence the extinction of light by an
21 aerosol. Since RH generally increases following sunset due to declining temperature
22 (assuming a constant dew point), particles usually grow after sunset. After sunrise RH
23 usually declines as temperature rises, causing particles to shrink as they release water to the
24 vapor phase.
25 Particles of certain inorganic salts commonly observed in the atmosphere (e.g.,
26 ammonium sulfate and sodium chloride) exhibit the phenomenon of deliquescence (i.e., an
27 abrupt transformation from solid particle to liquid droplet, and growth at a RH specific to
28 each compound). Above the deliquescent RH, the droplets absorb water and grow smoothly
29 as RH increases (Orr et al., 1958; Charlson et al., 1978b; Tang, 1980). As RH decreases,
30 salt particles that have already deliquesced do not crystallize until a RH well below the
31 deliquescent RH is achieved (Tang, 1980; Orr et al., 1958), a phenomenon generally referred
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1
2
3
4
5
6
to as hysteresis. Until crystallization occurs, droplets become supersaturated, lose water
gradually, and shrink gradually as RH declines. If crystallization has not occurred and RH
increases, the growth of droplets will follow the smoothly hygroscopic curve along which it
just fell. Figure 8-4 depicts the behavior of an ammonium sulfate particle.
o
i
of
o>
I
6
5
CO
*
t
S.
30
40
50
60
70
80
90
100
% Relative Humidity
Figure 8-4. Relative size growth is shown as a function of RH for an ammonium sulfate
particle at 25° C.
Source: Tang (1980).
1 Hysteresis explains the persistence of some hazes at RHs below that at which they
2 formed (Orr et al., 1958). The RH of crystallization depends on the size of insoluble nuclei
3 present in each droplet. The dissipation of a water-enhanced haze may not occur abruptly as
4 RH falls (even though it may have formed abruptly) because the sizes of nuclei within the
5 droplets may vary, causing the droplets to crystallize at different RHs.
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1 8.2.4.2 Light Extinction Budgets
2 Light extinction budgets (LEBs) attempt to assign a percentage of the total extinction to
3 each chemical species using the size distribution and refractive index. The great usefulness
4 of LEB's is to exonerate or implicate emission sources as primary causes of visibility
5 impairment.
6 Two approaches have been used to arrive at light extinction budgets: (1) measurement
7 of each species' size distribution and calculation of aext by Mie theory and (2) statistical
8 analysis, usually multiple linear regression. The first method requires detailed size
9 distributions for each species. This can result in a small error in the size distribution
10 measurement. Many significant species have MMD's at the steepest part of the extinction
11 efficiency curve, that may later cause a large error in the calculated extinction. Further,
12 detection limits, artifact formation, volatilization, unknown particle density, or imperfect
13 instrument performance often lead to substantial uncertainties in the size distribution. Still
14 this approach is not affected by interdependencies among pollutant concentrations and allows
15 an independent estimation of aext, which can then be compared to the observed aext.
16 The second approach, multiple linear regression, requires calculation of a coefficient
17 for each species that is then multiplied by that species' concentration to yield its contribution.
18 Calculation of the coefficients requires use of the observed aext, so this method does not
19 allow an independent check of the results. Only the fine particles of the species can be
20 included in the species' concentration measurement; otherwise the coarse portion (relatively
21 unimportant in visibility) will degrade the accuracy of the LEB.
22 No matter how accurately they may eventually be assessed, light extinction budgets are
23 predictions only for the present conditions of sources, meteorology, etc. Because of the
24 physical/chemical interactions among fine particles in the atmosphere, a good LEB may
25 prove untenable as conditions change.
26 8.3 VISIBILITY AND PERCEPTION
27 The term "visibility" is used colloquially to refer to various characteristics of the optical
28 environment, i.e., the clarity with which distant details can be resolved and the fidelity of
29 their apparent coloration. Traditionally, visibility has been defined in terms of visual range:
30 the distance from an object that corresponds to a minimum or threshold contrast between that
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1 object and some appropriate background. Threshold contrast refers to the smallest brightness
2 difference between two stimuli that the human eye can distinguish.
3 Visibility defined by visual range is a reasonably precise definition; however, visibility
4 is more than being able to see a target at a distance for which the contrast is reduced to the
5 threshold value. Visibility also includes seeing vistas at shorter distances and being able to
6 appreciate the details of line, texture, color, and form.
7 Visibility may be impaired by layered haze or uniform haze (Malm et al., 1980a,b,c).
8 Layered haze produces a visible spectral discontinuity between itself and background (sky or
9 landscape). Uniform haze reduces overall air clarity. Because changes in uniform haze take
10 place over hours or days, an evaluation of visual air quality change resulting from a change
11 in uniform haze requires remembering what the scene looked like before the change in air
12 pollution took place. An example of a layered haze is a tight, vertically constrained,
13 coherent plume. As the atmosphere changes from a stable to an unstable condition and the
14 plume mixes with the surrounding atmosphere, the diffused plume, may reduce overall air
15 clarity. Whether the pollution occurs as layered or uniform haze, judgments of visual air
16 quality as a function of air pollution might be altered by variations in sun angle, cloud cover,
17 and/or landscape features.
18 Human visual perception and changes in the optical characteristics of the atmosphere
19 must be considered when assessing visibility impairment produced by air pollution. The
20 perception of brightness, contrast, and color is not determined simply by the pattern and
21 intensity of incoming radiation; rather, it is a dynamic searching for the best interpretation of
22 the visible scene. The relative brightness of an object may vary as a function of its
23 background, even though its absolute brightness remains constant.
24 Malm et al. (1981) investigated the relationship of contrast and color, and of changes in
25 these variables, to the perception of visual air quality. They determined that the various
26 demographic backgrounds of visitors to a national park did not influence perception, but that
27 changes in color contrast did influence the accuracy and consistency of perception of visual
28 air quality. In photographic slides of a mountain scene used as the test vehicle, color
29 contrast was determined by variables such as weather condition, time of day, and ground
30 cover, as well as by the amount of air pollution. Although an incremental color contrast
31 change was perceived to be the same across air pollution levels, clean air environments
April 1995 347 DRAFT-DO NOT QUOTE OR CITE
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1 appeared to be more sensitive to contrast changes. The evidence indicates that a change in
2 air pollution level produces a larger contrast change in clean air than in relatively dirty air
3 and is, therefore, more perceptible.
4 For small objects, the size of the visual image on the retina of the eye also plays an
5 important role in the perception of contrast. As an object recedes from us and apparently
6 becomes smaller, details with low contrast become difficult to perceive. The reason for this
7 loss of contrast perception is not only that the relative brightness of adjacent areas changes,
8 but also that the visual system is less sensitive to contrast when the spacing of contrasting
9 areas decreases. If the contrast spacing is a regular pattern of light and dark bands, (e.g., a
10 picket fence), a "spatial frequency" can be readily described by the number of pattern
11 repetitions or "cycles" per degree of viewing angle.
12 Fine particle aerosols may change the perceived color of objects and sky. Because it is
13 difficult to specify perceived color, only a qualitative description is possible. In general, as
14 distance from the observer increase, the apparent color of a target fades toward the hue of
15 the horizon sky. Without particles, scattered air light is blue, and dark objects appear
16 increasingly blue with distance. The addition of small amounts (1 to 5 /^g/m3) of fine
17 particles throughout the viewing distance tends to whiten the horizon sky, making distant
18 dark objects and the intervening air light (haze), normally blue, appear more gray.
19 According to Charlson et al. (1978a), even though the visual range may be decreased only
20 slightly from the limit imposed by Rayleigh scattering, the change from blue to gray is an
21 easily perceived discoloration. The apparent color of white objects is less sensitive to
22 incremental fine particle loadings.
23 Aerosol haze may also degrade the view of the night sky by diminishing star brightness.
24 The perception of stars is also reduced by an increase in the brightness of the night sky
25 caused by scattering of available light. In or near urban areas, night sky brightness is
26 significantly increased by particle scattering of artificial light. Leonard et al. (1977) reported
27 that the combination of extinction of starlight and increased sky brightness markedly
28 decreased the number of stars visible in the night sky at fine particle concentrations of 10 to
29 30 jig/m3.
30
31
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1 8.4 SOURCES OF VISIBILITY IMPAIRMENT
2 Although natural sources of light scattering and light absorbing aerosols are important
3 in producing geographical and seasonal patterns of visibility impairment, analysis of visibility
4 trends and other information suggests that manmade air pollution has a significant impact on
5 visibility.
6 This section will briefly discuss both the natural and anthropogenic sources of visibility
7 impairing particles and aerosols. This section will also summarize the recently published
8 visibility trends data as reported in the Interim Findings on the Status of Visibility Research
9 (U.S. Environmental Protection Agency, 1995). For a detailed discussion of previously
10 published visibility trends data see the Air Quality Criteria for Paniculate Matter and Sulfur
11 Oxides (U.S. Environmental Protection Agency, 1982) and National Acid Precipitation
12 Assessment Program (Baedecker, 1991).
13
14 8.4.1 Natural Sources
15 The important sources of natural particles and aerosols include water (fog, rain, snow),
16 windblown dust, forest fires, volcanoes, sea spray, vegetative emissions, and decomposition
17 processes. The particle-free atmosphere scatters light and limits visual range to about 320
18 km (200 miles) at sea level. The natural contribution of fog, thunderstorms, snow, and other
19 forms of precipitation can cause severe degradation of visual air quality. However, rarely do
20 these intense events dominate the average visual range within the Continental U.S.; typically,
21 only a small percentage of the hours involve storms or fog.
22 The frequency of fog in the continental U.S. is quite variable. Fogs tend to be local
23 events and are rare during the summer months. According to Conway (1963) on an hourly
24 basis, fogs exist less than 1% of the time.
25 Snow is an important factor in reduced visibility in the North and in some mountainous
26 areas, occurring from 1 to 12% of the winter hours (Conway, 1963). Other forms of
27 precipitation may affect visibility as well. Areas east of Nevada experience from 30 to 50
28 days of thunderstorm activity per year. Since thunderstorm activity is generally brief, their
29 contribution to visibility reduction is less than 1 % a year.
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1 In the arid West, the contribution of windblown dust to degradation of visual air quality
2 is an important problem. Because human activities that disturb natural soil surfaces add sig-
3 nificantly to windblown dust, dust storms are only partially natural phenomena.
4
5 8.4.2 Anthropogenic Sources
6 The Clean Air Act established a goal to prevent further impairment of visibility in the
7 Class I areas (those areas designated as national parks, large wildness areas, and some
8 national monuments), and to correct existing visibility impairment in those areas.
9 Monitoring of visibility and particulate pollution is necessary to establish existing visibility
10 impairment, identify sources of particulate pollution, and evaluate long term progress.
11 Several monitoring networks have been developed to address the Congressional mandate.
12 These networks include, but are not limited to the Interagency Monitoring of Protected
13 Visual Environments (IMPROVE), Subregional Cooperative Electric Utility, and the National
14 Park Service, Environmental Protection Agency Study (SCENES). The IMPROVE
15 monitoring program is managed by the National Park Service, the Forest Service, the Fish
16 and Wildlife Service, the Bureau of Land Management and the Environmental Protection
17 Agency. The main objective is to monitor visibility and particulate components in Class I
18 areas. Tables 8-2 and 8-3 lists several visibility and aerosol data bases.
19 Records of visual range can be used to gain insight into the effects of changing
20 emission patterns on visibility. One of the best examples of effects on visibility produced by
21 atmospheric pollution was a strike that shut down the copper industry in the southwestern
22 U.S. for more than 9 mo in 1967 to 1968. Copper production accounted for over 90% of
23 the SOX emissions, less than 1% of the NOX emissions, and less than 10% of the
24 conventional particulate emissions (Marians and Trijonis, 1979). Substantial decreases in
25 sulfate occurred at 5 locations (Tucson, Phoenix, Maricopa County, White Pine, and Salt
26 Lake City) within 19 to 113 km (12 to 70 miles) of copper smelters. Sulfates dropped by
27 about 60% at Grand Canyon and Mesa Verde, 325 to 500 km (201 to 310 miles) from the
28 main smelter area in southeast Arizona. Comparing measurements taken during the strike
29 with those taken during the surrounding 4 or 6 years, Trijonis and Yuan (1978) found a large
30 decrease in Phoenix sulfate loadings, accompanied by a substantial improvement in visibility.
31 In fact, visibility improved at almost all locations during the strike, with the largest
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TABLE 8-2. LONG-TERM VISIBILITY AND AEROSOL DATA BASES
£•' Study/Data Base
Air Sheds
Period
Type of Data3
Purpose of Study
Comments
National and Regional Networks
National Weather Service
Airport Visibility Data
Rural and urban
airports all over the
nation.
1918 to present
Human estimates of
prevailing visibility mainly
in support of aircraft
operations
To assess visibility
trends; Assessment of
the role of meterology
on visibility impairment.
Quality varies from site to site;
natural causes of visibility
impairment (rain, snow, fog)
included in data.
Interagency Monitoring of Twenty remote
Protected Visual
Environments (Improve)
locations
nationwide, though
primarily in the
West.
1987 to present Aerosol and visibility; PM10 To establish baseline Employs "state-of-art" methods for
and fine particle mass. Fine values and identify
particle elements, ions,
organic and light absorbing
carbon. aext, aap , and
and photography.
Jsp
existing impairment in
visibility protected
federal Class I areas.
long term routine monitoring.
Operated jointly by EPA four
federal land managers.
oo
Eastern Fine Particle
Visibility Network
Five eastern rural
locations.
1988-89 Five
sites after 1989
two sites
Aerosol and visibility; fine A research monitoring
particle elements organic and program to provide
soot carbon, a,
ext'
a , and photography.
-------
TABLE 8-2 (cont'd). LONG-TERM VISIBILITY AND AEROSOL DATA BASES
~ Study/Data Base
Air Sheds
Period
Type of Data3
Purpose of Study
Comments
vo
Western Regional Air Eleven nonurban
Quality Study locations in the
(WRAQS) western U.S.
1981-1982
Aerosol and visibility; To document bacground Represents the highest times
PM15 and fine particle
mass, elements, ion.
levels of visibility and resolution for routinely collected
related aerosols, organic filter samples (two four-hour samples
and elemental carbon. each day).
asg and asp, observed
visual range and
photography.
National Air Urban & rural areas 1975 to present
Surveillance Network of U.S.
(NASH)
Aerosol only; TSP ions, Air quality monitoring.
and some elements.
No size-fractioned data; collected
only once every six days; artifact on
filter possible.
Inhalable Particle Urban and rural June 1979 to present Aerosol only; fine and Characterize inhalable Discrepancy exists between PM15 and
oo
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O
C!
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W
O
n
H—I
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Network (IP
Network)
Sulfate Regional
Experiment (SURE)
areas of U.S. Evans
(84) Rodes and
Evans (85)
Nonurban areas of
eastern U.S. (9
Class I sites and 45
Class II sites)
Eastern Regional Air Nine nonurban
Quality Studies
(ERAQS)
Ohio River Valley
Study
areas in
northeastern U.S.
SURE Class I sites.
Three rural sites in
Ohio River Valley.
1977-1978
asg and asp,
ffm, and
photography.
May 1980-August
1981
coarse aerosol mass, particles
PM15 mass, elements,
and ions (every fourth
sample).
Aerosol only; TSP, fine Sulfacte characterization
and coarse aerosol mass, pollutant source
ions and elements. characterization
IP mass (sum of fine and coarse).
Screening of the data required to
remove invalid data points (~25%).
Class I sites operated for 18 months
continuously; Class II sites operated
for one month every season for a
total of six.
Aerosol and
visibility; TSP, fine
and coarse aerosol
mass, ions, elements,
To characterize visibility To characterize visibility The only long-term instrumental
(at two sites only) and
air quality in the
northeastern U.S.
region.
Aerosol only; fine and
coarse aerosol mass and
elements.
(at two sites only) and
air quality in the
northeastern U.S.
region.
Characterization of fine
and coarse aerosols in
the region.
visibility data set generated in the
eastern U.S. Visibility monitored
only at 2 sites; intercomparison of
visibility measurement methods
made.
Portion of aerosol composition was
not accounted for due to limitations
in XRF analysis used. A long-term
daily monitoring of aerosol in rural
areas of the Ohio River Valley.
-------
TABLE 8-2 (cont'd). LONG-TERM VISIBILITY AND AEROSOL DATA BASES
e: Study/Data Base
Air Sheds
Period
Type of Data3
Purpose of Study
Comments
Harvard School of
Public Health's Six
Cities Study
RESOLVE
Portage, WI
Topeka, KS
Kingston, TN
Watertown, MA
St. Louis, MO
Steubenville, OH
Seven remote
sites in the
California
Mojave Desert
Spring 1979
Aerosol and visibility; fine
and coarse aerosol mass,
elements, SO4
H
6
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o
o
H
W
Great Smoky
Mountain National
Park Visibility and
Air Quality Study
(TVA)
Regional Air
Pollution Study
(RAPS)
Portland Aerosol
Characterization
Study (PACS)
Great Smoky
Mountain
National Park
100 km region
around St. Louis,
MO
1980-1983 Aerosol and visibility; fine
and coarse aerosol mass and
elements; as and asg and crext;
photography.
1974-1977 Aerosol only; fine and coarse
mass, SO4=, elements.
Characterize visibility and
aerosol.
Develop and evaluate
regional air quality models.
Because of instrument problems,
teleradio-meter data were lost. Total
paniculate matter mass only estimated
in some cases. PIXE analysis could
not provide some major elemental
data.
Comparison of Hi-Vol and
dichotomous samplers.
Two rural and July 1977-April Visibility and aerosol; fine and Aerosol characterization Significant role of carbonaceous
four urban areas 1978 coarse mass, TSP, ions, source apportionment. aerosols recorded.
in Portland, OR elements, asp and asg.
Visibility data include light scattering and light extinction measurements using integrating nephelometer, teleradiometers, cameras, and human observers.
Source: Baedecker (1991).
O
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TABLE 8-3. SHORT-TERM INTENSIVE VISIBILITY AND AEROSOL STUDIES
~ Study/Data Base
h—*
VO
Air Sheds
Period
Type of Data3
Purpose of Study
Comments
Rural Studies
Allegheny Mountain
Studies
Rural Allegheny
Mountain site
24 July- 11 Aug Visibility and aerosol;
1977 and Aug 1993 TSP, fine and coarse
aerosol mass, ions,
Characterization of
visibility and SO4= in the
region.
Filter artifact investigated;
no size fractionated data in
1977.
elements, crsp and asg.
Shenandoah Valley
Studies
Rural Shenandoah
Valley
15 July - 15 Au
1980
Visibility and aerosol; fine
and coarse aerosol mass,
ions, elements,
-------
TABLE 8-3 (cont'd). SHORT-TERM INTENSIVE VISIBILITY AND AEROSOL STUDIES
Co
Study /Data Base
California Aerosol
Characterization Study
(ACHEX)
Air Sheds
Fourteen southern
California cities
Period
July- Nov 72,
July - Oct 73
Type of Data3
Rural Studies
Aerosol and visibility TSP,
fine and coarse aerosol mass,
ions, elements, asg and asp.
Purpose of Study
Characterization of
urban aerosols in
California.
Comments
The most complete classic
aerosol experiment. New
methods sampling and analysis
tested.
Denver Winter Haze Denver, CO
Study I
Nov - Dec 78 Visibility and aerosol; fine Investigation of
and coarse aerosol mass, ions, sources of Denver
elements, asg and asp, and haze.
Role of local sources and the
significant role of carbon in the
air documented.
Jexf
Denver Winter Haze
Study II
Denver, CO
Jan 1982 Visibility and aerosol; fine Investigation of
and coarse aerosol mass, ions, sources of Denver
elements,
-------
TABLE 8-3 (cont'd). SHORT-TERM INTENSIVE VISIBILITY AND AEROSOL STUDIES
K Study/Data Base
Air Sheds
Period
Type of Data3
Purpose of Study
Comments
00
O
O
O
1
Northern New Jersey Air Newark, NJ
Winter 1982-1983 Aerosol only.
Pollution Study
Willamette Valley Field
and Slash Burning Study
San Joaquin Valley
Aerosol Study
Elizabeth, NJ
Camden, NJ
Ringwood, NJ
Willamette Valley,
OR
San Joaquin Valley,
CA
Summer 1978
Nov-Dec 78, Jul
and Sept. 79
Aerosol; fine and coarse
mass, TSP, elements
(carbon), ions
Aerosol only; fine and
coarse mass, ions.
Inhalation toxicology
studies.
Assessment of field and
slash burning on air
quality.
Characterize ambient
aerosols termittent data
sets.
Urban contributions of
carbonaceous particles to air
pollution episodes.
Significant role of
carbonaceous particles in
fine aerosol demonstrated.
"Visibility data include light scattering and light extinction measurements using integrating nephelometer, teleradiometers, cameras, and human observers.
Sourc: Baedecker (1991).
n
h— I
H
W
-------
1 improvements occurring near and downwind (north) of the copper smelters in southeast
2 Arizona and near the copper smelters in Nevada and Utah.
3 More recently, improvements in visibility have been reported in the east during the
4 summer months from 1978 to 1982 and from 1988 to 1992. Using data from 1948 to 1983,
5 Husar and Wilson (1993) reported that extinction coefficients calculated from visual range
6 data showed a direct correlation with sulfur emissions in the northeastern U.S.
7 Hofmann (1993), using balloon measurements from 1971 to 1990 over Laramie, WY,
8 showed a decrease of 1.6 to 1.8% per year of optically active tropospheric aerosols. Similar
9 results were reported by Pennick et al. (1993) in New Mexico from the mid 1970s to 1990.
10 Pennick et al. (1993) reported a slight decrease in optically active tropospheric aerosols but
11 no change in elemental black carbon. Hofmann (1993) suggested that the decrease in the
12 tropospheric aerosols was due to the reduction in SO2 emissions in the U.S. during that time.
13 Eldred and Cahill (1994) reported that sulfate concentrations in the west decreased or
14 remained unchanged except for during the winter months, when the sulfate concentrations
15 increased. An increase in sulfate concentrations was noted for areas in the east except for
16 during the winter months when a decrease was noted. Summer increases of sulfate in the
17 Shenandoah National Park were more dramatic. Eldred and Cahill (1994) based these
18 findings on monitoring data taken from 12 monitoring sites in remote Class I visibility areas
19 from June 1982 to August 1992.
20 Hildemann et al. (1994) found seasonal trends in ambient organic aerosol concentrations
21 in Los Angeles, CA. Strong peaks were noted in the fall and winter months. Husar and
22 Poirot (1992) found that particles of less than 10 /*m had different weekly patterns in
23 different parts of the U.S. El Paso, TX had lower concentrations during the weekends, the
24 highest concentrations for San Bernadino were reported on Mondays, and the highest
25 concentrations for Yosemite National Park and Oceanside were on Sundays.
26 White et al. (1994) examined back-trajectories for air arriving at the Grand Canyon
27 using the four quadrants (NE, NW, SE, and SW) as source zones. Back-trajectories were
28 calculated for air parcels arriving in the Grand Canyon during the hours of 11:00 am to
29 5:00 pm. Methylchloroform was used as a regional tracer for air from the Los Angeles
30 basin. White et al. (1994) concluded that the best visibility occurred at the Grand Canyon
31 when the air is from the north. They found high methylchloroform at the mouth of the
April 1995 8-27 DRAFT-DO NOT QUOTE OR CITE
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1 Canyon from April to October. The back-trajectories on the days of high methylchloroform
2 indicated that the air had been in the southwest quadrant several day prior. High levels of
3 sulfate were observed on days when the back-trajectory of the air parcel spent three quarters
4 of the time exclusively in one quadrant, but no specific quadrant could be identified as the
5 primary quadrant of concern. Each quadrant was determined to have at least one high
6 concentration day except the northwest quadrant. High RH and low visual range are
7 associated with air from the southwest.
8
9
10 8.5 ECONOMIC VALUATION OF EFFECTS OF PARTICIPATE
11 MATTER ON VISIBILITY
12 The effects of particulate matter on visibility were described in previous sections of this
13 chapter and are hazes and reductions in visual range in all of the U.S. This section discusses
14 the available economic evidence concerning the value of preventing or reducing these types
15 of effects on visibility. The following brief summary of economic estimation methods and
16 available results is derived from the document. Air Quality Criteria for Oxides of Nitrogen
17 (U.S. Environmental Protection Agency, 1993).
18
19 8.5.1 Basic Concepts of Economic Valuation
20 Visibility has value to individual economic agents primarily through its impact upon
21 activities of consumers and producers. Studies of the economic impact of visibility
22 degradation by air pollution have focused on consumer activities. Most economic studies of
23 the effects of air pollution on visibility have focused specifically on the aesthetic effects to
24 the individual. Some commercial activities, such as airport operations, may be affected by
25 visibility degradation by air pollution, but available evidence suggests that the economic
26 magnitude of the effects of haze on commercial operations probably is very small. In a 1985
27 report, the U.S. Enviromental Protection Agency concluded that some percentage of the
28 visibility impairment incidents sufficient to affect air traffic activity might be attributable, at
29 least in part, to manmade air pollutants (possibly 2% to 12% in summer in the eastern U.S.).
30 It is well established that people notice those changes in visibility conditions that are
31 significant enough to be perceptible to the human observer, and that visibility conditions
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1 affect the well-being of individuals. This has been verified in scenic and visual air quality
2 rating studies (Middleton et al., 1983; Latimer et al., 1981; Daniel and Hill, 1987), through
3 the observation that individuals spend less time at scenic vistas on days with lower visibility
4 (MacFarland et al., 1983), and through use of attitudinal surveys (Ross et al., 1987). The
5 intent of visibility-related economic studies has been to put a dollar value on changes in well-
6 being associated with visibility degradation.
7 Welfare economics defines a dollar measure of the change in individual well-being
8 (referred to as utility) that results from a change in the quality of any public good, such as
9 visibility, as the change in income that would cause the same change in well-being as that
10 caused by the change in the quality of the public good. One way of defining this measure of
11 value is to determine the maximum amount the individual would be willing to pay to obtain
12 improvements or prevent degradation in the public good (see Freeman [1979] for more
13 detail). For most goods and services traded in markets, this measure can be derived from
14 analysis of market transactions. For non-market goods, such as visibility, this economic
15 measure of value must be derived some other way.
16 For purposes of this discussion, consumer values for changes in visibility can be
17 divided into use and non-use values (there are slight variations in the way these are defined
18 by different economists). Use values are related to the direct influence of visibility on the
19 current and expected future activities of an individual at a site. Non-use values are the
20 values an individual places on protecting visibility for use by others (bequest value) and on
21 knowing that it is being protected regardless of current or future use (existence value). Total
22 value, combining use and non-use, is sometimes called preservation value.
23
24 8.5.2 Economic Valuation Methods for Visibility
25 Two main economic valuation methods have been used to estimate dollar values for
26 changes in visibility conditions in various settings: (1) the contingent valuation method
27 (CVM), and (2) the hedonic property value method. Both methods have important
28 limitations, and uncertainties surround the accuracy of available results for visibility.
29 Ongoing research continues to address important methodological issues, but at this time some
30 fundamental questions remain unresolved (Chestnut and Rowe, 1990a; Mitchell and Carson,
31 1989; Fischhoff and Furby, 1988; Cummings et al., 1986). Recognizing these uncertainties
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1 is important, but the body of evidence as a whole suggests that economic values for changes
2 in visibility conditions are probably substantial in many cases and that a sense of the likely
3 magnitude of these values can be derived in some instances from the available results
4 (Chestnut and Rowe, 1990a).
5
6 8.5.2.1 Contingent Valuation Method
7 The CVM involves the use of surveys to elicit values that respondents place on changes
8 in visibility conditions (see Rowe and Chestnut [1982], Mitchell and Carson [1989], and
9 Cummings et al. [1986] for more details on this method). The most common variation of the
10 CVM relies on questions that directly ask respondents to estimate their maximum willingness
11 to pay (WTP) to obtain or prevent various changes in visibility conditions. The potential
12 changes in visibility conditions are usually presented to the respondents by means of
13 photographs and verbal descriptions, and some hypothetical payment mechanism, such as a
14 general price increase or a utility bill increase, is posed.
15 The CVM offers economists the greatest flexibility and potential for estimating use and
16 non-use values for visibility. There are many types of changes in visibility for which total
17 values cannot be derived from market data. As a result, most recent visibility value
18 applications use the CVM. This approach continues to be controversial, however, and there
19 are those who question whether the results are useful for policy analysis (Fischhoff and
20 Furby, 1988; Kahneman and Knetsch, 1992). Smith (1992) has responded to some of the
21 questions raised about the CVM, but a consensus on its usefulness and reliability has not
22 been reached in the economics community. Cummings et al. (1986) and Mitchell and Carson
23 (1989) have conducted the most comprehensive reviews of the CVM approach to date and
24 have concluded that there is sufficient evidence to support the careful use of results from
25 well-designed CVM studies in certain applications.
26 Among the fundamental issues concerning the application of CVM for estimating
27 visibility values are (1) the ability of researchers to present visibility conditions in a manner
28 relevant to respondents and to design instruments that can elicit unbiased values; and (2) the
29 ability of respondents to formulate and report values with acceptable accuracy. As with any
30 survey instrument, it is important that the presentation be credible, realistic, and as simple as
31 possible. The optimal level of detail and the most critical pieces of information necessary in
April 1995 8-30 DRAFT-DO NOT QUOTE OR CITE
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1 the presentation to respondents to obtain useful CVM responses continue to be topics of
2 research and discussion. Another important issue in CVM visibility research concerns the
3 ability of respondents to isolate values related to visibility aesthetics from other potential
4 benefits of air pollution control such as protection of human health. Preliminary results
5 (Irwin et al., 1990; Carson et al., 1990) suggest that simply telling respondents before asking
6 the WTP questions to include only visibility is not adequate and may cause some upward bias
7 in the responses.
8
9 8.5.2.2 Hedonic Property Value Method
10 The hedonic property value method uses relationships between property values and air
11 quality conditions to infer values for differences in air quality (see Rowe and Chestnut [1982]
12 and Trijonis et al. [1984] for more detail on this method). The approach is used to
13 determine the implicit, or "hedonic," price for air quality in a residential housing market,
14 based on the theoretical expectation that differences in property values that are associated
15 with differences in air quality will reveal how much households are willing to pay for
16 different levels of air quality in the areas where they live. The major strength of this
17 approach is that it uses real market data that reflect what people actually pay to obtain
18 improvements in air quality in association with the purchase of their homes. The method can
19 provide estimates of use value, but non-use values cannot be estimated with this method.
20 There are many theoretical and empirical difficulties in applying the hedonic property
21 value method for estimating values for changes in visibility, but the most important limitation
22 is the difficulty in isolating values for visibility from other effects of air pollution at the
23 residence. Hedonic property value studies to date provide estimates of total value for all
24 perceived impacts resulting from air pollution at the residence, including health, visibility,
25 soiling, and damage to materials and vegetation. The potential for estimating separate values
26 for visibility with this method is limited for two reasons. First, the actual effects of air
27 pollution often are highly correlated, making it difficult to separate them statistically using
28 objective measures. Second, individuals are likely to perceive a correlation between these
29 effects and to act accordingly in their housing decisions, even if the effects are actually
30 separable using objective measures.
31
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1 8.5.3 Studies of Economic Valuation of Visibility
2 Economic studies have estimated values for two types of visibility effects potentially
3 related to particulate matter and NOX: (1) use and non-use values for preventing the types of
4 plumes caused by power plant emissions, visible from recreation areas in the southwestern
5 United States; and (2) use values of local residents for reducing or preventing increases in
6 urban hazes in several different locations.
7
8 8.5.3.1 Economic Valuation Studies for Air Pollution Plumes
9 Three CVM studies have estimated on-site use values for preventing an air pollution
10 plume visible from recreation areas in the southwestern U.S. (Table 8-4). One of these
11 studies (Schulze et al., 1983) also estimated total preservation (use and non-use) values held
12 by visitors and non-visitors for preventing a plume at the Grand Canyon. A fourth study
13 concerning a plume at Mesa Verde National Park (Rae, 1983) was not included because of
14 methodological problems with the contingent ranking approach used (Ruud, 1987). The
15 plumes in all three studies were illustrated with actual or simulated photographs showing a
16 dark, thin plume across the sky above scenic landscape features, but specific measures such
17 as contrast and thickness of the plume were not reported. Respondents were told that the
18 source of the plume was a power plant or an unspecified air pollution source. In one study
19 (Brookshire et al., 1976), a power plant was visible in the photographs.
20 The estimated on-site use values for the prevention or elimination of the plume ranged
21 from about $3 to $6 (1989 dollars) per day per visitor-party at the park. These value
22 estimates are comparable to values obtained in these and other studies for preventing fairly
23 significant reductions in visual range caused by haze at parks and recreation areas in the
24 Southwest. A potential problem common to all of these studies is the use of daily entrance
25 fees as a payment vehicle. Respondents may have anchored on the then-typical $2 per day
26 fee and stated an acceptable proportional increase in entrance fees rather than reporting a
27 maximum willingness to pay. This may have caused some downward bias in the responses,
28 but empirical exploration of this question is needed. An alternative payment vehicle to
29 consider might be total expenditures for the trip to the park.
30 The results of the Schulze et al. (1983) study suggest that on-site use values may be
31 easily dwarfed by total preservation values held by the entire population. For example, with
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TABLE 8-4. ECONOMIC VALUATION STUDIES FOR AIR POLLUTION PLUMES
3j
so
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Location
Study of Plume
Schulze et al. (1983) Grand Canyon
National Park
MacFarland et al. Grand Canyon
(1983) National Park
Brookshire et al. Glen Canyon
(1976) National
Recreation
Area (Lake
Powell)
aWTP = Willingness to pay.
Study Subjects
Urban residents
who have visited
or plan to visit
Grand Canyon
Urban residents
in Denver, Los
Angeles,
Chicago,
Albuquerque;
visitors and non-
visitors
Park visitors
Nearby residents
and lake visitors
Year of
Interviews Type of Value
1980 Daily use value
at park per
household
1980 Monthly
preservation
value per
household
1980 Daily use value
at park per
visitor-party
(household)
1974 Daily use value
at recreation
area per
visitor-party
(household)
Valuation
Method
Contingent
valuation, direct
WTPa question
Contingent
valuation, direct
WTPa question
Contingent
valuation, direct
o
WTP question
Contingent
valuation, direct
WTPa question
Payment Mean Results
Vehicle ($ 1989)
Daily park $6.17 per day at
entrance fee park per
household
Monthly utility $5.31 per month
bill increase per household
Daily park $2.84 per day at
entrance fee park per visitor-
party (household)
Daily entrance Visitors: $3.32
fee per day additional
to prevent visible
plume
Residents: $2.21
per day additional
to prevent visible
plume
-------
1 average annual visitation at the Grand Canyon of about 1.3 million visitor-parties (about
2 three people per party), annual on-site use values for preventing a visible plume every day
3 would be about $8 million based on the Schulze et al. results, whereas the implied
4 preservation value for preventing a visible plume most days (the exact frequency was not
5 specified) at the Grand Canyon would be about $5.7 billion each year when applied to the
6 total United States population. There is, however, considerable uncertainty in the
7 preservation value estimates from this study. Chestnut and Rowe (1990b) found that the
8 Schulze et al. (1983) preservation value estimates for haze at national parks in the Southwest
9 are probably overstated by a factor of two or three and the same probably applies to the
10 preservation value estimates for plumes.
11
12 8.5.3.2 Economic Valuation Studies for Urban Haze
13 Six economic studies concerning urban haze caused by air pollution are summarized in
14 Table 8-5. Five of these are CVM studies and one is a hedonic property value study.
15 Although many other hedonic property value studies concerning air quality have been
16 conducted (see Trijonis et al. [1984] and Rowe and Chestnut [1982] for reviews), the study
17 by Trijonis et al. (1984) is the only one that has used visibility as the measure of air quality.
18 The magnitudes of the changes in visual range considered in each study vary, making
19 direct comparisons of the results difficult. In Table 8-5 implicit values obtained for a 10%
20 change in visual range are reported to allow a comparison of results across the studies.
21 Values for a 10% change are shown to illustrate the range of results across the different
22 studies. These estimates are based on a model developed for comparison purposes that
23 assumes economic values are proportional to the percentage change in visual range. Values
24 for a 20% change, for example, would be about twice as large as those shown for a 10%
25 change, given the underlying comparison model. Each of these studies relied on a
26 reasonably representative sample of residents in the study area, such that a range of
27 socioeconomic characteristics and of neighborhood pollution levels was included in each
28 sample.
29 The first five studies in Table 8-5 all focused on changes in urban hazes with fairly
30 uniform features that can be described as changes in visual range. The sixth study (Irwin
31 et al., 1990) focused on visual air quality in Denver, where a distinct edge to the haze is
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TABLE 8-5. ECONOMIC VALUATION STUDIES ON URBAN HAZE
a.
vo
oo
£
o
£
\>
TJ
H
6
o
o
>^x
H
O
H
W
O
n
H
W
Study Location
Western Cities
Loehman et al. San Francisco
(1981)
Brookshire et al. Los Angeles
(1982)
Trijonis et al. San Francisco
(1984)
Los Angeles
Eastern Cities
Tolley et al. (1986) Chicago;
Atlanta;
Boston;
Mobile;
Washington,
D.C.;
Miami;
Cincinnati
Year Valuation Method3 Payment Vehicle
PARTI. UNIFORM URBAN HAZE
1980 Contingent valuation, Monthly utility bill
direct WTP question increases
1978 Contingent valuation, Monthly utility bill
direct WTP question increases
1978-79 Hedonic property
value
1978-79 Hedonic property
value
1982 Contingent valuation, Monthly payment
direct WTP question for visibility
improvement
program
Presentation/Definition
of Change in Visibility
Change in frequency
distribution illustrated
with local photos for
3 levels of air quality
Change in average
visibility illustrated with
local photos for 3 levels
of air quality
Light extinction based
on airport visibility data
Light extinction based
on airport visibility data
Change in average
visibility illustrated with
Chicago photos for
levels of air quality
Implied Mean Annual
WTPa for a 10% Change
in Visual Range
($ 1989)
$106 per household
$10 per household
$208-231 per household
$112-226 per household
$8-51 per household
-------
TABLE 8-5 (cont'd). ECONOMIC VALUATION STUDIES ON URBAN HAZE
Study
Location
Year
Valuation Method
Payment Vehicle
Presentation/Definition
of Change in Visibility
Implied Mean Annual
WTPa for a 10% Change
in Visual Range
($ 1989)
PART I (cont'd). UNIFORM URBAN HAZE
Rae (1984)
Cincinnati
1982 Contingent valuation,
direct WTP question
Monthly payment
for visibility
improvement
program
Change in average
visibility illustrated
with Chicago photos
for 3 levels of air
quality
$48 per household
PART II. URBAN HAZE WITH BORDER
oo
Irwin et al. (1990) Denver
1989 Contingent valuation,
direct WTP question
General higher
prices each year
1-step change in
7-point air quality
scale, illustrated with
photos
WTP = Willingness to pay.
Preliminary results
indicate mean annual
WTP of about $100 per
household for a 1-step
change in the 7-point
scale, with about one-
third of the value
attributed to visibility
alone
-------
1 often noticeable, making visual range a less useful descriptive measure because it would vary
2 depending on the viewpoint of the individual and whether the target was in or above the haze
3 layer. The studies conducted in Denver and in the California cities are likely to have a
4 higher NOX component than in the eastern cities.
5 Both of the CVM studies in California asked respondents to consider health and visual
6 effects but used different techniques to have respondents partition the total values. They
7 found that, on average, respondents attributed about one-third to one-half of their total values
8 to aesthetic visual effects. In spite of many similarities in the approaches used, the CVM
9 results for San Francisco are notably higher than for Los Angeles when adjusted to a
10 comparable percentage change in visual range. One potentially important difference in the
11 presentations was that Loehman et al. (1981) defined the change in visibility as a change in a
12 frequency distribution rather than simply a change in average conditions. This type of
13 presentation is more realistic but more complex; and it is unclear how it may affect responses
14 relative to presentation of a change in the average. It is possible that the distribution
15 presentation might elicit higher WTP responses because it may focus respondents' attention
16 on the reduction in the number of relatively bad days (and on the increase in the number of
17 relatively good days), whereas the associated change in the average may not appear as
18 significant. The implied change in average conditions in the Loehman et al. (1981)
19 San Francisco study was considerably smaller than that presented in the Brookshire et al.
20 (1982) Los Angeles study, which may have also resulted in a higher value when adjusted to a
21 comparable size change in average visual range because of diminishing marginal utility (i.e.,
22 the first incremental improvement is expected to be worth more than the second).
23 The California studies in Los Angeles and San Francisco provide some interesting
24 comparisons because two different estimation techniques were applied for the same locations.
25 Property value results for changes in air quality for both cities were found to be higher than
26 comparable values (for changes in total air quality) obtained in the CVM studies. This is as
27 expected given the theoretical underpinnings of each estimation method, although Graves
28 et al. (1988) have reported that subsequent analysis of the property value data revealed that
29 the estimates are more variable than the original results suggest. These property value
30 results are not reported here because they are for changes in air pollution indices that are not
31 tied to visual air quality.
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1 The property value study results reported in Table 8-5 from Trijonis et al. (1984) were
2 estimated using light extinction as the measure of air quality. However, as discussed in the
3 previous section on the hedonic property value method, these estimates are still likely to
4 include perceived benefits to human health for reductions in air pollution as well as values
5 for visual aesthetics. Consistent with this expectation, the results for a 10% change in light
6 extinction are higher than the CVM results for visual range changes for the same cities.
7 Respondents in several CVM studies have reported that, on average, they would attribute to
8 visibility aesthetics about one-fourth to one-half of their total WTP for improvements in air
9 quality. This would imply that the Trijonis et al. results may reflect $25 to $100 for a
10 change in visibility alone.
11 The results for the uniform urban haze studies in cities in the eastern U.S. fall between
12 the respective CVM results for the California cities. The changes in visual range presented
13 in these studies were similar to those presented in the Los Angeles study. In all of the
14 eastern studies respondents were simply asked to consider only the visual effects when
15 answering the WTP questions. This approach is now considered to be inadequate (Irwin
16 et al., 1990; Carson et al., 1990).
17 A recent study that has not as yet completed the peer-review process has applied the
18 approach recommended in recent methodological explorations to estimate values for changes
19 in visibility. McClelland et al. (1991) conducted a mail survey in 1990 in Chicago and
20 Atlanta. Residents were asked what they would be willing to pay to have an improvement in
21 air quality, which amounted to about a 14% improvement in annual average visual range.
22 Respondents were then asked to say what percentage of their response was attributable to
23 concern about health effects, soiling, visibility, or other air quality impact. Respondents, on
24 average, attributed about 20% of their total WTP to visibility. The authors conducted two
25 analyses and adjustments on the responses. One was to estimate and eliminate the potential
26 selection bias resulting from non-response to the WTP questions (including what has been
27 called protest responses). The other was to account for the potential skewed distribution of
28 errors caused by the skewed distribution of responses (the long tail at the high end). Both of
29 these adjustments caused the mean value to decrease. The annual average household WTP
30 for the designated visibility improvement was $39 before the adjustments and $18 after the
31 adjustments. This adjusted mean value implies about $13 per household for a 10%
April 1995 8-38 DRAFT-DO NOT QUOTE OR CITE
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1 improvement in visual range. This is at the low end of the range of estimates shown in
2 Table 8-5. If peer-review of this research effort confirms the appropriateness of the study
3 design and analysis, the results suggest that greater confidence should be placed in the lower
4 end of the range of results shown in Table 8-5 because this study represents an improvement
5 in approach over the other eastern-cities studies.
6 Irwin et al. (1990) have reported preliminary results for the Denver study (Part II,
7 Table 8-5). Comparison of these preliminary results with results from other studies is
8 difficult because the photographs used to illustrate different levels of air quality were not tied
9 to visual range levels. Instead, they were rated on a seven-point air quality scale by the
10 respondents, who were then asked their maximum WTP for a one-step improvement in the
11 scale. This study reports some important methodological findings. One of these is
12 confirmation that simply asking respondents to think only about visibility results in higher
13 WTP responses for visibility changes than when respondents are asked to give WTP for the
14 change in air quality and then to say what portion of that total they would attribute to
15 visibility only. The latter approach produced a mean WTP estimate for a one-step change in
16 visibility that was about one-half the size of the mean WTP estimate given when respondents
17 were simply asked to think only about visibility. This may result from the effect of budget
18 constraints on marginal values (the respondent has less to spend on visibility when he also is
19 buying health); however, the authors express the concern that some, but not all, of the value
20 for health may be included in the response when respondents are told to think only about
21 visibility. They recommend that respondents be asked to give total values for changes in
22 urban air quality and then be asked to say what portion is for visibility.
23
24
25 8.6 CLIMATIC EFFECTS
26 8.6.1 Introduction
27 Paniculate matter of submicrometer size in the earth's atmosphere perturbs the radiation
28 field sufficiently to warrant its consideration in any discussion of processes that maintain the
29 current climate. Perturbation of the radiation field generally is expressed as a radiative
30 forcing, which is the change in average net radiation at the top of the troposphere because of
31 a change in solar (shortwave) or terrestrial (longwave) radiation (Intergovernmental Panel on
April 1995 8-39 DRAFT-DO NOT QUOTE OR CITE
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1 Climate Change, 1990). Note that it is the net effect at the top of the troposphere (i.e., the
2 tropopause) that forces climate, and not the change at the surface, because the surface and
3 troposphere are intimately coupled through atmospheric energy exchange processes such as
4 dry and moist convection (Ramanathan et al., 1987). The radiative forcing due to aerosols is
5 negative (i.e., aerosols have a cooling effect through the enhanced reflection of solar
6 energy). This is in contrast to radiatively active trace ("greenhouse") gases associated with
7 industrial and agricultural activities, which produce a positive longwave radiative forcing
8 (i.e., "greenhouse" gases cause a warming of the earth-troposphere system). A large fraction
9 of atmospheric paniculate matter is of anthropogenic origin, the chief sources being the
10 emission of sulfur-containing aerosols by industry and the large-scale burning of biomass.
11 There is now little doubt that long-lived, optically thick, aerosol layers may have
12 modified the earth's climate in the past. Geologic evidence suggests that there have been
13 episodic injections of massive amounts of material into the earth's atmosphere as a result of
14 the impact of large asteroids or comets. The diminution of solar radiation reaching the
15 surface has been cited as the most likely cause of mass extinctions of species at the
16 Cretaceous-Tertiary boundary (Alvarez et al., 1980) and also in the Late Devonian (Claeys
17 et al., 1992). The possibility of a similar climatic catastrophe following a nuclear war has
18 also been raised (Turco et al., 1983, 1990). However, these are examples of massive
19 injections of paniculate matter that result in extremely large radiative forcings. Current
20 interest is focused on much more modest injections of materials that form thin aerosol layers
21 in the troposphere. Although the radiative effects are smaller and have been generally
22 ignored in climate model simulations (Hansen and Lacis, 1990), recent studies have estimated
23 that they are not negligible and that their radiative forcing may be comparable (but opposite
24 in sign) to the radiative effects of increased greenhouse gas emissions (Wigley, 1991;
25 Charlson et al., 1992; Penner et al., 1992). Because there is so much concern regarding
26 greenhouse gas-induced climate change, the study of this potential opposite effect of
27 industrial emissions is expected to be quite intense in the near future (Penner et al., 1994).
28
29 8.6.2 Radiative Forcing
30 To appreciate what is at issue here, it is necessary to understand the concept of
31 radiative forcing. Averaged globally and annually, about 240 watts per meter squared
April 1995 8-40 DRAFT-DO NOT QUOTE OR CITE
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1 (W m~2) of solar energy is absorbed by the earth-atmosphere system (Hartmann, 1994). This
2 must be balanced by an equal emission of thermal energy back to space for equilibrium. A
3 change in average net radiation at the tropopause, because of a change in either solar or
4 terrestrial radiation, perturbs the system and this perturbation is defined as the radiative
5 forcing. In response to this perturbation, the climate system will try and reach a new
6 equilibrium state. For example, the increase in longwave opacity of the atmosphere resulting
7 from enhanced concentrations of greenhouse gases such as carbon dioxide (CO2) and methane
8 (CH4) is a positive radiative forcing because it leads to a reduction in outgoing thermal
9 radiation. For equilibrium, given that there is no change in solar input, the temperature of
10 the surface-troposphere system must increase. The individual contributions to this positive
11 forcing, since pre-industrial times, is shown in Figure 8-5 (Intergovernmental Panel on
12 Climate Change, 1990). Carbon dioxide is the single most important contributor with a
13 radiative forcing of 1.50 W m"2 for the period 1765 to 1990. The total for all greenhouse
14 gases attributable to anthropogenic sources is 2.45 W m"2.
15 Human activity has also led to an increase in the abundance of tropospheric aerosols,
16 primarily as a result of enhanced sulfur dioxide emission, but also from biomass burning.
17 This aerosol layer produces a radiative forcing by perturbing the amount of solar energy that
18 is absorbed by the earth-atmosphere system. By increasing the amount of solar energy
19 reflected by the planet, aerosols produce a direct radiative forcing. They can also force the
20 climate system indirectly by modifying the microphysical properties of clouds, primarily by
21 reducing the effective drop size of water clouds. Both the direct and indirect radiative
22 forcing of aerosols are negative (i.e., in response to this perturbation, the planet will cool).
23 The succeeding sections of this chapter are devoted to the estimation of aerosol
24 radiative forcing. Translating this forcing into a climate response requires the incorporation
25 of the forcing into a climate model. The model simulations, of course, are only as reliable
26 as the models, which typically incorporate numerous feedbacks in the climate system that are
27 only represented to some degree of approximation. There are certainly many feedbacks
28 missing from current climate models, and it is quite possible that some feedbacks have been
29 modeled quite incorrectly. Moreover, the radiative forcing due to anthropogenic aerosols
30 needs to be estimated separately from that due to naturally occurring aerosols in order to
April 1995 8-41 DRAFT-DO NOT QUOTE OR CITE
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Legend
CFCs & HCFCs
STRAT H2O
N2O
1750
1800
1850 1900
Year
1950
2000
Figure 8-5. Changes in radiative forcing (W m"2) due to increases in greenhouse gas
concentrations between 1765 and 1990. Values are changes in forcing
from 1765 concentrations.
Source: Intergovernmental Panel on Climate Change (1990).
1 evaluate the impact of human activity. The relationship between these aspects of the problem
2 is shown in Figure 8-6 (Harshvardhan, 1993).
3 As has been mentioned, the radiative forcing due to aerosols is opposite in sign to that
4 due to greenhouse gases, but the degree of offset in forcing may not translate into offsetting
5 climatic consequences. We can only judge these by studying model simulations. Also, it
6 must be kept in mind that climate variations occur in the absence of radiative forcing as a
7 result of interactions between the atmosphere, oceans, and the various elements of the land
8 surface such as snow cover and vegetation.
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Natural Sulfate
Anthropogenic Sulfate
Sulfate Aerosols
Direct radiative forcing through
reduction in surface insolation
and increase in atmospheric
solar absorption
Indirect radiative forcing
through modification of
cloud and haze
microphysical properties
Feedbacks in the
climate system
CLIMATE RESPONSE
Figure 8-6. A schematic diagram showing the relationship between the radiative
forcing of sulfate aerosols and climate response.
Source: Harshvardhan (1993).
1 8.6.3 Solar Radiative Forcing by Aerosols
2 Aerosol radiative forcing results from enhanced reflection of solar energy which enters
3 the top of the earth's atmosphere as a collimated beam of infinite width, but is subsequently
4 scattered and absorbed to some degree even on the clearest day. Figure 8-7 shows this
5 process schematically. Throughout the troposphere molecules, constituting the atmosphere,
6 scatter sunlight by the process of Rayleigh scattering, which is highly wavelength dependent.
7 In the lower troposphere, sunlight is scattered by aerosols or haze and absorbed by aerosols
8 and water vapor. Because the aerosol loading is quite variable, this component of aerosol
9 scattered solar radiation is also very variable.
10
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Figure 8-7. Extinction of direct solar radiation by aerosols showing the diffusely
transmitted and reflected, as well as the absorbed components.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
The degree to which a layer of particles scatters solar radiation is primarily determined
by the nondimensional parameter referred to as the scattering optical depth of the layer, TS,
which in turn is the column integrated volume scattering coefficient, os (units are km"1, see
sections on visibility for details). Because as depends on wavelength, the attenuation of the
direct beam of sunlight is also wavelength dependent. This spectral behavior is usually
expressed by the proportionality
(8-5)
where X is the wavelength in micrometers (/xm). The exponent, a, is the turbidity parameter
introduced by Angstrom (1964) and varies between 0.5 and 1.5 for aerosols (Twomey,
1977). For particles that are very small compared to the wavelength (Rayleigh scattering),
a. = 4, and for relatively larger particles, such as cloud drops, a. = 0.
The downwelling portion of the radiation scattered by molecules and aerosols forms
diffuse skylight whereas the unattenuated beam of solar radiation is said to be the directly
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1 transmitted or beam radiation. The upwelling portion of scattered radiation, together with
2 energy reflected by the surface, is the diffuse reflection of the earth-atmosphere system. It is
3 the perturbation in this component of radiant energy by enhanced aerosol loadings that
4 constitutes the radiative forcing to the system by aerosols. The sum of directly and diffusely
5 transmitted solar energy is the global solar radiation incident on a surface.
6 Figure 8-8, from Iqbal (1983), shows computations of the spectral distribution of a
7 solar energy incident on a horizontal surface for a solar zenith angle of 60° (air mass = 2)
8 and standard clear conditions. The atmosphere contains 350 Dobson units of ozone (O3),
9 2 ppt/cm of water vapor, and a nonabsorbing aerosol layer corresponding to a surface
10 visibility of 28 km. The ground reflectance is 0.2. Some features of Figure 8-8 are worth
11 noting. Virtually all solar radiation at wavelengths less than 0.29 /*m is removed by O3
12 absorption. Rayleigh scattering by molecules is the predominant source of the diffuse
13 radiation at shorter wavelengths, but the contribution falls off very dramatically with
14 increasing wavelength because of the inverse fourth power dependence. Aerosol scattering
15 contributes to the diffuse component at visible and near-infrared wavelengths. Absorption by
16 the strong water vapor bands is quite evident in the near-infrared.
17 An increase in the optical depth of aerosols results in a decrease in the direct beam
18 radiation, which could be substantial, but the downwelling portion of the enhanced scattered
19 radiation compensates for this to a large extent. This is illustrated in Figure 8-9, which
20 shows surface measurements of direct, diffuse, and global solar radiation, made using a
21 multifilter rotating shadowband radiometer (Harrison and Michalsky, 1994; Harrison et al.,
22 1994) at Albany, NY, on two clear days in August of 1992 and 1993. The total atmospheric
23 optical depth in 1992 was influenced by the eruption of Mt. Pinatubo in June 1991.
24 Although the volcanic aerosols were in the stratosphere, their effect on direct and diffuse
25 transmitted radiation is similar to that due to tropospheric aerosols. The quantity plotted is
26 the spectral irradiance convolved with the average human eye response that peaks at 550 nm
27 and falls to zero at 400 and 700 nm. The main feature of the plot is the substantial
28 difference in direct and diffuse radiation, but quite similar global irradiances. Close
29 inspection shows that on the hazier day (in 1992), the global transmitted radiation was
30 somewhat less (i.e., the volcanic aerosol caused a negative radiative forcing to the earth-
31 atmosphere system by increasing the planetary albedo). Locally, tropospheric aerosol optical
April 1995 8-45 DRAFT-DO NOT QUOTE OR CITE
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1,000
E
2.
C\l
I
8
gj
I
to
fc
&
CO
1
I
o
X
750 -
500 -
250
0.29 0.5
1.0 1.5
Wavelength (\im)
2.0
2.5
Figure 8-8. Global, direct, and diffuse spectral solar irradiance on a horizontal surface
for a solar zenith angle of 60° and ground reflectance of 0.2. Atmospheric
conditions are visibility, 28 km; water vapor, 2 ppt/cm.; ozone,
350 Dobson units.
Source: Iqbal (1983).
1 depths are much larger than the stratospheric optical depth and one would expect a more
2 obvious diminution of global transmitted radiation than is shown here.
3
4 8.6.3.1 Modeling Aerosol Direct Solar Radiative Forcing
5 Some basic aspects of scattering and absorption by small particles typically present in
6 aerosol layers govern the sign and magnitude of the direct radiative forcing by aerosols. The
7 reflectance of an aerosol layer is chiefly determined by the optical depth, single scattering
8 albedo o>, and some measure of the scattering phase function. The w, is the ratio of the
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6:00 8:00 10:00 12:00 2:00 4:00 6:00
AM NOON PM
Local Time
Figure 8-9. Surface measurements of direct, diffuse, and global solar radiation
expressed as illuminance, at Albany, NY, on August 23, 1992, and
August 26, 1993.
Source: Harrison and Michalsky (1994).
1 volume scattering coefficient, os, to the volume extinction coefficient, oe, and is a measure of
2 the absorptance of the aerosol layer. Related quantities are the specific extinction and
3 scattering coefficients, \}/e and \f/s, which are defined as the coefficients per unit mass in units
4 of m2g"1. The scattering phase function, P(0), determines the probability that incident
5 radiation will scatter into a particular direction given by the scattering angle 0 measured
6 from the forward direction of the incident radiation.
7 At visible wavelengths, the optical depth of tropospheric aerosols ranges from less than
8 0.05 in remote, pristine environments to about 1.0 near the source of copious emissions
9 (Weller and Leiterer, 1988). The optical depth decreases quite rapidly with increasing
10 wavelength if the layer is composed of fine particles as can be seen from Equation 8-1.
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1 Aerosol layers, therefore, tend to be fairly transparent at thermal wavelengths and their
2 radiative forcing is confined to solar wavelengths. Because there are strong water vapor
3 absorption bands in the solar near-infrared (see Figure 8-8), the dominant effect of
4 tropospheric aerosols is in the visible wavelengths. Harshvardhan (1993) has shown that, to
5 first order, the change in the albedo with the addition of a thin aerosol layer over a surface
6 of reflectance, Rs, is
7
8 AR * Rfl(l - Rs)2 - 2\aRs (8-6)
9
10 where Ra and Aa are the reflectance and absorptance, respectively, of the aerosol layer. The
11 perturbation, AR, will be positive when
12
13 (1 - w)/w)3 < (1 - R//2R, (8-7)
14
15 where /3 is the average backscatter fraction and can be computed from the scattering phase
16 function. A positive value of AR implies a negative solar radiative forcing because the
17 planetary albedo increases and less solar energy is absorbed by the earth-atmosphere system.
18 From Equation 8-7, it is obvious that the sign of the forcing will be determined to a
19 large extent by w. At visible wavelengths, most constituents of tropospheric aerosols, with
20 the exception of elemental carbon, are nonabsorbing and to = 1.0 (Bohren and Huffman,
21 1983) so that AR will be positive. Aerosols with absorbing components can be modeled as
22 equivalent scatterers of refractive index, m = n — ik, with the imaginary index being a
23 measure of particle absorption. Figure 8-10, from Harshvardhan (1993), shows the
24 computed values of o at a wavelength of 0.63 /xm for single particles of varying radius.
25 The three separate curves are for aerosols composed of carbon (m = 2.0 — 0.640 and two
26 models of sulfate aerosols containing absorptive components. Given the properties of an
27 aerosol layer, AR can be computed from Equation 8-6. To calculate the radiative forcing,
28 one must also include the effects of other atmospheric constituents such as molecular
29 scattering, stratospheric O3, water vapor absorption, and, most importantly, cloud cover.
30
31
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1 8.6.3.2 Global Annual Mean Radiative Forcing
2 Charlson et al. (1991) calculated the global mean radiative forcing due to anthropogenic
3 aerosols by making the following assumptions. They assumed that the perturbation would be
4 exceedingly small over cloudy areas because cloud optical depths are one to two orders of
5 magnitude greater than aerosol optical depths (Rossow and Schiffer, 1991). For
6 nonabsorbing aerosols, they found that the change in planetary albedo could be expressed as
7
8 ARp ~ T2a,m (1 - Nc) (1 - R,2) (2jSr) (8-8)
9
10 where rTatm is the transmittance of the atmosphere above the aerosol layer and Nc is the
11 global mean cloud fraction. The planetary mean radiative forcing is then
12
13 AFR = ARpS0/4 (8-9)
14
15 where S0/4 is the annual global mean insolation of the earth-atmosphere system (Hartmann,
16 1994) with S0 being the solar constant, which equal to 1,370 W m"2. For generally accepted
17 values of Tato = 0.71, Nc = 0.6, R, = 0.15 and 0 = 0.3, Charlson et al. (1991) obtained
18
19 AFfl « 30.0r (8-10)
20
21 such that for T, the optical depth at visible wavelengths, ranging from 0.05 to 0.10, the
22 direct solar radiative forcing is 1.5 to 3.0 W m"2, a value comparable to the combined
23 long-wave radiative forcing of several minor greenhouse gases (Section 8.6.2).
24 The above estimate was refined by Charlson et al. (1992) in which the anthropogenic
25 sulfate aerosol burden was actually related to the source strength of anthropogenic sulfur
26 dioxide (SO2), the fractional yield of emitted SO2 that reacts to produce sulfate aerosol and
27 the sulfate lifetime in the atmosphere. The scattering properties of the sulfate aerosol were
28 also modeled in terms of a relative humidity factor that accounts for the increase in particle
29 size associated with deliquescent or hygroscopic accretion of water with increasing RH. The
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1.0
0.8
o
•a
!
CO
0.6
0.4
D)
C
CO
0.2
0.0
0.01
nliII
A. • 0.63 urn
m = 1.53-0.001 i
m = 1.53-0.011
m = 2.0-0.641
0.1
1.0
Radius (urn)
10
Figure 8-10. Single scattering albedo of monodispersed spherical aerosols of varying
radius and three different refractive indices at a wavelength of 0.63 pun.
Source: Harshvardhan (1993).
1
2
3
4
5
6
7
8
9
10
relationship between optical depth and the areal mean column burden of anthropogenic sulfate
aerosol, Bsulfate, is
T ~
Xsulfate
B
sulfate
(8-11)
where Xsulfate *s ^e m°lar scattering cross section of sulfate at a reference low RH (30%) and
f(RH) is the relative humidity factor. The sulfate burden, Bsulfate, is related to SO2 emissions
and sulfate lifetime. For an emission rate of 90 X 1012 g of sulfur per year, a yield fraction
of 0.4, a sulfate lifetime of 0.02 years (7 days) and Xsulfate °f 500 m2mor1 (corresponding to
a specific extinction coefficient, \l/e, of 5 m2g4), Charlson et al. (1992) estimated that AF^ =
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1 1.0 W m"2, uncertain to a factor of 2 which perhaps should be more considering that the
2 uncertainty in 4>e alone is more than that (Hegg et al., 1993, 1994; Anderson et al., 1994).
3 The above is an estimate for the forcing due to industrial emissions. Another
4 anthropogenic source of aerosols is biomass burning. Penner et al. (1992) have estimated
5 that the radiative forcing due to this activity could be as much as 0.9 W m"2, which is
6 comparable to the sulfate forcing. One difference is that the smoke produced is somewhat
7 absorbing and the atmosphere would experience a positive forcing of 0.5 W m"2. Estimates
8 of the global forcing due to biomass burning are even more uncertain than those for sulfate
9 because of the sparsity of data on the relevant radiative properties of biomass aerosols.
10
11 8.6.4 Climate Response
12 8.6.4.1 Early Studies
13 Global Background Aerosols
14 The role of aerosols in modifying the earth's climate through solar radiative forcing has
15 been a topic of discussion for many decades. Modeling studies assumed a climatological
16 background distribution of aerosols such as that of Toon and Pollack (1976). Two simple
17 types of climate models were used to calculate the effects of aerosols on climate: (1) the
18 radiative-convective model, which resolves radiative perturbations in an atmospheric column,
19 and (2) the energy balance model, which allows for latitudinal dependence, but parameterizes
20 all processes in terms of the surface temperature. A typical study was that of Charlock and
21 Sellers (1980) who used an enhanced one-dimensional radiative-convective model that
22 included the effects of meridional heat transport and heat storage. The model was run with
23 and without a prescribed aerosol layer of visible optical depth equal to 0.125 for conditions
24 representative of 40° and 50° N latitude. The annual mean surface temperature with
25 aerosols was 1.6 °C lower than that for the aerosol-free run.
26 Coakley et al. (1993) were the first to use an energy balance model to compute the
27 latitudinally dependent radiative forcing for the Toon and Pollack (1976) aerosol distribution,
28 including the effects of absorbing components. Even for moderately absorbing aerosols (m
29 = 1.5 - 0.010, the solar radiative forcing was negative, except in the 80° to 90° N latitude
30 belt, which has a very high surface albedo. Here the criterion given by Equation 8-7 is not
31 satisfied and the change in albedo, AR, is negative (i.e., the solar radiative forcing is
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1 positive). The model results showed global mean surface temperature decreases ranging
2 from 3.3 °C for nonabsorbing aerosols to 2.0 °C for the absorbing model. The maximum
3 temperature drop was at polar latitudes even for the absorbing layer because advective
4 processes responded to the aerosol-induced cooling at low- and middle-latitudes. Other two-
5 dimensional model studies have confirmed this basic picture (Jung and Bach, 1987).
6
7 Regional and Seasonal Effects
8 Apart from global studies, there have been several programs devoted to ascertaining the
9 effects of aerosols on regional and seasonal scales. An example is the radiative effect of
10 aerosols in the Arctic (Rosen et al., 1981). A field experiment, the Arctic Gas and Aerosol
11 Sampling Program, was conducted in 1983 (Schnell, 1984). It was determined that aerosols
12 had a substantial absorbing component. The study by MacCracken et al. (1986) used both
13 one- and two-dimensional climate models to evaluate the climatic effects. They found that
14 the initial forcing of the surface-atmosphere system is positive for surface albedos greater
15 than 0.17, and the equilibrium response of the one-dimensional radiative-convective model
16 showed surface temperature increases of 8 °C. Infrared emission from the warmer
17 atmosphere was found to be an important forcing agent of the surface. The two-dimensional
18 model was run through the seasonal cycle and had an interactive cryosphere. Peak warming
19 occurred in May, a month later than the peak radiative forcing, as a result of earlier snow
20 melt.
21
22 Massive Aerosol Loads
23 In the 1980s, there were several studies related to what became known as the "nuclear
24 winter" phenomenon (Turco et al., 1983) (i.e., the climatic consequences of widespread
25 nuclear war). Modeling efforts ranged from radiative-convective models (Cess et al., 1985)
26 to three-dimensional general circulation models (Thompson et al., 1987; Ghan et al., 1988),
27 and mesoscale models (Giorgi and Visconti, 1989) with interactive smoke generation and
28 removal processes and fairly detailed smoke optics. A review of modeling efforts has been
29 made by Schneider and Thompson (1988) and Turco et al. (1990). The latter study
30 summarized the best estimates of possible reduction in surface temperature from the smoke
31 lofted into the atmosphere during the initial acute phase.
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1 General Circulation Model (GCM) studies (Thompson et al., 1987; Ghan et al., 1988)
2 indicate that for a July smoke injection, the average land temperatures over the latitude zone
3 from 30° to 70° N, over a 5-day period, would decrease by 5 °C for smoke of optical depth
4 equal to 0.3, but could decrease by 22 °C for large loadings of optical depth equal to 3.
5 However, the temperature in the interior of land masses could drop by as much as 30 °C.
6 The temperature perturbations for smoke injections in other seasons are smaller. At lower
7 latitudes, the cooling is moderated by the delay in smoke transport (assuming initial injection
8 in high northern latitudes), and the more humid climate. Model studies also indicate a
9 dramatic decrease in rainfall over land and a failure of the Asian monsoon (Ghan et al.,
10 1988).
11
12 8.6.4.2 Recent Regional Studies
13 There have been more recent studies of possible climatic effects resulting from severe
14 aerosol loading on regional scales. The Arctic haze problem has been investigated
15 extensively. Blanchet (1989, 1991), using a GCM, studied the effects of increasing aerosol
16 loads north of 60° N. Although the solar heating rate in the troposphere increased quite
17 dramatically, the temperature did not rise substantially. The positive forcing of 0.1 to 0.3
18 Kday"1 resulted in a decrease in the meridional heat flux. Quite importantly, the simulated
19 cloud cover in the experiment was altered sufficiently to produce that the changes of an order
20 of magnitude greater in net radiative fluxes at the top were locally an order of magnitude
21 greater than the initial forcing. This implies that it may be very difficult to identify climate
22 change effects due to aerosols alone. Another effect of aerosols at high latitudes that has the
23 potential for affecting climate is the change in surface albedo due to deposition of soot. This
24 was studied with respect to the nuclear winter problem by Vogelmann et al. (1988). They
25 found that the cooling due to smoke aerosol could be moderated somewhat by the "dirty"
26 snow at very high latitudes.
27 Several studies have examined the effect of smoke from forest fires on climate. Since
28 these are natural phenomena, it is important to understand their effects in order to place
29 anthropogenic effects in context. Evidence of substantial climatic effects is present only
30 when the smoke loading is substantial. For example, Robock (1988) examined the situation
31 in northern California where a subsidence inversion trapped smoke in mountain valleys for
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1 several days in September 1987. One station recorded an anomaly in the maximum
2 temperature of -20 °C. Veltischev et al. (1988) analyzed data covering the period of major
3 historical fires in Siberia, Europe, and Canada. They estimated that the optical depth of
4 smoke following fires in Siberia in 1915 was about 3.0 and surface temperature dropped by
5 5 °C.
6 Other studies have also shown a relationship between smoke and surface temperature.
7 Robock (1991) studied the smoke from Canadian fires in July 1982. He compared forecasted
8 temperatures with observations and found that regions of negative anomaly were well
9 correlated with the smoke layer. Westphal and Toon (1991) used a mesoscale model with
10 interactive smoke physics and optics to simulate the smoke plume and its meteorological
11 effects. They calculated the albedo of the smoke-covered area to be 35%, and the resulting
12 surface cooling was 5 °C.
13 Perhaps the most extensive recent investigation of the possible climatic effects of heavy
14 aerosol burdens was the study of the Kuwait oil fires in 1991. Several modeling studies were
15 undertaken. Browning et al. (1991) simulated the smoke plume with a long-range dispersion
16 model and concluded that the smoke would remain in the troposphere and not be lofted into
17 the stratosphere where the residence time would be much longer. They estimated a
18 maximum temperature drop of 10 °C beneath the plume, within about 200 km (i.e., only a
19 regional, not global climatic effect). Bakan et al. (1991) used a GCM with an interactive
20 tracer model to simulate the plume dispersion and climatic effects. The maximum
21 temperature drop was estimated to be about 4 °C near the source. The local and regional
22 nature of the effect was confirmed during a field experiment undertaken in May/June, 1991.
23 The smoke from the oil fires had insignificant global effects because (1) particle emissions
24 were less than expected, (2) the smoke was not as black as expected, (3) the smoke was not
25 carried high in the atmosphere, and (4) the smoke had a short atmospheric residence time
26 (Hobbs and Radke, 1992).
27 The study of severe events such as those described above is useful for investigating
28 model response since such strong forcings usually provide unambiguous climate response
29 signals. The simulated climate response to the more modest radiative forcing due to the
30 distribution of natural and usual anthropogenic sulfate or smoke aerosols is well within the
31 internal model variability. However, an estimate of the magnitude of possible effects can be
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1 obtained by model simulations that integrate the chemistry, optics, and meteorology of
2 anthropogenic aerosols.
3
4 8.6.4.3 Integrated Global Studies
5 Ideally, one should study the problem in an integrated manner, in which the emissions
6 of sulfate precursors are tracked globally and the radiative forcing of the resulting aerosols
7 computed locally in space and time. A further step would be to let the radiative response
8 impact climate interactively. This latter step could be carried out by a GCM coupled to an
9 oceanic model. Recent studies have accomplished various elements in this scenario.
10 Global three-dimensional models of the tropospheric sulfur cycle treat emission,
11 transport, chemistry and removal processes for natural and anthropogenic sources. The
12 primary natural source is dimethylsulfide (DMS), which is released by oceanic phytoplankton
13 (Nguyen et al., 1983; Shaw, 1983; Charlson et al., 1987). The DMS reacts in air to form
14 sulfate aerosols. Anthropogenic emissions are over land, especially in the heavily
15 industrialized areas of the Northern Hemisphere. Examples of such sulfur cycle models are
16 the Lagrangian model of Walton et al. (1988) and Erickson et al. (1991), known as the
17 GRANTOUR model, and the Eulerian transport model of Langner and Rodhe (1991) and
18 Langner et al. (1992), known as the MOGUNTIA model. Both models use prescribed mean
19 winds, typically obtained from GCM simulations, to provide monthly mean concentrations of
20 sulfate aerosols.
21 With such detailed input, it is possible to construct global maps of the radiative forcing
22 due to sulfate and compare the magnitude with that due to greenhouse gases. Kiehl and
23 Briegleb (1993) carried out such a study using the monthly mean sulfate abundances from the
24 MOGUNTIA model. For meteorological parameters, they used monthly mean 1989 analyzed
25 temperature and moisture fields from the European Center for Medium Range Weather
26 Forecasting. Vertical distributions of clouds were taken from a GCM simulation using the
27 National Center for Atmospheric Research Community Climate Model (CCM2) since such
28 detailed observations are lacking. However, attempts were made to adjust the total cloud
29 cover to correspond to observations.
30 The radiative forcing was calculated by Kiehl and Briegleb using an 18-band 5-
31 Eddington model in the shortwave and a 100 cm"1 resolution band model in the longwave,
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1 which includes the contributions due to trace gases such as CH4, nitrogen dioxide (NO2), and
2 chlorofluorocarbons. The optical properties of sulfate aerosol were calculated spectrally
3 using the refractive indices for 75 % sulfuric acid (H2SO4) and 25 % water (H2O) and an
4 assumed log-normal size distribution that has a geometric mean diameter by volume of 0.42
5 /zm. The specific extinction, \j/e, of the dry particles was found to be a very strong function
6 of wavelength, decreasing from 10 m2g"1 at 0.3 /tm to less than 2.0 m2g"1 at 1.0 /^m. This is
7 significant in interpreting the computed forcing when comparisons are made with earlier
8 studies that used a constant value of \l/e.
9 The direct radiative forcing is calculated by adding the sulfate burden to the model and
10 computing the change in absorbed solar radiation. Figures 8-1 la and 8-lib, from Kiehl and
11 Briegleb (1993) show the annual mean direct solar radiative forcing resulting from
12 anthropogenic sulfate aerosols (global mean = -0.28 W m"2) and anthropogenic plus natural
13 sulfate (global mean = — 0.54 W m"2). The patterns are similar to those obtained earlier by
14 Charlson et al. (1991), but the magnitude is roughly half. Most of the difference is due to
15 the assumption of a constant value of 5.0 m2g"1 for \{/e in the earlier study, but there was also
16 a difference in the scattering phase function used. Therefore, assumptions regarding
17 radiative properties were able to account for all the differences. Points to note in the figure
18 are the local concentrations of anthropogenic forcing and particularly the hemispheric
19 asymmetry in the forcing, even when natural sulfate is included. Although the southern
20 hemisphere is largely ocean, the direct forcing due to natural sulfate is substantial only in the
21 clear oceanic areas since, in the presence of clouds, the additional sulfate effect is minimal.
22 To place the role of anthropogenic sulfate in perspective, Kiehl and Briegleb (1993)
23 compared the direct radiative forcing with that of increasing greenhouse gases from
24 preindustrial times to the present. The greenhouse gas forcing is calculated by computing the
25 spatial distribution of the change in the net longwave flux at the tropopause for the trace gas
26 increases from the preindustrial period to the present. The annual averaged results for
27 greenhouse gases alone and in combination with anthropogenic sulfate are shown in Figure
28 8-12a and 8-12b, respectively. The greenhouse gas forcing is, of course, positive and is the
29 greatest in the clear regions over the land and oceanic deserts. The global annual mean is
30 2.1 Wm"2. When the negative forcing of aerosols is added, the global annual mean direct
April 1995 8-56 DRAFT-DO NOT QUOTE OR CITE
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Annual Mean Forcing (W m2)
anthropogenic sulfate aerosols
-2.5 -2.0 -1.5 -1.0 -0.5 0
Figure 8-lla. Annual mean direct radiative forcing (W m"2) resulting from
anthropogenic sulfate aerosols.
Source: Kiehl and Briegleb (1993).
Annual Mean Forcing (W m2)
anthropogenic plus natural sulfate aerosols
-3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0
Figure 8-llb. Annual mean direct radiative forcing (W m'2) resulting from
anthropogenic and natural sulfate aerosols.
Source: Kiehl and Briegleb (1993).
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1 radiative forcing due to anthropogenic activities is 1.8 W m"2. However, locally, there are
2 regions where the anthropogenic sulfate forcing cancels the greenhouse forcing.
3 The forcing is simply an initial perturbation. One is actually interested in the climate
4 response. Because the sulfate forcing is in the shortwave and felt primarily at the surface
5 (for nonabsorbing aerosols), a coupled atmospheric-oceanic climate model is required.
6 Taylor and Penner (1994) have used the GRANTOUR model to provide the sulfate input to a
7 GCM (CCM1), which was coupled to a 50 m mixed-layer ocean model with sea ice and
8 specified meridional oceanic heat flux.
9 To assess the anticipated patterns of climate response to anthropogenic emissions of
10 both SO2 and CO2, Taylor and Penner performed four 20-simulated-year integrations in
11 which the atmospheric CO2 concentration was fixed at either the preindustrial level
12 (275 ppm) or the present day concentration (345 ppm). Anthropogenic sulfur emissions,
13 corresponding to 1980, were either included or excluded. Table 8-6 summarizes their annual
14 average results. The global average anthropogenic sulfate forcing was found to be
15 -0.95 W m"2; more than three times larger than calculated by Kiehl and Briegleb (1993).
16 The differences in the annual anthropogenic sulfate forcing value in the two studies is due
17 partially to the sulfate chemistry in the model used by Taylor and Penner, (1994). For
18 example, there is a stronger seasonal cycle with enhanced northern hemisphere concentrations
19 in summer. The remainder may be contributed to the use of a constant specific scattering
20 coefficient (8.5 m2g"1 at 0.55 pm) instead of the RH dependent model used by Kiehl and
21 Briegleb, (1993). As noted earlier, the value of \J/S chosen could be a gross overestimate
22 and, therefore the values of the sulfate forcing shown in Table 8-6 are probably much too
23 high.
24 Some noteworthy features of Table 8-1 are that the combined CO2 and sulfate forcing is
25 not linearly additive and there is a pronounced asymmetry in the climate response in the two
26 hemispheres. What is clear is that the anthropogenic sulfate is expected to reduce somewhat
27 the anticipated warming resulting from the increased emission of greenhouse gases, especially
28 in the northern hemisphere. On a regional scale, Taylor and Penner (1994) found that the
29 strongest response was in the polar regions associated with an increase in sea ice. Note that
30 the change in sea ice coverage (ASI), in the northern hemisphere is essentially zero as the
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Annual Mean Forcing (W m2)
greenhouse
t
•n
PKP
(••«f»WA •
«V,-'UV*T!
•o. ;><
0.50 1.0 1.5 2.0 2.5 3.0
Figure 8-12a. Annual averaged greenhouse gas radiative forcing (W m'2) from increases
in CO2, CH4, N2O, CFC-11, and CFC-12 from preindustrial time to the
present.
Source: Kiehl and Briegleb (1993).
Annual Mean Forcing (W m2)
greenhouse plus anthropogenic sulfate
-0.50 0 0.50 1.0 1.5 2.0 2.5 3.0
Figure 8-12b. Annual averaged greenhouse gas forcing plus anthropogenic sulfate
aerosol forcing (W m'2).
Source: Kiehl and Briegleb (1993).
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TABLE 8-6. RADIATIVE FORCING AND CLIMATE STATISTICS
3.
u>
00
ON
O
O
J>
H
6
o
2
o
H
0
d
0
H
ffl
O
Q
H
W
Case
Northern Hemisphere
Preindustrial
Present-day CO2
Present-day sulfate
Combined CO2 and sulfate
Observed climate statistics
Southern Hemisphere
Preindustrial
Present-day CO2
Present-day sulfate
Combined C02 and sulfate
Observed climate statistics
Global average
Preindustrial
Present-day CO2
Present-day sulfate
Combined CO2 and sulfate
Observed climate statistics
AF = radiative forcing; Ts = surface
Source: Taylor and Penner (1994).
AF
(W nT2)
1.26
-1.60
-0.34
1.25
-0.30
0.95
1.26
-0.95
0.31
temperature; P
TO
12.5
14.5
11.3
13.0
14.9
12.5
14.8
11.7
13.6
13.5
12.5
14.6
11.5
13.3
14.2
= precipitation;
ATS P
(°C) (mm d'1;
3.40
1.9 3.48
-1.2 3.36
0.5 3.43
2.6
3.54
2.3 3.61
-0.8 3.48
1.1 3.56
2.7
3.47
2.1 3.55
-1.0 3.42
0.8 3.49
2.7
C = cloud cover; SI
AP
) (mmd'1)
0.09
-0.04
0.03
0.08
-0.06
0.02
0.08
-0.05
0.02
C
56.6
55.0
56.9
55.8
58.9
62.4
61.1
63.1
62.1
65.6
59.5
58.0
60.0
58.9
62.2
AC SI
4.87
-1.7 4.13
0.3 5.54
-0.9 4.85
4.4
6.64
-1.3 4.39
0.7 7.24
-0.3 5.40
4.5
5.76
-1.5 4.26
0.5 6.39
-0.6 5.13
4.5
ASI
-0.74
0.67
-0.02
-2.26
0.59
-1.24
-1.50
0.63
-0.63
= sea ice coverage.
-------
1 sulfate completely cancels the CO2 effect. Also, the greatest cooling is found over broad
2 regions of the northern hemisphere continents where all the sulfur emission is occurring.
3 However, the maximum cooling is not over Europe where the maximum radiative forcing
4 occurs, but further north, and associated with changes in sea ice.
5
6 Comparative Lifetimes of the Forcing
7 One extremely important aspect in comparing the effects of CO2 and sulfur emissions is
8 the disparate lifetimes of the forcing mechanisms. The residence times of trace gases that
9 result in a positive longwave forcing of the climate system is from decades to a century or
10 more (Intergovernmental Panel on Climate Change, 1990). On the other hand, the cycling
11 time for sulfate in the troposphere is only about a week (Langner and Rodhe, 1991), which is
12 dependent on the frequency precipitation removal (Charlson et al., 1992). Therefore, any
13 changes in industrial emission patterns will be reflected immediately in the sulfate forcing,
14 but the concentration of CO2 and the accompanying forcing will continue to rise for more
15 than century even if emissions were kept constant at present levels. See Figure 8-13.
16 One could infer from the above discussion that sulfate emissions are providing some
17 amelioration of greenhouse warming, and that a curtailment of such emissions might result in
18 enhanced global warming. However, given the uncertainties in present estimates of the
19 effects of aerosols, especially the fact that many feedbacks are not fully included, it would
20 bepremature to base any decisions on these current discussions of the possible effects of
21 aerosols on climate. The detrimentalhealth effects of aerosols (and trace gases) covered
22 elsewhere in this report are far more definite and should certainly take precedence in
23 formulating regulatory policy.
24
25 8.6.5 Aerosol Effects on Clouds and Precipitation
26 8.6.5.1Indirect Solar Radiative Forcing
27 Cloud Microphysical Properties
28 A substantial portion of the solar energy reflected back to space by the earth system
29 is due to clouds. The albedo (i.e., reflectivity) of clouds, in turn, depends to a large extent
30 on the optical thickness, which is the column integrated extinction coefficient (see Section
31 8.6.3) The extinction coefficient is related to the size distribution and number concentration
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o
1
JD
I
O
«
.Q
O
O
Growth phase
Levelling-off
phase
Reduction phase
Time
Time
Figure 8-13. Schematic illustration of the difference between response times of climate
forcing due to CO2 (heating) and sulfate (cooling) during different patterns
of global fossil fuel consumption.
Source: Charlson et al. (1991)
1 of cloud droplets. Because these cloud droplets nucleate on aerosols, it is to be expected that
2 changes in aerosol loading could affect cloud albedo, particularly that marine stratiform
3 clouds. Because of their effect on the earth's radiative energy budget, marine status and
4 stratocumulus cloud systems are likely to influence climate and climate change. Their high
5 albedo compared with ocean background provide a large negative shortwave forcing which is
6 not compensated in thermal wavelengths because of their low altitude (Randall et al., 1984).
7 Stephens (1994) gave the volume extinction coefficient of a cloud of spherical
8 polydispersed drops ranging in size as:
9
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n(r)Qext (r)r2dr
1 where n(r) represents the size distribution and is the number concentration per unit volume
2 per unit radius increment and Qe;cr is the extinction efficiency which approaches the value of
3 2.0 for drops that are large relative to the wavelength. At visible wavelengths, this limit for
4 Qm is satisfied by cloud drops that are typically 10 /un in radius. Therefore,
5
^max
oe
-------
1 geometric depth of two cloud layers is the same and the column amount of liquid water is the
2 same, the cloud with more numerous, but smaller drops, will have a larger optical depth and
3 a higher albedo. This sets the stage for a potentially important indirect effect of
4 anthropogenic aerosols on the Earth's radiation balance. As suggested by Twomey (1974),
5 the addition of cloud nuclei by pollution can lead to an increase in the solar radiation
6 reflected by clouds, a negative radiative forcing that is in addition to the direct radiative
7 forcing discussed in Section 8.6.3.
8 Another radiative consequence of pollution is the emission of elemental carbon, which
9 can be incorporated into clouds and increase the absorptance at visible wavelengths at which
10 pure water is nonabsorbing. This mechanism decreases the single scattering albedo of the
11 cloud material (see Figure 8-10), causing a decrease in the reflectance of the layer. There
12 are, therefore, two competing mechanisms, but Twomey et al. (1984) assessed the relative
13 magnitudes of the two effects based on observations of clean and polluted air in Arizona, and
14 concluded that increases in albedo from increases in cloud droplet concentration would
15 dominate over the absorption effect.
16
17 Cloud Lifetimes
18 Another possible indirect effect of increased cloud condensation nuclei (CCN) is the
19 inhibition of precipitation (Albrecht, 1989; Twomey, 1991). With more droplets, coagulative
20 growth, which is the mechanism of water removal in liquid water clouds, will be hindered.
21 This will result in longer residence times for clouds and a higher mean albedo time, which,
22 again, is an indirect negative solar radiative forcing.
23
24 Cloud Chemistry
25 Novakov and Penner (1993) pointed out that anthropogenic activity could modify the
26 nucleating properties of anthropogenic sulfate. It has already been mentioned that carbon
27 black influences the direct radiative forcing. The presence of carbon black and other
28 organics can also alter the hygroscopic properties of sulfate aerosol. For instance, the
29 condensation of hydrophobic organics onto preexisting sulfate particles may render these
30 inactive as CCN. On the other hand, the condensation of sulfuric acid vapor on a
31 hydrophobic organic aerosol may convert it to a hydrophilic particle. Because the indirect
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1 radiative forcing depends on the ability of sulfate to nucleate, organics may enhance or
2 diminish the potential indirect radiative forcing.
3
4 8.6.5.2 Observational Evidence
5 The relationship between the availability of (CCN) and cloud droplet size distribution
6 has been a subject of research in cloud physics for decades. It has been known, for instance,
7 that continental clouds are composed of far more numerous, but smaller drops than maritime
8 clouds (Wallace and Hobbs, 1977). The more difficult question is whether the additional
9 contribution to CCN by anthropogenic activities has increased the reflectance of clouds over
10 large areas of the Earth. If so, this would be an additional indirect radiative forcing
11 attributable to sulfate emissions.
12 The most dramatic evidence of such an indirect effect (albeit on a small scale) is the
13 observation of "ship tracks" in marine stratocumulus (Conover, 1966; Coakley et al., 1987).
14 These are visible in satellite images as white lines against a gray background and follow the
15 path of ships that have been emitting effluents. King et al. (1993) reported the first radiation
16 and microphysics measurements on ship tracks obtained from a research aircraft as it flew
17 within marine stratocumulus clouds off California. Comparing the flight track with satellite
18 images, they were able to locate two distinct ship tracks in which they measured enhanced
19 droplet concentration, and liquid water contents, greater than in the surrounding clouds.
20 They also derived the effective radius of the cloud drops and found that there was a
21 significant decrease within the ship tracks. The radiation measurements were consistent with
22 increased optical depths in the ship tracks. The increased liquid water content is compatible
23 with the suppression of drizzle as a result of slower coagulative growth (Albrecht, 1989), an
24 indirect aerosol effect.
25 Twomey (1991) estimated that the visible reflectance of clouds, R, is affected by cloud
26 droplet concentration, N, according to the following relationship for a fixed liquid water
27 content, M.
fdR] _ R(l-R)
28
M 3N
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1 The parameter, dR/dN, the susceptibility, is a measure of the sensitivity of cloud reflectance
2 to changes in microphysics (Platnick and Twomey, 1994). It has a maximum value at R =
3 0.5 and is inversely proportional to TV such that when N is low as in marine clouds, the
4 susceptibility is high. It is, therefore, not surprising that emissions from ships can influence
5 cloud albedo.
6 To determine whether the indirect effect of aerosols on clouds is detectable on a global
7 scale, Schwartz (1988) compared cloud albedos in the two hemispheres and also historic
8 changes in surface temperature from preindustrial times. The sulfate signal is expected in
9 both: cloud albedos in the Northern Hemisphere should be higher, and the rate of
10 greenhouse warming should be slower. The results of his study were inconclusive in that no
11 inter-hemispheric differences were found.
12 However, more recent studies suggest some influence of sulfate emissions. Falkowski
13 et al. (1992) showed that cloud albedos in the central North Atlantic Ocean, far from
14 continental emission sources, were well correlated with chlorophyll in surface waters. These
15 correspond to higher ocean productivity and DMS emissions, indicating that natural sources
16 of sulfate emission can influence cloud albedo. More substantial evidence of the effect of
17 sulfate aerosol has been presented by Han et al. (1994) who made a near-global survey of the
18 effective droplet radii in liquid water clouds by inverting satellite visible radiances obtained
19 from advanced very-high-resolution radiometer (AVHRR) measurements. Han et al. (1994)
20 found systematic differences between the effective radius of continental clouds (global mean
21 re = 8.5 /um) and maritime clouds (global mean rg — 11.8 /wn), which is the expected result
22 based on differences in CCN concentrations. In addition, they found inter-hemispheric
23 differences in re over both land and ocean. Northern Hemisphere clouds had smaller
24 effective radii, the difference being 0.4 ^m for ocean and 0.8 /zm for land. However,
25 Southern Hemisphere clouds tended to be optically thicker, which explains why Schwartz
26 (1988) was unable to detect inter-hemispheric albedo differences.
27
28 8.6.5.3 Modeling Indirect Aerosol Forcing
29 If the appropriate radiative properties of aerosols are known, it is fairly straightforward
30 to model the direct solar radiative forcing of aerosols (Section 8.6.3) and estimate possible
31 climatic responses (Section 8.6.4). Calculations of the indirect forcing of aerosols, on the
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1 other hand, is much more difficult since several steps are involved and the uncertainty at
2 each level is high. Charlson et al. (1992) proposed that enhancements in albedo would occur
3 only for marine stratocumulus clouds and for a uniform global increase of droplet
4 concentration of 15% in only these clouds, the global mean solar radiative forcing would be
5 -1.0 W m"2, which is comparable to the direct forcing (Section 8.6.4) and of the same sign.
6 The greatest uncertainty in this estimate is the degree that cloud droplet number concentration
7 is enhanced by increasing emissions. The uncertainty has been estimated by Kaufman et al.
8 (1991) to be at least a factor of 2. Leaitch and Isaac (1994) have addressed this issue based
9 on their observations of the relationship between cloud droplet concentrations and cloud
10 water sulfate concentrations. They find that the assumptions in Kaufman et al. (1991) are
11 within reasonable bounds. The Scientific Steering Committee for the International Global
12 Aerosol Program concluded that the uncertainties involved in determining the indirect effects
13 of aerosols on the Earth's radiation balance are so great that no formal value can be given at
14 this time (Hobbs, 1994).
15 The indirect forcing has been included in climate model simulations by Kaufman and
16 Chou (1993) who used a zonally averaged multilayer energy balance model and by Jones
17 et al. (1994) who used a GCM. Kaufman and Chou (1993) modeled the competing effects of
18 enhanced anthropogenic emissions of CO2 and SO2 since preindustrial times. They
19 concluded that SO2 has the potential of offsetting CO2-induced warming by 60% for present
20 conditions and 25 % by the year 2060 given the Intergovernmental Panel on Climate Change
21 BAU (business as usual) scenario of industrial growth (Intergovernmental Panel on Climate
22 Change, 1990). They also found a small inter-hemispheric difference in climate response,
23 with the Northern Hemisphere cooler than Southern Hemisphere by about —0.2 °C.
24 Jones et al. (1994) used a GCM with a prognostic cloud scheme and a parameterization
25 of the effective radius of cloud water droplets that links effective radius to cloud type,
26 aerosol concentration and liquid water content. The parameterization is based on extensive
27 aircraft measurements. The distribution of column sulfate mass loading was obtained from
28 the model of Langner and Rodhe (1991) separately for natural and anthropogenic sources.
29 Simulated effective radius, re, distributions of low-level clouds showed land-ocean contrasts
30 and also inter-hemispheric differences as observed by Han et al. (1994). The indirect forcing
31 due to anthropogenic sulfate was estimated by performing a series of single-timestep
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1 calculations with the GCM. For present conditions, the mean Northern Hemisphere forcing
2 was calculated to be -1.54 W m"2 and the southern Hemisphere forcing was -0.97 W m"2.
3 This is comparable to the estimates of Charlson et al. (1992) and Kaufman and Chou (1993)
4 and substantially larger than the direct forcing estimates of Kiehl and Briegleb (1993). The
5 combined direct and indirect forcing is more than half the total positive forcing of
6 greenhouse gas emissions. It should be noted that the indirect effect is greatest when the
7 atmosphere is very clean and so, in principle, could saturate with time. The direct effect is
8 linear with emissions and may dominate in the future. In any case, the negative forcing of
9 sulfate aerosol must be considered in any overall estimate of the total anthropogenic effect on
10 climate.
11
12
13 8.7 SUMMARY
14 Traditionally, visibility has been defined in terms of the distance from an object that is
15 necessary to produce a minimum detectable contrast between that object and its background.
16 Although visibility is often defined by this "visual range," it includes not only being able to
17 see or not see a target, but also seeing targets at shorter distances and appreciating the details
18 of the target, including its colors. Visibility impairment can manifest itself in two ways: (1)
19 as a layer of haze (or a plume), which is visible because it has a visual discontinuity between
20 itself and its background, or (2) as a uniform haze which reduces atmospheric clarity. The
21 type and degree of impairment are determined by the distribution, concentrations, and
22 characteristics of atmospheric particles and gases, which scatter and absorb light traveling
23 through the atmosphere. Scattering and absorption determine light extinction.
24 On a regional scale, the extinction of light is generally dominated by particle scattering.
25 In urban areas, absorption by particles becomes important and occasionally dominant.
26 Extinction by particles is usually dominated by particles of diameter 0.1 to 2 /xm (fine par-
27 tides). In general, scattering by particles accounts for 50 to 95% of extinction, depending
28 on location, with urban sites in the 50 to 80% range and nonurban sites in the 80 to 95%
29 range.
30 The currently available visibility monitoring methods measure different aspects of visi-
31 bility impairment. Generally, contrast-type measurements (such as photography, telephoto-
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1 metry, and human eye observations) relate well to the perception of visual air quality, while
2 extinction or scattering measurements (such as transmissometry and nephelometry) relate to
3 the cause of visibility degradation. Each of the above measurement methods can be used to
4 approximate visual range.
5 Current knowledge indicates that fine particulate matter is composed of varying
6 amounts of sulfate, ammonium, and nitrate ions, elemental carbon, organic carbon
7 compounds, water, and smaller amounts of soil dust, lead compounds, and trace species.
8 Sulfate often dominates the fine mass and light scattering, while elemental carbon is
9 sometimes the primary visibility-reducing species. Ammonium ion is typically found to
10 account for 5 to 15% of the fine mass and often correlates well with sulfate levels. Data
11 indicate that mean nitrate concentrations can represent up to 37% of the total fine particle
12 mass in urban cities.
13 Visibility has value to individual economic agents primarily through its impact upon
14 activities of consumers and producers. Most economic studies of the effects of air pollution
15 on visibility have focused on the aesthetic effects to the individual, which are, at this time,
16 believed to be the most significant economic impacts of visibility degradation caused by air
17 pollution in the U.S. It is well established that people notice those changes in visibility
18 conditions that are significant enough to be perceptible to the human observer, and that
19 visibility conditions affect the well-being of individuals.
20 Welfare economics defines a dollar measure of the change in individual well-being
21 (referred to as utility) that results from the change in the quality of any public good, such as
22 visibility, as the change in income that would cause the same change in well-being as that
23 caused by the change in the quality of the public good. One way of defining this measure of
24 value is to determine the maximum amount the individual would be willing to pay to obtain
25 improvements or prevent degradation in the public good. Two economic valuation
26 techniques have been used to estimate willingness to pay for changes in visibility: (1) the
27 contingent valuation method, and (2) the hedonic property value method. Both methods have
28 important limitations, and uncertainties exist in the available results. Recognizing these
29 uncertainties is important, but the body of evidence as a whole suggests that economic values
30 for changes in visibility conditions are probably substantial in some cases, and that a sense of
31 the likely magnitude of these values can be derived from available results in some instances.
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1 Economic studies have estimated values for two types of visibility effects potentially related
2 to particulate air pollution: (1) use and non-use values for preventing the types of plumes
3 caused by power plant emissions, visible from recreation areas in the southwestern U.S.; and
4 (2) use values of local residents for reducing or preventing increases in urban hazes in
5 several different locations.
6 Available evidence suggests that visitors to major recreation areas in the southwestern
7 U.S. value the prevention of manmade plumes visible from the recreation area. The results
8 of two studies suggest values per visitor-party per day in the range of $3 to $6 (1989 dollars)
9 in additional park entrance fees to ensure that a thin, dark plume is not visible from a
10 popular observation point at Grand Canyon National Park. A similar study at Lake Powell
11 found somewhat smaller values, in the range of $2 to $3 per day.
12 The best economic information available for visibility effects is for on-site use values
13 related to changes in visual range in urban areas caused by uniform haze. These values fall
14 roughly between $10 and $100 per year per local household for a 10% change in visual
15 range in major urban areas in California and throughout the eastern U.S..
16 Very little work has been done regarding layered hazes in recreation or residential
17 settings. However, available evidence suggest annual residential household values of about
18 $30 for a noticeable improvement in visibility conditions in the Denver area, where layered
19 hazes are common. More information is needed about the specific visual characteristics of
20 such hazes that are most important to viewers, as well as about the value people may place
21 on reducing or preventing them.
22 Particulate matter of submicron size in the earth's atmosphere perturbs the radiation
23 field. There is no doubt that anthropogenic aerosol emissions primarily sulfur oxides, have
24 the potential to affect climate; the question is by how much. There are two chief avenues
25 through which aerosols impact the radiation budget of the earth. The direct effect is that of
26 enhanced solar reflection by the cloud-free atmosphere. Since aerosols, even those
27 containing some absorptive component, are primarily reflective, their impact is felt as a
28 negative radiative forcing (i.e., a cooling) on the climate system. Although there is some
29 uncertainty in the global distribution of such aerosols and in the chemical and radiative
30 properties of the aerosols, the radiative effects can still be modeled within certain bounds.
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1 Estimates of this forcing range from -0.3 W rn2 to about twice that value for current
2 conditions over pre-industrial times.
3 The indirect forcing results from the way in which aerosols affect cloud microphysical
4 properties. The most important is the effective radius of cloud droplets, which decrease in
5 the presence of higher concentrations of CCN. This effect is most pronounced when the
6 concentration, N, is very low, and clouds are moderately reflective. Other effects are the
7 enhancement of cloud lifetimes and also changes in the nucleating ability of CCN through
8 chemical changes. Although estimates of the indirect effect are uncertain by at least a factor
9 of 2, but perhaps much more, it appears to be potentially more important than the direct
10 effect. Taken together, on a global mean basis, anthropogenic emissions of anthropogenic
11 aerosols could have offset substantially the positive radiative forcing due to greenhouse gas
12 emissions. High priority should be given to acquiring the measurements needed to
13 quantifying these effects with greater accuracy.
14 The one crucial difference between aerosol forcing and greenhouse (gas) forcing is the
15 atmospheric lifetime of aerosols and gases and hence, forcing. The aerosol forcing is fairly
16 localized, whereas the greenhouse forcing is global. One should, therefore, expect
17 inter-hemispheric differences in the forcing and perhaps climate response. However, climate
18 models are not currently at the level of sophistication needed to determine climate response
19 unambiguously. Global observations of surface temperature can not yet separate natural and
20 anthropogenic causal mechanisms with few exceptions.
21 A relevant question for policy planning is whether reducing fossil-fuel emissions could
22 cause global warming by the reduction of negative radiative forcing. Given the uncertainties
23 in the database and in climate models, it would be premature to base such economic
24 decisions solely on the radiative forcing of aerosols. There is ample reason to believe that
25 some of the greenhouse warming expected since pre-industrial times has been masked by the
26 aerosol forcing. However, the suggestion that efforts to reduce aerosol emissions could
27 prove harmful by exacerbating greenhouse warming should not be considered when there are
28 other deleterious effects of these emissions.
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16 Ryan, W.M., C.R. Badgett-West, J.A. Cooper, and D.M. Ono (1988). "Reconciliation of Receptor and
17 Dispersion Modeling Impacts of PM10 in Hayden, AZ," In Transactions, PM10: Implementation of
18 Standards, C.V. Mathai and D.H. Stonefield, Eds. Air & Waste Management Association, Pittsburgh,
19 PA, pp. 419-429.
20
21 SAI, Inc. (1990). "User's Guide for the Urban Airshed Model Volume IV: User's Guide for the Emissions
22 Preprocessor System." Report No. SYSAPP 90/018d, Systems Applications, Inc., San Rafael, CA.
23
24 Seinfeld, J.H. (1986) Air Pollution: Physical and Chemical Fundamentals, 2nd ed., McGraw-Hill, New York,
25 NY.
26
27 Solomon, P.A. (1994). Planning and Managing Air Quality Modeling and Measurements Studies: A Perspective
28 through SJVAQS/AUSPEX, P.A. Solomon, ed. Lewis Publishers, Chelsea, MI, in conjunction with
29 Pacific Gas and Electric Company, San Ramon, CA, pp. 369-382.
30
31 South Coast Air Quality Management District (1994). "State Implementation Plan for PM10 in the Coachella
32 Valley: 1994 "BACM" Revision." South Coast Air Quality Management District, Diamond Bar, CA.
33
34 Svasek, T.N. and J.H. Terwindt (1974). "Measurement of Sand Transport by Wind on a Natural Beach."
35 Sedementology, 21:311-322.
36
37 Stedman, D.H., G.A. Bishop, S.P. Beaton, J.E. Peterson, P.L. Guenther, I.F. McVey, and Y. Zhang (1994).
38 "On-Road Remote Sensing of CO and HC Emissions in California." Final Report under Contract
39 A032-093 for the California Air Resources Board, Sacramento, CA.
40
41 Thanukos, L.C., T. Miller, C.V. Mathai, D. Reinholt, and J. Bennett (1992). "Intercomparison of PM10
42 Samplers and Source Apportionment of Ambient PM10 Concentrations in Rillito, Arizona." In
43 Transactions, PM10 Standards and Nontraditional Particulate Source Controls, J.C. Chow and D.M.
44 Ono, Eds. Air & Waste Management Association, Pittsburgh, PA, pp. 244-261.
45
46 Thornwaite, C.W. (1931). "The Climates of North America: According to a New Classification." Geophys.
47 Rev., 21:633-655.
48
49 U.S. Environmental Protection Agency, (1980a). National Air Pollutant Emissions Estimates, 1970-1978.
50 EPA-450/4-80-002. Research Triangle Park, NC
51
52 U.S. Environmental Protection Agency, (1980b). 1977 National Emissions Report.. EPA-450/4-80-005. Research
53 Triangle Park, NC
54
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1 U.S. Environmental Protection Agency, Air Quality Criteria for Paniculate Matter and Sulfur Oxides, Volumes I
2 and II, EPA-600/8-82-029a, December 1982, U.S. Environmental Protection Agency, Research Triangle
3 Park, NC (1982).
4
5 U.S. Environmental Protection Agency (1987a). "PM10 SIP Development Guidelines." EPA 450/2-86-001, U.S.
6 Environmental Protection Agency, Research Triangle Park, NC
7
8 U.S. Environmental Protection Agency (1987b). "Protocol for Reconciling Differences Among Receptor and
9 Dispersion Models." EPA 450/4-87-008, U.S. Environmental Protection Agency, Research Triangle
10 Park, NC.
11
12 U.S. EPA (1988). "Compilation of Air Pollutant Emission Factors. Volume I: Stationary Point and Area
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14 Planning and Standards, Research Triangle Park, NC.
15
16 Watson, J.G. (1979). Chemical Element Balance Receptor Model Methodology for Assessing the Sources of Fine
17 and Total Suspended Particulate Matter in Portland, OR. Ph.D. Dissertation, Oregon Graduate Center,
18 Beaverton, OR.
19
20 Watson J.G., Chow J.C., Richards L.W., Anderson S.R., Houck J.E., and Dietrich D.L. (1988a) The 1987-88
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24
25 Watson J.G., Chow J.C., Egami R.T., Frazier C.A., Goodrich A., and Ralph C. (1988b) PM10 source
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29
30 Watson, J.G., J.C. Chow, and C.V. Mathai (1989). "Receptor Models in Air Resources Management: A
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32
33 Watson, J.G., N.F. Robinson, J.C. Chow, R.C. Henry, B.M. Kim, T.G. Pace, E.L. Meyer and Q. Nguyen
34 (1990). The USEPA/DRI Chemical Mass Balance Receptor Model, CMB 7.0. Environ. Software, 5,
35 38-49.
36
37 Watson, J.G., J.C. Chow, L.C. Pritchett, J.A. Houck, R.A. Ragazzi and S. Burns (1990). Chemical Source
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39 Total Environ., 93, 183-190.
40
41 Watson, J.G., J.C. Chow, L.C. Pritchett, J.A. Houck, S. Burns and R.A. Ragazzi (1990). Composite Source
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43 Visibility and Fine Particles, C.V. Mathai, ed. Air & Waste Management Association, Pittsburgh, PA,
44 pp. 422-436.
45
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49
50 Watson, J.G., J.C. Chow, F. Lurmann and S. Musarra (1994). Ammonium Nitrate, Nitric Acid, and Ammonia
51 Equilibrium in Wintertime Phoenix, AZ. Air & Waste, 44, 261-268.
52
53 Watson, J.G., J.C. Chow and P.M. Roth (1994), Clear Sky Visibility as a Challenge for Society. Annual Rev.
54 Energy Environ., 19, 241-266.
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3 Atmos. Environ., 28(15), 2493-2505.
4
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8
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11
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13 EPA-450/3-73-009. US Environmental Protection Agency, Research Triangle Park, NC.
14
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16 PM10 Source Apportionment for the South Coast Air Basin, Technical Report V-F, South Coast Air
17 Quality Management District, El Monte, CA.
18
19
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1
9. EFFECTS ON MATERIALS
2
3 The deposition of airborne paniculate matter on surfaces of building materials and
4 culturally important articles (e.g., statuary) can cause soiling, thus reducing the aesthetic
5 appeal of such structures (National Research Council, 1979; Baedecker, 1991).
6 Furthermore, the presence of particulate matter on surfaces may also increase the physical
7 and chemical degradation of materials that occurs normally when these materials are exposed
8 to environmental factors such as wind, sun, temperature fluctuations, and moisture. Beyond
9 these effects, particulate, whether suspended in the atmosphere, or already deposited on a
10 surface, adsorbs or absorb acidic gases from other pollutants like sulfur dioxide (SO2) and
11 nitrogen dioxide (NO2) thus serving as nucleation sites for these gases. The deposition of
12 "acidified" particles on a susceptible material surface is capable of accelerating chemical
13 degradation of them aerial. Therefore, the concerns about the effect of particulate matter on
14 materials are for both the aesthetic appeal and the physical damage to the surface, both of
15 which may have serious economics consequences.
16 This chapter will briefly discuss the effects of particulate matter exposure on the
17 aesthetic appeal and physical damage to different types of building materials, and economic
18 consequences, including background information on the physics and chemistry of atmospheric
19 corrosion. For a more detailed discussion of the physics and chemistry of atmospheric
20 corrosion, see U.S. National Acid Precipitation Assessment Program (Baedecker, 1991).
21 Where possible, the chapter will discuss only those effects associated with particle exposure;
22 however, most of the available data are oh the effects of particles in combination with SC^.
23
24
25 9.1 CORROSION AND EROSION
26 9.1.1 Metals
27 Only limited information is available on the effects of particulate matter alone on
28 metals. Goodwin et al. (1969) reported damage to steel, protected with a nylon screen,
29 exposed to quartz particles. The damage did not, however, become substantial until the
30 particle size exceeded 5 ^m. Barton (1958) found that dust contributed to the early stages of
31 metal corrosion. The effect of dust was lessened as the rust layer formed. Still other early
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1 studies indicate that suspended particles can play a significant role in metal corrosion.
2 Sanyal and Singhania (1956) wrote that paniculate matter, along with other cofactors and
3 S02 promoted the corrosion of metals in India. Yocom and Grappone (1976) and Johnson et
4 al. (1977) reported that moist air containing both paniculate matter and SO2 resulted in a
5 more rapid corrosion rate than air polluted with SO2 alone. Russell (1976) stated that
6 particles serve as points for the concentration of active ionic species on electrical contact
7 surfaces, thereby, increasing the corrosion rate of sulfur dioxides (SOX). Other studies have
8 not established a conclusive statistical correlation between total suspended particulates (TSP)
9 and corrosion, possibly due to data limitations (Mansfeld, 1980; Haynie and Upham, 1974;
10 and Upham, 1967; Yocom and Upham 1977).
11 Edney et al. (1989) reported on the effects of SO2, nitrogen oxides (NOX), ozone (O3),
12 and particulates on galvanized steel panels exposed under actual field conditions in Research
13 Triangle Park, NC and Steubenville, OH between April 25 and December 28, 1987. The
14 panels were exposed under the following conditions: (1) dry deposition only; (2) dry plus
15 ambient wet deposition; and (3) dry deposition plus deionized water. The average
16 concentrations for SO2 and paniculate matter was 22 ppb and 70 /xg/m3 and < 1 ppb and 32
17 /ig/m3 for Steubenville and Research Triangle Park, respectively. By analyzing the runoff
18 from the steel panel the authors concluded that the dissolution of the steel corrosion products
19 for both sites was likely the result of deposited gas phase SC^ on the metal surface and not
20 paniculate sulfate.
21 Walton et al. (1982) performed a laboratory study of the direct and synergistic effects
22 of different types of paniculate matter and SOX on the corrosion of aluminum, iron, and zinc.
23 The four most aggressive species were salt and salt/sand from marine or deiced locations,
24 ash from iron smelters, ash from municipal incinerators, and coal mine dusts. Fly ashes of
25 various types were less aggressive. Coal ash with SOX did promote corrosion but oil fly ash
26 was relatively noncorrosive. This suggests that catalytic species in the ash promote the
27 oxidation of SOX and the presence of SOX alone is not sufficient to accelerate corrosion.
28 Other laboratory studies of metal corrosion provide considerable evidence that the catalytic
29 effect is not significant and that atmospheric corrosion rates are dependent on the
30 conductance of the thin-film surface electrolyte and that the first-order effect of contaminant
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1 particles is to increase solution conductance, and, hence corrosion rates (Skerry et al.,
2 1988a,b; Askey et al., 1993).
3
4 9.1.2 Paints
5 Paints, opaque film coatings, are by far the dominant class of manmade materials
6 exposed to air pollutants in both indoor and outdoor environments. Paints are used as
7 decorative coverings and protective coatings against environmental elements on a variety of
8 finishes including woods, metals, cement, asphalt, etc.
9 Paints primarily consists of two components: the filming forming component and the
10 pigments. Paints undergo natural weathering processes from exposure to environmental
11 factors such as sunlight (ultraviolet light), moisture, fungi, and varying temperatures. In
12 addition to the natural environmental factors, evidence exists that demonstrates the particulate
13 matter exposure alters the appearance of paint, giving it a dirty appearance (see Section
14 9.2.1.2) (National Research Council, 1979; U.S. Environmental Protection Agency, 1993).
15 Several studies also suggest that particles serve as carriers of other more corrosive pollutants,
16 allowing the pollutants to reach the underlying surface or serve as concentration sites for
17 other pollutants (Cowling and Roberts, 1954).
18 Finishes on automobiles have also been damaged by particulate matter. In an early
19 study, staining and pitting of automobile finishes was reported in industrial areas. The
20 damage was traced to iron particles emitted for nearby plants (Fochtman and Langer, 1957).
21 General Motors conducted a field test to determine the effect of various meteorological
22 events, the chemical composition of rain and dew, and the ambient air composition during
23 the event, on automotive paint finishes. The study was conducted in Jacksonville, Florida.
24 Painted (basecoat/clearcoat technology) steel panels were exposed for varying time periods,
25 under protected and unprotected conditions. Damage to paint finishes appeared as circular,
26 elliptical, or irregular spots, that remained after washing. Using scanning electron
27 microscopy (high magnification) the spot appeared as crater-like deformities in the paint
28 finish. Chemical analyses of the deposit determined calcium sulfate to be the predominant
29 species. The researches concluded that calcium sulfate was formed on the paints surface by
30 the reaction of calcium from dust and sulfuric acid contained in rain or dew. The damage to
31 the paint finish increased with increasing days of exposure (Wolff et al., 1990).
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1 The formulation of the paint will affect the paint's durability under exposure to varying
2 environmental factors and pollution; however, failure of the paint system results in the need
3 for more frequent repainting and addition cost.
4
5 9.1.3 Stone
6 Air pollutants are known to damage various building stones. Some of the more
7 susceptible stones are the calcareous stones, such as limestone, marble and carbonated
8 cemented stone. Baedecker et al. (1991) reviewed the published literature on calcareous
9 stones and concluded that the most significant damage to these stones resulted from the
10 exposure to natural constituents of nonpolluted rain water; carbonic acid from the reaction of
11 carbon dioxide with rain reacts with the calcium in the stone. Based on the work conducted
12 by the National Acid Precipitation Assessment Program, the largest percentage (20%) of
13 chemical weathering of marble and limestone was caused by wet deposition of hydrogen ions
14 from all acid species (Baedecker et al., 1991). Luckat (1972) suggested that dusts containing
15 heavy metals may accelerate stone erosion by converting ambient SO2 to sulfuric acid.
16 Under high wind conditions, particulates have been reported to result in slow erosion of the
17 surfaces, similar to sandblasting (Yocom and Upham, 1977).
18 Mansfeld (1980), after performing statistical analysis of damage to marble samples
19 exposed for 30 mo at nine air quality monitoring sites in St. Louis, MO, concluded that TSP
20 and nitrates were best correlated with stone degradation. However, there is some concern
21 over the statistical techniques used.
22 Generally, black and white areas can be observed on the exposed surfaces of any
23 building. The black areas, found in zones protected from direct rainfall and from surface
24 runs, are covered by an irregular, dendrite-like, hard crust composed of crystals of gypsum
25 mixed with dust, aerosols and paniculate matter of atmospheric origin. Among these the
26 most abundant are black carbonaceous particles originating from oil and coal combustion.
27 On the other hand, surfaces directly exposed to rainfall show a white color, since the
28 deterioration products formed on the stone surface are continuously washed out.
29 Del Monte et al. (1981) reported evidence of a major role for carbonaceous particles in
30 marble deterioration, using scanning electron microscopy. The majority of the carbonaceous
31 particles were identified as products of oil fired boiler/combustion. Particle median diameter
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1 was «10 urn. Sabbioni and Zappia (1992) analyzed samples of damaged layers on marble
2 and limestone monuments and historical buildings from eight urban sites in Northern and
3 Central Italy. Samples of black crust were taken from various locations at each site to be
4 representative of the entire site. The predominant species in the black crust matrix was
5 calcium sulphate dihydrate (gypsum). The evaluation of enrichment factors with respect to
6 the stone and to the soil dust show the main components of the atmospheric deposition to be
7 from the combustion of fuels and incineration. Saiz-Jimenez (1992) also found, after
8 analyzing the organic compounds extracted for black crusts removed for building surfaces in
9 polluted areas, that the main components were composed of molecular markers characteristic
10 of petroleum derivatives. The composition of each crust; however, is governed by the
11 composition of the particular airborne pollutants in the area.
12
13 9.1.4 Electronics
14 Exposure to ionic dust particles can contribute significantly to the corrosion rate of
15 electronic devices, ultimately leading to failure of that device. Natural and anthropogenically
16 derived particles ranging in size from tens of angstroms to 1 /tm cause corrosion of
17 electronics because many are sufficiently hygroscopic and corrosive at normal relative
18 humidities to react directly with non-noble metals and passive oxides, or to form sufficiently
19 conductive moisture films on insulating surfaces to cause electrical leakage. The effects of
20 particulates on electronic components were first reported by telephone companies, when
21 particulates high in nitrates caused stress corrosion cracking and ultimate failure of the wire
22 spring relays (Hermance, 1966; McKinney and Hermance, 1967). More recently, attention
23 has been directed to the effects of particles on electronic components, primarily in the indoor
24 environment.
25 Sinclair (1992) has discussed the relevance of particle contamination to corrosion of
26 electronics. Data collected during the eighties show that the indoor mass concentrations of
27 anthropogenically derived airborne particles and their arrival rates at surfaces are comparable
28 to the concentrations and arrival rates of corrosive gases for many urban environments.
29 Frankenthal et al. (1993) examined the effects of ionic dust particles, ranging from
30 0.01 to 1 /xm in size, on copper coupons under laboratory conditions. The copper coupons,
31 after being polished with diamond paste, were inoculated with ammonium sulfate
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1 [(NH4)2SO4)] particles and exposed to air at 100 °C at relative humidities ranging from 65 to
2 100% for up to 600 h. The particles were deposited on the metal surface by thermophoretic
3 deposition and cascade impaction.
4 Exposure of the copper coupons to (NH4)2SO4 at 65% relative humidity had little effect
5 on the corrosion rate. However, when the relative humidity was increased to 75%, the
6 critical relative humidity for (NH4)2SO4 at 100 °C, localized areas of corrosion were noted
7 on the metal surface. The corrosion product, determined to be brochantite, was only found
8 in areas where the (NH4>2SO4 was deposited on the metal surface. When the relative
9 humidity was increased to 100%, the corrosion became widespread (Frankenthal et al.,
10 1993).
11
12
13 9.2 SOILING AND DISCOLORATION
14 A significant detrimental effect of paniculate matter pollution is the soiling of manmade
15 surfaces. Soiling may be defined as a degradation mechanism that can be remedied by
16 cleaning or washing, and depending on the soiled material, repainting. Faith (1976)
17 described soiling as the deposition of particles of less than 10 ^m on surfaces by
18 impingement. Carey (1959) observed when particles descended continuously onto paper in a
19 room with dusty air, the paper appeared to remain clean for a period of time and then
20 suddenly appeared dirty. Increased frequency of cleaning, washing, or repainting over soiled
21 surfaces becomes an economic burden and can reduce the life usefulness of the material
22 soiled. In addition to the aesthetic effect, soiling produces a change in reflectance from
23 opaque materials and reduces light transmission through transparent materials (Beloin and
24 Haynie, 1975; National Research Council, 1979). For dark surfaces, light colored
25 particulate matter can increase reflectance (Beloin and Haynie, 1975).
26 Determining at what accumulated level particulate matter leads to increased cleaning is
27 difficult. For instance, in the study by Carey (1959), Carey found that the appearance of
28 soiling only occurred when the surface of the paper was covered with dust specks spaced
29 10 to 20 diameters apart. When the contrast was strong, e.g., black on white, it was
30 possible to distinguish a clean surface from a surrounding dirty surface when only 0.2% of
31 the areas was covered with specks, while 0.4% of the surface had to be covered with specks
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1 with a weaker color contrast. Still, the effect is subjective and not easy to judge between
2 coverages.
3 Support for Carey's (Carey, 1959) work was reported by Hancock et al. (1976). These
4 authors also found that with maximum contrast, a 0.2% surface coverage (effective area
5 coverage; EAC) by dust can be perceived against a clean background. A dust deposition
6 level of 0.7% EAC was needed before the object was considered unfit for use. The
7 minimum perceivable difference between varying gradations of shading was a change of
8 about 0.45% EAC. Using the information on visually perceived dust accumulation and a
9 telephone survey, Hancock et al. (1976) concluded that a dustfall rate of less than 0.17%
10 EAC/day would be tolerable to the general public.
11 Some materials that are soiled are indoors. In general, paniculate matter pollution
12 levels indoors may be affected by outdoor ambient levels; however, other factors generally
13 have greater effects on concentration and composition (Yocom, 1982). For that reason,
14 discussion of indoor soiling will be limited primarily to works of art.
15
16 9.2.1 Building Materials
17 Dose-response relationships for paniculate matter soiling were developed by Beloin and
18 Haynie (1975) using a comparison of the rates of soiling and TSP concentrations on different
19 building materials (painted cedar siding, concrete block, brick, limestone, asphalt singles,
20 and window glass) at five different study sites over a 2-year period. Paniculate matter
21 concentrations ranged from 60 to 250 mg/m3 for a rural residential location and an industrial
22 residential location, respectively. The results were expressed as regression functions of
23 reflectance loss (soiling) directly proportional to the square root of the dose. With TSP
24 expressed in mg/m3 and tune in months, the regression coefficients ranged from -0.11 for
25 yellow brick to +0.08 for a coated limestone depending on the substrate color and original
26 reflectance. For dark surfaces, light colored paniculate matter can increase reflectance. Not
27 all of the coefficients were significantly different from zero.
28 A theoretical model of soiling of surfaces by airborne particles has been developed and
29 reported by Haynie (1986). This model provides an explanation of how ambient
30 concentrations of paniculate matter are related to the accumulation of particles on surfaces
31 and ultimately the effect of soiling by changing reflectance. Soiling is assumed to be the
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1 contrast in reflectance of the particles on the substrate to the reflectance of the bare substrate.
2 Thus, the average reflectance from the substrate (R) equals the reflectance from the substrate
3 not covered by particles [Ro(l-X)] plus the reflectance from the particles (RpX) where X is
4 the fraction of surface covered by particles.
5 Under constant conditions, the rate of change in fraction of surface covered is directly
6 proportional to the fraction of surface yet to be covered. Therefore, after integration:
7 X = l-exp(-kt) where k is a function of particle size distribution and dynamics and t is time.
8 Lanting (1986) evaluated similar models with respect to soiling by paniculate elemental
9 carbon (PEC) in the Netherlands. He determined that the models were good predictors of
10 soiling of building materials by fine mode black smoke. Based on the existing levels of
11 PEC, he concluded that the cleaning frequency would be doubled.
12 An important particle dynamic is deposition velocity which is defined as flux divided by
13 concentration and is a function of particle diameter, surface orientation, and surface
14 roughness, as well as other factors such as wind speed, atmospheric stability, and particle
15 density. Thus, soiling is expected to vary with the size distribution of particles within an
16 ambient concentration, whether a surface is facing skyward (horizontal or is vertical), and
17 whether a surface is rough or smooth.
18 Van Aalst (1986) reviewed particle deposition models existing at that time and pointed
19 out both their benefits and their faults. The lack of significant experimental verification was
20 a major fault. Since then, Hamilton and Mansfeld (1991, 1993) have applied the model
21 reported by Haynie (1986) and Haynie and Lemmons (1990) to soiling experiments with
22 relatively good predictive success.
23 Tarrat and Joumard (1990) found that the simple plate method (a measurement of the
24 number of particles deposited on a flat inert plate of material), as well as the measurement of
25 reflectance and transmission of the light really showed the amount of soiling deposit in a
26 town. The simple plates are more suitable for a high particles pollution and the optical
27 methods are more suitable for a low pollution. This study also gave evidence that the main
28 responsibility in soiling the facades along roads was motor vehicles.
29
30
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1 9.2.1.1 Fabrics
2 No recent information on the effects of paniculate matter on fabrics was located in the
3 published literature. Earlier studies indicate particles are only damaging to fabrics when they
4 are abrasive. Yocom and Upham (1977) reported that curtains hanging in an open window
5 often split in parallel lines along the fold after being weakened by particle exposure. The
6 appearance and life usefulness also may be lessened from increased frequencies of washing as
7 a result of paniculate matter 'soiling'. Rees (1958) described the mechanisms (mechanical,
8 thermal, and electrostatic) by which cloth is soiled. Tightly woven cloth exposed to moving
9 air containing fine carbon particles was found to be the most resistant to soiling. Soiling by
10 thermal precipitation was related to the surface temperature of the cloth versus that of the air.
11 When the surface temperature of the cloth was greater than that of the air, the cloth resisted
12 soiling. When cloth samples were exposed to air at both positive and negative pressure, the
13 samples exposed to positive pressure showed greater soiling than those exposed to equivalent
14 negative pressure.
15
16 9.2.1.2 Household and Industrial Paints
17 As indicated earlier, research suggest that particles can serve as carriers of more
18 corrosive pollutants, allowing the pollutants to reach the underlying surface or serve as
19 concentration sites for other pollutants on painted surfaces (Cowling and Roberts, 1954).
20 Paints may also be soiled by liquids and solid particles composed of soot, tarry acids, and
21 various other constituents.
22 Haynie and Lemmons (1990) conducted a soiling study at an air monitoring site in a
23 relatively rural environment in Research Triangle Park, NC. The study was designed to
24 determine how various environmental factors contribute to the rate of soiling of white painted
25 surfaces. White painted surfaces are highly sensitive to soiling by dark particles and
26 represent a large fraction of all manmade surfaces exposed to the environment. Hourly
27 rainfall and wind speed, and weekly data for dichotomous sampler measurements and TSP
28 concentrations were monitored. Gloss and flat white paints were applied to hardboard house
29 siding surfaces and exposed vertically and horizontally for 16 weeks, either shielded from or
30 exposed to rainfall. Measurements of exposed samples were taken at 2, 4, 8, and 16 weeks.
31 Reflectance was measured at 2, 4, 8, and 16 weeks. The scanning electron microscopy
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1 stubs, that had been flush-mounted on the hardboard house siding prior to painting, were also
2 removed at these intervals.
3 The unsheltered panels were initially more soiled by ambient pollutants that the
4 sheltered panels; however, washing from rain reduced the effect. The vertically exposed
5 panels soiled at a slower rate than the horizontally exposed panels. This was attributed to
6 additional contribution to particle flux from gravity. The reflectivity was found to decrease
7 faster on glossy paint than on the flat paint (Haynie and Lemmons, 1990).
8 Least squares fits through zero of the amounts on the surfaces with respect to exposure
9 doses provided the deposition velocities. There was no statistical difference between the
10 horizontal and vertical surfaces for the fine mode and the combined data given a deposition
11 velocity of 0.00074 + 0.000048 cm/s (which is lower than some reported values). The
12 coarse mode deposition velocity to the horizontal surfaces at 1.55 cm/s is around five times
13 greater than to vertical surfaces at 0.355 cm/s. By applying assumptions these deposition
14 velocities can be used to calculate rates of soiling for sheltered surfaces. The empirical
15 prediction equation for gloss paint to a vertical surface based on a theoretical model (Haynie,
16 1986) is:
17
18 R = R0 exp (-0.0003 [0.0363Cf + 0.29CJt)
19
20 where R and RO are reflectance and original reflectance respectively, Cf and Cc are coarse
21 and fine mode paniculate matter concentrations in mg/m3, respectively, and t is time in
22 weeks of exposure.
23 The fine mode did not appear to be washed away by rain, but most of the coarse mode
24 was either dissolved to form a stain or was washed away. Therefore, for the surfaces
25 exposed to rain, the 0.0363 coefficient for the fine mode should remain the same as it is for
26 sheltered surfaces but there should be a tune-dependent difference in the coefficient for the
27 coarse mode.
28 Based on the results of this study, the authors concluded that: (1) coarse mode particles
29 initially contribute more to soiling of both horizontal and vertical surfaces than fine mode
30 particles; (2) coarse mode particles, however, are more easily removed by rain than are fine
31 mode particles; (3) for sheltered surfaces reflectance changes is proportional to surface
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1 coverage by particles, and particle accumulation is consistent with deposition theory; (4) rain
2 interacts with particles to contribute to soiling by dissolving or desegregating particles and
3 leaving stains; and (5) very long-term remedial actions are probably taken because of the
4 accumulation of fine rather than coarse particles (Haynie and Lemmons, 1990).
5 Similar results were also reported by Creighton et al. (1990). They found that
6 horizontal surfaces, under the test conditions, soiled faster than did the vertical surfaces, and
7 that large particles were primarily responsible for the soiling of horizontal surfaces not
8 exposed to rainfall. Soiling was related to the accumulated mass of particles from both the
9 fine and coarse fractions. Exposed horizontal panels stain because of dissolved chemical
10 constituents in the deposited particles. The size distribution of deposited particles was
11 bimodal, and the area of coverage by deposited particles was also bimodal with a minimum
12 at approximately 5 /mi. The deposition velocities for each of the size ranges onto the
13 horizontal, sheltered panel was in general agreement with both the theoretical settling
14 velocity of density 2.54 g/cm3 spheres and the reported results of laboratory tests. An
15 exponential model (Haynie, 1986) was applied to the data set and gave a good fit.
16 Beloin and Haynie (1975) determined by reflectance measurements that the degree of
17 soiling of painted surfaces was directly proportional to the square root of the paniculate
18 matter dose, accounting for 74 to 90% of the measured variability.
19 Spence and Haynie (1974) reported on the published data on the effects of paniculate
20 matter on the painted exterior surfaces of homes in Steubenville and Uniontown, Ohio,
21 Suitland and Rockville, Maryland, and Fairfax, Virginia. There was a direct correlation
22 between the ambient concentration of particulate matter in the city and the number of years
23 between repainting. The average repainting time for homes in Steubenville, where
24 particulate matter concentrations reached 235 pig/m3, was approximately one year. In the
25 less pollutant city, Fairfax, the time between repainting was 4 years. Parker (1955) reported
26 the occurrence of black specks on the freshly paint surface of a building in an industrial area.
27 The black specks were not only aesthetically unappealing, but also physically damaged the
28 painted surface. Depending on the concentration of particulate matter, the building required
29 repainting every 2 to 3 years.
30
31
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1 9.2.1.3 Soiling of Works of Art
2 Ligocki et al. (1993) studied potential soiling of works of art. The concentrations and
3 chemical composition of suspended paniculate matter were measured in both the fine and
4 total size modes inside and outside five Southern California museums during summer and
5 winter months. The seasonally averaged indoor/outdoor ratios for paniculate matter mass
6 concentrations ranged from 0.16 to 0.96 for fine particles and from 0.06 to 0.53 for coarse
7 particles, with lower values observed for buildings with sophisticated ventilation systems that
8 include filters for particulate matter removal. Museums with deliberate particle filtration
9 systems showed indoor fine particle concentrations generally averaging less than 10 /zg/m3.
10 One museum with no environmental control system showed indoor fine particles
11 concentrations averaging nearly 60 jtig/m3. Analysis of indoor versus outdoor concentrations
12 of major chemical species indicated that indoor sources of organic matter may exist at all
13 sites, but that none of the other measured species appear to have major indoor sources at the
14 museums studied. The authors concluded that a significant fractions of the dark-colored fine
15 elemental carbon and soil dust particles present in outdoor had penetrated to the indoor
16 atmosphere of the museums studied and may constitute a soiling hazard to displayed works of
17 art.
18 Methods for reducing the soiling rate in museums that included reducing the building
19 ventilation rate, increasing the effectiveness of particle filtration, reducing the particle
20 deposition velocity onto surfaces of concern, placing objects within display cases or glass
21 frames, managing a site to achieve lower outdoor aerosol concentrations, and eliminating
22 indoor particle sources were proposed by Nazaroff and Cass (1991). According to model
23 results the soiling rate can be reduced by at least two orders of magnitude through practical
24 application of these control measures. Combining improved filtration with either a reduced
25 ventilation rate for the entire building or low-air-exchange display cases is a very effective
26 approach to reducing the soiling hazard in museums.
27
28
29 9.3 ECONOMIC ESTIMATES
30 Several types of financial losses result from damage and soiling. These losses include
31 the reduction in service life of a material, decreased utility, substitution of a more expensive
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1 material, losses due to an inferior substitute, protection of susceptible materials, and
2 additional required maintenance, including cleaning. The major losses of amenity, as defined
3 by Maler and Wyzga (1976), are associated with enduring and suffering soiled, damaged, or
4 inferior products and materials because of particulate pollution and any corrosive pollutant
5 that may be absorbed on or adsorbed to particles. In addition, amenity losses are suffered
6 when pollution damage repair or maintenance procedures result in inconvenience or other
7 delays in normal operations. Some of these losses, such as effects on monuments and works
8 of art, are especially difficult to specify (Maler and Wyzga, 1976).
9 Like the effects of other pollutants, the reduced value and attractiveness of property and
10 the costs of cleaning and maintenance resulting from paniculate matter pollution must be
11 considered when evaluating monetary losses. In calculating monetary damage, the approach
12 selected depends on whether financial losses or losses of amenity are emphasized, the type of
13 damage being considered, and the availability of cost information. Generally, damage
14 estimates are based on physical damage approaches (willingness-to-pay approaches: physical
15 damage function, nonmarket, and indirect market approaches); however, one may proceed
16 directly from ambient pollutant levels to economic damage estimates. Willingness-to-pay
17 approaches try to estimate a monetary value to damage caused by changes in pollutant
18 concentrations that all affected parties assign to the effect.
19 The damage function approach, the most widely used method for evaluating economic
20 loss or cost, uses the relationship of pollutant exposure to physical damage. The physical
21 damage is then linked to a dollar estimate of willingness-to-pay. The nonmarket approach
22 generally uses surveys that attempt to determine the monetary value assigned to the pollutant
23 related effect. The willingness-to-pay for nonmarketed environmental attributes that are
24 closely related to marketed goods is used by the indirect market approach (Freeman, 1979a).
25 In the damage function approach, physical damage (any undesirable change in the
26 function of specific materials, including appearance, leading to failure of specific
27 components) is determined before economic cost is estimated. Physical damage is estimated
28 from ambient pollutant concentrations over a specified period of tune. Depending on the
29 material damaged, both short-term and long-term exposure data may be needed. The damage
30 function is expressed in terms appropriate to the interaction of the pollutant and material.
31 For example, the corrosion of metal may be expressed hi units of thickness lost, while the
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1 deterioration of paint from soiling may be expressed in units of reflectance lost. It is,
2 however, difficult to estimate financial loss because reliable information on physical damage
3 is not available for all economically important materials, and on the spatial and temporal
4 distribution of the materials being used. Further, techniques do not reflect the use of more
5 resistant and reduced maintenance materials, and loss estimates may assume that substitute
6 materials cost more than the original materials, and that the cost differential is attributable
7 solely to pollution, in this case, paniculate matter.
8 A critical damage level, the level at which the service life or functional utility of the
9 material has ended or is severely impaired, must be established before an economic loss
10 estimate is place on the material damaged by pollution. The damage from a specified
11 pollutant exposure is calculated by comparing the amount of material damage in a polluted
12 area with that from a clean area.
13 A major problem in developing reliable damage functions is the inability to separate
14 pollutant effects from natural weathering processes due to various meteorological parameters
15 (temperature, relative humidity, wind speed, and surface wetness). Since weathering in a
16 natural phenomenon, proceeding at an finite rate irrespective of anthropogenic pollution,
17 materials damage estimates must represent only that damage directly produced by
18 anthropogenic pollutant exposure. Also, this approach cannot account for irreplaceable items
19 such as works of art or national monuments.
20 In the studies where estimations of monetary damage associated with soiling are not
21 dominated by the physical damage approach, the loss of amenity has been considered as well
22 as direct financial loss (no market and indirect market approaches). These approaches have
23 been used to relate changes in the amount of money to reduce air pollution. A major source
24 of error using these approaches is the requirement that all factors that affect cost other than
25 air quality have to be accounted for. In general, however, all approaches to estimating costs
26 of air pollution effects on materials are limited by the difficulty in quantifying the human
27 response to damage based upon the ability and the incentive to pay additional costs (Yocom
28 and Grappone, 1976).
29 Only limited new information was located in the published literature on the economic
30 cost of soiling and corrosion by paniculate matter. The following sections will, therefore, be
31 primarily a summarization of some of the more important earlier studies. A more detailed
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1 discussion of these studies can be found in the 1982 criteria document, Air Quality Criteria
2 for Paniculate Matter and Sulfur Oxides (U.S. Environmental Protection Agency, 1982).
3
4 9.3.1 Economic Loss Associated with Materials Damage and Soiling
5 To be able to accurately estimate the economic costs of damage to construction
6 materials from pollution, information on the geographic distribution of various types of
7 exposed materials is needed. Lipfert and Daum (1992) analyzed the efforts done in this area.
8 They focused on the identification, evaluation and interpretation of data describing the
9 distribution of exterior construction materials, primarily in the United States. Materials
10 distribution surveys for 16 cities in the United States and Canada and five related data bases
11 from government agencies and trade organizations were examined. Data on residential
12 buildings were more available than non-residential buildings; little geographically resolved
13 information on distributions on materials in infrastructure was found.
14 Lipfert and Daum (1992) observed several important factors relating pollution to
15 distribution of materials. In the United States, buildings constitute the largest category of
16 surface areas potentially at risk to pollution damage. Within this category, residential
17 buildings are the most important. On average, commercial and industrial buildings tend to
18 be larger than residential buildings and to use more durable materials. However, because
19 they are more numerous (and use less durable materials) more surface area for residential
20 buildings is exposed to potentially damaging pollutants. For residential buildings in general,
21 painted surfaces are preferred over masonry in the Northeastern United States (with the
22 exception of large inner cities), brick is popular in the South and Midwest) and stucco in the
23 West. The use of brick appears to be declining, painted wood increasing, and the use of
24 vinyl siding is gaining over aluminum. One of the factors underlying the present regional
25 distribution of materials is their durability under the environmental conditions which exist
26 when they were installed. Thus, changing pollution levels have possibly affected materials
27 selection and is expected to do so.
28
29 9.3.1.1 Metals and Other Material Damage
30 In an early study, Bennett et al. (1978) examined the cost of corrosion in the United
31 States in 1975. The report estimated the total annual metallic corrosion cost at $82 billion;
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1 however, the damage costs were not pollutant-specific. Fink et al. (1971) also estimated the
2 economic loss from pollutant-induced damage of external metal structures. The estimated
3 annual cost of metallic corrosion was $1.45 billion; however, like the Bennett et al. (1978)
4 study, this study was not pollutant-specific, nor were the damage costs associated directly
5 with ambient pollutant concentrations.
6
7 9.3.1.2 Soiling of Paint and Other Materials
8 One of the earliest studies on national estimates of soiling costs was the Beaver report
9 (1954). This study suggested an annual total fast of 152 million pounds sterling for damage
10 by all forms of air pollution in Great Britain.
11 Michelson and Tourin (1966) compared cleaning and maintenance costs in Steubenville,
12 Ohio with Uniontown, Pennsylvania. The average TSP levels were 383 and 115 /ig/m3,
13 respectively. These researchers, reported that per capita costs for cleaning and maintenance
14 were $84 higher in Steubenville, based on 30% response to a questionnaire mailed to 2 to
15 6% of the population of these communities. In a second study (Suitland and Rockville,
16 Maryland and Fairfax, Virginia), Michelson and Tourin (1967) also showed an increase in
17 cleaning frequency with increased TSP. However, there were errors with the measurement
18 techniques, averaging over a community, and the influence of socioeconomic factors was not
19 considered.
20 In 1968, the National Air Pollution Control Administration (NAPCA), the forerunner of
21 the U.S. EPA, commissioned the Booz, Allen and Hamilton, Inc. (1970) (BAH) study to
22 determine residential soiling costs of particulate ah- pollution for the 11-county Philadelphia
23 area, including areas in Delaware and New Jersey. The primary purpose of the study was to
24 determine the residential soiling costs in the 11 county area. It was also to provide methods
25 of estimating residential soiling costs under various abatement strategies and develop a
26 sampling methodology that could be applied in other metropolitan areas. The finding of this
27 study was that there were no measurable effects on cleaning cost based on the annual
28 particulate levels (» 50 to 150 mg/m3) in the Philadelphia area. However, the study did not
29 consider the value of the direct personal labor or time of a "do-it-yourself" as a cost.
30 Further, the reason why exterior soiling costs were not statistically different may have been
31 associated with the use of more soil resistant materials and the pollution levels. All but five
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1 of the houses surveyed in the region of highest pollution were brick (80% of the structures in
2 Philadelphia were brick or masonry).
3 Salmon (1970) calculated the economic loss for materials (stainless steel, zinc, building
4 stone, leather and paper, cotton, and paint) by first determining the value of the materials
5 and then multiplying that figure by the estimated difference in useful lifetime between clean
6 rural and polluted urban areas. The purpose of the study was to rank potential
7 pollutant/materials damage problems. Soiling costs attributed to paniculate matter were
8 estimated to be $99 billion. The study estimated the economic loss for stainless steel, zinc,
9 building stone, leather and paper, cotton, and paint. According to the author, the cost
10 estimation represented susceptibility to economic loss or potential loss, and not actual
11 incurred loss. However, the study has been used quantitatively in many of the national
12 estimates for materials damage attributed to air pollution.
13 Spence and Haynie (1972) reported an estimated total annual economic loss of $540
14 million in 1968 dollars for increased exterior household painting. The calculation was based
15 on the assumption that exterior household paint service life is reduced by half in an (urban)
16 area averaging 110 mg/m3 TSP compared to a service life of 6 years in a (rural) area
17 averaging 40 mg/m3 TSP.
18 Narayanan and Lancaster (1973), using a questionnaire survey, reported that the cost of
19 maintaining a house in the Mayfield area (a polluted area in New South Wales, Australia)
20 was about $90/year higher than in the relatively unpolluted Rotar area. The cost differential
21 was attributed to higher levels of air pollution and airborne particulate matter in Mayfield.
22 This study did not consider socioeconomic factors, including respondents' attitude and how
23 these factors could bias the estimates.
24 Waddell (1974), using Salmon's (1970) list of economically important materials
25 significantly affected by air pollution and other published studies to date on material effects,
26 concluded that particulate matter had no significant economic effect in terms of household
27 maintenance and cleaning. However, when he examined published reports on property value
28 differentials to air pollution, he postulated the property value estimate for loss in aesthetic
29 appeal and soiling cost $2.9 billion, a total of $5.8 billion for particulate matter and SO2
30 combined.
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1 Liu and Yu (1976) designed a study to generate physical and economic damage
2 functions, by receptor, for both TSP and SO2 to establish a cost/benefit relationship. The
3 study used the BAH results (Booz, Allen and Hamilton Inc., 1970) on cleaning frequency
4 and related those results to TSP levels in 148 standard metropolitan statistical areas
5 (SMSAs). The study included effects of TSP exposure on health, materials, vegetation, and
6 household soiling. The technique, using Monte Carlo technique, created a sample of data
7 pairs for each cleaning tasks. The study concluded soiling from TSP exposure cost $5
8 billion nationwide. The authors did not, however, take into consideration the socioeconomic
9 factors in the BAH data base and the insensitivity of high-cost cleaning and maintenance
10 tasks to TSP levels.
11 Watson and Jaksch (1978), building on the results reported by Booz, Allen and
12 Hamilton, Inc., (1970), introduce the benefits of pollution control; the psychological and
13 other advantages of living in a cleaner environment. The value of these psychological and
14 health benefits were estimated by applying the standard measure of net contribution to
15 consumer welfare. In estimating the cost of achieving a given level of cleanliness, the
16 authors relied on a formula derived by Beloin and Haynie (1975). This formula estimated
17 the cost of maintaining a given level of reflectance, which is not the same thing as the
18 perceived level of cleanliness. "Cleanliness," as posed by Watson and Jaksch (1978), is the
19 reciprocal of the difference between the actual reflectance of a surface and its maximum
20 reflectance, raised to a power that depends on the rate at which reflectance decreases over
21 tune. Based on this definition, the marginal cost (or price to the consumer) of maintaining a
22 given average level of cleanliness, may be expressed as
23
24 MC = aP"Q,
25
26 where a and n are empirical constants, P denotes the ambient concentration of paniculate
27 matter, and Q represents the given average level of cleanliness. Of importance is that this
28 formula depends on both the empirical studies of reflectance and the assumed relationship
29 between reflectance and perceived cleanliness.
30 Watson and Jaksch (1978), using the data from the Booz, Allen and Hamilton, Inc.
31 (1970) study, concluded that out-of-pocket costs of home maintenance are not affected by
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1 paniculate matter; however, psychological satisfication is. They suggested that consumers
2 can be expected to choose the level of cleanliness at which the cost of further improvement is
3 equal to the amount they are willing to pay. People will tolerate lower levels of cleanliness
4 in heavily polluted areas than in less polluted areas because of the maintenance costs.
5 Watson and Jaksch (1982) compared the changes in consumer welfare with changes in
6 particulate matter concentrations (using supply and demand functions) by calculating the level
7 of cleanliness the would be chosen as a function of the ambient particulate matter
8 concentration. A demand curve for cleanliness was estimated based on the assumption that
9 households prefer more cleanliness to less. The estimates were made for households in the
10 BAH study survey and extrapolated to cover the entire Philadelphia metropolitan area, and
11 later extended to cover 123 SMS As in the United States. Allowances were made for the
12 differing particulate matter concentrations in the different SMS As. Watson and Jaksch
13 (1982) estimated that the nationwide gains to consumers, in 1978 dollars, from attaining the
14 primary TSP standard in all SMS As ranged from $1.4 to $5.1 billion dollars. An estimated
15 $2.4 to $9.1 billion dollars would be saved from attaining the secondary standard.
16 Using the framework developed by Watson and Jaksch (1982), Hamilton (1979)
17 estimated benefits from reduced TSP in six SMS As (Fresno, Los Angeles-I^ong Beach,
18 Sacramento, San Bernadino-Riverside-Ontario, San Diego, and San Francisco-Oakland) in
19 California. Benefits were estimated to be $40 per household (1978 dollars) based on a 25%
20 reduction in TSP levels. The total estimated benefit was $223 million.
21 Haynie (1989) performed a risk assessment of particulate matter soiling of exterior
22 house paints. Much of the data that was used is from the same data sets analyzed and
23 discussed by Lipfert and Daum (1992). County-wide census of housing data for 1970 and
24 1980 were linearly extrapolated to 1990. From reported survey data, the average exterior
25 wall surface for single-family houses was taken as 325 m2. For multi-family units the value
26 was 100 m2. About 10% of survey respondents painted because of dirt. Using national
27 average painting costs and frequencies, $1.74 billion of annual national residential repainting
28 costs could be attributed to soiling.
29 The geographic distribution of fine and coarse mode particles were calculated from the
30 1987 EPA AIRS data base for PM10, and TSP. A regression coefficient was obtained for the
31 relationship between PM10 and TSP from data at co-located sites. This value was used to
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1 estimate missing data. Since most counties do not have monitoring sites, a geographic linear
2 extrapolation scheme was developed to obtain those estimates as county-wide averages.
3 Dichotomous sampler data was used to determine the fractions of PM10 in the fine and coarse
4 modes.
5 Haynie (1990) used the methodology developed in a risk assessment of soiling of
6 painted exterior residential walls (Haynie, 1989) to calculate potential effects of PM10
7 nonattainment. The data base was updated with 1988 and 1989 AIRS data. An extreme
8 value statistical model was used to adjust every sixth day monitoring to 365 days for
9 counting violation days (one violation in 60 does not translate to 6 violations in 360). The
10 resulting paint cost due to soiling was subjected to a sensitivity analysis using various
11 assumed values. When the model is restricted to only a national average of 10% of
12 households repainting because of soiling, the effects of other assumptions become inversely
13 related and tend to cancel out each other (possibly associated with individual cost
14 minimization choices).
15 The top twenty counties were ranked by estimated soiling costs. Fourteen of the
16 counties with actual violation days in 1989 were in this group. All but three were west of
17 the Mississippi. A total of 29 counties with measured violations are in the set of
18 123 counties for which PM10 nonattainment soiling costs were calculated. When the given
19 set of behavior assumptions was used, there were no costs calculated for 19 counties that
20 actually measured violations in 1989. The distribution of a national estimated $1 billion in
21 painted exterior residential wall soiling costs is shown in Figure 9-1.
22 Haynie and Lemmons (1990) experimentally determined soiling function for
23 unsheltered, vertically exposed house paint was used to determine painting frequency.
24 An equation was set up to express paint life in integer years because when exterior painting
25 is done is usually controlled by seasonal weather. Different values for normal paint life
26 without soiling and levels of unacceptable soiling could be used in the equation. If four was
27 taken as the most likely average paint life for other than soiling reasons, then painting
28 because of soiling would likely be done at 1, 2, or 3 year intervals.
29 Soiling costs by county were calculated and ranked by decreasing amounts and the
30 logarithm of costs plotted by rank. The plot consisted of three distinct straight lines with
31 intersections at ranks 4 and 45. The calculated cost values provide a reasonable ranking of
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>100 10-100 1-10 0.1-1 0.01-0.1
County Paint Soiling Costs - Million Dollars
Figure 9-1. Geographic distribution of paint soiling costs.
Source: Haynie (1990).
1
2
3
4
5
6
7
8
9
10
11
12
the soiling problem by county, but do not necessarily reflect actual painting cost associated
with extreme concentrations of particulate matter. Households exposed to extremes are not
expected to respond with average behavior. Several alternatives can be selected that will
lower painting costs. First, individuals can learn to live with higher particulate matter levels,
accepting greater reductions in reflectance before painting. Second, they may wash painted
surfaces rather than paint as often. Third, they may select other materials or paint colors
that do not tend to show dirt. An example of the latter is the predominant use of beige
colored stucco in the desert southwest where wind blown soil is a problem.
Extrapolating the middle distribution of costs to the top four ranked counties reduces
their estimated costs considerably. For example Maricopa County, AR, was calculated to
rank first at $70.2 million if all households painted each year as predicted, but was calculated
to be only $29.7 million based on the distribution extrapolation.
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1 Based on these calculations and error analysis, the national soiling costs associated with
2 repainting the exterior walls of houses probably were within the range of $400 to $800
3 million a year in 1990. This sector represents about 70% of the exterior paint market, so
4 that extrapolating to all exterior paint surfaces gives a range of from $570 to $1,140 million
5 (Haynie and Lemmons, 1990).
6
7
8 9.4 SUMMARY OF ECONOMIC DAMAGE OF PARTICULATE
9 MATTER TO MATERIALS
10 A significant detrimental effect of paniculate matter pollution is the soiling of painted
11 surfaces and other building materials. Soiling is defined as a degradation mechanism that can
12 be remedied by cleaning or washing, and depending on the soiled surface, repainting.
13 Available data on pollution exposure indicates that paniculate matter can result in increased
14 cleaning frequency of the exposed surface, and may reduce the life usefulness of the material
15 soiled. Data on the effects of paniculate matter on other surfaces are even less well
16 understood. Some evidence also shows damage to fabrics, electronics, and works of art
17 composed of one or more materials, but this evidence is largely qualitative and sketchy.
18 The damaging and soiling of materials by airborne pollutants have an economic impact,
19 but this impact is difficult to measure. The accuracy of economic damage functions is
20 limited by several factors. One of the problems has been to separate costs related to
21 paniculate matter-related materials from other pollutants, as well as from those related to
22 normal maintenance. Cost studies typically involve broad assumptions about the kinds of
23 materials that are exposed in a given area and then require complex statistical analysis to
24 account for a selected number of variables. Attitudes regarding maintenance may vary
25 culturally, further confounding the problem of quantifying economic impact.
26 The nature and extent of damage to materials by paniculate matter have been
27 investigated by field and laboratory studies. Both physical and economic damage functions
28 have been developed for specific damage/effect parameters associated with exposure to
29 paniculate matter. To date, only a few of these functions are relatively reliable in
30 determining damage, while none has been generally accepted for estimating costs.
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1 In recent years fairly reliable damage functions for soiling of exterior wall paints have
2 been developed. The available damage functions are few in number but represent a major
3 fraction of the total surface that is exposed and sensitive to pollution damage.
4 Although their still remains a lack of sensitive materials distribution data, the
5 geographic resolution of available data is about as good as that of environmental monitoring
6 data. These limitations may hinder accurate estimates of total material damage and soiling,
7 but they do not prevent estimates within ranges of error. Studies have used various
8 approaches to determine pollutant-related costs for extra cleaning, early replacement, more
9 frequent painting, and protective coating of susceptible materials, as well as other indicators
10 of the adverse economic effects of pollutants. No study has produced completely satisfactory
11 results, and estimates of cost vary widely. In 1978 dollars, the estimated economic loss for
12 1970 TSP exterior soiling of residential structures was $2 billion. Damage functions indicate
13 that reductions in pollutants will decrease physical and, therefore, economic damage.
14 Approaches to cost estimation with data requirements different from those necessary for the
15 physical damage function approach have been attempted. These, however, do not directly
16 relate cause to effect.
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28 Guttman, H. (1968) Effects of atmospheric factors on the corrosion of rolled zinc. In: Metal corrsion in the
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37 Guttman, H.; Sereda, P. J. (1968) Measurement of atmospheric factors affecting the corrosion of metals.
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45 Hamilton, R. S.; Mansfield, T. A. (1993) The soiling of materials in the ambient atmosphere. Atmos. Environ.
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48 Haynie, F. H. (1980) Theoretical air pollution and climate effects on materials confirmed by zinc corrosion data.
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11 Haynie, F. H.; Lemmons, T. J. (1990) Paniculate matter soiling of exterior paints at a rural site. Aerosol Sci.
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14 Haynie, F. H.; Stiles, D. C. (1992) Evaluation of an atmospheric corrosion rate monitor as a time-of-wetness
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20 Haynie, F. H.; Upham, J. B. (1974) Correlation between corrosion behavior of steel and atmospheric pollution
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25 Haynie, F. H.; Spence, J. W.; Upham, J. B. (1976) Effects of gaseous pollutants on materials—a chamber study.
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27 Laboratory; EPA report no. EPA-600/3-76/015. Available from: NTIS, Springfield, VA; PB-251580.
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29 Hermance, H. W. (1966) Combatting the effects of smog on wire-spring relays. Bell Lab. Rec.
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32 Johnson, J. B.; Elliott, P.; Winterbottom, M. A.; Wood, G. C. (1977) Short-term atmospheric corrosion of mild
33 steel at two weather and pollution monitored sites. Corros. Sci. 17: 691-700.
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35 Kottori, M. S. (1980) The corrosion rate of metals exposed to pulp mill and smelter emissions. Presented at: the
36 73rd annual meeting of the Air Pollution Control Association; June; Montreal, PQ, Canada.
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38 Ligocki, M. P.; Salmon, L. G.; Fall, T.; Jones, M. C.; Nazaroff, W. W.; Cass, G. R. (1993) Characteristics of
39 airborne particles inside southern California museums. Atmos. Environ. Part A 27: 697-711.
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41 Lipfert, F. W.; Daum, M. L. (1992) The distribution of common construction materials at risk to acid deposition
42 in the United States. Atmos. Environ. Part B 26: 217-226.
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44 Lipfert, F. W.; Benarie, M.; Daum, M. L. (1985) Derivation of metallic corrosion damage functions for use in
45 environmental assessments. Upton, NY: Brookhaven National Laboratory; internal report.
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47 Luckat, S. (1972) Untersuchungen zum Schutz von Sachgutern aus Naturstein vor Luftverunreinigungen
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49 Luft 32: 217-220.
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51 Maler, K. G.; Wyzga, R. E. (1976) Economic measurement of environmental damage: a technical handbook.
52 Paris, France: Organisation for Economic Co-operation and Development.
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2 Triangle Park, NC: U.S. Environmental Protection Agency, Environmental Sciences Research
3 Laboratory; EPA report no. EPA-600/4-80-007. Available from: NTIS, Springfield, VA; PB81-126351.
4
5 Mansfeld, F.; Kenkel, J. V. (1976) Electrochemical monitoring of atmospheric corrosion phenomena. Corros.
6 Sci. 16: 111-122.
7
8 Mansfeld, F.; Vijaykumar, R. (1988) Atmospheric corrosion in Southern California. Corros. Sci. 28: 939-946.
9
10 McKinney, N.; Hermance, H. W. (1967) Stress corrosion cracking rates of a nickel-brass alloy under applied
11 potential. In: Stress corrosion testing: a symposium presented at the sixty-ninth annual meeting of the
12 American Society for Testing and Materials; June-July 1966; Atlantic City, NJ. Philadelphia, PA:
13 American Society for Testing and Materials; pp. 274-291. (ASTM special technical publication no. 425).
14
15 Michelson, I.; Tourin, B. (1966) Comparative method for studying costs of air pollution. Public Health Rep.
16 81: 505-511.
17
18 Michelson, I.; Tourin, B. (1967) Report on study of validity of extension of economic effects of air pollution
19 damage from upper Ohio River Valley to Washington, DC area. Environmental Health and Safety
20 Research Associates.
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22 Narayanan, R. L.; Lancaster, B. W. (1973) Household maintenance costs and paniculate air pollution. Clean Air
23 (Melbourne, Australia) 7: 10-13.
24
25 National Research Council. (1979) Airborne particles. Baltimore, MD: University Park Press.
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27 Parker, A. (1955) The destructive effects of air pollution on materials, national smoke abatement society annual
28 conference, proceedings, london, September 28, 1955, pp. 3-15.
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30 Russell, C. A. (1976) How environmental pollutants diminish contact reliability. Insul. Circuits 22: 43-46.
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32 Sabbioni, C.; Zappia, G. (1992) Atmospheric-derived element tracers on damaged stone. Sci. Total Environ.
33 126: 35-48.
34
35 Saiz-Jimenez, C. (1992) Deposition of airborne organic pollutants on historic buildings. Atmos. Environ. Part B
36 27: 77-85.
37
38 Salmon, R. L. (1970) Systems analysis of the effects of air pollution on materials. Raleigh, NC: National Air
39 Pollution Control Administration, Economic Effects Research Division; report no. APTD-0943. Available
40 from: NTIS; Springfield, VA; PB-209192.
41
42 Sanyal, B.; Singhania, G. K. (1956) Atmospheric corrosion of metals: part I. J. Sci. Ind. Res. Sect. B
43 15: 448-455.
44
45 Schwarz, H. (1972) On the effect of magnetite on atmospheric rust and on rust under a coat of paint. Werkst.
46 Korros. 23: 648-663.
47
48 Sereda, P. J. (1958) Measurement of surface moisture. Philadelphia, PA: American Society for Testing and
49 Materials; ASTM bulletin 228.
50
51 Sereda, P. J. (1974) Weather factors affecting corrosion of metals. In: Corrosion in natural environments: three
52 symposia presented at the 76th annual meeting of the American Society for Testing and Materials; June
53 1973; Philadelphia, PA. Philadelphia, PA: American Society for Testing and Materials; pp. 7-22; ASTM
54 Special Technical Publication no. 558.
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1 Simpson, J. W.; Horrobin, P. J., eds. (1970) The weathering and performance of building materials. New York,
2 NY: Wiley-Interscience; p. 286.
3
4 Sinclair, J. D. (1992) The relevance of particle contamination to corrosion of electronics in processing and field
5 environments. Proc. Electrochem. Soc. 93-1: 325-335.
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7 Skerry, B. S.; Johnson, J. B.; Wood, G. C. (1988a) Corrosion in smoke, hydrocarbon and SO2 polluted
8 atmospheres—I. General behaviour of iron. Corros. Sci. 28: 657-695.
9
10 Skerry, B. S.; Wood, J. C.; Johnson, J. B.; Wood, G. C. (1988b) Corrosion in smoke, hydrocarbon and SO2
11 polluted atmospheres—II. Mechanistic implications for iron from surface analytical and allied techniques.
12 Corros. Sci. 28: 697-719.
13
14 Spence, J. W.; Haynie, F. H. (1972) Paint technology and air pollution: a survey and economic assessment.
15 Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Programs;
16 publication no. AP-103. Available from: NTIS, Springfield, VA; PB-210736.
17
18 Spence, J. W.; Haynie, F. H. (1974) Design of a laboratory experiment to identify the effects of environmental
19 pollutants on materials. In: Corrosion in natural environments. Philadelphia, PA: American Society for
20 Testing and Materials; ASTM special technical publication no. 558; pp. 279-291.
21
22 Sydberger, T.; Ericsson, R. (1977) Laboratory testing of the atmospheric corrosion of steel. Werkst. Korros.
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24
25 Tomashov, N. D. (1966) The science of corrosion. New York, NY: The Macmillan Co.
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27 U.S. Environmental Protection Agency. (1982) Air quality criteria for paniculate matter and sulfur oxides.
28 Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria
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30 VA; PB84-156777.
31
32 Upham, J. B. (1967) Atmospheric corrosion studies in two metropolitan areas. J. Air Pollut. Control Assoc.
33 17: 398-402.
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35 Vernon, W. H. J. (1931) A laboratory study of the atmospheric corrosion of metals, part I. Trans. Faraday Soc.
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37
38 Vernon, W. H. J. (1935) A laboratory study of the atmospheric corrosion of metals. Trans. Faraday Soc.
39 31: 1668-1700.
40
41 Waddell, T. E. (1974) The economic damages of air pollution. Washington, DC: U.S. Environmental Protection
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43 NTIS, Springfield, VA; PB-235701.
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45 Walton, J. R.; Johnson, J. B.; Wood, G. C. (1982) Atmospheric corrosion initiation by sulphur dioxide and
46 particulate matte: I. Test-cell apparatus for simulated atmospheric corrosion studies. Br. Corros. J.
47 17: 59-64.
48
49 Watson, W. D.; Jaksch, J. A. (1982) Air pollution: household soiling and consumer welfare losses. J. Environ.
50 Econ. Manage. 9: 248-262.
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52 Wolff, G. T.; Collins, D. C.; Rodgers, W. R.; Verma, M. H.; Wong, C. A. (1990) Spotting of automotive
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1 Yocom, J. E.; Grappone, N. (1976) Effects of power plant emissions on materials. Palo Alto, CA: Electric
2 Power Research Institute; report no. EPRI/EC-139. Available from: NTIS, Springfield, VA; PB-257539.
3
4 Yocom, J. E.; McCaldin, R. O. (1968) Effects of air pollution on materials and the economy. In: Stern, A. C.,
5 ed. Air pollution, v. I. 2nd ed. New York, NY: Academic Press; pp. 617-654.
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i 10. DOSIMETRY OF INHALED PARTICLES IN THE
2 RESPIRATORY TRACT
3
4
5 10.1 INTRODUCTION
6 Almost all studies of the health effects of paniculate matter (PM) investigate exposure-
7 response' relationships or associations. In controlled studies, an animal or human volunteer
8 breathes a measured concentration of PM for a specified duration (i.e., the exposure), and
9 responses, such as pulmonary function or clearance rates, are measured. In epidemiological
10 studies, an index of exposure from personal or stationary monitors of selected pollutants is
11 analyzed for associations with health outcomes, such as morbidity or mortality. However, it
12 is a basic tenet of toxicology that the dose delivered to the target site, not the external
13 exposure, is the proximal cause of a response. Therefore, there is increased emphasis on
14 understanding the exposure-dose-response relationship. Exposure is what gets measured (or
15 estimated) in the typical study and what gets regulated; dose is the causative factor. Dose is
16 quite important to intra and interspecies extrapolations. For example, a healthy individual
17 and a person with emphysema will not get identical doses to specific lung regions even if
18 their external exposure is identical. Knowledge of how and to what extent disease factors
19 affect dose can assist in characterizing susceptible subpopulations. If a rat and a human are
20 identically exposed, they will receive different doses to regions of the respiratory tract.
21 Insofar as this is quantitatively understood, laboratory animal data can be more useful in
22 assessing human health risks.
23 The exposure-dose-response relationship is quite complex, beginning with definitions.
24 Although dose is a common generic term, for PM it can and has been defined as delivered
25 dose or retained dose; as a net dose over a unit time or a dose-rate; as a paniculate mass,
26 number or surface area; and as a compound (e.g., sulfuric acid) or a component of that
27 compound (e.g., hydrogen ion). Even if dose could be easily defined, it fits within a
28 complex continuum. For example, as illustrated in Figure 10-1, it is ultimately desirable to
29 have a comprehensive biologically-based dose-response model that incorporates the
30 mechanistic determinants of chemical disposition, toxicant-target interactions, and tissue
31 response integrated into an overall model of pathogenesis. Mathematical dosimetry models
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Chemical „_. „ T . . . .
Exposure v Dose * Toxicological
Concentration Response
Protective
i
Predictive
Exposure >• ^^^^^91 ^" ResP°nse
Default
z~
Exposure ^ 1 Tissue]
^ Mechanisms^, Dose
Disposition Models ' "
X — 71
Exposure >> Tissue I
Dose /
JSL
[?•• ^ Response
/~7\
^. Toxicant ^. Response
r Tissue J K
Interaction /
Mechanisms ^ ^ Mechanisms,
Disposition Models Toxicant-Target Models
/ — 71
Exposure >• Tissue I
Dose /
/ — 71
> ^ssT J ^ ResP°nse
Interaction /
r Mechanisms ^ ^ Mechanisms _, ^ Mechanisms v i
Disposition Models Toxicant-Target Models Tissue Response Models
Qualitative
r
Quantitative
Figure 10-1. Schematic characterization of comprehensive exposure-dose-response
continuum and the evolution of protective to predictive dose-response
estimates.
Adapted from Conolly (1990) and Andersen et al. (1992).
1
2
3
4
5
6
1
that incorporate mechanistic determinants of disposition (deposition, absorption, distribution,
metabolism, and elimination) of chemicals have been useful in describing relationships along
this continuum (e.g., between exposure concentration and target tissue dose), particularly as
applied to describing these relationships for the exposure-dose-response1 component of risk
assessment. With each progressive level, incorporation and integration of mechanistic
determinants allow elucidation of the exposure-dose-response continuum and, depending on
the knowledge of model parameters and fidelity to the biological system, a more accurate
8
9
lnResponse" is an indication of an alteration influence regardless of whether the data were measured as quanta!,
count, continuous, or ordered categorical; response and effect are used interchangeably.
April 1995
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1 characterization of the pathogenetic process. Due to the increase in accuracy of the
2 characterization with each progressive level, exposure-dose-response estimates also progress
3 from more protective to predictive, although there will always be some degree of
4 uncertainty.
5 This chapter addresses exposure-dose relationships, primarily discussing the mechanistic
6 determinants of inhaled dose and the available mathematical dosimetry models for humans
7 and laboratory animals in order to provide background on the potential extrapolations that
8 may be applied to the observed response data in both Chapter 11 (human and animal toxicity
9 data) and Chapter 12 (epidemiologic data). The chapter deals exclusively and generically
10 with aerosols (i.e., both airborne droplets and solid particles, including the hygroscopic,
11 acidic variety). It briefly reviews selected studies that have been reported in the literature on
12 particle deposition and retention since the publication of the 1982 Air Quality Criteria
13 Documents on Paniculate Matter and Sulfur Oxides and the 1989 Acid Aerosols Issue Paper
14 (U.S. Environmental Protection Agency; 1982, 1989), but the focus is on newer information.
15 After an overview of general considerations for extrapolation modeling, the chapter proceeds
16 to describe important particle characteristics and the basic mechanisms of particle deposition
17 and clearance in the respiratory tract. After the available deposition and clearance data are
18 reviewed, various models are described. Because dosimetry models may provide insight on
19 what the appropriate dose metric may be for characterizing the exposure-dose-response
20 relationships for PM, human and laboratory animal dosimetry models were chosen to
21 extrapolate data for various exposures and endpoints. A later section discusses the choice of
22 the extrapolation model and illustrates calculations to determine plausible dose metrics for
23 different endpoints. This information should be useful to the interpretation of health effects
24 data in Chapters 11 and 12.
25
26 10.1.1 General Considerations for Extrapolation Modeling
27 Major factors that affect the disposition (deposition, uptake, distribution, metabolism,
28 and elimination) of inhaled particles include the physicochemical properties of the particles
29 (e.g., particle diameter, distribution, hygroscopicity) and anatomic (e.g., upper respiratory
30 tract architecture, regional surface areas, airway diameters, airway lengths, branching
31 patterns) and physiologic (e.g., ventilation rates, clearance mechanisms) parameters of
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1 individual mammalian species. The relative contribution of each of these factors is a
2 dynamic relationship. Further, the relative contribution of these determinants is also
3 influenced by exposure conditions such as concentration and duration. A comprehensive
4 description of the exposure-dose-response continuum is desired for accurate extrapolation.
5 Therefore, a dosimetry model should incorporate all of the various deterministic factors into
6 a computational structure. Clearly, many advances in the understanding and quantification of
7 the mechanistic determinants of particle disposition, toxicant-target interactions, and tissue
8 responses (including species sensitivity) are required before an overall model of pathogenesis
9 can be developed for a specific aerosol. Such data do exist to varying degrees, however, and
10 may be incorporated into less comprehensive models that nevertheless are useful in
11 describing delivered doses or in some cases, target tissue interactions.
12
13 10.1.1.1 Model Structure and Parameterization
14 Data on the mechanistic determinants of particle disposition, toxicant-target interactions,
15 and tissue responses to incorporate into a model vary in degree of availability for chemicals
16 and species. A theoretical mathematical model to describe particle deposition would require
17 detailed information on all of the influential parameters (e.g., respiratory rates, exact airflow
18 patterns, complete measurement of the branching structure of the respiratory tract,
19 pulmonary region mechanics) across different humans or across various laboratory species of
20 interest. An empirical model (i.e., a system of equations fit to experimental data) is an
21 alternative approach. Depending on the relative importance of these various mechanistic
22 determinants, models with less detail may be used as a default to adequately describe
23 differences in dosimetry for the purposes of extrapolation.
24 An understanding of the basis for model structures also allows development of a
25 framework for the evaluation of whether one available model structure may be considered
26 optimal relative to the another. A model structure might be considered more appropriate
27 than another for extrapolation when default assumptions or parameters are replaced by more
28 detailed, biologically-motivated descriptions or actual data, respectively. For example, a
29 model could be preferred if it incorporates more chemical or species-specific information or
30 if it accounts for more mechanistic determinants. Empirical models may differ in the quality
April 1995 10-4 DRAFT-DO NOT QUOTE OR CITE
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1 or appropriateness of the data used to estimate equations. These considerations are
2 summarized in Table 10-1.
3
4
TABLE 10-1. HIERARCHY OF MODEL STRUCTURES FOR
DOSIMETRY AND EXTRAPOLATION
Optimal model structure
Structure describes all significant mechanistic determinants of particle disposition,
toxicant-target interaction, and tissue response
Uses chemical-specific and species-specific parameters
Dose metric described at level of detail commensurate to epidemiologic or toxicity
data
Default model structure
Limited or default description of mechanistic determinants of particle disposition,
toxicant-target interaction, and tissue response
Uses categorical or default values for chemical and species parameters
Dose metric at generic level of detail
Adapted from U.S. Environmental Protection Agency (1994); Jarabek (1994).
1 The sensitivity of the model to differences in structure may be gauged by their relative
2 importance in describing the response function for a given chemical. For example, a model
3 which incorporates many parameters may not be any better at describing ("fitting") limited
4 response data than a simpler model.
5 Woodruff et al. (1992) used Monte Carlo analyses to assess the impact that structure
6 and parameterization of physiologically-based pharamcokinetic (PBPK) models has on output
7 predictions and variability. Nonphysiologically based (NPB) models of three or two
8 compartments were compared with PBPK models that either used five compartments
9 (PBPK5) to describe the body (well-perfused, poorly-perfused, fat, bone marrow, and liver
10 tissue compartments) or that "lumped" the body into three (fat, bone marrow, and central)
11 compartments (PBPK3). Comparisons were run for different data sets from inhalation to
12 benzene. The two main influences on variability of model output predictions were (1) the
13 quantity and type of data used to calibrate the model and (2) the number of parameters in the
14 model. While some differences existed between the models' average predictions when
April 1995 10-5 DRAFT-DO NOT QUOTE OR CITE
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1 calibrated to the same experimental data, these differences were smaller than the differences
2 between the predictions made by the same model fitted to different data sets. An excessive
3 number of parameters was shown to lead to overparameterization and cause large variability
4 in the output. The similarities in the average predictions of the NPB and PBPK models
5 supported the use of NPB models in some cases. The NPB models have fewer parameters
6 and are potentially easier to fit. The PBPK models did show greater reliability for
7 extrapolation, but NPB models provided reliable results with less effort needed in fitting data
8 when the objective was to interpolate from the current data. Issues addressed in the review
9 by Woodruff et al. (1992) and others (Hattis et al., 1989; Farrar et al., 1989; Portier and
10 Kaplan, 1989; Bois et al., 1990) regarding evaluation of the uncertainty in input parameters
11 and the variability of predictions due to alternate structures and data sets, should be
12 considered when evaluating different available model structures.
13
14 10.1.1.2 Intraspecies Variability
15 There are essentially three areas of concern in assessing the quality of epidemiologic or
16 toxicity data. These involve the design and methodological approaches for (1) exposure
17 measures, (2) effect measures, and (3) the control of covariables and confounding variables.
18 Although these topics are discussed in detail in other chapters, it is important to also consider
19 these concerns when evaluating potential dosimetry models for extrapolation of such data.
20 For example, although the epidemiologic investigations attempt to relate an exposure to a
21 given health effect, the way the exposure is characterized may influence the choice of an
22 appropriate dosimetry model. Characterization of a particular health effect in a human
23 population may include pre-existing pathologic conditions (e.g., lung disease) that may alter
24 inhalation dosimetry and have implications for model choice. The broad genetic variation of
25 the human population in processes related to chemical disposition and tissue response (e.g.,
26 age, gender, disease status) may cause individual differences in sensitivity to inhaled
27 aerosols. Dosimetry models could be exercised as a means of analyzing the sensitivity of
28 model outputs to ranges for various parameters (e.g., range in ventilation due to gender).
29
30
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1 10.1.1.3 Extrapolation of Laboratory Animal Data to Humans
2 Both qualitative and quantitative extrapolation of laboratory animal data to humans are
3 of interest. Qualitative extrapolation refers to the "class" of the effects. For example, if the
4 function of rabbit alveolar macrophages is depressed by sulfuric acid, will it also be
5 depressed in humans, albeit at an unknown exposure? This type of extrapolation is limited to
6 known homologous effects. For example, given the similarities in of human and laboratory
7 animal alveolar macrophages, and likely toxicity mechanisms, the qualitative extrapolation is
8 reasonable. However, in some cases, the homology is not understood adequately. For
9 example, what is the laboratory animal model comparison to the mortality observed in the
10 epidemiological studies? Several hypotheses exist, but at present, there is inadequate
11 evidence for concensus. Once a qualitative extrapolation has been performed, a quantitative
12 extrapolation can be initiated. In order for the laboratory animal data to be useful to the risk
13 assessment of paniculate matter, interspecies extrapolation should account for differences in
14 dosimetry and species sensitivity. Dosimetry, here, is used broadly to represent the effective
15 dose to target site which may be some complex combination of delivered dose and retained
16 dose. Given the identical exposure, this dose will be different in different species. Even if
17 knowledge on dose were complete, there still needs to be an understanding of species
18 differences in sensitivity to that dose. For example, perhaps one species has more efficient
19 repair or chemical defense mechanisms than another, making that one species more sensitive
20 to a given dose.
21
22
23 10.2 CHARACTERISTICS OF INHALED PARTICLES
24 Information about particle size distribution aids in the evaluation of the effective inhaled
25 dose. Because the characteristics of inhaled particles interact with the other major factors
26 controlling comparative inhaled dose, this section discusses aerosol attributes requiring
27 characterization and provides general definitions.
28 An aerosol is a suspension of paniculate matter in air. It is intrinsically unstable, and
29 hence, tends to deposit both continuously and inelastically onto exposed surfaces. From the
30 perspective of health-related actions of aerosols, interest is limited to particles that can
31 penetrate, at least, into the nose or mouth and that deposit on respiratory tract surfaces. For
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1 humans, this constraint ordinarily eliminates very coarse particles, viz, greater than about
2 100 (j,m diameter. Particles between 1 /*m and 20 /an diameter are commonly encountered in
3 the work place and the ambient air. Still smaller, i.e., submicron diameter particles,
4 especially between 0.1 to 1.0 /im diameter, are perhaps the most numerous in the
5 environmental air. Even particles down to the nanometer (nm) size domain are found in the
6 atmosphere and are of interest, although until recently, these "ultrafine" particles were of
7 greater interest to atmospheric scientists than to biomedical scientists. Typically, "ultrafine"
8 aerosols are produced by highly energetic reactions (e.g., high temperature sublimation and
9 combustion, or by gas phase reactions involving atmospheric pollutants). Note that 10 nm =
10 100 Angstroms = 0.01 nm or 1 XlO'6 cm diameter.
11 Because aerosols can consist of almost any material, descriptions of aerosols in simple
12 geometric terms can be misleading unless important factors relating to size, shape, and
13 density are considered. Aerosols are usually described in terms of geometric or aerodynamic
14 sizes. Additionally, aerosols may be defined in terms of particle surface area. It is
15 important to note that aerosols present in natural and work environments all have
16 polydisperse size distributions. This means that the particles comprising the aerosols have a
17 range of geometric size, aerodynamic size, and surface area and are more appropriately
18 described in terms of size distribution parameters. Aerosol sampling devices can be used to
19 collect bulk or size fractions of aerosols to allow defining the size distribution parameters.
20 In this procedure, the fraction of particles in defined size parameter groups (number, mass,
21 or surface area) is divided by the total number, mass, or surface of all particles collected and
22 divided also by the size interval for each group. Data from the sampling device are then
23 expressed in terms of the fraction of particles per unit size interval. The next step is to use
24 this information to define an appropriate particle size distribution.
25 The lognormal distribution has been widely used for describing size distributions of
26 radioactive aerosols (Raabe, 1971) and is also generally used as a function to describe other
27 kinds of aerosols. For many aerosols, their size distributions may be described by a
28 lognormal distribution, meaning that the distribution will resemble the bell-shaped Gaussian
29 error curve, if the frequency distribution is based on the logarithms of the particle size. The
30 lognormal distribution is a skewed distribution characterized by the fact that the logarithms of
31 particle diameter are normally distributed. In linear form, the logarithmic mean is the
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1 median of the distribution. The standard deviation, a, of this logarithmic normal distribution
2 is a logarithm, so that addition and subtraction of this logarithm to and from the logarithmic
3 mean is equivalent to multiplying and dividing the median by the factor ae, with In oe = a.
£> &
4 The factor OB is defined as the geometric standard deviation. When any aerosol distribution
o
5 is "normalized", it acquires parameters and properties equivalent to those of the Gaussian
6 distribution. Accordingly, the only two parameters needed to describe the log normal
7 distribution are the median diameter and the geometric standard deviation, ae, (ratio of the
&
8 log 84%/log 50% size cut or log 50%/log 16% size cut, where the 50% size cut is the
9 median). While there may be occasions when the number of the particles is of the greatest
10 interest, the distribution of mass in an aerosol according to particle size is of interest if
11 particle mass determines the dose of interest. This is essentially a matter of converting a
12 diameter distribution to a diameter-cubed distribution since the volume of a sphere with
13 diameter d is ?rd3/6 and mass is simply the product of particle volume and physical density.
14 For a distribution formed by counting particles, the median is called the count median
15 diameter (CMD).
16 The cumulative distribution of a lognormally distributed size distribution is conveniently
17 evaluated using log-probability graph paper on which the cumulative distribution forms a
18 straight line (Figure 10-2). This distribution can be used for all the three lognormally
19 distributed particle size parameters discussed above, which are related as indicated in
20 Figure 10-2. The characteristic parameters of this distribution are the size and
-------
10;
5
1:
3 0-5-
5
-------
1 For most aerosols, it is useful to define particle size in terms of its aerodynamic size
2 wherein particles of differing geometric size, shape and density are compared
3 aerodynamically with the instability behavior of particles that are unit density (1 gm/cm3)
4 spheres. The aerodynamic behavior of unit density spherical particles can be determined,
5 both experimentally and theoretically, consequently, they constitute a useful standard by
6 which all particles can be compared in matters of inertial impaction and gravitational settling.
7 Thus, if the terminal settling velocity of a unit density sphere of 10 pm diameter is measured
8 in tranquil air, the velocity induced by gravity would be -3X10"1 cm/s. If the gravitational
9 settling of an irregularly shaped particle of unknown density was measured and the same
10 terminal velocity was obtained, the particle would have a 10 /xm aerodynamic diameter (dae).
11 Its tendency to deposit by inertial processes on environmental surfaces or onto the surfaces of
12 the human respiratory tract will be the same as for the 10 /xm unit density sphere.
13 A term that is frequently encountered is mass median aerodynamic diameter (MMAD),
14 which refers to the mass median of the distribution of mass with respect to aerodynamic
15 diameter. With commonly-encountered aerosols having low to moderate polydispersity, og
16 <2.5, the Task Group on Lung Dynamics (TGLD) (1966) showed that mass deposition in
17 the human respiratory tract could be approximated by the deposition behavior of the particle
18 of median aerodynamic size in the mass distribution, the so-called MM AD. This is
19 successful because the particles which dominate control of the mass distribution are those
20 which deposit mainly by settling and inertial impaction.
21 In many urban environments, the aerosol frequency and mass distributions have been
22 found to be bimodal or trimodal (Figure 10-3), usually indicating a composite of several log
23 normal distributions where each aerosol mode was presumably derived from different
24 formation mechanisms or emission sources (John et al., 1986). Conversely, in the
25 laboratory, experimentalists often create aerosol distributions which are lognormal, and very
26 frequently, they generate monodisperse aerosols consisting of particles of nearly one size.
27 The use of monodisperse aerosols of nearly uniform, unit density, spherical particles greatly
28 simplifies experimental deposition and retention measurements and also instrument
29 calibrations. With uniform particles, the mass, surface area and frequency distributions are
30 nearly identical, another important simplification.
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o
T~
X
^
S
1.2r
1.0
- o0.8
21
<0.6
0.4
10.2
CO
0.01
0.1 1
Particle diameter (urn)
10
Figure 10-3. These normalized plots of number, surface and volume (mass)
distributions from Whitby (1975) show a bimodal mass distribution in a
smog aerosol. Historically, such particle size plots were described as
consisting of a coarse mode (2.5 to 15 jim), a fine mode (0.1 to 2.5 /tm),
and a nuclei mode (< 0.05/on). The nuclei mode would currently fall
within the ultrafine particle range (0.005 to 0.1 jon).
1 The terms count median aerodynamic diameter (CMAD) and surface median
2 aerodynamic diameter (SMAD) might be encountered. These distributions are useful in that
3 they include consideration of aerodynamic properties of the particles. If the particle
4 aerodynamic or diffusive diameter is determined when sizing is done, then the median of the
5 particle size distribution is the CMAD, or count median diffusive (or thermodynamic)
6 diameter (CMDD or CMTD), respectively. If the mass of particles is of concern, then the
7 median that is derived is the MMAD or mass median diffusive (or thermodynamic) diameter
8 (MMDD or MMTD). Generally, MMDs or MMADs are generally used to evaluate particle
9 deposition patterns in the respiratory tract because deposition of inhaled aerosol particles, as
10 discussed in detail later in this chapter, is determined primarily by particle diffusive and
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1 aerodynamic properties of the particles rather than simply particle physical size, surface area,
2 volume, or mass. Activity median aerodynamic diameter (AMAD) is the median of the
3 distribution of radioactivity or toxicological or biological activity with respect to size. Both
4 MMAD and AMAD are determined using aerosol sampling devices such as multistage
5 impactors. When particles become smaller than about 0.1 /nm diameter, their instability as
6 an aerosol depends mainly on their interaction with air molecules. Like particles in
7 Brownian motion, they are caused to "diffuse". For these small particles and especially for
8 ultrafme particles, this interaction is independent of the particle density and varies only with
9 geometric particle diameter. Very small particles are not expressed in aerodynamic
10 equivalency, but instead to a thermodynamic-equivalent size. The thermodynamic particle
11 diameter (dTH) is the diameter of a spherical particle that has the same diffusion coefficient in
12 air as the particle of interest. The activity median thermodynamic diameter (AMTD) is the
13 diameter associated with 50 percent of the activity for particles classified thermodynamically.
14 The selection of the particle size distribution to associate with health effects depends on
15 decisions about the importance of number of particles, mass of particles, or surface area of
16 particles in producing the effects. In some situations, numbers of particles or mass of
17 particles phagocytized by alveolar macrophages may be important; in other cases, especially
18 for particles that contain toxic constituents, surface area may be the most important
19 parameter that associates exposures with biological responses or pathology. These particle
20 distributions should all be considered during the course of evaluating relationships between
21 inhalation exposures to particles and effects resulting from the exposures.
22 Most of the discussion in the remainder of this chapter will focus on MMAD because it
23 is the most commonly used measure of aerosol distributions. If MMAD is not measured
24 directly, an alternative is to determine MMAD from one of the particle size distributions that
25 is based on physical size of the particles (CMD, MMD, and SMD), which can all be readily
26 converted to MMAD. The approximate conversion of MMD to MMAD is made using the
27 following relationship (neglecting slip)
28
1 MMAD = MMD • (particle density)0-5. (10-3)
2
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1 By definition, MMDD = CMDT or MMDD, because behavior of particles in this size
2 category does not depend on aerodynamic properties.
3 Because aerosols of small particles contain such a large surface area, they acquire
4 greater reactivity. For example, tantalum is a very stable, unreactive metal, whereas
5 aerosols of tantalum particles can be caused to explode by a spark. The rates of oxidation
6 and solubility are proportional to surface area as are the processes of gas adsorption and
7 desorption, and vapor condensation and evaporation. Accordingly, special concerns arise
8 from gas-particle mixtures and from "coated" particles. For a general review of atmospheric
9 aerosols, their characteristics and behavior, the publication Airborne Particles prepared under
10 the aegis of the National Research Council (1979) is recommended.
11
12
13 10.3 ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY TRACT
14 The respiratory systems of humans and various experimental animals differ in anatomy
15 and physiology in many quantitative and qualitative ways. These differences affect air flow
16 patterns in the respiratory tract, and in turn, the deposition of an inhaled aerosol. Particle
17 deposition connotes the removal of particles from their airborne state due to their inherent
18 instabilities in air and to their induced-instabilities in air when additional external forces are
19 applied. For example, in tranquil air, a 10 /xm diameter, unit density particle only undergoes
20 sedimentation due to the force of gravity. If a 10 ^m particle is transported in a fast moving
21 air stream, it acquires an inertial force which can cause it to deposit on a surface projecting
22 into the air stream without significant regard to gravitational settling. For health-related
23 issues, interest in particle deposition is limited to that which occurs in the respiratory tract of
24 humans and laboratory animals during the respiration of dust-laden air.
25 Once particles have deposited onto the surfaces of the respiratory tract, some will
26 undergo transformation, others will not, but subsequently, all will be subjected either to
27 absorptive or non-absorptive particulate removal processes, e.g., mucociliary transport, or a
28 combination thereof. This will result in their removal from the respiratory tract surfaces.
29 Following this, they will undergo further transport which will remove them, to a greater or
30 less degree, from the respiratory tract. Such particulate matter is said to have undergone
31 clearance. To the extent particulate matter is not cleared, it is retained. The temporal
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1 persistence of uncleared (retained) particles within the structure of the respiratory tract is
2 termed retention.
3 Thus, either the deposited or retained dose of inhaled particles in each region is
4 governed by the exposure concentration, by the individual species anatomy (e.g., airway size
5 and branching pattern) and physiology (e.g., breathing rate, cell types, and clearance
6 mechanisms), and by the physicochemical properties (e.g., particle size, distribution,
7 hygroscopicity, solubility) of the aerosol. The anatomic and physiologic factors are
8 discussed in this section. The physicochemical properties of particles were discussed in
9 Section 10.2. Deposition and clearance mechanisms will be discussed in Section 10.4.6.
10 The respiratory tract in both humans and various experimental mammals can be divided
11 into three regions on the basis of structure, size, and function: the extrathoracic (ET) region
12 or upper respiratory tract (URT) that extends from just posterior to the external nares to the
13 larynx, i.e., just anterior to the trachea; the tracheobronchial region (TB) defined as the
14 trachea to the terminal bronchioles where proximal mucociliary transport begins; and the
15 alveolar (A) or pulmonary region including the respiratory bronchioles and alveolar sacs.
16 The thoracic (TH) region is defined as the TB and A regions combined. The anatomic
17 structures included in each of these respiratory tract regions are listed in Table 10-2, and
18 Figure 10-4 provides a diagrammatic representation of these regions as described in the
19 International Commision on Radiological Protection (ICRP) Human Respiratory Tract Model
20 (ICRP66, 1994).
21 Figure 10-5 depicts how the architecture of the respiratory tract influences the airflow
22 in each region and thereby the dominant deposition mechanisms. The 5 major mechanisms
23 (gravitational settling, inertial impaction, Brownian diffusion, interception and electrostatic
24 attraction) responsible for particle deposition are schematically portrayed in Figure 10-5 and
25 will be discussed in detail in Section 10.4.1.
26 The nasal hairs, anterior nares, turbinates of the nose and glottic aperture in the larynx
27 are areas of especially high air velocities, abrupt directional changes, and turbulence, hence,
28 the predominant deposition mechanism in the ET region is inertial impaction. In this
29 process, changes in the inhaled airstream direction or magnitude of air velocity streamlines
30 or eddy components are not followed by airborne particles because of their inertia. Large
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TABLE 10-2. RESPIRATORY TRACT REGIONS
Region
Extrathoracic (ET)
Anatomic Structure
Nose
Mouth
Nasopharynx
Other Terminology
Head airways region
Nasopharynx (NP)
Upper respiratory tract (URT)
Tracheobronchial (TB)
Alveolar (A)
Oropharynx
Laryngopharynx
Larynx
Trachea
Bronchi
Bronchioles (including
terminal bronchioles)
Respiratory bronchioles
Alveolar ducts
Alveolar sacs
Alveoli
Lower conducting airways
Gas exchange region
Pulmonary region
Adapted from: Phalen et al. (1988a).
1 particles ( > 5 pm in humans) are more efficiently removed from the airstream in this region.
2 The respiratory surfaces of the nasal turbinates are in very close proximity to and designed to
3 warm and humidify the incoming air, consequently they can also function effectively as a
4 diffusion deposition site for very small particles and an effective absorption site for water-
5 soluble gases. The turbinates and nasal sinuses are lined with cilia which propel the
6 overlying mucous layer posteriorly via the nasopharynx to the laryngeal region. Thus, the
7 airways of the human head are major deposition sites for the largest inhalable particles (> 10
8 jwn aerodynamic diameter) as well as the smallest particles (<0.1 micrometers diameter).
9 For the most part, the ET structures are lined with a squamous, non-ciliated mucous
10 membrane. Collectively, the movement of upper airway mucus, whether transported by cilia
11 or gravity, is mainly into the gastrointestinal tract.
12 As air is conducted into the airways of the head and neck during inspiration, it first
13 passes through either the nasal passages or mouth. Whereas nasal breathing is normal with
14 most people most of the time, this option usually depends upon the work load. Work loads
15 which tend to treble or quadruple minute ventilation i.e., go from 10 L/m to 30 to 40 L/m,
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Directional
Change
Very
Abrupt
Air
Velocity
Less
Abrupt
Mild
(Gravitational
Settling)
0
Electrostatic
Attraction
Figure 10-5. Schematic representation of five major mechanisms causing particle
deposition where airflow is signified by the arrows and particle trajectories
by the dashed line.
Source: Adapted from Casarett (1975); Raabe (1979); Lippmann and Schlesinger (1984).
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1 cause most subjects to change from nasal to oronasal breathing. In either case, the inspired
2 air then passes through the pharyngeal region into the larynx.
3 From the larynx, the inspired air passes into the trachea, a cylindrical,
4 muscular-cartilaginous tube. The trachea measures approximately 1.8 cm diameter x 12 cm
5 long in humans. The trachea, like other conducting airways of the lungs, is ciliated and
6 richly endowed with secretory glands and mucus-producing goblet cells. The major or main
7 stem bronchi are the first of approximately 16 generations of branching that occur in the
8 human bronchial "tree". For modeling purposes, Weibel (1963; 1980) described bronchial
9 branching as regular and dichotomous, i.e., where the branching parent tube gives rise,
10 symmetrically, to two smaller (by \J2) tubes of the same diameter. While this pattern
11 provides a simplification for modeling, the human bronchial tree actually has irregular
12 dichotomous branching, wherein the parent bronchi gives rise to two smaller tubes of
13 differing diameter and length. The number of generations of branching occurring before the
14 inspired air reaches the first alveolated structures varies from about 8 to 18 (Raabe et al.
15 1976, Weibel 1980).
16 Impaction remains a significant deposition mechanism for particles larger than 2.5 jim
17 aerodynamic equivalent diameter (dae) in the larger airways of the TB region in humans and
18 competes with sedimentation, with each mechanism being influenced by mean flow rate and
19 residence time, respectively. As the airways successively bifurcate, the total cross-sectional
20 area increases. This increases airway volume in the region, and the air velocity is decreased.
21 With decreases in velocity and more gradual changes in air flow direction as the branching
22 continues, there is more time for gravitational forces (sedimentation) to deposit the particle.
23 Sedimentation occurs because of the influence of the earth's gravity on airborne particles.
24 Deposition by this mechanism can occur in all airways except those very few that are
25 vertical. For particles ~4 pm dae, a transition zone between the two mechanisms, from
26 impaction to predominantly sedimentation, has been observed (U.S. Environmental Protection
27 Agency, 1982). This transition zone shifts toward smaller particles for nose breathing.
28 The surface area of the human TB region is estimated to be about 200 cm2 and its
29 volume is about 150 to 180 mL, the so-called anatomical dead space. At the level of the
30 terminal bronchiole, the most peripheral of the distal conducting airways, the mean airway
31 diameter is about 0.3 to 0.4 mm and their number is estimated at about 6xl04. As to the
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1 variability of bronchial airways of a given size, Weibel's (1963) considered a 0.2 cm
2 diameter airways and noted that such airways occur from the 4th to 14th generations of
3 branching, peaking in frequency around the 8th generation. An insight into the variabilities
4 in various lung models was provided by Forrest (1993) who indicated that the number of
5 terminal bronchioles incorporated in Weibel's model was about 66,000, whereas, Findeisen
6 (1935) used 54,000 and Horsfield and Cummings (1968) estimated only 28,000 (op cit). The
7 transitional airways of the human lung, the respiratory bronchioles and alveolar ducts,
8 undergo another 6 generations of branching according to Weibel (1980) before they become
9 alveolar sacs. On this basis, the dichotomous lung model indicates there should be about
10 8.4xlO6 branches (223), serving 3xl08 alveoli. The recent "typical path" model of Yen and
11 Schum (1980), adopted by the National Council on Radiation Protection (NCRP) (Cuddihy et
12 al., 1988), cites «33,000 terminal bronchioles. The International Commission on
13 Radiological Protection (ICRP) utilized the dimensions from three sources hi its human
14 respiratory tract model (ICRP66, 1994).
15 The parenchymal tissue of the lungs surrounds all of the distal conducting airways
16 except the trachea and portions of the mainstem bronchi. This major branch point area is
17 termed the mediastinum; it is where the lungs are suspended in the thorax by a band of
18 pleura called the pulmonary ligament, where the major blood vessels enter and leave the
19 hilus of each lung, and the site of the mediastinal pleura which envelopes the heart and
20 essentially subdivides the thoracic cavity.
21 Humans lungs are demarcated into 3 right lobes and 2 left lobes by the pleural lining.
22 The suspension of the lungs in an upright human gives rise to a gradient of compliance
23 increasing from apex to base. Subdivisions of the lobes, segments, are not symmetrical due
24 to a fusion of 2 (middle left lung) of the 10 lobar segments of the lung and occasionally an
25 underdeveloped segment in the lower left lobe. Lobar segments can be related to specific
26 segmental bronchi and are useful anatomical delineators for bronchoalveolar lavage.
27 The lung parenchyma is composed primarily of alveolated structures of the A region
28 and the associated blood vessels and lymphatics. The parenchyma is organized into
29 functional units called acini which consist of the dependent structures of the first order
30 respiratory bronchioles. The alveoli are polyhedral, thin-walled structures numbering
31 approximately 3xlO8 in the adult human lung. Schreider and Raabe (1981) provided a range
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1 of values, viz, 2 X 108 to 5.7 X 108. The parenchymal lung tissue can be likened to a thin
2 sheet of pneumocytes (0.5 to 1.0 /xm thickness) that envelopes the pulmonary capillary bed
3 and is supported by a lattice of connective tissue fibers: these fibers enclose the alveolar
4 ducts (entrance rings), support the alveolar septa, and anchor the parenchymal structures
5 axially (e.g. from pulmonary veins) and peripherally (from the pleural surface).
6 The alveolar walls or septa are constructed of a network of meandering capillaries
7 consisting mainly of endothelial cells, an epithelium made of membranous Type I
8 pneumocytes (97% of the surface) with a few Type II pneumocytes (3% of the surface), and
9 an interstitium which contains interstitial histiocytes and fibroblasts. For about one-half of
10 the alveolar surface, the Type I pneumocytes and the capillary endothelia share a fused
11 basement membrane. Otherwise, there is an interstitial space within the septa which
12 communicates along the capillaries to the connective tissue cuffs around the airways and
13 blood vessels. The connective tissue spaces or basal lamina of these structures are served by
14 pulmonary lymphatic vessels whose lymph drainage, mainly perivascular and peribronchial,
15 is toward the hilar region where it is processed en route by islets of lymphoid tissue and
16 filtered principally by the TB lymph nodes before being returned to the circulation via the
17 subclavian veins. From the subpleural connective tissue, lymphatic vessels also arise whose
18 drainage is along the lobar surfaces to the hilar region (Morrow, 1972).
19 The epithelial surface of the A region is covered with a complex lipo-proteinaceous
20 liquid called pulmonary surfactant. This is a misnomer as this complex liquid contains a
21 number of surface-active materials, primarily phospholipids, with a predominance of
22 dipalmitoyl lecithin. This surfactant materials exists on the respiratory epithelium non-
23 uniformly as a thin film (<0.01 /im thick) on a hypophase approximately 10 tunes thicker.
24 This lining layer stabilizes alveoli of differing dimensions from collapsing spontaneously and
25 helps to prevent the normal capillary effusate from diffusing from the interstitium into the
26 alveolar spaces. The role of the lining layer as an environmental interface is barely
27 understood, especially in terms of how the layer may modify the physicochemical state of
28 deposited particles and vice versa.
29 The epithelial surface of the A region, which can exceed 100 m2 in humans, maintains
30 a population of mobile phagocytic cells, the alveolar macrophage (AM), that have many
31 important functions, e.g. removing cellular debris, eliminating bacteria and elaborating many
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1 cytologic factors. The AM is also considered to play a major role in non-viable particle
2 clearance. The resident AM population varies, inter alia, according to conditions of particle
3 intake, as do their state of activation. An estimate of the normal AM population in the lungs
4 of non-smokers is about 7xl09 (Crapo et al. 1982) while in the Fischer 344 rat, estimates
5 are about 2.2X107 AM (Lehnert et al. 1985). According to prevailing views, the importance
6 of AM-mediated particle clearance via the bronchial airways in the rat and human lungs may
7 be different (refer to Section 10.4.2.).
8 The respiratory tract is a dynamic structure. During respiration, the caliber and length
9 of the airways changes as do the angles of branching at each bifurcation. The structural
10 changes that occur during inspiration and expiration differ. Since respiration, itself, is a
11 constantly changing volumetric flow, the combined effect produces a complex pattern of
12 airflows during the respiratory cycle within the conducting airways and volumetric variations
13 within the A region. Even if the conducting airways were rigid structures and a constant
14 airflow was passed through the diverging bronchial tree, the behavior of air flow within these
15 structures would differ from that produced by the identical constant flow passed in the
16 reverse or converging direction. Consequently, important distinctions exist between
17 inspiratory and expiratory airflows through the airways, especially those associated with the
18 glottic aperture and nasal turbinates. Distinctions occurring in particle deposition during
19 inspiration and expiration are not as marked as those in airflow. This is because the particles
20 with the greatest tendency to deposit, will deposit during inspiration and will mostly be
21 absent from the expired air.
22 At rest, the amount of air that is inspired, the tidal volume (TV), is normally about
23 500 mL. If a maximum inspiration is attempted, about 3300 mL of air can be added; this
24 constitutes the Inspiratory Reserve Volume. During breathing at rest, the average expired
25 TV is essentially unchanged from the average inspired TV. At the end of a normal
26 expiration, there still remains in the lungs about 2200 ml, the FRC. When a maximum
27 expiration is made at the end of a normal tidal volume, approximately 1000 mL of additional
28 air will move out of the lung: this constitutes the Expiratory Reserve Volume. Remaining
29 in the lungs after a maximal expiration is the Residual Volume (RV) of approximately 1200
30 mL. These volumes and capacities are illustrated in Figure 10-6. From the perspective of
31 air volumes within the respiratory tract, estimates are based on both anatomic and
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TLC
VC
RV
1C
Maximal Inspiratory
Level
Resting Expiratory Level
Maximal Expiratory Level
Figure 10-6. Lung volumes and capacities. Diagrammatic representation of various
lung compartments, based on a typical spirogram. TLC, total lung
capacity; VC, vital capacity; RV, residual volume; FRC, functional
residual capacity; 1C, inspiratory capacity; VT, tidal volume; IRV,
inspiratory reserve volume; ERV, expiratory reserve volume. Shaded
areas indicate relationships between the subdivisions and relative sizes as
compared to the TLC. The resting expiratory level should be noted, since
the remains more stable than other identifiable points during repeated
spirograms, hence is used as a starting point for FRC determinations, etc.
Source: Ruppel (1979).
1
2
3
4
5
6
physiologic measurements. The ET airways have a volume in the average adult of about 80
mL, whereas the composite volume of the transitional airways is about 440 mL. At rest, the
total gas-exchange volume in the lungs is usually around 2200 ml and is called the Functional
Residual Capacity (FRC). This gas exchange volume is in contact with between 60 and 100
m2 of alveolar epithelium depending on the state of lung inflation, viz, Alvsa = 22 (VL)2/3
where the surface area (Alvsa) is in m2 and the lung volume (VjJ) in liters. The alveolar
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1 volume is juxtaposed with a variably estimated (70 to 230 mL) pulmonary capillary blood
2 volume which contacts an endothelial surface area of comparable size to the alveolar.
3 The average respiratory frequency of an adult human at rest is about 12 to 15 cycles
4 per min. This indicates a cycle length of 5 s: about 2 s for inspiration and 3 s for
5 expiration. With a 500 mL TV, this results in a Minute Ventilation (MV) of about 6 to 7.5
6 L/min: about 60 to 70% of the MV is considered alveolar ventilation due to the dead space
7 volume constituting about 30 to 40% of the TV. With the foregoing assumptions, the mean
8 inspiratory and expiratory air flows will be about 250 mL/s and 166 mL/s, respectively.
9 During moderate to heavy exercise, the MV will often quadruple and this can be assumed to
10 be accomplished by a doubling of both TV and RF, although there is considerable individual
11 variability. One impact of such an assumed change in MV is that the duration of the
12 respiratory phases become shorter and more similar, consequently, the mean inspired and
13 expired air flows will both likely increase to about 800 mL/s. With nose breathing, an
14 inspiratory airflow of 800 ml/sec would be expected to produce linear velocities in the
15 anterior nares greater than 10 m/sec.
16 Because of the irregular anatomic architecture of the nasal passages, the incoming air
17 induces many eddies and turbulence in the ET airways. This is also true in the upper
18 portions of the TB region largely due to the turbulence created by the glottic aperture. As
19 the collective volume and cross sectional area of the bronchial airways increases, the mean
20 airflow rates fall, but "parabolic airflow", a characteristic of laminar airflow does not
21 develop because of the renewed development of secondary flows due to the repetitive airway
22 branching. Conditions of true laminar flow probably do not occur until the inspired air
23 reaches the transitional airways. Whether air flow in a straight circular tube is laminar or
24 turbulent is determined by a dimensionless parameter known as the Reynolds number (Re)
25 which is defined by the ratio paDaU/^t where pa is the air density, Da is the tube diameter, U
26 the air velocity, and \i is the viscosity of air. As a general rule, when Re is below 2000, the
27 flow is expected to be laminar (Owen, 1969). See Table 10-3.
28 Pattle (1961) was the first investigator to demonstrate that the nasal deposition of
29 particles was proportional to the product of the aerodynamic diameter dae squared and the
30 mean inspiratory flow rate (dae2Q); where the aerodynamic diameter is the diameter of a unit
31 density sphere having the same terminal settling velocity (see Section 10.2) as the particle of
April 1995 10-24 DRAFT-DO NOT QUOTE OR CITE
-------
I
TABLE 10-3. ARCHITECTURE OF THE HUMAN LUNG ACCORDING TO
MODEL A, WITH REGULARIZED DICHOTOMY
WEIBEL'S
(1963)
*O At flow of 1 L/sec
Ui
>-»
s
o
>
3
i
O
o
as
o
H
O
cj
O
H
W
0
o
H
W
Region
Trachea0
Main bronchus
Lobar bronchus
Segmental bronchus
Bronchi with
cartilage
in wall
Terminal bronchus
Bronchioles with
muscle in wall
Terminal bronchiole
Resp. bronchiole
Resp. bronchiole
Resp. bronchiole
Alveolar duct
Alveolar duct
Alveolar duct
Alveolar sac
Alveoli, 21 per duct
"Area = total cross sectional area.
bcum. = cumulative.
Generation
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Number
1
2
4
8
16
32
64
128
256
512
1,020
2,050
4,100
8,190
16,400
32,800
65,500
131 x 103
262 x 103
524 x 103
1.05 X 106
2.10 X 106
4.19 x 106
8.39 x 106
300 X 106
Diameter
(mm)
18
12.2
8.3
5.6
4.5
3.5
2.8
2.3
1.86
1.54
1.30
1.09
0.95
0.82
0.74
0.66
0.60
0.54
0.50
0.47
0.45
0.43
0.41
0.41
0.28
Length
(mm)
120.0
47.6
19.0
7.6
12.7
10.7
9.0
7.6
6.4
5.4
4.6
3.9
3.3
2.7
2.3
2.0
1.65
1.41
1.17
0.99
0.83
0.70
0.59
0.50
0.23
Cum."
Length (mm)
120
167
186
194
206
217
226
234
240
246
250
254
257
260
262
264
266
267
269
270
271
271
272
273
273
Areaa
(cm)
2.6
2.3
2.2
2.0
2.6
3.1
4.0
5.1
7.0
9.6
13
19
29
44
70
113
180
300
534
944
1,600
3,200
5,900
12,000
Volume
(ml)
31
11
4
2
3
3
4
4
4
5
6
7
10
12
16
22
30
42
61
93
139
224
350
591
3,200
Cum.b
Volume (mL)
31
42
46
47
51
54
57
61
66
71
77
85
95
106
123
145
175
217
278
370
510
734
1,085
1,675
4,800
Speed
(cm/s)
393
427
462
507
392
325
254
188
144
105
73.6
52.3
34.4
23.1
14.1
8.92
5.40
3.33
1.94
1.10
0.60
0.32
0.18
0.09
Reynolds
Number
4,350
3,210
2,390
1,720
1,110
690
434
277
164
99
60
34
20
11
6.5
3.6
2.0
1.1
0.57
0.31
0.17
0.08
0.04
°Dead space, approx. 175 mL + 40 mL for mouth.
Source: Y.C. Fung (1990).
-------
1 concern. Albert et al. (1967) and Lippmann and Albert (1969) were among the earliest to
2 report experimentally that the same general relationship governed inertial deposition of
3 different uniformly-sized particles in the conducting airways of the TB region. Recent
4 papers by Martonen (1994a,b) have considered the influence of both the cartilaginous rings
5 and the carinal ridges of the upper TB airways on the dynamics of airflow. As in the case of
6 the glottic aperture, these structures appear to contribute to the non-uniformity of particulate
7 deposition sites within these airways. Concomitantly, Martonen et al. have pointed to the
8 limitations incurred by assuming smooth tubes in modeling the aerodynamics of the upper TB
9 airways.
10 Smaller particles, i.e. those with an aerodynamic size of between 0.1 and 0.5 ptm, are
11 the particles with the greatest airborne stability. They are too small to gravitate appreciably,
12 they are too large to diffuse, hence they tend to persist the inspired air as a gas would, but in
13 matters of alveolar mixing, they behave as "non-diffusible" gas. The study of these particles
14 have provided very useful information on the distribution of tidal air under different
15 physiologic conditions (Heyder et al., 1985). A recent analysis of airflow dynamics in
16 human airways, conducted by Chang and Menon (1993), concluded that the measurement of
17 flow dynamics aids in the understanding of particle transport and the development of
18 enhanced areas of particle deposition.
19 Sedimentation becomes insignificant relative to diffusion as the particles become
20 smaller. Deposition by diffusion results from the random (Brownian) motion of very small
21 particles caused by the collision of gas molecules in air. The terminal settling velocity of a
22 particle approaches 0.001 cm/s for a unit density sphere with a physical diameter of 0.5 pan,
23 so that gravitational forces become negligible at smaller diameters. The main deposition
24 mechanism is diffusion for a particle whose physical (geometric) size is <0.5 /im.
25 Impaction and sedimentation are the main deposition mechanisms for a particle whose size is
26 greater than 0.5 pm. Hence, dae = 0.5 jun is convenient for use as the boundary between
27 the diffusion and aerodynamic regimes. Although this convention may lead to confusion in
28 the case of very dense particles, most environmental aerosols have densities below 3 g/cm3
29 (U.S. Environmental Protection Agency, 1982). Diffusional deposition is important in the
30 small airways and in the A region where distances between the particles and airway
April 1995 10-26 DRAFT-DO NOT QUOTE OR CITE
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1 epithelium are small. Diffusion has also been shown to be an important deposition
2 mechanism in the ET region for small particles (Cheng et al., 1988, 1990).
3 With mouth-only breathing, the regional deposition pattern changes dramatically
4 compared to nasal breathing, with ET deposition being reduced and both TB and A
5 deposition enhanced. Oronasal breathing (partly via the mouth and partly nasally), however,
6 typically occurs in healthy adults while undergoing moderate to heavy exercise. Therefore,
7 the appropriate activity pattern of subjects for risk assessment estimation remains an
8 important issue. Miller et al. (1988) examined ET and thoracic deposition as a function of
9 particle size for ventilation rates ranging from normal respiration to heavy exercise. A
10 family of estimated deposition curves were generated as a function of breathing pattern.
11 Anatomical and functional differences between adults and children are likely to yield complex
12 interactions with the major mechanisms affecting respiratory tract deposition, again with
13 implications for risk assessment.
14 Humidification and warming of the inspired air begins in the nasal passages and
15 continues into the deep lung. This conditioning of the ambient air is not significant to
16 particle deposition unless the particulate material is intrinsically hygroscopic, in which case,
17 it is very important. For both droplet and particulate aerosols that are hygroscopic, there are
18 physical laws that control both particle growth and deposition and these have been modeled
19 extensively. In a recent review of this general subject (Morrow, 1986), many experimental
20 measurements of the humidity (RH) and temperature of the air within the respiratory tract
21 have been reported, but because of the technical problems involved, uncertainties remain.
22 Two major problems prevail: the accurate measurement of temperature requires a sensor
23 with a very rapid response time; hygrometric measurements of conditions of near saturation
24 (>99% RH) are the most difficult to make. The latter technicality is of special significance,
25 because the growth of hygroscopic aerosols are greatest near saturation. For example,
26 distinguishing the difference between 99.0% and 99.9% is more important than measuring
27 the difference between 20 and 80% RH. A more complete discussion of models and
28 experimental determinations of the deposition of hygroscopic aerosols are given in
29 Section 10.4.
30 The differences in respiratory tract anatomy summarized briefly in this section are the
31 structural basis for the species differences in particle deposition. In addition to the structure
April 1995 10-27 DRAFT-DO NOT QUOTE OR CITE
-------
1 of the respiratory tract, the regional thickness and composition of the airway epithelium (a
2 function of cell types and distributions) is an important factor in clearance (Section 10.4).
3 Characteristic values and ranges for many respiratory parameters have been published for
4 "Reference Man" by the International Commission on Radiological Protection (ICRP) (1975)
5 and they are also available from many reference sources (Altose, 1993; Collett et al., 1988;
6 Cotes, 1979). A typical description of respiratory tract morphology, cytology, histology,
7 structure, and function is given in Table 10-4. This description of the respiratory tract is
8 used in the human dosimetry model applied in Section 10.7 (ICRP66, 1994). For additional
9 information on human respiratory tract structure, the papers of Weibel (1963,1980), Hatch
10 and Gross (1964); Proctor (1977), Forrest (1993), and Gehr (1994) are recommended.
11
12
13 10.4 FACTORS CONTROLLING COMPARATIVE INHALED DOSE
14 As discussed in Section 10.1, comprehensive characterization of the exposure-dose-
15 response continuum is the fundamental objective of any dose-response assessment. Within
16 human and species differences in anatomical and physiological characteristics, the
17 physicochemical properties of the inhaled aerosol, the diversity of cell types that may be
18 affected, and a myriad of mechanistic and metabolic differences combine to make the
19 characterization particularly complex for the respiratory tract as the portal of entry. This
20 section attempts to discuss these factors within the exposure-dose-response context in order to
21 present unifying concepts. These concepts are used to construct a framework by which to
22 evaluate the different available dosimetry models; appreciate why they are constructed
23 differently, and determine which are the most appropriate for extrapolation of the available
24 toxicity data. The section discusses the major factors controlling the disposition of inhaled
25 particles. Note that disposition is defined as encompassing the processes of deposition,
26 absorption, distribution, metabolism, and elimination.
27 It must be emphasized that dissection of the factors that control inhaled dose into
28 discrete topic discussions is deceptive and masks the dynamic and interdependent nature of
29 the intact respiratory system. For example, although deposition in a particular respiratory
30 region will be discussed separately from the clearance mechanisms for that region, retention
April 1995 10-28 DRAFT-DO NOT QUOTE OR CITE
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TABLE 10-4. MORPHOLOGY, CYTOLOGY, HISTOLOGY, FUNCTION, AND STRUCTURE OF THE
RESPIRATORY TRACT AND REGIONS USED IN THE ICRP (1994) HUMAN DOSIMETRY MODEL.
o
£>
Functions
Air Conditioning:
Temperature and
HumicSty, a/xJ
Cleaning: Fast
'article Clearance:
Air Conduction
Air Conduction;
Gas Exchange:
Slow Particle
Clearance
Gas Exchange:
Very Slow Particle
Clearance
Cytology (Epithelium)
Respiratory Epithelium with Goblet Cete:
Cell Types: -Ciliated Cells
-Noncfliated Cells:
•Goblet Cells
• Mucous (Secretory) Cells
•Serous Cells
•Brush Cells
•Endocrine Cells
•Basal Cells
• Intermediate Cells
Respiratory Epithelium with Clara Cells
(No Goblet Cells)
CeB Types: -dialed Cells
- Nonc*ated Cells
• Clara (Secretory) Cete
Respiratory Epithelium Consisting Mainly
of Clara Gets (Secretory) and Few
Ciliated Cete
Squamous Alveolar Epithelial Cells
(Type 1). Covering 93% of Alveolar
Surface Areas
Cuboidal Alveolar Epithelial eels (Type II,
Surfactant-Producing). Covering 7% of
Alveolar Surface Area
Alveolar Macrophages
Histology (Walls)
Mucous Membrane, Respiratory
Epithelium (Pseudostratified. Ciliated,
Mucous), Glands
Mucous Membrane, Respiratory or
Stratified Epithelium. Glands
Mucous Membrane, Respiratory
Epithelium. Cartilage Rings. Glands
Mucous Membrane, Respiratory
Epithelium. Cartilage plates. Smooth
Muscle Layer, Glands
Mucous Membrane, Respiratory
Epithelium, No Cartilage, No Glands,
Smooth Muscle Layer
Mucous Membrane. Single-Layer
Respiratory Epithelium. Less Ciliated.
Smooth Muscle Layer
Mucous Membrane. Single-Layer
Respiratory EpHhelum of Cuboidal
CeBs, Smooth Muscle Layers
Wan Consists ol Alveolar Entrance
Rings. Squamous Epithelial Layer.
Surfactant
Interalveolar Septa Covered by
Squamous Epithelium, Containing
Capillaries, Surfactant
Generation
Number
0
1
2-8
9-14
15
16-18
(c)
(c)
Anterior Nasal Passages
Vl Mouth *C Posterior
S ^V 1 Esophagus
Trachea Id
MainBroncN,^'^
*^X1 J
Bronchi *^ R
'p
i
Bronchioles I1!
Terminal^X '/
BroochiolosX \
Respiratocy J(
-fttez
£cf" ^/^^j
Lymphatics
Regions used in Model
New
ET,
^2
BB
Ob
Al
LNn
^
Old*'
(N-P)
fT-B)
p
L
Zones
(Air)
'
|
I
1
"7
rt
'o
M
s
5
"E
M
0
5
Location
1
'
I
1
Airway
Surface"
2x10-3m2
4.5 x 10'2 m2
2.9x10'2m8
(a)
(a)
7.5m2
140m2
Number of
Airways
511 (a)
6.5 x 10* (a)
4.6x10* (a)
4.5x107(b)
"Dimensions from three sources (James, 1988; adapted from Weibul, 1963; Yeh and Schum, 1980; and Phalen et al., 1985) were averaged after all were adjusted to a
funtional residual capacity (FRC) of 3.3 x 10'3m3 (Yu and Diu, 1982; James, 1988).
bCalculated from Hansen and Ampaya (1975) and scaled to a funtional residual capacity (FRC) of 3.3 x 10~3m3.
cUnnumbered because of imprecise information.
dPrevious ICRP Model.
eAs described in the text, lymph nodes are located only in BB region but drain the broncholar and alveolar-interstitial regions as well as the bronchial region.
-------
1 (the actual amount of inhaled agent found in the respiratory tract at any time) is determined
2 by the relative rates of deposition and clearance. Retention and the toxicologic properties of
3 the inhaled agent are related to the magnitude of the pharmacologic, physiologic, or
4 pathologic response. Therefore, although the deposition mechanisms, clearance mechanisms,
5 and physicochemical characteristics of particles are described in distinct sections, assessment
6 of the overall dosimetry and toxic response requires integration of the various factors.
7 Inasmuch as particles occur in the environmental air which are too massive to be
8 inhaled, the description "inhalability" has been used to denote the overall spectrum of particle
9 sizes which are potentially capable of entering the respiratory tract of humans and depositing
10 therein. Except under conditions of microgravity (spaceflight) and possibly some other rare
11 circumstances, unit density particles > 100 pun diameter have a negligible probability of
12 entering the mouth or nose. Nevertheless, there is no sharp cutoff to zero probability
13 because the settling velocity of > 100 pun particles can become comparable to air velocities
14 into the nose or mouth during heavy breathing and be inhaled, provided such particles are in
15 close proximity to the subject's breathing zone. Since particles of this size settle at terminal
16 velocities >25 cm/s, the presence of such particles in the breathing zone air would require
17 the subject to be close to the point of the aerosol generation. Inhalability can be defined as
18 the ratio of the number concentration of particles of a certain aerodynamic diameter, d.^, that
19 are inspired through the nose or mouth to the number concentration of the same dae present
20 in the inspired volume of ambient air (ICRP66, 1994). The concept of aerodynamic
21 diameter is discussed in Section 10.2. In studies with head and torso models, inhalability has
22 been considered generally under conditions of different wind velocities and horizontal head
23 orientations.
24 Description of a "respirable dust fraction" was first suggested by the British Medical
25 Research Council and implemented by C.N. Davies (1952) using the experimentally-
26 estimated pulmonary deposition curve of Brown et al. (1950). This curve described the
27 respirable dust fraction as that which would be available to deposit in the alveolated lung
28 structures including the respiratory bronchioles, thereby making "respirable dusts" applicable
29 to pneumoconiosis-producing dusts. The horizontal elutriator was chosen as a particle size
30 selector, and respirable dust was defined as that dust passing an ideal horizontal elutriator.
31 The elutriator cutoff was chosen to result in the best agreement with experimental lung
April 1995 10-30 DRAFT-DO NOT QUOTE OR CITE
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1 deposition data. The Johannesburg International Conference on Pneumoconiosis in 1959
2 adopted the same standard (Orenstein, 1960). Later, an Atomic Energy Commission
3 working group defined "respirable dust" by a deposition curve which indicated 0% deposition
4 at 10 ptm dae; and 100% deposition for particles <2.0 /urn dae. "Respirable dust" was
5 defined as that portion of the inhaled dust which penetrates to the nonciliated portions of the
6 lung (Hatch and Gross, 1964). The AEC respirable size deposition curve was pragmatically
7 adjusted to 100% deposition for <2 pm dae particles so that the "respirable" curve could be
8 approximated by a two-stage selective sampler and because comparatively little dust mass
9 was represented by these small particles (Mercer 1973a). This definition was not intended to
10 be applicable to dusts that are readily soluble in body fluids or are primarily chemical
11 intoxicants, but rather only for "insoluble" particles that exhibit prolonged retention in the
12 lung.
13 Other groups, such as the American Conference of Governmental Industrial Hygienists
14 (ACGIH), incorporated respirable dust sampling concepts in setting acceptable exposure
15 levels for other toxic dusts. Such applications are more complicated, since laboratory animal
16 and human exposure data, rather than predictive calculations, from the data base for
17 standards. The size-selector characteristic specified in the ACGIH standard for respirable
18 dust (Threshold Limits Committee, 1968) was almost identical to that of the AEC, differing
19 only at 2 /urn Dae, where it allowed for 90% passing the first-stage collector instead of 100
20 percent. The difference between them appeared to be a recognition of the properties of real
21 particle separators, so that, for practical purposes, the two standards could be considered
22 equivalent (Lippmann, 1978).
23 The cutoff characteristics of the precollectors preceding respirable dust samplers are
24 defined by these criteria. The two sampler acceptance curves have similar, but not identical,
25 characteristics, due mainly to the use of different types of collectors. The BMRC curve was
26 chosen to give the best fit between the calculated characteristics of an ideal horizontal
27 elutriator and available lung deposition data; on the other hand, the design for the AEC curve
28 was based primarily on the upper respiratory tract deposition data of Brown et al. (1950).
29 The separation characteristics of cyclone type collectors simulate the AEC curve. Whenever
30 the particle size distribution has a ag > 2, samples collected with instruments meeting either
31 criterion will be comparable (Lippmann, 1978). Various comparisons of samples collected
April 1995 10-31 DRAFT-DO NOT QUOTE OR CITE
-------
1 on the basis of the two criteria are available (Knight and Lichti, 1970; Breuer, 1971;
2 Maquire and Barker, 1969; Lynch, 1970; Coenen, 1971; Moss and Ettinger, 1970).
3 The various definitions of repsirable dust were somewhat arbitrary, with the BMRC and
4 AEC definitions being based on the "insoluble" particles that reach the A region. Since part
5 of the aerosol that penetrates to the alveoli remains suspended in the exhaled air, respirable
6 dust samples are not intended to be a measure of A deposition but only a measure of aerosol
7 concentration for those particles that are the primary candidates for A deposition. Given that
8 the "respirable" dust standards were intended for "insoluble dusts", most of the samplers
9 developed to satisfy their criteria have been relatively simple two-stage instruments. In
10 addition to an overall size-mass distribution curve, multistage aerosol sampler data can
11 provide estimates of the "respirable" fraction and deposition in other functional regions.
12 Field application of these samplers has been limited because of the increased number and
13 cost of sample analyses and the lack of suitable instrumentation. Many of the various
14 samplers, along with their limitations and deficiencies, were reviewed by Lippman (1978).
15 PMjo dust is based on the PM10 sampler efficiency curve promulgated by the U.S.
16 Environmental Protection Agency. This sample is equivalent to the thoracic dust sample
17 defined by the American Conference of Governmental Industrial Hygienists (Raabe, 1984).
18 The American Conference of Governmental Industrial Hygienists (1985) has expressed
19 inhalability in terms of an intake efficiency of a hypothetical sampler. This expression was
20 replaced in 1989 by international definitions for inspirable (also called inhalable) thoracic and
21 respirable fractions of airborne particle (Solderholm, 1989). Each definition is expressed as
22 a sampling efficiency (S) which is a function of particle aerodynamic diameter (dae) and
23 specifies the fraction of the ambient concentration of airborne particles collected by an ideal
24 sampler. For the inspirable fraction,
SI(dae) - 0.5(1 + e-
25
26 For the thoracic fraction,
ST(dae) =SI(dae)[l -F(x)], (10-5)
27
April 1995 10-32 DRAFT-DO NOT QUOTE OR CITE
-------
where
x = ln(dae/r), T = 11.64 ^ I - 1.5. dO-6)
2
3 F(x) is the cumulative probability function of a standardized normal random variable. For
4 the respirable fraction,
SR(dae) = SI(dae)[l - F(x)], (10-7)
5
6 where
7
T = 4.25 jan, £ =1.5. (1Q-8)
8
9 Swift (1976) estimated the deposition of particles by impaction in the nose, based on a
10 nasal entrance velocity of 2.3 m/s and a nasal entrance width of 0.5 cm, and deduced that
11 particles >61 /xm dae have a negligible probability of entering the nasal passages due to the
12 high impaction efficiency of the external nares. Experiments by Breysse and Swift (1990) in
13 tranquil air estimated a practical upper limit for inhalability to be ~ 40 pirn dae for
14 individuals breathing at 15 breaths per min at rest. No information on tidal volumes was
15 provided. Studies reported by Vincent (1990) of inhalability made use of a mannequin with
16 mouth and nasal orifices that could be placed in a wind tunnel and rotated 360 degrees
17 horizontally. At low wind speeds, the intake efficiency approached 0.5 for particle sizes
18 between 20 jwm and 100 yum dae. The empirical relationship derived from these studies of
19 Vincent led to its adoption by the ICRP for its new lung model (ICRP66, 1994), viz
20
21 rj! (sampler) = 0.5 [1 + exp(-0.06 dae) = 1 X 10'5 U2-75 exp (0.055 dae), (10-9)
22
23 where nt is the intake efficiency of the sampler, dae is the aerodynamic diameter, and U is
24 the wind speed. The filtration efficiency of the respiratory tract is the complement of the
25 term "inhalability" or intake efficiency, i.e., 17 j. Particle inhalability is assumed to depend
26 on dae and generally to decrease with increasing dae. However, for large particles, the
April 1995 10-33 DRAFT-DO NOT QUOTE OR CITE
-------
1 mhalability is assumed to increase with windspeed. For particles with d.,e < 10 pun, the
2 expression was modified to increase accuracy
3
4 rj! = 1 - 0.5 ((1 - [7.6 x 10 -* (dae) 2-8 + I]4)) + 1 x lO'5 U2-75 (0.055 dae),(10-10)
5
6 where dae is hi pm and U is the windspeed in (m s-1) (for D < U < 10 ms"7).
7
8 While there is some contention about the practical upper size limit of inhalable particles
9 in humans, there is no lower limit to inhalability as long as the particle exceeds a critical
10 (Kelvin) size where the aggregation of atomic or molecular units is stable enough to endow it
11 with "paniculate" properties, in distinction to those of free ions or gas molecules. Inter alia,
12 particles are considered to experience inelastic collisions with surfaces and with each other.
13 The lower limit for the existence of aerosol particles is assumed to be around 1 nanometers
14 for some materials (refer to Section 10.2.). If the paniculate material has an appreciable
15 vapor pressure, particles of a certain size may "evaporate" as fast as they are formed. For
16 example, pure water droplets as large as 1 pm diameter will evaporate in less than 1 second
17 even when they are in water-saturated air at 20° Celsius (Greene and Lane, 1957).
18
19 10.4.1 Deposition Mechanisms
20 This section will review briefly the aerosol physics that both explains how and why
21 particle deposition occurs and provides the theoretician a capability to develop predictive
22 deposition models. Some of these models will be described in Section 10.5, together with
23 recent experimental results on particle deposition. The ability of the experimentalist to
24 measure deposition quantitatively has continued to advance, but theoretical models remain the
25 only practical way for predicting the impact of aerosol exposures and for delineating the
26 patterns of intra-regional deposition.
27 The motion of an airborne particle between 1 and 100 jum dae is primarily related to its
28 mass, and the resulting resistive force of air is proportional to
29
30 fj.vd, (10-11)
31
April 1995 10-34 DRAFT-DO NOT QUOTE OR CITE
-------
1 where pt is the viscosity of air, v is the velocity of the particle relative to the air, and d is the
2 particle diameter. This is a statement of Stokes law for viscous resistance which is
3 appropriate to sphere moving in air at low particle Reynolds numbers, i.e., less than 1. The
4 particle Reynolds number (Rep) is defined as
5
6 Padv/M, (10-12)
7
8 where pa is the density of air. When the particle velocity relative to air is sufficiently slow
9 that the airflow pattern around the sphere is symmetrical and only viscous stresses resist the
10 sphere's motion, Stokes law applies. As the value of Rep increases, asymmetrical flow about
11 the moving sphere and a pressure drop across the sphere, both progressively develop. These
12 changes in flow signify the condition of inertial resistance prevails and Stokes law does not
13 pertain (Mercer, 1973b).
14 For the range of particle sizes just discussed (1 to 100 jon), the motion of airborne
15 particles is characterized by a rapid attainment of a constant velocity whereby the viscous
16 resistance of air matches the force(s) on the sphere responsible for its motion. This constant
17 velocity is termed the terminal velocity of the particle. For the size region below 1 ^im
18 diameter, particle motion is also based on the viscous resistance of air and described by its
19 terminal velocity. In this region of particle size, the viscous resistance of air on the particle,
20 using Stokes law, begins to be overestimated and the particle's terminal velocity,
21 underestimated. This general phenomenon is termed "slip"; consequently, Slip Correction
22 Factors have been developed. These slip corrections become more important as the particle
23 diameter nears, or is less than, the mean free path of air molecules (« 0.068 ^m at 25 °C
24 and 760 mm Hg air pressure).
25
26 10.4.1.1 Gravitational Settling or Sedimentation
27 All aerosol particles are continuously influenced by gravity, but for practical purposes,
28 particles with an dae > 0.5 pm are mainly involved. Within the respiratory tract, an dae of
29 100 /xm will be considered as an upper cut-off. A spherical, compact particle within these
30 arbitrary limits will acquire a terminal settling velocity when a balance is achieved between
April 1995 10-35 DRAFT-DO NOT QUOTE OR CITE
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1 the acceleration of gravity, g, acting on the particle of density, p, (g/cm3) and the viscous
2 resistance of the air according to Stokes law
3
(7r/6)pd3g = Sir/xdv,. (10-13)
4
5 The left hand side of Equation 10-13 is the force of gravity on the particle, neglecting the
6 effect of the density of air. Solving for the terminal velocity, vt, gives
7
vt =
(10-14)
8
9 In Equation 10-14 a slip correction factor, K,. is added to account for the slip effect on
10 particles with diameters about or below 1 /mi. For particles as small as 0.02 /mi, the K,,
11 used by Knudsen and Weber increases vt six fold (cited by Mercer, 1973c).
12 The relationship for the terminal settling velocity, just described, is not restricted to
13 measurements in tranquil air. For example, moving air in a horizontal airway will tend to
14 carry the particle at right angles to gravity at an average velocity, U. The action of gravity
15 on the particle will nonetheless result in a terminal settling velocity, vt; consequently the
16 particle will follow, vectorially, the two velocities and provided the airway is sufficiently
17 long or the settling velocity is relatively high, the particle will sediment in the airway. For
18 every orientation of the airways with respect to gravity, it is possible to calculate the
19 particle's settling behavior using Stokes law.
20
21 10.4.1.2 Inertial impaction
22 Sudden changes in airstream direction and velocity, cause particles to fail to follow the
23 streamlines of airflow as depicted in Figure 10-5. As a consequence, the relatively massive
24 particles impact on the walls or branch points of the conducting airways. The ET and upper
25 TB airways have been described as the dominant sites of high air velocities and sharp
26 directional changes, hence, they dominate as sites of inertial impaction. Because the air (and
27 particle) velocities are affected by the breathing pattern, it is easy to imagine that even small
April 1995 10-36 DRAFT-DO NOT QUOTE OR CITE
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1 particles also experience some inertial impaction. Moreover, as nasal breathing shifts to oral
2 breathing during work or exercise, the particle that would normally be expected to impact in
3 the ET region will pass into the TB region greatly increasing TB deposition. That all
4 impaction sites become lower down in the TB region when such a shift occurs, is also
5 expected.
6 The probability that a particle with a diameter, d, moving in an air stream with an
7 average velocity, U, will impact at a bifurcation is related to a parameter called the Stokes
8 number, Stk; defined as:
pd2 U/9M Da , dO-15)
9
10 or
U/9MDt. (1°-16)
11
12 As far as particulate properties are concerned, the aerodynamic diameter (dae) is again
13 the significant parameter (see Section 10.2). In Landahl's lung deposition model (1950a) of
14 impaction in the TB region, impaction efficiency was proportional to
15
pd2Uj sin 0j / Dai SM, (10-17)
16
17 where Uj is the air velocity in the airway generation i, fy is the branching angle between
18 generations i and i-1, Dai is diameter of the airway of generation i, and SiA is the total cross
19 sectional area of airway generation i-1.
20 Prevailing TB models have simplistically targeted the airways as smooth, bifurcating
21 tubes. Martonen et al. (1993,1994) have predicted that the cartilaginous rings and carinal
22 ridges perturb the dynamics of airflow and help to explain the non-uniformity of particle
23 deposition.
24 It should be evident that both gravitational settling and inertial impaction cause the
25 deposition of many particles within the same size range. These deposition forces are always
April 1995 10-37 DRAFT-DO NOT QUOTE OR CITE
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1 acting together in the ET and TB regions, with inertial impaction dominating in the upper
2 airways and gravitational settling becoming increasingly dominant in the lower conducting
3 airways, and especially for the largest of the particles which can penetrate into the
4 transitional airways and alveolar spaces.
5 For sedimenting particles with diameters between 0.1 ptm to 1.0 pirn, their Slip
6 Correction Factor will be greater than 1.0, although the magnitude of their respective vt will
7 only range from about 1 /xm/s to 35 jum/s. Concurrently, 0.1 /im diameter particles are
8 affected by diffusion such that the root mean displacement they experience in one second is
9 about 0.3 p.m. The size region, 1.0 /zm down to about 0.1 /xm, is frequently described as
10 consisting of particles which are too small to settle and too large to diffuse. Indeed, it is this
11 circumstance that makes them the most persistent and stable particles in aerosols and those
12 which undergo the least deposition in the respiratory tract. As any aerosol ages and
13 continuously undergoes deposition without particle replenishment, the ultimate aerosol will
14 exist largely within this same size range, i.e., have a median size of about 0.5 /xm diameter.
15
16 10.4.1.3 Brownian diffusion
17 Particles < 1 /xm diameter are increasingly subjected to diffusive deposition as their size
18 decreases. Even particles in the nanometer diameter range are large compared to individual
19 air molecules, hence, the collisions resulting between air molecules, undergoing random
20 thermal motion, and the surface of a particle produce numerous very small changes in the
21 particle's spatial position. These frequent, minute excursions are each made at a constant or
22 terminal velocity due to the viscous resistance of air. The root mean square (r.m.s.)
23 displacement that the particle experiences in a unit of time along a given cartesian
24 coordinate, x, y or z is a measure of its diffusivity. For instance, a 0.1 /*m diameter particle
25 has a r.m.s. displacement of about 37 pm during one s. This 1 /^m displacement in one s
26 does not describe a velocity of particle motion because the displacement resulted from
27 numerous relatively high velocity excursions.
28 The diffusion of particles by Brownian motion is described by the Einstein-Stokes'
29 equation
30
April 1995 10-38 DRAFT-DO NOT QUOTE OR CITE
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1 where Ax is the root-mean-square displacement in one second along coordinate x, D is the
2 diffusion coefficient for the particle expressed in cm2/s, t is time in seconds. The diffusion
3 coefficient of a particle of diameter, d, is
4
D = KTKs/37r/id, (10-20)
5
6 where K is the Boltzmann constant, and T the absolute temperature, collectively describing
7 the average kinetic energy of the gas molecules.
8 It is apparent that the density of the particle is ordinarily unimportant in determining
9 particle diffusivity which increases as K^ increases and d decreases. Instead of having an
10 aerodynamic equivalent size, diffusive particles of different shapes can be related to the
11 diffusivity of a thermodynamic equivalent size based on spherical particles (Heyder and
12 Scheuch, 1983). In terms of the architecture of the respiratory tract, diffusive deposition of
13 particles, is favored by proximate surfaces and by relatively long residence times for
14 particles, both conditions occurring in the alveolated structures of the lungs, the PU region.
15 Experimental studies with diffusive particles (<0.5 /mi) in replicate casts of the human nose
16 and theoretical predictions, both indicate a rising deposition efficiency for the nasal airways
17 as d becomes very small (Cheng et al., 1988).
18
19 10.4.1.4 Interception
20 The interception potential of any particle depends on its physical size. As a practical
21 matter, particles that approach airway sizes > 150 /mi in more than one dimension, will be
22 too massive to be inhaled. Airborne fibers, on the otherhand, frequently exceed 150 /mi in
23 length and appear to be relatively stable in air. This is because their aerodynamic size is
24 determined predominantly by their diameter, not their length. Fibers, therefore, are the chief
25 concern in the interception process, especially as their length approaches the diameters of
26 peripheral airways (> 150 /mi).
27 The theoretical model of Asgharian and Yu (1988, 1989) for the deposition of fibrous
28 particles in the respiratory tract is complex. While the model includes interception as an
29 important process for long fibers, it also depends on a combination of inertial, gravitational
April 1995 10-39 DRAFT-DO NOT QUOTE OR CITE
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
and diffusional forces to explain fiber deposition. The deposition efficiencies of the three
deposition mechanisms cited have been developed for spherical particles, but these can be
extended to fibrous particles by considering orientation effects which are strongly related to
the direction of airflow. The orientation of fibers depends upon the velocity shear of the
airflow and Brownian motion.
For their analysis of orientational effects throughout the respiratory tract, Asgharian
and Yu (1988, 1989) defined the equivalent mass diameter, d^, of fibers as
dam = df 0
1/3
(10-21)
where df is the fiber diameter and /3 is its aspect ratio (length/diameter). For example, a
fiber 100 yum long and 3 /urn diameter has a dem of 10 /xm diameter. In Figure 10-7, two
sets of TB deposition predictions for the rat are reproduced from Asgharian and Yu (1989)
that clearly show an example of the relative importance of particle interception.
0.5i
w
so
o# *v
so 100^ ^
Figure 10-7. Estimated TB deposition in the rat lung, via the trachea, with no
interceptional deposition, Graph A, is shown in relation to total TB
deposition, via the trachea, Graph B, for the same fibrous aerosol under
identical respiratory conditions.
Source: Asgharian and Yu (1989).
April 1995
10-40
DRAFT-DO NOT QUOTE OR CITE
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1 Several general reviews of particle deposition mechanisms in the human respiratory
2 tract have been published, e.g, Stuart (1973), Lippmann (1977), and Brain and Blanchard
3 (1993), and are recommended to the reader, as is the excellent review of particle deposition
4 mechanisms prepared by Phalen (1984).
5
6 10.4.1.5 Electrostatic Precipitation
7 The minimum charge an aerosol particle can have is zero, which is when it is
8 electrically neutral. This condition is rarely achieved because of the random charging of
9 aerosol particles by the omnipresent air ions. Every cubic centimeter of air contains about
10 103 ions in approximately equal numbers of positive and negative ions. Aerosol particles that
11 are initially neutral will acquire charges from these ions by collisions with them due to their
12 random thermal motion. Aerosols that are initially charged will lose their charge slowly as
13 the charged particles attract oppositely charged ions. An equilibrium state of these
14 competing processes is eventually achieved. The Boltzmann equilibrium represents the
15 charge distribution of an aerosol in charge equilibrium with bipolar ions. The minimum
16 amount of charge is very small, with a statistical probability that some particles will have no
17 charge and others will have one or more charges.
18 The electrical charge on some particles may result in an enhanced deposition over what
19 would be expected from size alone. This is due to image charges induced on the surface of
20 the airway by these particles or to space-charge effects whereby repulsion of particles
21 containing like charges results in increased migration toward the airway wall. The effect of
22 charge is inversely proportional to particle size and airflow rate. This deposition is probably
23 small compared to the effects of turbulence and other deposition mechanisms and is generally
24 a minor contributor to overall particle deposition, but it may be important in some laboratory
25 studies. This deposition is also negligible for particles below 0.01 /zm because so few of
26 these particles carry any charge at Boltzmann equilibrium.
27
28 10.4.1.6 Comparative Aspects of Deposition
29 The various species used in inhalation toxicology studies that serve as the basis for
30 dose-response assessment do not receive identical doses in a comparable respiratory tract
31 region (ET, TB, or A) when exposed to the same aerosol or gas (Brain and Mensah, 1983).
April 1995 10-41 DRAFT-DO NOT QUOTE OR CITE
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1 Such interspecies differences are important because the adverse toxic effect is likely more
2 related to the quantitative pattern of deposition within the respiratory tract than to the
3 exposure concentration; this pattern determines not only the initial respiratory tract tissue
4 dose but also the specific pathways by which the inhaled material is cleared and redistributed
5 (Schlesinger, 1985). Differences in ventilation rates and in the URT structure and size and
6 branching pattern of the lower respiratory tract between species result in significantly
7 different patterns of airflow and particle deposition. Disposition varies across species and
8 with the respiratory tract region. For example, interspecies variations in cell morphology,
9 numbers, types, distributions, and functional capabilities contribute to variations in clearance
10 of initially deposited dose. Tables 10-5, 10-6, and 10-7 summarize some of these differences
11 for the ET, TB, and A regions, respectively. This section only briefly summarizes these
12 considerations. Comprehensive and detailed reviews of species differences are recommended
13 (Phalen and Oldham, 1983; Patra, 1986; Crapo, 1987; Gross and Morgan, 1991; Mercer and
14 Crapo, 1991; Parent, 1991).
15 The geometry of the upper respiratory tract exhibits major interspecies differences
16 (Gross and Morgan, 1992). In general, laboratory animals have much more convoluted nasal
17 turbinate systems than do humans, and the length of the nasopharynx in relation to the entire
18 length of the nasal passage also differs between species. This greater complexity of the nasal
19 passages, coupled with the obligate nasal breathing of rodents, is generally thought to result
20 in greater deposition in the upper respiratory tract (or ET region) of rodents than in humans
21 breathing orally or even nasally (Dahl et al., 1991), although limited data are available.
22 Species differences in gross anatomy, nasal airway epithelia (e.g., cell types and location)
23 and the distribution and composition of mucous secretory products have been noted
24 (Harkema, 1991; Guilmette, 1989). The extent of upper respiratory tract removal affects the
25 amount of particles or gas available to the distal respiratory tract.
26 Airway size (length and diameter) and branching pattern affect the aerodynamics of the
27 respiratory system in the following ways:
28
29 • The airway diameter affects the aerodynamics of the air flow and the distance from
30 the particle to the airway surface.
31
32 • The cross-sectional area of the airway determines the airflow velocity for a given
33 volumetric flow.
34
April 1995 10-42 DRAFT-DO NOT QUOTE OR CITE
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I
1—*
I—1
o
u>
O
£
3
O
O
1
a
o
H
m
0
o
I— H
3
TABLE
Body weight
Naris cross-section
Bend in naris
Length
Greatest vertical diameter
Surface area (both sides of
nasal cavity)
Volume (both sides)
Bend in nasopharynx
Turbinate complexity
10-5. INTERSPECIES COMPARISON OF NASAL CAVITY CHARACTERISTICS
Sprague-Dawley Rat Guinea Pig Beagle Dog Rhesus Monkey Humana
250 g 600 g 10kg 7kg =70 kg
0.7mm2 2.5mm2 16.7mm2 22.9mm2 140mm2
40° 40° 30° 30°
23 cm 3.4 cm 10 cm 5.3 cm 7-8 cm
9.6 mm 12.8 mm 23 mm 27 mm 40-45 mm
10.4cm2 27.4cm2 220.7cm2 61.6cm2 181cm2
0.4 cm3 0.9 cm3 20 cm3 8 cm3 16-19 cm3 (does not
include sinuses)
15° 30° 30° 80° «90°
Complex scroll Complex scroll Very complex membranous Simple scroll Simple scroll
"Adult male.
Source: Schneider (1983); Gross and Morgan (1991).
-------
TABLE 10-6. COMPARATIVE LOWER AIRWAY ANATOMY AS REVEALED ON CASTS
"2
3.
(S
h— *
9
•*»•
!>
3
O
2
O
H
O
cj
O
H
W
0
50
n
Mammal/
Body Mass
Human/70 kg
Rhesus
monkey /2 kg
Beagle dog/
10kg
Ferret/
0.61 kg
Guinea pig/
1kg
Rabbit/
4.5kg
Rat/0.3 kg
Golden
hamster/
0.14 kg
Left Lung
Lobes
Upper and
lower
Superior,
middle, and
inferior
Apical,
intermediate,
and basal
NRa
Superior
and
inferior
Superior
and
inferior
One lobe
Superior
and
inferior
Right Lung
Lobes
Upper, middle,
and lower
Superior,
middle, and
inferior,
azygous
Apical,
intermediate,
and basal
NR
Superior,
middle, and
inferior
Cranial,
middle, caudal,
and postcaval
Cranial,
middle, caudal,
and postcaval
Cranial, middle,
caudal, and
postcaval
Gross Structure
Airway
Branching
Relatively
symmetric
Monopodial
Strongly
monopodial
strongly
monopodial
Monopodial
Strongly
monopodial
Strongly
monopodial
Strongly
monopodial
Major
Trachea Airway
length/diameter (cm) Bifurcations
12/2 Sharp for about
the first 10
generations,
relatively
blunt thereafter
3/0.3 Mixed blunt
and sharp
17/1.6 Blunt trachea!
bifurcation,
others sharp
10/0.5 Sharp
5.7/0.4 Very sharp
and high
6/0.5 Sharp
2.3/0.26 Very sharp and
very high
throughout lung
2.4/0.26 Very sharp
Typical Structure
(Generation 6)
Average Branch Angles Typical Number
Airway (Major Daughter/ of Branches
L/D Minor Daughter) to Terminal Respiratory
(ratio) (degrees) Bronchiole Bronchioles
2.2 11/33 14-17 About 3-5 orders
2.6 20/62 10-18 About 4 orders
1.3 8/62 15-22 About 3-5 orders
2.0 16/57 12-20 About 3-4 orders
1.7 7/76 12-20 About 1 order
1.9 15/75 12-20 About 1-2 orders
1.5 13/60 12-20 Rudimentary
1.2 15/63 10-18 About 1 order
aNR = Not reported.
Source: Phalen
and Oldham (1983);
Patra (1986); Crapo
(1987).
-------
I
VO
o
&
D
H
b
o
1
0
d
1
o
50
n
H
w
TABLE 10-7. ACINAR MORPHOMETRY
Species Fixation1 Number/Lung
Human
27,992
75% TLC 23,000
80,000
TLC 26,000-32,000
FRC 43,000
Rabbit 17,900
55% TLC 18,000
Guinea pig 5,100
FRC 4,097
Rat 2,500
2,487
FRC 2,020
70% TLC 5,993
V(mm3)
1.33-30.9
160.8
15.6
187.0
51.0
2.54
3.46
1.25
1.09
1.0
5.06
1.9
1.46
'Volume of lung at fixation (TLC, total lung capacity; FRC,
2Acinar size (D, diameter; L, length)
Source: Mercer and Crapo (1991).
Number
D or L Alveoli/Acinus
(mm)2
15,000
10,714
7.04 (L) 14,000-20,000
5.1(L) 7,100
8.8 (L) 10,344
6.0 (D) 8,000
1.95 (L)
1.56(D) 6,890
1.5 (D) 5,243
1.5 (L)
function residual capacity).
Alveolar
Duct
Generations
6
9
2-5
8-12
9
9
6
9-12
10-12
6
References
Pump (1964)
Horsfield and Cuming (1968);
Parker et al. (1971)
Hansen and Ampaga (1975);
Hansen et al. (1975)
Boyden (1971)
Schreider and Raabe (1981)
Haefeli-Bleuer and Weibel (1988)
Mercer, personal communication
Kliment (1973)
Rodriguez et al. (1971)
Kliment (1973)
Mercer, personal communication
Kliment (1973)
Yeh et al. (1979)
Mercer and Crapo, (1987)
Rodriguez et al. (1988)
-------
1 • Airway length, airway diameter, and branching pattern variations affect the mixing
2 between tidal and reserve air.
3 The airways show a considerable degree of within species variability (e.g., size and
4 branching pattern) and this is most likely the primary factor responsible for the deposition
5 variability seen within single species (Schlesinger, 1985a).
6 Larger airway diameter results in greater turbulence for the same relative flow velocity
7 (e.g., between a particle and air). Therefore, flow may be turbulent in the large airways of
8 humans, whereas for an identical flow velocity, it would be laminar in the smaller
9 experimental animal. Relative to humans, experimental animals also tend to have tracheas
10 that are much longer in relation to their diameter. This could result in increased relative
11 deposition in humans because of the increased likelihood of laryngeal jet flow extending into
12 the bronchi. Human airways are characterized by a more symmetrical dichotomous
13 branching than that found in most laboratory mammals, which have highly asymmetrical
14 airway branching (monopodial). The more symmetrical dichotomous pattern in humans is
15 susceptible to deposition at the carina because of its exposure to high air flow velocities
16 toward the center of the air flow profile.
17 Alveolar size also differs between species, which may affect deposition efficiency due
18 to variations on the distance between the airborne particle and alveolar walls (Dahl et al.,
19 1991).
20 Addressing species differences in ventilation, which affects the tidal volume and
21 ventilation to perfusion ratios, is also critical to estimating initial absorbed dose. Due to the
22 expected variations in airflows within the respiratory tract, the variabilities among lungs in
23 the human or animal population, and the variations in respiratory performance that members
24 of the population experience during their normal activities, e.g. sleep and exercise, must be
25 considered in order to gain some insight into the variability that might be expected in particle
26 deposition, total and regional, of particles in the urban atmosphere. The experimentalist
27 must try to keep respiratory parameters relatively constant to obtain reasonably consistent
28 deposition data.
29
30 10.4.1.7 Additional Factors Modifying Deposition
31 The available deposition data in humans are commonly for healthy adult Caucasian
32 males using stable, monodisperse, low electrostatic charge particles. When these conditions
April 1995 10-46 DRAFT-DO NOT QUOTE OR CITE
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1 do not hold, changes in deposition are expected to occur. In the following, the effects of
2 different factors on deposition are summarized based upon the information reported from
3 various studies.
4
5 Gender
6 Average females have a smaller thoracic size than males. The diameter of the female
7 trachea is approximately 75% that of the male (Warwick and Williams, 1973) and the size of
8 the bronchi is approximately linearly dependent on the size of the trachea (Weibel, 1963). In
9 addition, the minute ventilation and inspiratory flow rate are smaller for females. It is
10 therefore expected that deposition will be different in females than males. Using radioactive-
11 labeled polystyrene particles in the 2.5 to 7.5 fim size range, Pritchard et al. (1986)
12 measured total and regional deposition in 13 healthy nonsmoking female adults at mouth
13 breathing through a tube. Because deposition of particles in this particle size range in the ET
14 region is controlled by impaction, they reported the data as a function of da^ Q to
15 accommodate the difference in flow rate between male and female. Their data are shown in
16 Table 10-8. At a comparative value of da^ Q, females were found to have higher ET and TB
17 deposition and smaller A deposition. The ratio of A deposition to total thoracic deposition in
18 females was also found to be smaller. The differences in depositions were attributed by
19 Pritchard et al. (1986) to the differences in the airway size between males and females.
20
21
22 TABLE 10-8. DEPOSITION DATA FOR MEN AND WOMEN
Deposition as a Fraction of
Inhaled Material (%) ± Standard Error
Sex
Female
Male
AQ ,
(urn2 Lmin"1)
405 ± 47
430 ± 41
Total
75.9 ± 1.7
81.5 ± 1.8
ET
21.2 + 2.4
19.9 ± 2.5
TB
16.9 ± 1.5
14.7 ± 1.7
A
37.5 ±
46.9 ±
2.5
2.7
April 1995 10-47 DRAFT-DO NOT QUOTE OR CITE
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1
2
3
4
5
6
7
8
9
10
11
Age
As a human grows from birth to adulthood, both airway structure and respiratory
conditions vary with age. These variations are likely to alter the deposition pattern of
inhaled particles. Total deposition data for particles of 1 to 3.1 /mi size range were reported
by Becquemin et al. (1987, 1991) for a group of 41 children at 5 to 15 years of age and by
Schiller-Scotland et al. (1992) for 29 children at two age groups (6.7 and 10.9 years).
Although Bequemin et al. (1987, 1991) did not find a clear dependence of total deposition on
age, slightly higher deposition was found by Schiller-Slotland et al. (1992) for each diameter
when children breathed at their normal rates (see Figure 10-8), than found in adults.
1
.1 0.8
LJL
c 0.6
W
§- 0.4
Q
3
,2 0.2
23
Particle Size (urn)
* I: 2,3
— adults A 1: 1 ^m A I: 2
n I: 3 urn T II: 1 urn • H: 2 urn 4 H: 3
Figure 10-8. Total deposition data in children with/during spontaneous breathing as a
function of particle diameter (unit density). Group I (10.6 ± 2.0 yrs);
Group II (5.3 ± 1.5 yrs). The adult curve represents the mean valve of
deposition from the data of Stahlhofen et al. (1989).
Source: Schiller-Scotland et al. (1992).
April 1995
10-48
DRAFT-DO NOT QUOTE OR CITE
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1 Mathematical models for children have been developed by many workers (Hofmann,
2 1982; Crawford, 1982; Xu and Yu, 1986; Yu and Xu, 1987;Phalen et al., 1988b; Hofmann
3 et al., 1989; Yu et al., 1992; Martenon and Zhang, 1993). Phalen et al. (1988b) reported
4 morphometric data of twenty TB airway casts of children from 21 days to 21 years. With
5 the use of these data, they calculated a higher TB deposition in children during inhalation for
6 particle diameters between 0.01 and 10 pm. If the entire respiratory tract and a complete
7 breathing cycle at normal rate are considered in the modeling, the results show that ET
8 deposition in children is higher than adults, but that TB and A deposition in children may be
9 either higher or lower than the adult depending upon the particle size (Xu and Yu, 1986).
10
11 Respiratory Tract Disease
12 Effect of airway diseases on deposition have been studied extensively. In 8 healthy
13 nonsmokers, Svartengren et al. (1986, 1989) found that A deposition at different flow rates
14 were lower (26% versus 48% of thoracic deposition) in subjects after induced
15 bronchoconstriction. The degree of bronchoconstriction was quantified by measurements of
16 airway resistance using a whole-body plethysmograph. A close relation between airway
17 resistance and A deposition was formed with a decrease of A deposition with an increase of
18 airway resistance. The data from the same laboratory (Svartengren et al., 1990, 1991) using
19 2.6 nm dae particles with maximally deep inhalations at 0.5 L/min showed no significant
20 changes in mouth and throat deposition in asthmatics but thoracic deposition was higher than
21 healthy subjects (83% versus 73% of total deposition). TB deposition was also found higher
22 in asthmatics. The results are similar to those found in subjects with obstructive lung disease
23 (e.g., Dolovich et al., 1976; Itoh et al., 1981; Anderson et al., 1990).
24 Another extensive study of the relationship between deposition and lung abnormality
25 was made by Kim et al. (1988). One-hundred human subjects with various lung conditions
26 (normal, asymptomatic smoker, smoker with small airway disease, chronic simple bronchitis
27 and chronic obstructive bronchitis) breathed 1 /mi test particles from a bag at a rate of 30
28 breaths/min. The number of rebreathing breaths resulting in 90% aerosol loss from the bag
29 was determined. From these data, they estimated total deposition and found that total
30 deposition increased with increasing level of airway obstruction.
31
April 1995 10-49 DRAFT-DO NOT QUOTE OR CITE
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1 Particle charge
2 Many of the freshly generated particles are electrostatically charged. Experimental
3 studies in a lung cast (Chan et al., 1978) and measurements in rats and humans (Melandri et
4 al., 1977, 1983; Tarroni et al., 1980; Jones et al., 1988; Scheuch et al., 1990) all showed
5 that particle charge increased deposition. For low particle number concentration (< 105 cm"
6 3), the deposition increase is due to the presence of electrostatic image force acting on the
7 particle by particle-wall interaction (Yu, 1985). Figure 10-9 shows the experimental data on
8 human deposition of Melandri et al. (1983) and Tarroni et al. (1980) for three particle sizes
9 and the modeling results by Yu (1985). The vertical axis in Figure 10-9 is the deposition
10 increment, defined as
11
12 AT = (DE - DE0)/(1 - DE0), (10-22)
13
14 where DE is total deposition at particle charge level, q, and DE0 is the total deposition of
15 particles at Boltzmann charge equilibrium. It is seen for each particle size, deposition
16 increments increase linearly with q. Figure 10-9 also shows that there exists a threshold
17 charge level above which the increase in deposition becomes significant. For 1 /xm particles,
18 the threshold charge was found to be about 54 elementary charges (Yu, 1985).
19
20 Particle Polydispersity
21 Aerosol particles are often generated poly disperse and can be approximated by a
22 lognormal distribution (Section 10.2). The mass deposition of spherical particles in the
23 respiratory tract depends upon mass median diameter (MMD), geometric standard deviation,
24 ag, and physical density (Diu and Yu, 1983; Rudolf et al., 1988). For large particle (dae >
25 1 /mi) deposition governed by impaction and sedimentation, the dependence on MMD and
26 mass density can be combined with the use of mass medium aerodynamic diameter
27 (MMAD), as suggested by TGLD (1966). However, this method is not valid for particles in
28 the size range where diffusion deposition becomes important. Figure 10-10 shows the
29 calculated total and regional mass deposition results by Yeh et al. (1993) for poly disperse
30 aerosols of unit density with various ag as function of MMD at quiet mouth breathing. The
April 1995 10-50 DRAFT-DO NOT QUOTE OR CITE
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140
Particle Charge, q
Figure 10-9. Deposition increment data versus particle electronic charge q for three
particle diameters at 0.3, 0.6, and 1.0 nm (unit density). The solid lines
represent the theoretical predictions.
Source: Yu (1985).
1 dependence of deposition on
-------
o
1.0-1
0.8-
0.6-
u_
'*5 0.4 ~
0.2-
0.0
0.001
0.01
0.1 1 10
Mass Median Diameter, Dp, urn
100
o
1.0 n
0.8-
0.6
0.4
0.2-
0.0
o0-1
0.001 0.01 0.1 1
Mass Median Diameter, Dp,
i
10
100
Figure 10-10. Calculated mass deposition from polydisperse aerosols of unit density
with various geometric standard deviations (ag) as a function of MMD for
quiet breathing (tidal volume = 750 mL, breathing frequency =
15 min*1). The upper panel is total deposition and the lower panel is
regional deposition (NOPL = Naso-oro-pharyngo-laryngeal, TB =
Tracheobronchial, A = Alveolar).
Source: Yeh et al. (1993).
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1 particles travel along the humid respiratory tract, they grow in size and, as a result, the
2 deposition pattern is altered. A discussion on deposition of hygroscopic particles follows in
3 Section 10.4.3.1.
4
5 Fibrous Particles
6 For elongated particles such as fibers, deposition depends upon both diameter and
7 length although the dependence on the diameter is stronger (Yu and Asgharian, 1993).
8 Because of the difficulty encountered in generating monodisperse fibers, size-selective but
9 polydisperse fibers have been normally used in animal deposition studies (e.g., Evans et al.,
10 1973; Morgan et al. 1975, 1978, 1980). At present, no deposition data is available for
11 humans although there have been several attempts to measure local deposition of fibers in
12 human airway casts (Sussman et al., 1991a,b; Myojo, 1987, 1990). Regional deposition in
13 the human respiratory tract can be estimated from mathematical models (Asgharian and Yu,
14 1988; Yu and Asgharian, 1993). Figure 10-11 presents the regional deposition results in
15 humans calculated by Yu and Asgharian (1993). A complete discussion of fiber deposition in
16 the lung is beyond the scope of this document.
17
18 10.4.2 Clearance and Translocation Mechanisms
19 Particles which deposit upon airway surfaces may be cleared from the respiratory tract
20 completely, or may be translocated to other sites within this system, by various regionally
21 distinct processes. These clearance mechanisms, which are outlined in Table 10-9, can be
22 categorized as either absorptive, i.e., dissolution, or nonabsorptive, i.e., transport of intact
23 particles, and may occur simultaneously or with temporal variations. It should be mentioned
24 that, particle solubility in terms of clearance refers to solubility in vivo within the respiratory
25 tract fluids and cells. Thus, an "insoluble" particle is considered to be one whose rate of
26 clearance by dissolution is insignificant compared to its rate of clearance as an intact particle.
27 For the most part, all deposited particles are subject to clearance by the same mechanisms,
28 with their ultimate fate a function of deposition site, physicochemical properties (including
29 any toxicity), and sometimes deposited mass or number concentration. Clearance routes
April 1995 10-53 DRAFT-DO NOT QUOTE OR CITE
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100
10
100
I10
100
E
10
0.1 1 10
Diameter (urn)
0.1 1 10
Diameter (urn)
: tf> '
0.1 1 10
Diameter (urn)
Figure 10-11. Calculated regional deposition fraction of unit-density fibers in humans at
quiet mouth breathing.
Source: Yu and Asgharian (1993).
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TABLE 10-9. OVERVIEW OF RESPIRATORY TRACT PARTICLE CLEARANCE
AND TRANSLOCATION MECHANISMS
Extrathoracic region
Mucociliary transport
Sneezing
Nose wiping and blowing
Dissolution (for "soluble" particles) and absorption into blood
Tracheobronchial region
Mucociliary transport
Endocytosis by macrophages/epithelial cells
Coughing
Dissolution (for "soluble" particles) and absorption into blood
Alveolar region
Macrophages, epithelial cells
Interstitial
Dissolution for "soluble" and "insoluble" particles (intra-and
extracellular)
Source: Schlesinger (1995)
1 from the various regions of the respiratory tract are schematically outlined in Figures 10-12
2 and 10-13. Furthermore, clearance is a continuous process and all mechanisms operate
3 simultaneously for deposited particles.
4
5 10.4.2.1 Extrathoracic Region
6 The clearance of insoluble particles deposited in the nonolfactory portion of nasal
7 passages occurs via mucociliary transport, and the general flow of mucus is backwards, i.e.,
8 towards the nasopharynx (Figure 10-12). However, the epithelium of the most anterior
9 portion of the nasal passages is not ciliated, and mucus flow just distal to this is forward,
10 clearing deposited particles to a site (vestibular region) where removal is by sneezing (a
11 reflex response), wiping, or blowing (mechanisms known as extrinsic clearance).
12 Soluble material deposited on the nasal epithelium will be accessible to underlying cells
13 if it can diffuse to them through the mucus prior to removal via mucociliary transport.
14 Dissolved substances may be subsequently translocated into the bloodstream following
April 1995 10-55 DRAFT-DO NOT QUOTE OR CITE
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Nasal Passages
Anterior
Posterior
Extrinsic Clearance
I
Pharynx
Tracheobronchial Tree
Blood
Figure 10-12. Major clearance pathways from the extrathoracic region and
tracheobronchial tree.
1 movement within intercellular pathways between epithelial cell tight junctions or by active or
2 passive transcellular transport mechanisms. The nasal passages have a rich vasculature, and
3 uptake into the blood from this region may occur rapidly.
4 Clearance of insoluble particles deposited in the oral passages is by swallowing into the
5 gastrointestinal tract. Soluble particles are likely rapidly absorbed after deposition (Swift and
6 Proctor, 1988).
7
8 10.4.2.2 Tracheobronchial Region
9 Insoluble particles deposited within the tracheobronchial tree are cleared primarily by
10 mucociliary transport, with the net movement of fluid towards the oropharynx, followed by
11 swallowing. Some insoluble particles may traverse the epithelium by endocytotic processes,
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Deposited Particle
-
t
Phagocytosis by
Alveolar Macrophages
Movement within •<-
Alveolar Lumen
Bronchiolar/ Bronchial
Lumen ^-
Mucociliary Blanket
Endocyl
^ 1 ype I f
Epitheli,
^4 T
Passage Through
"~ Alveolar Epithelium "^'"
T;
OS
tlvc
?K
MHI
^•••- Interstitium ^
t
Lymphatic Channels ^ —
is by
jolar
Passage through
Pulmonary Capillary
Endothelium
f A
t i
•••»•»•• *^^^
Phagocytosis by
>• Interstitial
^ Macrophages J
Gl Tract
Figure 10-13. Diagram of known and suspected clearance pathways for insoluble
particles depositing in the alveolar region. (?) = speculated routes.
Source: Schlesinger (1995).
1 entering the peribronchial region (Masse et al., 1974; Sorokin and Brain, 1975). Clearance
2 may also occur following phagocytosis by airway macrophages, located on or beneath the
3 mucus lining throughout the bronchial tree, which then move cephalad on the mucociliary
4 blanket, or via macrophages which enter the airway lumen from the bronchial or bronchiolar
5 mucosa (Robertson, 1980).
6 As in the nasal passages, soluble particles may be absorbed through the mucus layer of
7 the tracheobronchial airways and into the blood, via intercellular pathways between epithelial
8 cell tight junctions or by active or passive transcellular transport mechanisms.
9 The bronchial surfaces are not homogeneous; there are openings of daughter bronchi
10 and islands of non-ciliated cells at bifurcation regions. In the latter, the usual progress of
11 mucus movement is interrupted, and bifurcations may be sites of relatively retarded
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1 clearance. The efficiency with which such non-ciliated regions are traversed is dependent
2 upon the traction of the mucus layer.
3 Another method of clearance from the tracheobronchial region, under some
4 circumstances, is cough, which can be triggered by receptors located in the area from the
5 trachea through the first few bronchial branching levels. While cough is generally a reaction
6 to some inhaled stimulus, in some cases, especially respiratory disease, it can also serve to
7 clear the upper bronchial airways of deposited substances by dislodging mucus from the
8 airway surface.
9
10 10.4.2.3 Alveolar Region
11 Clearance from the A region occurs via a number of mechanisms and pathways, but the
12 relative importance of each is not always certain and may vary between species.
13 Particle removal by macrophages comprises the main nonabsorptive clearance process
14 in the A region. Alveolar macrophages reside on the epithelium, where they phagocytize and
15 transport deposited material that they contact by random motion, or more likely via directed
16 migration under the influence of local chemotactic factors (Warheit et al, 1988). Contact
17 may be facilitated as some deposited particles are translocated, due to pressure gradients or
18 via capillary action within the alveolar surfactant lining, to sites where macrophages
19 congregate (Schurch et al., 1990; Parra et al., 1986).
20 Alveolar macrophages normally comprise =3 - 5% of the total alveolar cells in healthy
21 (non-smoking) humans and other mammals, and represent the largest subpopulation of
22 nonvascular macrophages in the respiratory tract (Gehr, 1984; Lehnert, 1992). However, the
23 actual cell count may be altered by particle loading. While a low number of deposited
24 particles may not result in an increase in cell number, above some level macrophage numbers
25 will increase proportionally to particle number until a saturation point is reached (Adamson
26 and Bowden, 1981; Brain, 1971). Since the magnitude of this increase is related more to the
27 number of deposited particles than to total deposition by weight, equivalent masses of an
28 identical deposited substance may not produce the same response if particle sizes differ; thus,
29 smaller particles would tend to result in a greater elevation in cell number than would larger
30 ones.
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1 Particle-laden macrophages may be cleared from the A region along a number of
2 pathways (Figure 10-13). One route is cephalad transport via the mucociliary system after
3 the cells reach the distal terminus of the mucus blanket. However, the manner by which
4 macrophages actually attain this is not certain. The possibilities are chance encounter;
5 passive movement along the alveolar surface due to surface tension gradients between the
6 alveoli and conducting airways; directed locomotion along a gradient produced by
7 chemotactic factors released by macrophages ingesting deposited material; or passage through
8 the alveolar epithelium and the interstitium, perhaps through aggregates of lymphoid tissue
9 (bronchus associated lymphoid tissues, BALT) located at bronchioalveolar junctions (Sorokin
10 and Brain, 1975; Kilburn, 1968; Brundelet, 1965; Green, 1973; Corry et al., 1984; Harmsen
11 etal., 1985).
12 Some of the cells which follow interstitial clearance pathways are likely resident
13 interstitial macrophages which have ingested particles that were transported through the
14 alveolar epithelium, probably via endocytosis by Type I pneumocytes (Brody et al., 1981;
15 Bowden and Adamson, 1984). Particle-laden interstitial macrophages can also migrate across
16 the alveolar epithelium, becoming part of the alveolar macrophage cell population (Adamson
17 and Bowden, 1978).
18 Macrophages which are not cleared via the bronchial tree may actively migrate within
19 the interstitium to a nearby lymphatic channel or, along with uningested particles, be carried
20 in the flow of interstitial fluid towards and into the lymphatic system (Harmsen et al., 1985).
21 Passive entry into lymphatic vessels is fairly easy, since the vessels have loosely connected
22 endothelial cells with wide intercellular junctions (Lauweryns and Baert, 1974). Lymphatic
23 endothelium may also actively engulf particles from the surrounding interstitium (Leak,
24 1980). Particles within the lymphatic system may be translocated to tracheobronchial lymph
25 nodes, which often become reservoirs of retained material. Particles penetrating the nodes
26 and subsequently reaching the post-nodal lymphatic circulation may enter the blood.
27 Uningested particles or macrophages in the interstitium may traverse the
28 alveolar-capillary endothelium, directly entering the blood (Raabe, 1982; Holt, 1981);
29 endocytosis by endothelial cells followed by exocytosis into the vessel lumen seems,
30 however, to be restricted to particles <0.1 jtm diameter, and may increase with increasing
31 lung burden (Lee et al., 1989; Oberdorster, 1988). Once in the systemic circulation,
April 1995 10-59 DRAFT-DO NOT QUOTE OR CITE
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1 transmigrated macrophages, as well as uningested particles, can travel to extrapulmonary
2 organs. Some mammalian species have pulmonary intravascular macrophages, which can
3 remove particles from circulating blood and which may play some role in the clearance of
4 material deposited in the alveoli (Warner and Brain, 1990) .
5 Uningested particles and macrophages within the interstitium may travel to perivenous,
6 peribronchiolar or subpleural sites, where they become trapped, increasing particle burden.
7 The migration and grouping of particles and macrophages within the lungs can lead to the
8 redistribution of initially diffuse deposits into focal aggregates (Heppleston, 1953). Some
9 particles can be found in the pleural space, often within macrophages which have migrated
10 across the visceral pleura (Sebastien et al., 1977; Hagerstrand and Siefert, 1973). Resident
11 pleural macrophages do occur, but their role in clearance, if any, is not certain.
12 During clearance, particles can be redistributed within the alveolar macrophage
13 population (Lehnert, 1992). One mechanism is by death of the macrophage, and release of
14 free particles to the epithelium followed by uptake by other macrophages. Some of these
15 newly freed particles may, however, translocate to other clearance routes.
16 Clearance by the absorptive mechanism involves dissolution in the alveolar surface
17 fluid, followed by transport through the epithelium and into the interstitium, and diffusion
18 into the lymph or blood. Some soluble particles translocated to and trapped in interstitial
19 sites may be absorbed there. Although the factors affecting the dissolution of deposited
20 particles are poorly understood, it is influenced by the particle's surface to volume ratio and
21 other surface properties (Morrow, 1973; Mercer, 1967). Thus, materials generally
22 considered to be relatively insoluble may have high dissolution rates and short dissolution
23 half-times if the particle size is small.
24 Some deposited particles may undergo dissolution in the acidic milieu of the
25 phagolysosomes after ingestion by macrophages, and such intracellular dissolution may be
26 the initial step in translocation from the lungs for these particles (Kreyling, 1992; Lundborg
27 et al, 1985). Following dissolution, the material can be absorbed into the blood. Dissolved
28 particles may then leave the lungs at rates which are more rapid than would be expected
29 based upon their normal dissolution rate in lung fluid. Because of this, the clearance rate of
30 such a material can vary with the form in which it is inhaled and where the particle resides.
31 For example, while insoluble (in lung fluid) MnO2 dissolves in the macrophage, soluble
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1 manganese chloride (MnCl2) likely dissolves extracellularly and is not ingested, resulting in
2 manganese clearing at different initial rates depending upon the form in which it was initially
3 inhaled (Camner et al, 1985). Differences in rates of clearance may also occur for particles
4 whose rate of dissolution is pH dependent (Marafante et al., 1987).
5 Finally, some particles can bind to epithelial cell membranes or macromolecules, or
6 other cell components, delaying clearance from the lungs.
7
8 10.4.2.4 Clearance Kinetics
9 Although deposited particles may be cleared completely from the respiratory tract, the
10 actual time frame over which this occurs affects dose delivered to the respiratory tract, as
11 well as to extrapulmonary organs. Particle-tissue contact and retained dose in the
12 extrathoracic region and tracheobronchial tree are often limited by rapid clearance from
13 these regions and are, thus, approximately proportional to toxicant concentration and
14 exposure duration, dependent on particle size and distribution. On the other hand, the dose
15 from material deposited in the A region is highly dependent upon the characteristics of the
16 particles.
17 Various experimental techniques have been used to assess clearance rates in both
18 humans and experimental animals (Schlesinger, 1985b). Because of technical differences and
19 the fact that measured rates are strongly influenced by the specific methodology, comparisons
20 between studies are often difficult to perform. However, regional clearance rates, i.e., the
21 fraction of the deposit which is cleared per unit time, are well defined functional
22 characteristics of an individual human or experimental animal when repeated tests are
23 performed under the same conditions; but, as with deposition, there is a substantial degree of
24 inter-individual variability.
25
26 Extrathoracic Region
27 Mucus flow rates in the posterior nasal passages are highly nonuniform. Regional
28 velocities in the healthy adult human may range from < 2 to > 20 mm/min (Proctor, 1980),
29 with the fastest flow occurring in the midportion of the nasal passages. The median rate in a
30 healthy adult human is about 5 mm/min, the net result being a mean transport tune of about
31 10-20 min for insoluble particles deposited within the nasal passages (Stanley et al., 1985;
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1 Rutland and Cole, 1981). However, particles deposited in the anterior portion of the nasal
2 passages are cleared more slowly, at a rate of 1-2 mm/h (Hilding, 1963). Since clearance at
3 this rate may take upwards of 12 h, such deposits are usually more effectively removed by
4 sneezing, wiping, or nose blowing, in which case clearance may occur in 0.5 h (Morrow,
5 1977; Fry and Black, 1973).
6
7 Tracheobronchial Region
8 Mucus transport in the tracheobronchial tree occurs at different rates in different local
9 regions; the velocity of movement is fastest in the trachea, and it becomes progressively
10 slower in more distal airways. In healthy non-smoking humans, and using non-invasive
11 procedures and no anesthesia, average tracheal mucus transport rates have been measured at
12 4.3 to 5.7 mm/min (Leikauf et al., 1981, 1984; Yeates et al., 1975, 1981b; Foster et al.,
13 1980), while that in the main bronchi has been measured at «2.4 mm/min (Foster et al.,
14 1980). While rates of movement in smaller airways have not been directly determined,
15 estimates for human medium bronchi range between 0.2-1.3 mm/min, while those in the
16 most distal ciliated airways range down to 0.001 mm/min (Yeates and Aspin, 1978; Morrow
17 et al., 1967b; Cuddihy and Yeh, 1988).
18 It is not certain whether the transport rate for deposited insoluble particles is
19 independent of their nature, i.e., shape, size, composition. While particles of different
20 materials and sizes have been shown to clear at the same rate in the trachea in some studies
21 (Man et al., 1980; Patrick, 1983; Connolly et al., 1978), other studies (using instillation)
22 have indicated that the rate of mucociliary clearance may be greater for smaller particles
23 (<2jum) than for larger ones (Takahashi et al, 1992). Reasons for such differences between
24 these studies are not known. There may, however, be more than one phase of clearance
25 within individual tracheobronchial airways. For example, the rat trachea shows a biphasic
26 clearance pattern, consisting a rapid phase within the first 2-4 h after deposition clearing up
27 to 90% of deposited particles with a half time of < 0.5 h, followed by a second, slower
28 phase clearing most of the remaining particles with a half-time of 8-19 h (Takahashi et al,
29 1992). But in any case, most of the particles deposited in the trachea are cleared very
30 rapidly, within about 2 to 4 h after deposition.
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1 The total duration of bronchial clearance, or some other time parameter, is often used
2 as an index of mucociliary kinetics yet the temporal clearance pattern is not certain. In
3 healthy adult non-smoking humans, 90% of insoluble particles depositing within the
4 tracheobronchial tree were found to be cleared from 2.5 to 20 h after deposition, depending
5 upon the individual subject and the size of the particles (Albert et al., 1973); while this latter
6 does not affect surface transport, it does affect the depth of particle penetration and
7 deposition and the subsequent pathway length for clearance. Due to differences in regional
8 transport rates, clearance times from different regions of the bronchial tree will differ.
9 While removal of a TB deposit is generally 99% completed by 48 h after exposure (Bailey et
10 al., 1985a), there is the possibility of longer-term retention under certain circumstances.
11 Studies with rodents, rabbits, and humans have indicated that a small fraction (~ 1%)
12 of insoluble material may be retained for a prolonged period of time within the upper
13 respiratory tract (nasal passages) or tracheobronchial tree (Patrick and Stirling, 1977; Gore
14 and Patrick, 1982; Watson and Brain, 1979; Radford and Martell, 1977; Svartengren et al.,
15 1981). The mechanism(s) underlying this long-term retention is unknown, but may involve
16 endocytosis by epithelial cells with subsequent translocation into deeper (submucosal) tissue,
17 or merely passive movement into this tissue. In addition, uptake by the epithelium may
18 depend upon the nature, or size, of the deposited particle (Watson and Brain, 1980). The
19 retained particles may eventually be cleared to regional lymph nodes, but with a long half
20 time that may be > 80 days (Patrick, 1989; Oghiso and Matsuoka, 1979).
21 There is some suggestion of a greater extent of long term retention in the bronchial
22 tree. Stahlhofen et al. (1986), using a specialized inhalation procedure, noted that a
23 significant fraction, up to 40%, of particles which were likely deposited in the conducting
24 airways were not cleared up to six days post-deposition. They also noted that the size of the
25 particles influenced this retention, with smaller ones being retained to a greater extent than
26 were larger ones (Stahlhofen et al., 1987, 1990). Although the reason for this is not certain,
27 the suggested presence of a surfactant film on the muccous lining of the airways (Gehr et al.,
28 1990) may result in a reduced surface tension which, in turn, influences the displacement of
29 particles into the gel layer and subsequently into the sol layer towards the epithelial cells.
30 Particles which reach the latter may then be phagocytized, increasing retention time in the
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1 lungs. However, the issue of retention of large fractions of tracheobronchial deposit is not
2 resolved.
3 Long-term TB retention patterns are not uniform. There is an enhancement at
4 bifurcation regions (Cohen et al., 1988; Radford and Martell, 1977; Henshaw and Fews,
5 1984), the likely result of both greater deposition and less effective mucus clearance within
6 these areas. Thus, doses calculated based upon uniform surface retention density may be
7 misleading, especially if the material is, toxicologically, slow acting. Solubilized material
8 may also undergo long-term retention in ciliated airways due to binding to cells or
9 macromolecules.
10
11 Alveolar Region
12 Clearance kinetics in the A region are not definitively understood, although particles
13 deposited there generally remain longer than do those deposited in airways cleared by
14 mucociliary transport. There are limited data on rates in humans, while within any species
15 rates vary widely due to different properties of the particles used in the various studies.
16 Furthermore, some of these studies employed high concentrations of insoluble particles,
17 which may of itself have interfered with normal clearance mechanisms, producing rates
18 different from those which would occur at lower exposure levels. Prolonged exposure to
19 high particle concentrations is associated with what is termed particle "overload." This is
20 discussed in greater detail in Section 10.4.2.7.
21 There are numerous pathways of A region clearance, and these may depend upon the
22 nature of the particles being cleared. Thus, kinetic generalizations are difficult to make,
23 especially since the manner in which particle characteristics affect kinetics is not resolved.
24 Nevertheless, A region clearance can be described as a multiphasic process, each component
25 considered to represent removal by a different mechanism or pathway, and often
26 characterized by increasing retention half-times with time post-exposure.
27 Clearance of inert, insoluble particles in healthy, nonsmoking humans has been
28 generally observed to consist of two phases, with the first having a half-time measured in
29 days, and the second in hundreds of days. Table 10-10 presents some observed times for the
30 longer, second phase of clearance as reported in a number of studies. Although wide
31 variations in retention reflect a dependence upon the nature of the deposited material (e.g.,
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1 particle size) once dissolution is accounted for, mechanical removal to the gastrointestinal
2 tract and/or lymphatic system appears to be independent of size, especially for particles < 5
3 fj,m (Snipes et al., 1983). Although not evident from Table 10-10, there is considerable
4 intersubject variability in the clearance rates of identical particles, which appears to increase
5 with time post-exposure (Philipson et al, 1985; Bailey et al, 1985a). The large differences hi
6 clearance kinetics among different individuals suggests that equivalent chronic exposures to
7 insoluble particles may result in large variations in respiratory tract burdens.
8
TABLE 10-10. LONG-TERM RETENTION OF INSOLUBLE PARTICLES FROM
THE ALVEOLAR REGION IN NON-SMOKING HUMANS
Particle
Material
Polystyrene latex
Polystyrene latex
Polystyrene latex
Polystyrene latex
Teflon
Aluminosilicate
Aluminosilicate
Iron oxide (Fe2O3)
Iron oxide (Fe2O3)
Iron oxide (Fe3O4)
Size (/*m)
5
5
0.5
3.6
4
1.2
3.9
0.8
0.1
2.8
Retention half-time3
(days) Reference
150 to 300
144 to 340
33 to 602
296
100 to 2,500
330
420
62
270
70
Booker et al. (1967)
Newton et al. (1978)
Jammett et al. (1978)
Bohning et al. (1982)
Philipson et al. (1985)
Bailey et al. (1982)
Bailey et al. (1982)
Morrow et al. (1967a,b)
Waite and Ramsden (1971)
Cohen et al. (1979)
"Represent the half-time for the slowest clearance phase observed.
1 While the kinetics of overall clearance from the A region have been assessed to some
2 extent, much less is known concerning relative rates along specific pathways and available
3 information is generally from studies with laboratory animals. The usual initial step in
4 clearance, i.e., uptake of deposited particles by alveolar macrophages, is very rapid. Unless
5 the particles are cytotoxic or very large, ingestion by macrophages occurs within 24 h of a
6 single inhalation (Naumann and Schlesinger, 1986; Lehnert and Morrow, 1985). But the
7 actual rate of subsequent macrophage clearance is not certain; perhaps 5% or less of their
8 total number is translocated from the lungs each day for rodents (Lehnert and Morrow, 1985;
9 Masse et al., 1974).
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1 The rate and amount of particle uptake by macrophages is likely governed by particle
2 size and surface properties (Tabata and Ikada, 1988). For example, the effect of particle size
3 was examined by incubating mouse peritoneal macrophages with polymer microspheres
4 (0.5 to 5 /im). Both the number of particles ingested per cell and the volume of these
5 particles per cell reached a maximum for particle diameters of 1-2 /nm, declining on either
6 side of this range. In terms of particle surface, those with hydrophobic surfaces were
7 ingested to a greater extent than were those with hydrophilic surfaces. Phagocytosis also
8 increased as the surface charge density of a particle increased, but for the same charge
9 density there was no difference in uptake between positively or negatively charged particles.
10 The time for clearance of particle-laden alveolar macrophages via the mucociliary
11 system depends upon the site of uptake relative to the distal terminus of the mucus blanket at
12 the bronchiolar level. Furthermore, clearance pathways, and subsequent kinetics, may
13 depend to some extent upon particle size. For example, some smaller ultrafine particles
14 (perhaps < 0.02 /tm) may be less effectively phagocytosed than are larger ones
15 (Oberdorster, 1993). But once ingestion occurs, alveolar macrophage-mediated kinetics are
16 independent of the particle involved, as long as solubility and cytotoxicity are low.
17 In terms of other clearance pathways, uningested particles may penetrate into the
18 interstitium, largely by Type I cell endocytosis, within a few hours following deposition
19 (Ferin and Feldstein, 1978; Sorokin and Brain, 1975; Brody et al., 1981). This
20 transepithelial passage seems to increase as particle loading increases, especially to a level
21 above the saturation point for increasing macrophage number (Adamson and Bowden, 1981;
22 Ferin, 1977). It may also be particle size dependent, since insoluble ultrafine particles
23 (< 0.1 /un diameter) of low toxicity show increased access to and greater lymphatic uptake
24 than do larger ones of the same material (Oberdorster et al., 1992). However, ultrafine
25 particles of different materials may not enter the interstitium to the same extent. Similarly, a
26 depression of phagocytosis by toxic particles or the deposition of large numbers of smaller
27 ultrafine particles may increase the number of free particles in the alveoli, enhancing removal
28 by other routes. In any case, free particles and alveolar macrophages may reach the lymph
29 nodes, perhaps within a few days after deposition (Lehnert et al., 1988; Harmsen et al.,
30 1985), although this route is not certain and may be species dependent.
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1 The extent of lymphatic uptake of particles may depend upon the effectiveness of other
2 clearance pathways. For example, lymphatic translocation likely increases when phagocytic
3 activity of alveolar macrophages is decreased (Greenspan, et al., 1988). This may be a
4 factor in lung overload, as discussed in Section 10.4.2.7. However, it seems that the
5 deposited mass or number of particles must reach some threshold below which increases in
6 loading do not affect translocation rate to the lymph nodes (Ferin and Feldstein, 1978;
7 LaBelle and Brieger, 1961).
8 The rate of translocation to the lymphatic system may be somewhat particle size
9 dependent. Although no human data are available, translocation of latex particles to the
10 lymph nodes of rats was greater for 0.5 to 2 /nm particles than for 5 and 9 pm particles
11 (Takahashi et al, 1992), and smaller particles within the 3-15 //m size range were found to be
12 translocated at faster rates than were larger sizes (Snipes and Clem, 1981). On the other
13 hand, translocation to the lymph nodes was similar for both 0.4 jim barium sulfate or 0.02
14 ^im gold colloid particles (Takahashi et al, 1987). It seems that particles < 2 pm clear to
15 the lymphatic system at a rate independent of size, and it is particles of this size, rather than
16 those > 5 fjan, that would have significant deposition within the pulmonary region following
17 inhalation.
18 In any case, and regardless of any particle size dependence, the normal rate of
19 translocation to the lymphatic system is quite slow, on the order of 0.02-0.003%/day
20 (Snipes, 1989), and elimination from the lymph nodes is even slower, with half-times
21 measured in tens of years (Roy, 1989).
22 Soluble particles depositing in the A region may be rapidly cleared via absorption
23 through the epithelial surface into the blood, but there are few data on dissolution and
24 transfer rates to blood in humans. Actual rates depend upon the size of the particle (i.e.,
25 solute size), with smaller ones clearing faster than larger ones. Chemistry also plays a role,
26 since water soluble compounds generally clear at a slower rate than do lipid soluble
27 materials.
28 Absorption may be considered as a two stage process, with the first stage dissociation
29 of the deposited particles into material that can be absorbed into the circulation (dissolution)
30 and the second stage the uptake of this material. Each of these stages may be time
31 dependent. The rate of dissolution depends upon a number of factors, including particle
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1 surface area and chemical structure. Uptake into the circulation is generally considered as
2 instantaneous, although a portion of the dissolved material may be absorbed more slowly due
3 to binding to respiratory tract components. Accordingly, there is a very wide range for
4 absorption rates depending upon the physicochemical properties of the material deposited.
5 For example, a highly soluble particle may be absorbed at a rate faster than the particle
6 transport rate and significant uptake may occur in the conducting airways. On the other
7 hand, a particle that is less soluble and remains in the lungs for years would have a much
8 lower rate, perhaps < 0.0001 %/day.
9
10 10.4.2.5 Factors Modifying Clearance
11 A number of host and environmental factors may modify normal clearance patterns,
12 affecting the dose delivered by exposure to inhaled particles. These include aging, gender,
13 workload, disease and irritant inhalation. However, in many cases, the exact role of these
14 factors is not resolved.
15
16 Age
17 The evidence for aging-related effects on mucociliary function in healthy individuals is
18 equivocal, with studies showing either no changes or some slowing in mucous clearance
19 function with age after maturity (Goodman et al., 1978; Yeates et al., 1981a; Puchelle et al,
20 1979). However, it is often difficult to determine whether any observed functional
21 decrement was due to aging alone, or to long-term, low level ambient pollutant exposure
22 (Wanner, 1977). In any case, the change in mucous velocity between approximately age 20
23 and 70 in humans is about a factor of two (Wolff, 1992) and would likely not significantly
24 affect overall kinetics.
25 There are few data to allow assessment of aging-relating changes in clearance from the
26 pulmonary region. Although functional differences have been found between alveolar
27 macrophages of mature and senescent mice (Esposito and Penm'ngton, 1983), no age-related
28 decline in macrophage function has been seen in humans (Gardner et al., 1981).
29 There are also insufficient data to assess changes in clearance in the growing lung.
30 Nasal mucociliary clearance time in a group of children (average age = 7 yrs) was found to
31 be «10 min (Passali and Ciampoli, 1985); this is within the range for adults. There is one
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1 report of bronchial clearance in children (12 yrs old), but this was performed in patients
2 hospitalized for renal disease (Huhnerbein et al., 1984).
3
4 Gender
5 No gender related differences were found in nasal mucociliary clearance rates in
6 children (Passali and Ciampoli, 1985) nor in tracheal transport rates in adults (Yeates et al.,
7 1975). Slower bronchial clearance has been noted in male compared to female adults, but
8 this was attributed to differences in lung size (and resultant clearance pathway length) rather
9 than to inherent gender related differences in transport velocities (Garrard et al., 1986).
10
11 Physical Activity
12 The effect of increased physical activity upon mucociliary clearance is unresolved, with
13 the available data indicating no change to a speeding with exercise (Wolff et al., 1977;
14 Pavia, 1984). There are no data concerning changes in pulmonary region clearance with
15 increased activity levels, but CO2-stimulated hyperpnea (rapid, deep breathing) was found to
16 have no effect on early pulmonary clearance and redistribution of particles (Valberg et al.,
17 1985). Increased tidal volume breathing was noted to increase the rate of particle clearance
18 from the pulmonary region, and this was suggested to be due to distension related evacuation
19 of surfactant into proximal airways, resulting in a facilitated movement of particle-laden
20 macrophages or uningested particles due to the accelerated motion of the alveolar fluid film
21 (John etal., 1994).
22
23 Respiratory Tract Disease
24 Various respiratory tract diseases are associated with clearance alterations. The
25 examination of clearance in individuals with lung disease requires careful interpretation of
26 results, since differences in deposition of tracer particles used to assess clearance function
27 may occur between normal individuals and those with respiratory disease, and this would
28 directly impact upon the measured clearance rates, especially in the tracheobronchial tree. In
29 any case, nasal mucociliary clearance is prolonged in humans with chronic sinusitis,
30 bronchiectasis, or rhinitis (Majima et al., 1983; Stanley et al., 1985), and in cystic fibrosis
31 (Rutland and Cole, 1981). Bronchial mucus transport may be impaired in people with
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1 bronchial carcinoma (Matthys et al., 1983), chronic bronchitis (Vastag et al., 1986), asthma
2 (Pavia et al., 1985), and in association with various acute infections (Lourenco et al., 1971;
3 Camner et al., 1979; Puchelle et al., 1980). In certain of these cases, coughing may enhance
4 mucus clearance, but it generally is effective only if excess secretions are present.
5 Normal mucociliary function is essential to respiratory tract health. Studies of
6 individuals with a syndrome characterized by impaired clearance, i.e., primary ciliary
7 dyskinesia (PCD), may be used to assess the importance of mucociliary transport and the
8 effect of its dysfunction upon respiratory disease, and to provide information on the role of
9 clearance in maintaining the integrity of the lungs. The lack of mucolciliary function in PCD
10 is directly responsible for the early development of recurrent respiratory tract infections and,
11 eventually, chronic bronchitis and bronchiectasis (Rossman et al., 1984; Wanner, 1980). It
12 is, however, not certain whether partial impairment of the mucociliary system will increase
13 the risk of lung disease.
14 Rates of pulmonary region particle clearance appear to be reduced in humans with
15 chronic obstructive lung disease (Bohning et al., 1982) and in experimental animals with
16 viral infections (Creasia et al., 1973). The viability and functional activity of macrophages
17 was found to be impaired in human asthmatics (Godard et al., 1982).
18 Studies with experimental animals have also found disease related clearance changes.
19 Hamsters with interstitial fibrosis showed an increased degree of pulmonary clearance (Tryka
20 et al., 1985). Rats with emphysema showed no clearance difference from control (Damon et
21 al., 1983), although the co-presence of inflammation resulted in prolonged retention (Hahn
22 and Hobbs, 1979). On the other hand, inflammation may enhance particle and macrophage
23 penetration through the alveolar epithelium into the interstitium, by increasing the
24 permeability of the epithelium and the lymphatic endothelium (Corry et al., 1984).
25 Neutrophils, which are phagocytic cells present in alveoli during inflammation, may
26 contribute to the clearance of particles via the mucociliary system (Bice et al., 1990).
27 Macrophages have specific functional properties, namely phagocytic activity and
28 mobility, which allow them to adequately perform their role in clearance. Alveolar
29 macrophages from calves with an induced interstitial inflammation (pneumonitis) were found
30 to have enhanced phagocytic activity compared to normal animals (Slauson et al, 1989). On
31 the other hand, depressed phagocytosis was found with virus-induced acute bronchiolitis and
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1 alveolitis (Slauson et al, 1987). How such alterations affect clearance from the pulmonary
2 region is not certain, since the relationship between macrophage functional characteristics
3 and overall clearance is not always straightforward. While changes in macrophage function
4 do impact upon clearance, the manner by which they do so may not always be easily
5 predictable. In any case, the modification of functional properties of macrophages appear to
6 be injury specific, in that they reflect the nature and anatomic pattern of disease.
7
8 Inhaled Irritants
9 Inhaled irritants have been shown to have an effect upon mucociliary clearance function
10 in both humans and experimental animals (Schlesinger, 1990; Wolff, 1986). Single
11 exposures to a particular material may increase or decrease the overall rate of
12 tracheobronchial clearance, often depending upon the exposure concentration (Schlesinger,
13 1986). Alterations in clearance rate following single exposures to moderate concentrations of
14 irritants are generally transient, lasting < 24 h. However, repeated exposures may result in
15 an increase in intra-individual variability of clearance rate and persistently retarded clearance.
16 The effects of irritant exposure may be enhanced by exercise, or by coexposure to other
17 materials.
18 Acute and chronic exposures to inhaled irritants may also alter PU region clearance
19 (Cohen et al., 1979; Ferin and Leach, 1977; Schlesinger et al., 1986; Phalen et al., 1994),
20 which may be accelerated or depressed, depending upon the specific material and/or length
21 of exposure. While the clearance of insoluble particles from conducting airways is due
22 largely to only one mechanism, i.e., mucociliary transport, clearance from the respiratory
23 region involves a complex of multiple pathways and processes. Because transit times along
24 these different pathways vary widely, a toxicant-induced change in clearance rate could be
25 due to a change in the time for removal along a particular pathway and/or to a change in the
26 actual route taken. Thus, it is often quite difficult to delineate specific mechanisms of action
27 for toxicants which alter overall clearance from respiratory airways. Alterations in alveolar
28 macrophages likely underlay some of the observed changes, since numerous irritants have
29 been shown to impair the numbers and functional properties of these cells (Gardner, 1984).
30 Since a great number of people are exposed to cigarette, it is of interest to summarize
31 effects of this irritant upon clearance processes. Smoke exposed animals and humans show
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1 increased number of macrophages recoverable by bronchopulmonary lavage (Brody and
2 Davis, 1982; Warr and Martin, 1978; Matulionis, 1984; Zwicker et al., 1978). However,
3 the rate of particle clearance from the pulmonary region of the lungs appears to be reduced
4 in cigarette smokers (Bohning et al., 1982; Cohen et al., 1979).
5 While cigarette smoking has been shown to affect tracheobronchial mucociliary
6 clearance function, the effects range from acceleration to slowing. Some of the apparent
7 discrepancies in different studies is related to differences in the effects of short-term versus
8 long-term effects of cigarette smoke. Long term smokers appear to have mucolciliary
9 clearance which is slower than that in nonsmokers (Lourenco et al., 1971; Albert et al.,
10 1971) and which also show certain anomalies, such as periods of intermittent clearance
11 stasis. On the other hand, the short term effects of cigarette smoke range from acceleration
12 to retardation depending upon the number of cigarettes smoked (Albeit et al, 1971;
13 Lippmann et al., 1977; Albeit et al., 1974).
14
15 10.4.2.6 Comparative Aspects of Clearance
16 As with deposition analyses, the inability to study the retention of certain materials in
17 humans for direct risk assessment requires use of experimental animals. Since dosimetry
18 depends upon clearance rates and routes, adequate toxicologic assessment necessitates that
19 kinetics in these animals be related to that occurring in humans. The basic mechanisms and
20 overall patterns of clearance from the respiratory tract appear to be similar in humans and
21 most other mammals. However, regional clearance rates can show substantial variation
22 between species, even for similar particles deposited under comparable exposure conditions
23 (Snipes, 1989).
24 Dissolution rates and rates of transfer of dissolved substances into the blood may or
25 may not be species independent, depending upon certain chemical properties of the deposited
26 material (Griffith et al., 1983; Bailey et al., 1985b; Roy, 1989). For example, lipophilic
27 compounds of comparable molecular weight are cleared from the lungs of various species at
28 the same rate (dependent solely upon solute molecular weight and the lipid/water partition
29 coefficient), but hydrophilic compounds do show species differences.
30 On the other hand, there are distinct interspecies differences in rates of mechanical
31 transport in the conducting and A airways. While mucous transport rates in the nasal
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1 passages seem to be similar in humans and the limited other species examined (Morgan et al,
2 1986; Whaley, 1987), tracheal mucous velocities vary among species as a function of body
3 weight (Felicetti et al., 1981; Wolff, 1992).
4 In the A region, macrophage-mediated clearance of insoluble particles is species
5 dependent, with small mammalian species generally exhibiting faster clearance than larger
6 species, with the exception of the Guinea pig which clears slower than rodents. This may
7 result from interspecies differences in macrophage-mediated clearance of insoluble particles
8 (Valberg and Blanchard, 1992; Bailey et al., 1985b); transport of particles from the A region
9 to pulmonary lymph nodes (Snipes et al., 1983; Mueller et al., 1990); phagocytic rates and
10 chemotactic responses of alveolar macrophages (Warheit and Hartsky, 1994); or the
11 prevalence of HALT (Murray and Driscoll, 1992). These likely result in species-dependent
12 rate constants for these clearance pathways, and differences in regional (and perhaps total)
13 clearance rates between some species are a reflection of these differences in mechanical
14 processes. For example, the relative proportion of particles cleared from the PU region in
15 the short and longer term phases of clearance differs between rodents and larger mammals,
16 with a greater percentage cleared in the faster first phase in rodents. The end result of
17 interspecies differences in deposition and clearance is that the retention of deposited particles
18 can differ between species, and this may result in differences in response for similar inhaled
19 paniculate atmospheres.
20
21 10.4.2.7 Lung Overload
22 Some experimental studies using rodents employed high exposure concentrations of
23 relatively nontoxic, insoluble particles, which interfered with normal clearance mechanisms,
24 producing clearance rates different from those which would occur at lower exposure levels.
25 Prolonged exposure to high particle concentrations is associated with what is termed particle
26 "overload." This is a nonspecific effect noted in experimental studies, generally in rats,
27 using many different kinds of insoluble particles (including TiO2, volcanic ash, diesel exhaust
28 particles, carbon black, and fly ash) and results in PU region clearance slowing or stasis,
29 with an associated inflammation and aggregation of macrophages in the lungs and increased
30 translocation of particles into the interstitium (Muhle et al., 1990; Lehnert, 1990; Morrow,
31 1994). While overload induced effects are reversible, the extent of such reversibility
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1 decreases as the degree of overloading increases. Furthermore, it appears that once some
2 critical particle burden is reached, particles of all sizes (those studies ranged from ultrafine to
3 4 urn) show increased interstitialization (Oberdorster et al, 1992). This phenomenon
4 involves macrophage-mediated clearance, and has been suggested to be due to the inhibition
5 of alveolar macrophage mobility.
6 While the exact amount of deposition needed to induce overload is not certain, it has
7 been hypothesized that it will likely begin, at least in the rat, when deposition approaches 1
8 mg particles/g lung tissue (Morrow, 1988). When the concentration reaches 10 mg
9 particles/g lung tissue, macrophage-mediated clearance of the particles would effectively
10 cease. However, overload may be related more to the volume of particles ingested than to
11 the total mass (Morrow, 1988; Oberdorster et al, 1992b). Furthermore, tumors and fibrosis
12 may develop following the overloading and retardation of lung clearance in rats, subsequent
13 accumulation of particles, inflammation, and the interaction of inflammatory mediators with
14 cell proliferative processes and DNA (Mauderly, 1994).
15 Lung overload may result from two types of exposure scenarios. One is repeated
16 exposures to relatively insoluble materials until some critical lung burden is reached. Until
17 this occurs, clearance is normal, but above this threshold level, clearance becomes
18 progressively retarded and associated other changes occur. The other scenario is that
19 overload is a function of the amount of such particles which deposit daily, i.e., deposition
20 rate (Muhle, 1988). Clearance retardation was suggested to occur if exposure reached levels
21 of 3 mg/m3 or higher. Thus, some critical deposition rate over a sufficient exposure
22 duration would result in retardation of clearance (Yu et al, 1989).
23 The relevance of lung overload to humans, and even to nonrodent animal species, is not
24 clear. While it is, however, likely to be of little relevance for most "real world" ambient
25 exposures of humans, it is of concern in interpreting some long-term experimental exposure
26 data. It may, however, be of some concern to humans occupationally exposed to some
27 particle types (Mauderly, 1994), since overload may involve all insoluble materials and affect
28 all species if the particles are deposited at a sufficient rate (Pritchard, 1989), (i.e., if the
29 deposition rate exceeds the clearance rate). In addition, the relevance to humans is also
30 clouded by the suggestion that macrophage-mediated clearance is normally slower and
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1 perhaps less important in humans than in rats (Morrow, 1994), and that there will be
2 significant differences in macrophage loading between the two species.
3
4 10.4.3 Acidic Aerosols
5 An Issue Paper on Acid Aerosols was published by the Environmental Protection
6 Agency in 1989. Section 3 of that document was devoted to the deposition and fate of acid
7 aerosols. Moreover, that Section provided an update of particle deposition data from both
8 human and experimental animal studies, described hygroscopic aerosol studies reported
9 between 1977 and 1987, and presented a thorough discussion of the neutralization of acid
10 aerosols by airway secretions and absorbed ammonia.
11 This section consists of two subsections: the first concerns the phenomenon of
12 hygroscopicity; and the second presents current information on acidic aerosol neutralization.
13 Deposition data and models appropriate to acidic aerosols are reviewed in Section 10.6.3.
14
15 10.4.3.1 Hygroscopicity of Acidic Aerosols
16 Hygroscopicity can be defined as the propensity of a material for taking up and
17 retaining moisture under certain conditions of humidity and temperature. It is well known
18 that action of ocean waves continuously disperses tons of hygroscopic saline particles into the
19 atmosphere and these contribute to the worldwide meteorologic phenomena. As the growth
20 of industrialization has expanded, the evolution of gaseous pollutants, especially the oxides of
21 sulfur and nitrogen, has caused a greatly increased atmospheric burden of aerosols mainly
22 derived from gas-phase reactions. These aerosols are predominantly both acidic and
23 hygroscopic, consisting of mixtures of partially neutralized nitric, sulfuric and hydrochloric
24 acids: i.e., inorganic salts, such as nitrites, bisulfates, sulfates and chlorides. In addition,
25 small amounts of organic acid salts, e.g., formate and acetate, are present as are a variety of
26 trace elements, e.g., cadmium, carbon, vanadium, chromium and phosphorus, whose oxides
27 and other chemical forms tend also to be acid forming (Aerosols, 1986).
28 Two reviews on hygroscopic aerosols (Morrow, 1986; Hiller, 1991) have been
29 published which consider the implications of hygroscopic particle growth on deposition in the
30 human respiratory tract. Much of the treatment of hygroscopic particle growth is based on
31 theoretical models (e.g., Xu and Yu, 1985; Perron et al., 1988; Martonen and Zhang, 1993)
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1
2
3
4
5
6
7
8
9
which will be reviewed in Section 10.5. Suffice it to say, paniculate sodium chloride has
been commonly utilized in these models and to a lesser extent, sulfuric acid droplets, and
ammonium sulfate and ammonium bisulfate particles. There are no major distinctions in the
growth of these several hygroscopic materials except that sulfuric acid does not manifest a
deliquescent point (when the particle becomes an aqueous droplet). It can be seen in
Figure 10-14 that the growth rate of hygroscopic particles is controlled by the relative
humidity (RH): the closer to saturation (100% RH), the faster the growth rate.
4.0
o
1
I3-0
o
0)
N
o>
75
tr
(0
D.
2.0
1.0
10 20
30 40
50
60
70
80 90 100
% Relative Humidity
Figure 10-14. Theoretical growth curves for sodium chloride, sulfuric acid, ammonium
bisulfate and ammonium sulfate aerosols in terms of the initial (d0) and
final (d) size of the particle. Note that the H2SO4 curve, unlike those for
the three salts, has no deliquescence point.
Source: Tang and Munkelwitz (1977).
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1 Hygroscopic particles or droplets of different initial size will experience different
2 growth rates: the smallest particles being the fastest to reach an equilibrium size. For
3 example, a 0.5 jum diameter particle will require approximately 1 s, whereas a 2.0 fim
4 particle will require close to 10 s. It is immediately evident that many inhaled hygroscopic
5 particles will not reach their equilibrium size (maximum growth) during the duration of a
6 single respiratory cycle (ca 4 s). Conversely, the growth of ultrafine particles does not
7 resemble that for particles >0.1 ^m and thereby represents a special case. Moreover, the
8 hygroscopic growth characteristics of aqueous droplets, containing one or more solutes,
9 depend not only on their initial size, but their initial composition. The study of Cocks and
10 Fernando (1982), using the condensation model of Fukata and Walter (1970), with
11 ammonium sulfate droplets illustrate both of these last points (Figure 10-15).
12 The direct measurement of the RH of alveolar air and the temperature of air at the
13 alveolar surface have been attempted, but because of technical limitations, the direct
14 experimental determinations of these and other values at different levels of the respiratory
15 tract have only been considered reliable for conditions in the conducting airways
16 (Morrow 1986). Fortunately, indirect methods for these determinations have been
17 successful. For deep-lung temperature, Edwards et al. (1963) used solubility of a helium-
18 argon mixture in arterial blood. By this approach they found the mean pulmonary capillary
19 temperature in five normal subjects to be 37.52 °C. Because of individual variability, they
20 also provided an equation for estimating the deep lung temperature in an individual from a
21 measurement of rectal temperature.
22 Perron and co-workers (1983, 1985) made the logical assumption that the RH of the
23 alveolar air was determined by an equilibrium with the vapor pressure of blood serum at the
24 capillary level. The osmolarity of serum at 37 °C (287 + 4 mmol/kg) provided these
25 investigators a sound basis for selecting 99.5% RH as the value to use in all of the modeling
26 estimations. In Figure 10-16 (from Xu and Yu, 1985) the calculated equilibrium diameters
27 for sodium chloride particles on the basis of their initial size (dj is depicted. The
28 equilibrium diameters (d00) that can be achieved theoretically for each particle size is shown
29 as a function of three different RH values. For an RH of 99.5%, the growth of salt particles
30 with an initial size greater than 0.5 jim, yields about a 6-fold increase in diameter.
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10
Time (s)
X0= 40%
XQ= 40%
XQ= 20%
X0= 20%
Figure 10-15. Distinctions in growth (r/r^ of aqueous (NH^SO^ droplets of 0.1 and
1.0 /tin initial size are depicted as a function of their initial solute
concentrations (X0).
Source: Cocks and Fernando (1983).
1 Perron et al. (1988) calculated the RH in the human airways by employing a transport
2 theory for heat and water vapor using cylindrical coordinates. Several parameters of the
3 theory were chosen to best fit the available experimental data. These authors also used the
4 transport theory to model the growth and deposition of three salts, viz., NaCl, CoCl2 5^0,
5 and ZnSO4 7H2O, which were selected because these differentially hydrated particles have
6 large, moderate and small hygroscopic growth potentials, respectively. Figure 10-17 depicts
7 the growth of these three salts when their initial dry particle size is 1.0 /xm diameter, the
8 average inspired airflow is 250 cc/s, and the inhalation is by mouth. In this depiction, the
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H - 0.995
I
I
I
0.01 0.02 0.05 0.1
0.2
0.5 1
5 10
Figure 10-16. The initial diameter of dry NAC1 particles (d^ and equilibrium diameter
achieved (d) are shown for three relative humidity assumptions.
Source: Xu and Yu (1985).
1 particle growth is expressed as the ratio of the achieved aerodynamic diameter to the initial
2 aerodynamic size.
3 A recent experimental study by Anselm et al. (1990) used an indirect method, similar
4 to that employed earlier by Tu and Knudsen (1984), to validate the 99.5% RH assumption
5 for alveolar air. In this instance, monodisperse NaCl particles between 0.2 and 0.5 /mi were
6 made by vibrating orifice generator and administered, by mouth, as boli during a constant
7 inspiratory airflow. During expiration, the particles suspended in the same volume element
8 were size classified. To determine equilibrium particle sizes, 600 cc of aerosol was inspired
9 followed by 400 cc of clean air. Expiration was initiated after different periods of breath
10 holding and the behavior of NaCl particles (loss and settling velocities) was compared to that
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'ae,s
4.0-
3.0-
2.0-
1.0-
0.0
0.01
Q = 250 cm3/s
mouth
inhalation
NaCI
ZnSO4-7H,p
(c)
0.1
1
Time (s)
10
100
Figure 10-17. The initial dry diameter (dae,) of three different salts is assumed to be
1.0 fim. Their subsequent growth to an equilibrium diameter at
99.5%RH is shown by the ratio (dae/dae s). The highly hydrated salts of
cobalt chloride and zinc sulfate exhibits a reduced growth potential
compared to sodium chloride.
Source: Perron et al. (1988).
1 of a stable (nonhygroscopic) aerosol. Through this approach, the investigators found that the
2 diameters of the NaCI particles initially 0.2 ^im and 0.25 /xm, increased 5.55 and 5.79-fold,
3 respectively. These values were found to be consistent with a 99.5% RH.
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1 To make the transport theory model estimations more pragmatic, Perron and coworkers
2 (1992, 1993) made estimations for heterodisperse aerosols of salts with the range of growth
3 potentials used in their 1988 study. Also, deposition estimates for H2SO4 aerosols,
4 incorporating variabilities in age-related airway morphometry and in physical activity levels,
5 have been reported by Martonen and Zhang (1993) using some unique modeling assumptions.
6 In his excellent review of hygroscopic particle growth and deposition and their
7 implications to human health, Killer (1991) concluded that despite the importance of models,
8 there remains insufficient experimental data on total and regional deposition of hygroscopic
9 aerosols in humans to confirm these models adequately.
10
11 10.4.3.2 Neutralization and Buffering of Acidic Particles
12 The toxicity of acidic particles may be modulated following their inhalation. This may
13 occur within the inhaled air, by neutralization reaction with endogenous respiratory tract
14 ammonia, or following deposition, due to buffering within the fluid lining of the airways.
15
16 Reaction of Acidic Particles with Respiratory Tract Ammonia
17 Ammonia (NH3) is present in the air within the respiratory tract. Measurements of
18 taken in exhaled air have found that the NH3 concentration varies depending upon the site of
19 measurement, with levels obtained via oral breathing greater than those measured in the nose
20 or trachea (Larson et al, 1977; Vollmuth and Schlesinger, 1984). Because of these
21 concentration differences between the oral and nasal passages, the route of acidic particle
22 inhalation likely plays a significant role in determining the hydrogen ion (H+) available for
23 deposition in the lower respiratory tract. Thus, for the same mass concentration of acidic
24 particles, inhalation via the mouth will result in more neutralization compared to inhalation
25 via the nose, and less H+ available for deposition in the lungs (Larson et al, 1982). The
26 toxicity of acidic particles may be due to the H+, as discussed in Chapter 11 (human and
27 animal toxicity data).
28 The possibility that endogenous ammonia could chemically neutralize inhaled acidic
29 particles to their ammonium salts prior to deposition on airway surfaces, thereby reducing
30 toxicity, was originally proposed by Larson et al (1977) in relation to acidic sulfate aerosols.
31 Since, stoichiometrically, 1 pg, of NH3 can convert 5.8 /xg of H2SO4 to ammonium bisulfate
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1 (NH4HSO4), or 2.9 pg of H2SO4 to ammonium sulfate [(NH4)2SO4], they determined, based
2 upon the range of NH3 levels measured in the exhaled air of humans, that up to 1,500 ^ig/m3
3 of inhaled H2SO4 could be converted to (NH4)2SO4. For a given sulfate content in an
4 exposure atmosphere, both ammonium bisulfate and ammonium sulfate are less potent
5 irritants than is sulfuric acid, as discussed in Chapter 11.
6 Complete neutralization of inhaled sulfuric acid or ammonium bisulfate would produce
7 ammonium sulfate. However, partial neutralization of sulfuric acid would reduce to varying
8 extends the amount of H+ available for deposition, thereby modulating toxicity. The extent
9 of neutralization has been shown to play a role in measured toxicity from inhaled sulfuric
10 acid. Utell et al (1986) exposed asthmatic subjects to sulfuric acid under conditions of high
11 or low levels of expired ammonia. The response to inhaled acid exposure was greater when
12 exposure was conducted under conditions of low oral ammonia levels.
13 The extent of reaction of ammonia with acid sulfates depends upon a number of factors.
14 These include residence tune within the airway, which is a function of ventilation rate, and
15 inhaled particle size. In terms of the latter, for a given amount of ammonia, the extent of
16 neutralization is inversely proportional to particle size, at least within the range of 0.1-10 fim
17 (Larson et al, 1993). In addition, for any given ammonia concentration, the extent of
18 neutralization of sulfuric acid increases as mass concentration of the acid aerosol decreases
19 (Schlesinger and Chen, 1994).
20 Cocks and McElroy (1984) presented a model analysis for neutralization of sulfuric acid
21 particles in human airways. Particle acidity was a function of both dilution by particle
22 growth and neutralization by ammonia. As an example of their results, neutralization would
23 be complete in 3 sec for H2SO4 (3M) having a particle size of 0.5 /urn and a mass
24 concentration of 100 jug/m3, with the ammonia level at 500 /xg/m3. If the NH3 level is
25 reduced to 50 /xg/m3, neutralization would take longer.
26 Larson (1989) presented another model for neutralization of inhaled acidic sulfate
27 aerosols in humans. It was concluded that significant deposition of acid in the lower
28 respiratory tract would occur in the presence of typical respiratory tract NH3 levels, for both
29 oral or nasal inhalation of H2SO4 particles at 0.3/mi. However, particles at 0.03/im should
30 be completely neutralized in the upper respiratory tract. While this latter seems to contradict
31 findings of significant biological responses in guinea pigs following exposure to ultrafine acid
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1 particles (Chapter 11), this could reflect differences in residence times and ammonia levels
2 between different species. On the other hand, response to ultrafine acid particles has not
3 been examined in humans, so the model predictions have not been tested as yet.
4 Furthermore, it is likely that under most circumstances, only partial neutralization of inhaled
5 sulfuric acid occurs prior to deposition (Larson et al, 1977). In any case, these conclusions
6 support toxicological findings of biological effects following inhalation of sulfuric acid
7 concentrations that should, based solely upon stoichiometric considerations, be completely
8 neutralized, and highlights the complexity of neutralization processes in the respiratory tract.
9 Larson et al (1993) examined the role of ammonia and ventilation rate on response to
10 inhaled (oral) sulfuric acid, by estimating, using the model of Larson (1989), the acid
11 concentrations to which the lungs would be exposed during oral inhalation. They concluded
12 that combinations of high ammonia and low ventilation rate or low ammonia and high
13 ventilation rate produce smaller or larger amounts of acid deposition, respectively, even if
14 the acid concentration at the point of inhalation remained constant. The former condition
15 resulted in greater neutralization than did the latter.
16
17 Buffering by Airway Surface Fluid (Mucus)
18 Mucus lining the conducting airways has the ability to buffer acid particles which
19 deposit within it. The pH of mammalian tracheobronchial mucus has been reported to be
20 within a range of about 6.5 to 8.2 (Boat et al, 1994; Gatto, 1981; Holma et al, 1977). This
21 variability may be due to differences in the methods used and species examined, as well as
22 the likelihood that the acid-base equilibrium differs at different levels of the tracheobronchial
23 tree, but may also reflect variations in secretion rate and the occurrence of inflammation.
24 The influence on pH of various other endogenous factors, such as secretion of hydrogen or
25 bicarbonate ions, and the role of specific mucus constituents, such as secreted acidic
26 glycoproteins and basic macromolecules, have not been extensively examined.
27 The buffering capacity of human sputum, a mixture of saliva and mucus, was examined
28 by Holma (1985), by titrating sputum equilibrated with 5% carbon dioxide at 37 °C and
29 100% relative humidity (RH) with sulfuric acid. While the buffering capacity was variable,
30 depending upon the sputum sample examined, depression of pH from 7.25 to 6.5 required
31 the addition of approximately 6 junol of hydrogen ion (H+) per ml of sputum. Assuming a
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1 tracheobronchial mucus volume of 2.1 mL, between 8 and 16 fimol of H+, if evenly
2 distributed through the airways, would be required to depress mucus pH from 7.4 to 6.5.
3 Since 1 /xg H+ is obtained from 49 jig of sulfuric acid, between 390 and 780 /xg of sulfuric
4 acid would be required to cause this change in pH. With an inhalation exposure duration of
5 0.5 h, ventilation at 20 L/min and 50% deposition (in the total respiratory tract) of 100
6 jttg/m3 sulfuric acid (at 1M), 0.6 /xmol of H+ would be deposited in the lungs. However, the
7 distribution of submicrometer acid particles in the respiratory tract is not uniform and,
8 therefore, greater changes in pH may be anticipated on a regional basis in those areas having
9 higher than average deposition. If, for example, 30 fig of acid deposited in 0.2 ml of mucus,
10 a greater change in pH would likely occur.
11 The above example may apply to healthy individuals. However, the buffering capacity
12 of mucus may be altered in individuals with compromised lungs. For example, sputum from
13 asthmatics had a lower pH than that from healthy subjects, and a reduced buffering capacity
14 (Holma, 1985). This group may, therefore, represent a portion of the population which is
15 especially sensitive to inhaled acidic particles. The potential sensitivity of asthmatics to acid
16 particles is discussed in greater detail in Chapter 11.
17 While biological responses following the inhalation of acidic aerosols are likely due to
18 the H+ component of these particles (as discussed in Chapter 11), it has been suggested that
19 pH may not be the sole determinant of response to acid particles, but that response may
20 actually depend upon total available hydrogen ion, or titratable acidity, depositing upon
21 airway surfaces. Fine et al (1987) hypothesized that buffered acid aerosols (with a greater
22 H+ pool) would cause a greater biological response than would unbuffered acid aerosols
23 having the same pH. Since airway surface fluids have a considerable capacity to buffer acid,
24 it was suggested that the buffered acid would cause a more persistent decrease in airway
25 surface fluid pH. Thus, it appears that the specific metric of acidity used, i.e., pH or
26 titratable acid, would, therefore, be reflected in the relationship between amount of deposited
27 acidity and resultant biological response.
28
29
30
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1 10.5 DEPOSITION DATA AND MODELS
2 The background information in Sections 10.4 demonstrates that a knowledge of where
3 particles of different sizes deposit in the respiratory tract and the amount of their deposition
4 is necessary for understanding and interpreting the health effects associated with exposure to
5 particles. As was seen, the respiratory tract can be divided into the ET, TB and A regions
6 on the basis of structure, size and function. Particles deposited in the various regions have
7 large differences in clearance pathways and consequently retention times. This section
8 discusses the available data on particle deposition in humans and laboratory animals.
9 Different approaches for modeling these data are also discussed. Theoretical models must
10 assume average values and simplifying conditions of respiratory performance in order to
11 make reasonable estimates. This latter approach was initiated by the meteorologist Findeisen
12 (1935), over fifty years ago when he developed a simplified anatomic model of the
13 respiratory tract and assumed steady inspiratory and expiratory air flows in order to estimate
14 the interactions between the anatomy of the respiratory tract and particle deposition based on
15 physical laws. Despite much progress in respiratory modeling, there are not major
16 distinctions in total particle deposition predictions among models and experimental
17 verifications have been generally satisfactory.
18
19 10.5.1 Humans
20 The deposition of particles within the human respiratory tract have been assessed using
21 a number of techniques (Valberg, 1985). Unfortunately, the use of different experimental
22 methods and assumptions results in considerable variations in reported values. This section
23 discusses the available particle deposition data in humans for either total or regions of the
24 respiratory tract.
25
26 10.5.1.1 Total Deposition
27 If the quantity of aerosol particles deposited in the entire respiratory tract is divided by
28 that inhaled, the result is called total deposition fraction or total deposition. Thus, total
29 deposition can be measured by comparing particle concentrations of the inhaled and exhaled,
30 but the regional involvement cannot be distinguished. By the use of test aerosol particles
31 with radiolabels, investigators have been able to separate deposition by region, beginning
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1 from the ET region with either nasal and nasopharyngeal deposition for nose breathing or
2 oral and pharyngeal deposition for mouth breathing. The measurement of clearance of the
3 radiolabeled particles from the thorax can be used to separate fast clearance, usually assumed
4 to be an indicator of TB deposition, from the more slowly cleared A deposition (see below
5 for more discussion).
6 Total human deposition data, as a function of particle size with nose and mouth
7 breathing compiled by Schlesinger (1988), are depicted in Figure 10-18. These data were
8 obtained by various investigators using different sizes of test spherical particles in healthy
9 male adults under different ventilation conditions. Deposition with nose breathing is
10 generally higher than that with mouth breathing because mouth breathing bypasses the
11 filtration capabilities of the ET region. For large particles with aerodynamic diameters d,,e
12 greater than 1 pm, deposition is governed by impaction and sedimentation and it increases
13 with increasing dae. When dae > 10 /*m, almost all inhaled particles are deposited. As the
14 particle size decreases from 0.1 jan, diffusional deposition becomes dominant and total
15 deposition depends more upon the physical diameter d of the particle. Decreasing particle
16 diameter leads to an increase in total deposition in this particle size range. Total deposition
17 shows a minimum for particle diameters in the range of 0.1 pim to 0.5 pun where both
18 sedimentation and diffusion deposition are about equally important. The particle diameter at
19 which the minimum deposition occurs is different for nose breathing and mouth breathing
20 and it depends upon flow rate and airway dimensions. For all particle sizes, mixing of the
21 tidal air and functional residual air can also contribute to deposition. This factor is more
22 significant for particle sizes for which deposition is low. Good deposition experiments
23 therefore should account for mixing into the residual volume by requiring subjects fully
24 exhale.
25 Although various studies in Figure 10-18 all appear to show the same trend, there is a
26 significant amount of scatter in the data. Some of this scatter can be explained by the use of
27 different test particles and methods in the experimental studies, as well as different breathing
28 modes and ventilation conditions employed by the subjects. However, a good portion of the
29 scatter is caused by the differences in airway morphology and breathing pattern among
30 subjects (Heyder et al., 1982, 1988; Yu et al., 1979; Yu and Diu, 1982a,b; Bennett and
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100
80
_" O
60
o
•*=
'w
§.
0)
Q
40
20
O Human (Oral)
• Human (Nasal)
O O
1
'GD
I
0.01
0.1 1.0
Particle Diameter (urn)
10
Figure 10-18. Total deposition data (percentage deposition of amount inhaled) in
humans as a function of particle size. Particle diameters are
aerodynamic (MMAD) for those > 0.5 /on.
Source: Schlesinger (1988).
1 Smaldone, 1987; Bennett, 1988). In addressing the health-related issues of inhaled particles,
2 this intersubject variability is an important factor which must be taken into consideration.
3 Indeed, for well controlled experiments and controlled breathing patterns (constant
4 inspiratory flow in half a cycle and constant expiratory flow in another half cycle and no
5 pause), total deposition data do not have the amount of scatter shown in Figure 10-18.
6 Figure 10-19 shows the data by Heyder et al. (1986) and Schiller et al. (1986, 1988)
7 reported by Stahlhofen et al. (1989) at controlled mouth breathing for particle size ranging
8 from 0.005 /zm to 15 /un and three different ventilation conditions. Total deposition was
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0.8-
c
1 0.6H
o
o.
0)
o
0.4-1
0.2-
o.o-
Total Deposition
(unit density spheres)
mouth breathing
Symbols: Experimental data
Curves : Model calculations
AA «O ma
Tidal volume cm3 500 1,000 2,000
Volumetric flow rate cm3g-i 250 250 250
Breathing frequency min-1 15 7.5 3.75
0.01
0.1 1
Diameter of unit density spheres / u,m
10
Figure 10-19. Total deposition as a function of the diameter of unit density spheres in
humans for variable tidal volume and breathing frequency.
Experimental data are by Heyder et al. (1986) and Schiller et al. (1988).
The curves represent empirical fitting.
Source: Stahlhofen et al. (1988).
1 found higher for larger tidal volume while the minimum deposition occurred at about 0.4
2 for all three ventilation conditions.
3
1 10.5.1.2 Extrathoracic Deposition
2 The fraction of inhaled particles depositing in the ET region can be quite variable,
3 depending on particle size, flow rate, breathing frequency and whether the breathing is
4 through the nose or through the mouth. During exertion, the flow resistance of the nasal
5 passages cause a shift to mouth breathing in almost all individuals, thereby bypassing much
6 of the filtration capabilities of the head and leading to increased deposition in the lung (TB
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1 and A regions). For nose breathing, the usual technique for measuring inspiratory deposition
2 is to draw the aerosol through the nose and out of the mouth while the subject holds his
3 mouth open (Pattle, 1961; Lippmann, 1970; Hounam et al., 1969, 1971). The aerosol
4 concentration is measured before it enters the nose and after it leaves the mouth. Neglecting
5 mouth deposition during expiration, inspiratory nasal deposition can be calculated from the
6 concentration difference. Another method to measure the nasal deposition is to use the lung
7 as a part of the experimental system (Giacomelli-Maltoni et al., 1972; Martens and Jacobi,
8 1973; Rudolph, 1975). The deposition of particles in the nose is calculated from total
9 deposition of particles in the entire respiratory tract for mouth, nose, mouth-nose and nose-
10 mouth breathing. Because mouth deposition is not significant under the experimental
11 conditions, this method allows the determination of nasal deposition for both inspiration and
12 expiration.
13 Deposition in the mouth for expiration is normally assumed to be negligible. For
14 inspiration, the deposition in mouth has been measured using radioactive aerosol particles
15 (Rudolph, 1975; Lippmann, 1977; Foord et al., 1978; Stahlhofen et al., 1980; Chan and
16 Lippmann, 1980; Stahlhofen et al., 1981, 1983). The amount of deposition is obtained from
17 the difference of activity measurements, one immediately after exposure and the other after
18 the deposited particles are removed with mouthwash or other means. Because the subjects in
19 these experiments breathe through a large bore tube, the deposition via the mouth occurs
20 predominantly in the larynx. Rudolf et al. (1984, 1986) have suggested to name this
21 laryngeal deposition. Mouth deposition by natural mouth breathing without using a
22 mouthpiece was measured in an earlier study by Dennis (1961) and recently by Bowes and
23 Swift (1989) during natural oronasal breathing at moderate and heavy exercise conditions.
24 The data showed a much greater deposition than breathing through a mouth-piece.
25 For dae > 0.2 /mi, ET deposition is usually expressed as a function of dag Q where Q
26 is the flow rate since this is the appropriate parameter for normalizing impaction-dominated
27 deposition when the actual flow rates in the experimental studies are not identical. Even with
28 this normalization, deposition data in the extrathoracic region by various workers exhibit a
29 very large amount of scatter as shown in Figures 10-20 and 10-21, respectively, for
30 inspiratory nasal and mouth deposition. Besides uncertainty in measurement techniques, one
31 major source of this scatter, similar to the case of total deposition comes from intersubject
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t
a Landahl&Tracewell 1949
V Rattle 1961
• LJppmann 1970
Hounametal. 1971
O Giacomelli-Maltoni et al. 1972
Martens & Jacob!
O Rudolf
10"
cm3s1
Figure 10-20. Inspiratory deposition A of the human nose as a function of d^eQ. The
curve represents equation (10-23).
Source: Stahlhofen et al. (1988).
1 and intrasubject variabilities. The intersubject variability may arise from the difference in
2 anatomical structure and dimensions, number of nasal hairs, breathing pattern, etc., while the
3 intrasubject variability may be caused by the degree of mouth opening and by the nasal
4 resistance cycle in which airflow may be redistributed from one side to the other .side, by as
5 much as 20-80%.
6 Mathematical model studies on the deposition in the nose and mouth are very limited.
7 There have been only two attempts to determine nasal deposition during inspiration (Landahl,
8 1950b; Scott et al., 1978). At present, formulas useful for predicting ET deposition are
9 derived empirically from experimental data (Pattle, 1961; Yu et al., 1981; Rudolf et al.,
10 1983, 1984, 1986; Miller et al., 1988; Zhang and Yu, 1993). The formulas by Rudolf et al.
11 (1983, 1984, 1986) given below with a minor modification, have been adopted by the
12 International Commission on Radiological Protection (ICRP, 1994) in their dosimetry model.
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'M
t
Q. cmV1 V. cm3
500 ~1,000
1,000
1,000
1,000
250
500
1,000
1,500
Figure 10-21. Inspiratory extrathoracic deposition data in humans during mouth
breathing as a function of d£e Q2/3VT1/4. The curve represents equation
(10-24).
Source: Stahlhofen et al. (1988).
1
2
3
1
2
1
2
3
Deposition efficiency of the nose on inhalation (T/N) is expressed in terms of an impaction
parameter as
(10-23)
where dae is in the unit of /im, Q in cm3/s, and VT is the tidal volume in cm3.
An equal amount of deposition is assumed to occur in the posterior nasal passages
(compartment ET2 in Table 10-4).
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r,M = 1 - [5.5xlO-5(diQ2/3VT~1/4)L7 + I]-1. (10- 24)
1
2 Equation 10-23 applies to both inspiration and expiration since the data by Heyder and
3 Rudolf (1977) do not show a systematic difference between the two efficiencies. The
4 inclusion of VT in Equation 10-24 is caused by the fact that the size of the ET region during
5 mouth breathing increases with increasing flow rate and with increasing tidal volume.
6 For ultrafme particles (d < 0.1 fim), deposition in the ET region is controlled by the
7 mechanism of diffusion which depends only on the particle geometric diameter, d. At this
8 tune, ET deposition for this particle size range has not been studied extensively in humans.
9 George and Breslin (1969) measured nasal deposition of radon progeny in three subjects but
10 the diffusion coefficient of the progeny was uncertain. Schiller et al. (1986, 1988) later
11 obtained inspiratory nasal deposition from total deposition measurements using a nose in -
12 mouth out and mouth in-nose out maneuver. However, their data cannot be considered
13 reliable because mouth deposition is not negligible compared to nose deposition.
14 The only data available to date for ET deposition of ultrafine particles are from cast
15 measurements (Cheng et al., 1988, 1990, 1993; Yamada et al., 1988; Gradon and Yu, 1989;
16 Swift et al, 1992). Figure 10-22 shows these data on inspiratory nasal deposition from
17 several laboratories reported by Swift et al. (1992) as a function of the diffusion parameter
18 D1/2Q~1/8 where D is the particle diffusion coefficient in cm2/sec and Q is the flow rate in
19 L/min. Swift et al. (1992) also proposed an equation to fit the data in the form
20
r,N = 1 - exp[ - 12.65D 1/2Q-1/8], (10-25)
21
22 which was adopted by ICRP (1994) in the dosimetry model. Expiratory nasal deposition for
23 particles between 0.005 pm to 0.2 pim was found to have the same trend as Figure 10-22 but
24 was approximately 10% higher than the inspiratory nasal deposition (Yamada et al., 1988).
25 Cheng et al. (1993) derived the following empirical equations to fit the data
r,Nex = 1 -exp[- 15.0D i/2Q-"8] , and (10-26)
26
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0.05
D Cast A, Harwell
• Cast G, Harwell
<> CastC, ITRI
• CastB, ITRI
A Cast A, Clarkson
V Cast B, Clarkson
A Cast G, Clarkson
0.1 0.15 0.2
Dl/2Q-l/8
0.25
0.3
Figure 10-22. Inspiratory deposition efficiency data and fitted curve for human nasal
casts plotted versus Q-1/8D1/2 (Lmfa-1)-1/8(anV1)1/2. Dotted lines are 95%
confidence limits.
Source: Swift et al. (1992).
(10-27)
1
2
3
for inspiration, and
r/M = l-exp(-8.51Z)1/2Q-1/8)
(10-28)
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1.0n
0.0
0.0001
0.0010
0.0100
0.1000
1.0000
10.0000
Di/2 Q-i/8
Figure 10-23. Inspiratory deposition efficiency data in human oral casts plotted versus
Q-i/8Di/2 (LmhvV^cnvV1)172. The solid curve represents equation
(10-27) and the broken curves are the 95% confidence limits.
Source: Cheng et al. (1993).
1 for expiration. The inspiratory deposition efficiency function fit to the data is shown in
2 Figure 10-23. Contrary to nasal deposition, deposition in the mouth is slightly higher for
3 inspiration than for expiration.
4
5 10.5.1.3 Tracheobronchial (TB) Deposition
6 Particles escaping from deposition in the ET region enter the lung, but their regional
7 deposition in the lung cannot be precisely measured. All the available regional deposition
8 data have been obtained from experiments with radioactive labeled insoluble particles above
9 0.1 /im in diameter. The amount of activity retained in the lung as a function of time
10 normally exhibits a fast and slow decay component which have been identified as mucociliary
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1 and macrophage clearance. Since the tracheobronchial airways are ciliated, the rapidly
2 cleared fraction of initial activity can be considered as a measure of the amount of material
3 deposited in the TB region, whereas the slowly cleared fraction corresponds to the material
4 deposited in the A region. However, there is experimental evidence that a significant
5 fraction of material deposited in the TB region is retained much longer than 24 h (Stahlhofen
6 et al., 1986a,b; Scheuch and Stahlhofen, 1988; Smaldone et al., 1988). This may be caused
7 by the fact that the TB airway surface is lined with ciliated epithelium, but not all of the
8 ciliated epithelium is covered with mucus all the time (Stahlhofen et al., 1989). Other
9 mechanisms for prolonged TB clearance include phagocytosis by airway macrophages and
10 deposition of particles further down into the A region due to mixing of flow during
11 inspiration. Thus, tracheobronchial and pulmonary deposition measured based upon the
12 clearance of radioactive labeled particles have been suggested as the "fast-cleared" and
13 "slow-cleared" thoracic deposition (Stahlhofen et al., 1989).
14 Figure 10-24 shows the data from various investigators (Lippmann, 1977; Foord et al.,
15 1978; Chan and Lippmann, 1980; Emmett et al., 1982; and Stahlhofen et al., 1980, 1981,
16 1983) on TB deposition or fast-cleared thoracic deposition for mouth breathing as a function
17 of dae reported by Stahlhofen et al. (1989). Again, the data are quite scattered due to
18 differences in experimental technique and intersubject and intrasubject variabilities that have
19 been cited previously. Another cause for the scatter is from the difference in the flow rate
20 employed by various studies. For dae > 0.5 /xm, deposition in the TB region is contributed
21 by both impaction and sedimentation. Whereas the impaction deposition is governed by the
22 parameter dae2Q, sedimentation deposition is controlled by the parameter dae2/Q. It is
23 therefore not possible to have a single relationship between deposition and dae for different
24 flow rates.
25 Data in Figure 10-24 show that TB deposition does not increase monotonically with dae.
26 A higher dae leads to a greater ET deposition and consequently a lower TB deposition. For
27 the range of flow rates employed in various studies, the maximum TB deposition occurs at
28 about 4 pm dae. It is also seen that the data by Stahlhofen et al. (1980, 1981, 1983) in
29 Figure 10-24 are considerably lower than those from other investigators. Chan and
30 Lippmann (1980) cited two possible reasons for this difference. One was that Stahlhofen and
31 coworkers used constant respiratory flow rates in their studies as opposed to the variable
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LO-
"IB
t
0.8-
0.6-
0.4-
0.2-
Q.cm3^ V.cm3
A~500 ~1,000 Lippmann 1977
• 500 1,000 Foordetal. 1978
• ~500 ~1,000 Chan & Lippmann 1980
n 333 1,000 Emmettetal. 1982
<> 250 250
A 250 500
O 250 1,000
O 750 1,500
1980
Stahlhofen et al. - 1981
1983
0.1
ae
Figure 10-24. TB deposition data in humans at mouth breathing as a function o
The solid curve represents the approximate mean of all the experimental
data; the broken curve represents the mean excluding the data of
Stahlhofen et al.
Source: Stahlhofen et al. (1988).
1
2
3
4
5
6
7
8
9
10
11
flow rates used by others. The second reason was that different methods of separating the
initial thoracic burden into TB and A regions were used. Stahlhofen et al. (1980)
extrapolated the thoracic retention values during the week after the end of fast clearance back
to the time of inhalation; they considered A deposition to be the intercept at that time, with
the remainder of the thoracic burden considered as TB deposition. This approach yields
results similar to, but not identical with, those obtained by treating TB deposition as
equivalent to the particles cleared within 24 h. Another possibility for the differences is that
Fe2O3 particles used in experiment by Chan and Lippman (1980) are hygroslopic, resulting
in higher TB deposition.
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1
2
3
4
5
6
7
8
9
10
11
10.5.1.4 Alveolar Deposition
The A deposition data as a function of dae for mouth breathing are shown in
Figure 10-25. These data are from the same studies which reported TB deposition in
Figure 10-24 but there is a better agreement between different studies than with the TB data.
Alveolar deposition is favored by slow and deep breathing. The data of Stahlhofen et al.
(1980, 1981, 1983) at 1000 cm3 tidal volume and 250 cm3/sec flow rate thus are higher than
other data. Figure 10-25 also shows that A deposition reaches the maximum at about
3.5 /mi dae and that for dae between 0.2 /mi and 1.0 /mi, A deposition does not show
significant change although a minimum deposition may occur near 0.5 /im.
DE*
t
0.1
dae /
Figure 10-25. Slow-cleared or alveolar deposition data in humans as a function of dae.
The solid curve represents the mean of all the data; the broken curve is
an estimate of deposition for nose breathing by Lippmann (1977).
Source: Stahlhofen et al. (1988).
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1 By switching from mouth breathing to nose breathing, alveolar deposition will decrease.
2 Lippmann (1977) made an estimate by analysis of the difference in the ET deposition for
3 nose and mouth breathing. The nose breathing result is also shown in Figure 10-25. For
4 dae greater than 7 /mi, practically no particles deposit in the A region in this breathing mode.
5 During exercise, most subjects switch from nose breathing to breathing partly through
6 the mouth (Niinimaa et al., 1981). The amount of inhaled material that deposits in the lungs
7 is affected because mouth and nose have different filtration efficiencies. Niinimaa et al.
8 (1981) found that in thirty subjects, twenty switched to oro-nasal breathing (normal
9 augmenters), typically at a ventilation rate of about 35 L/min, five continued to breathe
10 through the nose, the rest who were habitual mouth breathers breathed oro-nasally at all
11 levels of exercise. These data were reviewed by Miller et al. (1988) and used to estimate
12 thoracic deposition (TB and A deposition) at different ventilation rates. At higher ventilation
13 rate, Miller et al. (1988) predicted little difference in thoracic deposition between normal
14 augmenters and mouth breathers, but for ventilation rate less than 35 L/min they predicted
15 substantially lower deposition in normal argumenters compared to mouth breathers. Based
16 upon this finding, ICRP (1994) recommended a different breathing pattern for normal
17 augmenters and mouth breathers that typifies the breathing habits of adult males as a function
18 of ventilation rate. The split in airflow for the recommended breathing patterns by ICRP
19 (1994) is shown in Figure 10-26. Table 10-11 provides the same information on the
20 percentages of total ventilatory airflow passing through the nose versus mouth at reference
21 levels of physical exertion for a normal augmenter and a mouth breather adult male. These
22 are the same levels of exercise and values for fraction of nasal ventilatory airflow used to
23 construct the activity patterns in Section 10.7. In the absence of specific data, it must be
24 assumed that a similar breathing pattern applies to young healthy subjects at equivalent levels
25 of exercise. Alveolar deposition at different ventilation rates can be estimated from Figure
26 10-26 or Table 10-11. For example, a mouth breather doing light exercise (VE = 1.5 m3/h)
27 has about 40% ventilatory air-flow passing through the nasal route. At a particle size of 2
28 /urn dae Figure 10-26 gives, respectively, 0.24 and 0.36 A deposition for mouth and nose
29 breathing. Thus, the resultant A deposition at this ventilation rate is 0.4 x 0.36 -I- 0.6 X
30 0.24 = 0.288.
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100
80
LJJ
60
-------
1 10.5.1.5 Nommiform Distribution of Deposition and Local Deposition Hot Spots
2 The deposition data in different regions of the respiratory tract presented above do not
3 provide information on deposition nonuniformity in each region and local deposition intensity
4 at a specific site. Such information may be of great importance from a toxicology
5 perspective. Because airway structure and its associated air flow patterns are exceedingly
6 complex (Change and Menon, 1993), and ventilation distribution of air in different parts of
7 the lung is uneven (Milic-Emili et al., 1966), it is expected that particle deposition patterns in
8 ET, TB and A regions are highly nonuniform. Fry and Black (1973) measured regional
9 deposition in the human nose using radiolabelled particles and found that most of deposition
10 occurred in the anterior region of the nose. Sclesinger and Lippmann (1978) found
11 nonuniform deposition in the trachea by the airflow disturbance of the larynx. In a single
12 airway bifurcation model, measurements show that deposition occurs principally around the
13 carinal ridge (e.g., Bell and Friedlander; Lee and Wang, 1977) Martonen and Lowe, 1983;
14 Kim and Iglesias, 1989 a,b). Similar result was observed in the alveolar duct bifurcations in
15 rats and mice (Brody and Roe, 1983). Figure 10-27 shows the data on local deposition
16 pattern obtained by Kim and Iglesias (1989a,b) in a bifurcating tube for both inspiration and
17 expiration. The peak deposition occurs in the daughter tube during inspiration and the parent
18 tube during expiration, but always near the carinal ridge. In addition, airways are not
19 smooth tubes. More recently, Martonen et al. (1994 a,b,c) have called attention to the
20 existence of cartilaginous rings on the wall of airways in the tracheobronchial region. Using
21 a numerical analysis, they showed that such surface structure can lead to a considerable
22 alteration of the flow pattern and enhancement of deposition.
23 Deposition measurements in small rodents (Raabe et al., 1977) also showed differences
24 in lobar distribution with up to 60 percent higher than the average in the right apical lobe
25 (corresponding to the human upper lobe). The difference was greater for large particles than
26 for small particles. Raabe et al. (1977) further showed that these differences in relative lobar
27 deposition were related to geometric mean number of airway bifurcations between trachea
28 and terminal bronchioles in each lobe for rats and hamsters. Since similar morphologic
29 differences occur in the human lungs, nonuniform lob distribution should also occur.
April 1995 10-100 DRAFT-DO NOT QUOTE OR CITE
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100 -,
80-
60-
•8
3S
40-
20-
r
A
I I
B C
Branch Sections
\
D
•5
100 -,
80-
60-
40-
20-
o 6-30°
6-45°
A
B C
Branch Sections
Figure 10-27. Local deposition pattern in a bifurcating tube for inhalation (top panel)
and exhalation (bottom panel).
Source: Kim and Iglesias (1989a,b).
1 10.5.1.6 Summary
2 Mathematical models of lung deposition have been developed in recent years to help
3 interpret experimental data and to make predictions of deposition for cases where data are
4 not available. A review of various mathematical models was given by Morrow and Yu
5 (1993). There are three major elements involved in mathematical modeling. First, a model
6 of airways simulating the real structure must be specified. Secondly, deposition efficiency in
7 each airway due to various mechanisms must be derived. Finally, a computational procedure
8 must be developed to account for the transport and deposition of the particles in the airways.
9 Three different approaches have been used in the mathematical modeling. The first
10 approach is a compartmental model first formulated by Findeisen (1935). Starting with the
11 trachea, Findeisen divided the airways into nine compartments based upon the anatomical
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1 structure. Particles which did not deposit in one compartment remained airborne and
2 transported to the next compartment for deposition. Findeisen's lung model and analysis
3 were later modified by Landahl (1950a, 1963) and Beeckmans (1965). Detailed calculations
4 of regional deposition with additional consideration of nasal deposition based upon the
5 Findeisen-Landahl-Beeckmans theory were later published in a report by the Task Group on
6 Lung Dynamics (TGLD) in 1966.
7 Because of advancement in measuring techniques, refined airway models have become
8 available (as discussed in Section 10.2). Several new models based upon the compartmental
9 analysis have been proposed (e.g., Gerrity et al., 1979; Yeh and Schum, 1980; Martonen
10 and Graham, 1987). The expressions used for deposition efficiency of each compartment
11 differed somewhat in these models. In the absence of any careful comparison with the
12 experimental data, it is difficult to assess the applicability of these models to deposition
13 prediction. However, one difficulty often encountered in the compartmental model is the
14 derivation of deposition efficiency in each airway for combined mechanisms of impaction,
15 sedimentation and diffusion. A commonly used assumption is that each deposition
16 mechanism is independent, thus the joint efficiency can be written in the form
17
r, = l-d-ifcXl-ifcXl-i/u), (10-29)
18
19 where T/J, r;s, and r/D are, respectively, deposition efficiency in an airway or compartment by
20 the individual mechanisms of impaction, sedimentation and diffusion, and tj is th joint
21 efficiency. Yu et al., (1977) have shown, in a detailed mathematical analysis of a combined
22 sedimentation and diffusion problem, that the above equation is an inaccurate expression of
23 deposition when r/ s and r;D are not small and have about the same magnitude. Another
24 difficulty in the compartmental model is that air-mixing effect (mixing of tidal air and lung
25 air) on deposition cannot be easily accounted for. Such effect is important for transient
26 exposure. However, the compartmental model is easy to formulate and to understand
27 conceptually.
28 The second approach to deposition modeling was put forward by Yu and coworkers
29 (Taulbee and Yu, 1975; Yu, 1978; Yu and Diu, 1983) and later by Egan et al. (1985, 1989).
April 1995 10-102 DRAFT-DO NOT QUOTE OR CITE
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1 In this approach, the many generations of airways are viewed as a chamber shaped like a
2 trumpet. The cross-sectional area of the chamber varies with airway depth measured from
3 the beginning of the trachea according to the anatomical data. The concentration of inhaled
4 particles in the chamber as a function of airway depth and time during breathing is described
5 by a convective diffusion equation with a loss-term accounting for airway deposition. This
6 equation can be solved either exactly (without longitudinal diffusion) or numerically with
7 appropriate initial and boundary conditions. Deposition at different sites in the airways in
8 then calculated once the concentration is known.
9 The deposition model formulated in this manner has some advantages over the
10 compartmental model. First, the use of differential airway length in the model allows the
11 joint deposition efficiency per unit airway length to be the superposition of efficiencies by
12 each individual mechanism. Secondly, the variation of airway dimensions during breathing is
13 accounted for in the model. Thirdly, the model is time-dependent, thus can be applied to
14 any breathing pattern and transient exposure condition. Fourthly, air-mixing and uneven
15 airway path lengths can be accounted for with the use of an equivalent longitudinal diffusion
16 term in the convective-diffusion equation. Finally, in the case of no longitudinal diffusion,
17 the exact solution of the convective-diffusion is obtainable, thus reducing the time required
18 for deposition calculation.
19 The airway geometry of the human lungs is not identical over a population. In a given
20 lung, the dimension of the airways in a specified generation is also not uniform and the
21 bifurcation is not symmetric (Weibel, 1963). The above two approaches of modeling have
22 been extended to account for the randomness of the airway geometry (Yu et al., 1979; Yu
23 and Diu, 1982a,b; Koblinger and Hofmann, 1990; Hofmann and Koblinger, 1990). Yu and
24 Diu (1982b) compared their modeling results with total and regional deposition data of
25 Stahlhofen et al. (1981) and Heyder et al. (1982) at controlled breathing and found that the
26 difference in lung morphology was probably the principal cause for intersubject variability
27 observed in deposition.
28 Another approach to deposition modeling is an empirical one proposed by Rudolf et al.
29 (1983, 1984, 1986, 1990) similar to that developed for ET deposition. This model considers
30 the lung as a series of two filters representing the TB and A regions of the lung. The model
31 requires no assumptions on airway geometry, airflow pattern and distribution, nor on particle
April 1995 10-103 DRAFT-DO NOT QUOTE OR CITE
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1 deposition efficiency in each airway. However, the construction of the model relies heavily
2 on experimental data of regional deposition for a wide range of particle sizes (monodisperse)
3 and breathing conditions. These data are not always available. Additional difficulty in the
4 empirical modeling is the development of deposition equations in each region for combined
5 deposition mechanisms. As discussed earlier, impaction, sedimentation and diffusion
6 deposition depend, respectively, on the parameters dae2Q, Dae2/Q and D/Q, where D is a
7 function of particle geometrical diameter. It is a very difficult task to come up with an
8 equation for deposition in terms of these parameters which can match all experimental data.
9 Furthermore, because only a few compartments are used in the empirical model, more
10 detailed deposition information such as deposition at a specific air-way generation cannot be
11 predicted. However, as mentioned, with an empirical model the geometry and relative
12 importance of mechanisms and airflow splits are all "correct" in the subjects tested and are
13 reflected in the measured deposition. This may be an advantage over theoretical models that
14 must rely on extremely limited information on geometry. An empirical model is simple
15 mathematically and a semi-emperical model has been adopted by the International
16 Commission on Radiological Protection (ICRP66, 1994) for deposition predictions with a
17 theoretical component for scaling size between gender and different ages.
18
19 10.5.2 Laboratory Animals
20 Since much information concerning inhalation toxicology is collected with canines or
21 rodents, the comparative regional deposition in these experimental animals must be
22 considered to help interpret, from a dosimetric viewpoint, the possible implications of animal
23 toxicological results to humans. In evaluating deposition studies in terms of interspecies
24 extrapolation, it is not adequate to express the amount of deposition merely as a percentage
25 of the total inhaled. For some particle sizes, regional deposition in humans and experimental
26 animals may be quite similar and appears to be species independent (McMahan et al., 1977;
27 Brain and Mensah, 1983). However, different species exposed to identical particles at the
28 same exposure concentration will not receive the same particle mass per unit exposure time
29 because of their differences in tidal volume and breathing rate. In addition, because of
30 differences in the lung weight and airway surface area, the amount of deposition normalized
31 to these quantities are also very different between species.
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1 However, it is difficult to systematically compare interspecies deposition patterns
2 obtained from various reported studies, because of variations in experimental protocols,
3 measurement techniques, definitions of specific respiratory tract regions, and so on. For
4 example, tests with humans are generally conducted under protocols that standardize the
5 breathing pattern, whereas those using experimental animals involve a wider variation in
6 respiratory exposure conditions (for example, spontaneous breathing versus controlled
7 breathing as well as various degrees of sedation). Much of the variability in the reported
8 data for individual species is due to the lack of normalization for specific respiratory
9 parameters during exposure. In addition, the various studies have used different exposure
10 techniques, such as nasal mask, oral mask, oral tube, or tracheal intubation. Regional
11 deposition may be affected by the exposure route and delivery technique employed.
12 Figure 10-28 shows the regional deposition data versus particle diameter in commonly
13 used experimental animals obtained by various investigators and compiled by Schlesinger
14 (1988). Although there is much variability in the data, it is possible to make some
15 generalizations concerning comparative deposition patterns. The relationship between total
16 respiratory tract deposition and particle size is approximately the same in humans and most
17 of these animals; deposition increases on both sides of a minimum, which occurs for particles
18 of 0.2 to 0.9 fj.m. Interspecies differences in regional deposition occur due to anatomical and
19 physiological factors. In most experimental animal species, deposition in the ET region is
20 near 100 percent for dae greater than 2 ^m, indicating greater efficiency than that seen in
21 humans. In the TB region, there is a relatively constant, but lower, deposition fraction for
22 dae greater than 1 /un in all species compared to humans. Finally, in the A region,
23 deposition fraction peaks at a lower particle size (dae about 1 pirn) in experimental animals,
24 than in humans.
25 Asgharian et al. (1995) developed an empirical model of particle deposition in the A
26 region based on the published data of Schlesinger (1985). Although restricted to the A
27 region, the approach could be applied to other regions. A deposition function (tj) was
28 described using a polynomial regression of the form
- N ajOog^d)4 for d
-------
IUU
80
60
40
20
n
i
o
D
i i life90
Rat II F
Hamster &\
A Mouse 1 1
O Guinea Pig Q
V
ET
-
-
V
i
Dog
/
, _
L
1
I
Ja[ -
svl ~
kte ^ d5a f1
^T
0.5 pan and geometric (or diffusion equivalent) for those < 0.5 urn.
Source: Schlesinger (1988).
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10-106 DRAFT-DO NOT QUOTE OR CITE
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r,(d)=0 for d >dcut.off. (10-31)
1
2 where N is the degree of the polynomial, d is the particle diameter in micrometers, and dcut.
3 off is the diameter at which the deposition efficiency becomes zero. Since Equation 10-30 is
4 a 4th-degree polynomial, it will give a non-zero value for dcut.off. For this reason, Equation
5 10-31 was added to be consistent with the deposition data and dcut.off was determined by
6 setting Equation 10-30 to zero. Newton's method was employed to find d^.^ for different
7 cases. Particle deposition was then integrated with particle distributions differing in median
8 particle and ae to calculate deposition mass fraction. The approach is similar to that
b
9 employed by Menache et al. (1995) but inhalability was not addressed. Also, the deposition
10 data set included both monodisperse and polydisperse particles which may have contributed
11 to scatter in the particle size versus deposition efficiency data.
12 Mathematical deposition models in rats, hamsters, and guinea pigs have been developed
13 by several investigators (e.g., Schum and Yeh, 1980; Xu and Yu, 1987; Martonen et al.,
14 1992) in a similar manner as the human models without including diffusion deposition in the
15 ET region. Although the modeling results are generally in agreement with experimental
16 data, there is a considerable uncertainty in the respiratory parameters of the laboratory
17 animals used in the modeling studies. In addition, the airway branching patterns in the
18 animals are commonly monopodial as compared to the dichotomous branching in the human
19 lung. The deposition efficiency of an airway (the amount of deposition in an airway divided
20 by the amount entered) developed in the human model may not be applicable to laboratory
21 animal species. Despite some of these difficulties, modeling studies in laboratory animals
22 remain to be a useful step to extrapolate exposure-dose-response relationships from
23 experimental animals to the human (Yu et al., 1991).
24 Menache et al. (1995a) developed a revised empirical model to estimate fractional
25 regional deposition efficiency for dosimetric adjustment factors used in the U.S. EPA's
26 methodology for derivation of inhalation dose-response estimates or inhalation reference
27 concentrations (U.S. Environmental Protection Agency, 1994). This approach will be
28 described more fully in Section 10.7. This revised model represents significant refinement of
29 previously published models used for dosimetric interspecies extrapolation in the 1990
April 1995 10-107 DRAFT-DO NOT QUOTE OR CITE
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1 interim RfC methods (Jarabek et al., 1989, 1990; Miller et al., 1988). For example, rather
2 than linear interpolation between the published (Raabe et al., 1988) means for deposition
3 measured at discrete particle diameters, as previously done for the laboratory animal
4 deposition modeling, equations have now been fit to an expanded set of raw data.
5 The equations describing fractional deposition were fit using data on particle deposition
6 in CFj mice, Syrian golden hamsters, Fischer 344 rats, Hartley guinea pigs, and New
7 Zealand rabbits. A description of the complete study including details of the exposure may
8 be found elsewhere (Raabe et al., 1988). Briefly, the animals were exposed to radiolabelled
9 ytterbium (169Yb) fused aluminosilicate spheres in a nose-only exposure apparatus. Twenty
10 unanesthetized rodents or eight rabbits were exposed simultaneously to particles of
11 aerodynamic diameters (dae) about 1, 3, 5, or 10 /mi. Half the animals were sacrificed
12 immediately post exposure; the remaining half were held 20 h post exposure. One-half of
13 the animals at each time point were male and the other half were female. The animals were
14 dissected into 15 tissue compartments, and radioactivity was counted in each compartment.
15 The compartments included the head, larynx, GI tract, trachea, and the five lung lobes. This
16 information was used directly in the calculation of the deposition fractions. Radioactivity
17 was also measured in other tissues including heart, liver, kidneys, and carcass; and
18 additionally in the urine and feces of a group of animals held 20 h. In the animals sacrificed
19 immediately post exposure, these data were used to ensure that there was no contamination
20 of other tissue while the data from the animals held 20 h were used in the calculation of a
21 fraction used to partition thoracic deposition between the TB and A regions. This partition is
22 discussed below briefly and described in detail elsewhere (Raabe et al., 1977). Finally,
23 radioactivity was measured in the pelt, paws, tail, and headskin as a control on the exposure.
24 Although there are some other studies of particle deposition in laboratory animals (see
25 review by Schlesinger, 1985), no other data have the level of detail or the experimental
26 design (i.e., freely breathing, unanesthetized, nose-only exposure) required to provide
27 deposition equations representative of the animal exposures used in many inhalation
28 toxicology studies. However, many inhalation toxicology studies are not nose-only
29 exposures. While this is a necessary exposure condition to determine fractional particle
30 deposition, adjustments for particle inhalability and ingestion can be made to estimate
31 deposition fractions under whole-body exposure conditions.
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1 The advantages of using the data of Raabe et al. (1988) to develop the deposition
2 equations include:
3
4 • the detailed measurements were made in all tissues in the animal, providing mass
5 balance information and indicating that there was no contamination of nonrespiratory
6 tract tissue with radioactivity immediately post exposure,
7
8 •the use of five species of laboratory animals under the same exposure conditions,
9
10 • the use of unanesthetized, freely breathing animals, and
11
12 • the use of an exposure protocol that makes it virtually impossible for the animals to
13 ingest any particles as a result of preening.
14
15 Regional fractional deposition, Fr, was calculated as activity counted in a region
16 normalized by total inhaled activity (Table 10-12). The proportionality factor, fL, in
17 Equations 10-33 and 10-34 is used to partition thoracic deposition between the TB and A
18 regions. It was calculated using the 0 and 20-h data and is described in detail by Raabe and
19 co-workers (1977).
20
21
TABLE 10-12. REGIONAL FRACTIONAL DEPOSITION
P _ Activity Counted in a Region
r Total Inhaled Activity ~
[head + GI tract + larynxln ,, 1A ~~
Extrathoracic (ET): FFT = Oh 10-32
bl Total Inhaled Activity
5
tracheao h + fL x £ lobei>0 h 10_33
Tracheobronchial (TB): FTB = - i=1
Pulmonary (PU): FPU = i=1
Total Inhaled Activity
5
- fL) x £ lobei)0 h 10_34
Total Inhaled Activity
Source: U.S. Environmental Protection Agency (1994).
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1 These regional deposition fractions, Fr, however, are affected not only by the minute
2 volume (VE), MMAD and 0.5 /xm, efficiencies increase
7 monotonically and are bounded below by 0 and above by 1. The logistic function has
8 mathematical properties that are consistent with the shape of the efficiency function (Miller et
9 al., 1988)
10
11 E(rjr) = ^[og x, (10-35)
12
13 where E(r/r) is the expected value of deposition efficiency (r;r) for region r, and x is
14 expressed as an impaction parameter, dae2Q, for extrathoracic deposition efficiency and as
15 aerodynamic particle size, dae, for TB and PU deposition efficiencies. The flow rate, Q, in
16 the impaction parameter may be approximated by VE/30. The parameters a and /3 are
17 estimated using nonlinear regression techniques.
18 To fit this model, efficiencies must be derived from the deposition fractions that were
19 calculated as described in Table 10-12. Efficiency may be defined as activity counted in a
20 region divided by activity entering that region. Then, considering the region as a sequence
21 of filters in steady state, efficiencies may be calculated as follows
22
23 r,ET = FET (10-36)
24 5
25 trachea0 h + fL x £ Iobeit0 h
26 'ID (1 - r?ET)
27
28 5
29 <* - fL> x £ lobei,o h ao-38)
30 'ru (1 - i?ET) (1 - rjTB)
31
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1
2
3
4
5
6
7
8
9
Using these calculated regional efficiencies in the individual animals, the logistic
function was fit for the ET, TB, and A regions for the five animal species and
parameter estimates from these fits are listed in Table 10-13. Curves produced
humans. The
by these
equations have been compared where applicable to the data reported in Schlesinger (1985),
and the results are not inconsistent. As discussed by Schlesinger (1985), there
are many
sources of variability that could explain differences in predicted deposition using this model
and the observed deposition data in the studies reported by Schlesinger (1985).
TABLE 10-13. DEPOSITION EFFICIENCY EQUATION
ESTIMATED PARAMETERS
ET (Nasal) TB
Species a (3 a j3 a
Human 7.1293 -1.957a 3.298 -4.588 0.523
Rat 6.559 -5.524 1.873 -2.085 2.240
Mouse 0.666 -2.171 1.632 -2.928 1.122
Hamster 1.969 -3.503 1.870 -2.864 1.147
Guinea Pig 2.253 -1.282 2.522 -0.865 0.754
Rabbit 4.305 -1.628 2.819 -2.281 2.575
PU
18
-1.389
-9.464
-3.196
-7.223
0.556
-1.988
"Source: Miller et al., 1988.
1 The fitted equations are then used to generate predicted efficiencies (r)) as a function of
2 impaction in the ET region and of aerodynamic particle size in the TB and A regions.
3 Finally, the predicted efficiencies are multiplied together and adjusted for inhalability, I, as
4 shown in Equations 10-39 through 10-41 to produce predicted deposition fractions (Fr) for
5 monodisperse and near monodisperse (ag < 1.3) particles
6
7 FET = I x r)ET (10-39)
8
9 FTB = I X (1 - f,ET) x r,TB (10-40)
10
11 FPU = I x (1 - r,ET) x (1 - r)TB) x T)PU. (10-41)
April 1995 10-111 DRAFT-DO NOT QUOTE OR CITE
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1 Inhalability, I, is an adjustment for the particles in an ambient exposure concentration
2 that are not inhaled at all. For humans, an equation has been fit using the logistic function
3 (Menache et al., 1995b). Using the experimental data of Breysse and Swift (1990):
4
5
6 The logistic function was also fit to the data of Raabe et al. (1988) for laboratory animals
7 (Menache et al., 1995b):
8
1 = 1- _ 1 _ . (10-43)
j + e2.57-2.81 Iog10dae ^ U 9)
9
10 Figure 10-29 illustrates the relationship between the predicted efficiencies and predicted
11 depositions using this model for the mice. A qualitatively similar set of curves could be
12 produced for any of the other four species. The particles were assumed to be monodisperse.
13 A default body weight (BW) for the mice of 0.0261 kg was used to calculate a default VE
14 using allometric scaling (U.S. Environmental Protection Agency, 1994). Regional deposition
15 efficiencies and fractions were calculated for particles with dae ranging from 0.5 to 10 pm.
16 These calculated points were connected to produce the smooth curves shown in Figure 10-29.
17 The three panels on the left of Figure 10-29 are plots of the predicted regional deposition
18 efficiencies; the three panels on the right show the predicted regional deposition fractions
19 derived from the estimated efficiencies and adjusted for inhalability. The vertical axis for the
20 predicted deposition efficiency panels range from 0 to 1 . Although the deposition fraction is
21 also bounded by 0 and 1, the vertical axes in the figure are less than 1 in the TB and
22 A regions. The top two panels of Figure 10-29 are the predicted deposition efficiency and
23 fraction, respectively, for the ET region. These two curves are plotted as a function of the
24 impaction parameter described for Equation 10-35. The middle two and lower two panels
25 show the predicted deposition efficiencies and fractions for the TB and A regions,
26 respectively. These four curves are plotted as a function of dae. When a particle is from a
27 monodisperse size distribution, the dae and the MM AD are the same. If, however, the
April 1995 10-112 DRAFT-DO NOT QUOTE OR CITE
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Predicted Regional Deposition Efficiency
Predicted Regional Deposition Fraction
1.0
g.0.8
£ 0.6
is
t) 0.4
02
0.0
0.1 1 10
Impaction, (\im)2 ml/sec
1.0
0.8
io.6
tj 0.4
02.
0.0
100 0.1 1 10
Impaction, (urn)2 ml/sec
100
10
Aerodynamic diameter, urn
Aerodynamic diameter,
1.0
0.8
s
I
0.6
'0.4
02
0.0
0.1 1
Aerodynamic diameter, urn
0.03
-n 0.00
10
0.1 1
Aerodynamic diameter, urn
n
10
Figure 10-29. Comparison of regional deposition efficiencies and fractions for the
mouse. A default body weight of 0.0261 kg (U.S. Environmental
Protection Agency, 1994) was used in these calculations. The fractional
deposition (solid line) and inhalability (dashed line) are shown in the
upper right panel.
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1 particle is from a polydisperse size distribution, the particle can not be described by a single
2 dae; the average value of the distribution, the MMAD, must be used. In the aerodynamic
3 particle size range, the deposition efficiency curves all increase monotonically as a function
4 of the independent variable (i.e., either the impaction parameter or dae) and have both lower
5 and upper asymptotes. The curves describing the deposition fractions, however, have
6 different shapes that are dependent on the respiratory tract region. Deposition fractions in all
7 three regions are nonmonotonic—initially increasing as a function of particle size but
8 decreasing as particle sizes become larger. This is because particles that have been deposited
9 in proximal regions are no longer available for deposition in distal regions. As an extreme
10 example, if all particles are deposited in the ET region, no particles are available for
11 deposition in either the TB or A regions. In the ET region, the nonmonotonic shape for
12 fractional deposition is due to the fact that not all particles in an ambient concentration are
13 inhalable.
14 As discussed in Section 10.2, particles in an experimental or ambient exposure are
15 rarely all a single size but rather have some distribution in size around an average value.
16 As this distribution becomes greater, the particle is said to be polydisperse. Panel A of
17 Figure 10-30 illustrates the range of particle sizes from a distribution that is approximately
18 monodisperse (ag = 1.1) and particles that come from a lognormal highly polydisperse
19 distribution (
-------
1.0
u.
§ °-8
1
S- 0.4
OX)
0.1
f(dae)
Lognormal Distribution
og-1.0 MMAD-4.0 urn
10 20 30 40
Aerodynamic Diameter (dge),
Extrathoracic Deposition
Mouse
(B)
1.0
0.8
0.4
02
0.0
10
0.1
MMAD, jim
(A)
SO
GO
Extrathoracic Deposition
Human
(C)
-1.0
10
MMAD, |
Figure 10-30. Range of particles for lognormal distributions with same MMAD but
differing geometric standard deviations (A). Effect of poly disperse
particles on predicted extrathoracic deposition fractions in mice (B) and
humans (C).
1
2
3
4
5
6
7
X
1
dae(log(O\/27r
x exp
-1/2-
(logdae - logMMAD)2
dd.
(10-44)
ae
where log refers to the natural logarithm, [Fr]p is the predicted polydisperse fractional
deposition for a given MMAD, and [Fr]m is the predicted monodisperse fractional deposition
for particles of size dae. The limits of integration are defined from 0 to oo but actually
include only four standard deviations (99.95% of the complete distribution). For each
particle size in the integration, [Fr]m is calculated and then multiplied by the probability of
observing a particle of that size in a particle size distribution with that MMAD and
-------
1 Panels B and C of Figure 10-30 illustrate one of the principal effects of polydisperse
2 particle size distributions on predicted deposition fractions in the ET region, which is to
3 flatten the deposition curve as a function of MM AD. This same effect is observed also in
4 the TB and PU regions. (Note that the curves in panels B and C are expressed as a function
5 of MMAD. They were generated as a function of the impaction parameter but are expressed
6 as a function of MMAD for ease of comparison between species. A VE of 37.5 mL/min was
7 used for the mouse and of 13.8 L/min for the human.) Rudolf and colleagues (1988) have
8 also investigated the effect of polydisperse particle size distributions on predicted regional
9 uptake of aerosols in humans and present a more detailed discussion of these and related
10 issues.
11
12 10.5.3 Acidic Aerosols
13 Experimental studies on deposition of acid aerosols are limited. There have been two
14 studies in experimental animals using H2SO4 aerosols. Dahl and Griffith (1983) measured
15 regional deposition of these aerosols in the size range from 0.4 to 1.2 /mi MMAD generated
16 at 20% and 80% relative humidities. Their data showed greater total and regional deposition
17 of H2S04 aerosols in rats compared to nonhygroscopic aerosols having the same MMAD's
18 (Figure 10-31). Deposition of H2SO4 aerosols generated at 20% RH was also higher than
19 those generated at 80% RH, indicating that the increase in deposition was caused by the
20 growth of the particles in the highly humid environment of the respiratory tract.
21 However, a similar study by Dahl et al. (1983) found that deposition of H2SO4 aerosols
22 in beagle dogs at these two relative humidities was similar to that of nonhygroscopic aerosols
23 having the same size although deposition at 20% RH was again higher than that at 80% RH.
24 The inconsistent results were explained by Dahl et al. (1985) to be caused by the large
25 intersubject variability of deposition in dogs.
26 In humans, deposition of acid aerosols in the respiratory tract has only been obtained by
27 model studies. In a recent study, Martonen and Zhang (1993) calculated deposition of
28 H2SO4 aerosols in the human lung of various ages at three different activity levels. The
29 H2SO4 aerosols was considered to be in equilibrium with atmospheric conditions outside the
30 lung prior to being inhaled. The results of their calculation at rest breathing without
31 considering extrathoracic deposition are shown in Figure 10-32. Comparing to
April 1995 10-116 DRAFT-DO NOT QUOTE OR CITE
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Tracheocbronchial Deposition Fraction
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1 hygroscopicity of H2SO4 aerosols is to increase total lung deposition, whereas for smaller
2 particles the opposite occurs.
3
4
5 10.6 CLEARANCE DATA AND MODELS
6 As discussed in previous sections, the biologic effects of inhaled particles are a function
7 of their disposition. This, in turn, depends on their patterns of both deposition — i.e., the
8 sites within which they initially come into contact with airway epithelial surfaces and the
9 amount removed from the inhaled air at these sites, and clearance — i.e., the rates and
10 routes by which deposited materials are physically removed from the respiratory tract.
11 Deposition and clearance mechanisms were discussed in Sections 10.5 and 10.6, respectively.
12 Respiratory-tract clearance begins immediately upon deposition of inhaled particles.
13 Given sufficient time, the deposited particles may be completely removed by these clearance
14 processes. However, single inhalation exposures may be the exception rather than the rule.
15 It is generally accepted that repeated or chronic exposures are common for environmental
16 aerosols. As a result of such exposures, A accumulations of the particles may occur.
17 Chronic exposures produce respiratory tract burdens of inhaled particles that continue to
18 increase with time until the rate of deposition is balanced by the rate of clearance. This is
19 defined as the "equilibrium respiratory tract burden". The accumulation patterns are unique
20 to each laboratory animal species, and possibly unique to the inhaled material, especially if
21 the inhaled material alters deposition and/or clearance patterns.
22 It is important to evaluate these accumulation patterns, especially when assessing
23 ambient chronic exposures, because they dictate what the equilibrium respiratory tract
24 burdens of inhaled particles will be for a specified exposure atmosphere. Equivalent
25 concentrations can be defined as "species-dependent concentrations of airborne particles
26 which, when chronically inhaled, produce equal lung deposits of inhaled particles per gram
27 of lung during a specified exposure period". This section presents available data and
28 approaches to evaluating exposure atmospheres to laboratory animals and humans that
29 produce similar respiratory tract burdens.
30
31
April 1995 10-119 DRAFT-DO NOT QUOTE OR CITE
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1 10.6.1 Humans
2 Models for deposition, clearance, and dosimetry of the respiratory tract of humans have
3 been available for the past four decades and continue to evolve. The International
4 Commission on Radiological Protection (ICRP) has recommended three different
5 mathematical models during this time period (ICRP 1959, 1979, 1994). The models changed
6 substantially in structure, expanding from two compartments in the 1959 model (ICRP, 1959)
7 to five compartments in the 1994 model (ICRP, 1994). These models have always
8 represented an important aspect of radiation protection programs for inhaled radioactive
9 materials. The models make it possible to calculate the absorbed radiation doses received by
10 different parts of the respiratory tract and provide the necessary mathematical descriptions of
11 the translocation of portions of the deposited radionuclides to other organs and tissues beyond
12 the respiratory tract. The structure and complexity of the ICRP models increased with each
13 version. These increases in complexity reflect both the expanded knowledge of the behavior
14 and dosimetry of inhaled materials in the respiratory tract that has become available and an
15 increased need for models that can be applied to a broader range of uses. Earlier uses of
16 these models were primarily for general prospective health protection planning purposes and
17 to support routine workplace monitoring. As the models have become more detailed and
18 flexible in their application, increasing uses have been made of them for site-and process-
19 specific applications, as well as retrospective analyses of individual exposures.
20 The 1959 model (ICRP, 1959) had a very simple structure in which the respiratory tract
21 was divided into an upper respiratory tract (URT), and a lower respiratory tract (LRT). No
22 information was given on the anatomical division between the URT and the LRT. In the
23 1959 model, 50% of inhaled particles deposited in the URT, 25% deposited in the LRT, and
24 the remaining 25% was exhaled. No information on the effects of the sites or magnitude of
25 particle deposition was given, and relationships between particle size, deposition, and
26 clearance were not incorporated into the 1959 model. The URT was considered an air
27 passage from which all deposited particles cleared quickly by mucociliary activity and
28 swallowed. Particles deposited in the LRT were classified as soluble or insoluble. For
29 soluble particles, chemical constituents of all 25% of the inhaled particles that reach the LRT
30 were assumed to be rapidly absorbed into the systemic circulation. For insoluble particles,
31 12.5% were assumed to clear by mucociliary activity and swallowed during the first 24 h
April 1995 10-120 DRAFT-DO NOT QUOTE OR CITE
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1 following deposition. The remaining 12.5% was assumed to be retained with a biological
2 half-time of 120 d. No clearance of particles to the regional lymph nodes was included in
3 the 1959 model.
4 The 1979 model (ICRP, 1979) was based on the Task Group Lung Model (TGLM)
5 report (Morrow et al., 1966) and was divided into three compartments (nasopharyngeal, NP;
6 tracheobronchial, TB; and pulmonary, PU). The NP region including anatomical structures
7 from the tip of the nose to the larynx; the TB region extended from the trachea to the end of
8 the terminal bronchioles; and the PU region was the remaining, non-ciliated pulmonary
9 parenchyma. Deposition probabilities were given for the NP, TB, and PU regions for
10 activity median aerodynamic diameters (AMAD) of inhaled particles that covered about two
11 orders of magnitude (0.2 - 10 /un). This incorporation of particle size considerations and the
12 AMAD concept were major improvements in the health protection aspects of modeling
13 related to inhaled radioactive particles. The 1979 ICRP model also incorporated
14 consideration for clearance rates using three classes (D, W, Y). Class D particles cleared
15 rapidly (T1/2 = 0.5 d), class W particles cleared at an intermediate rate (T1/2 = 50 d), and
16 class Y particles cleared slowly (T1/2 = 500 d). It was also recognized that the competing
17 processes of dissolution-absorption and physical clearance operated on the deposited particles,
18 but inadequate information was available to differentiate between the two mechanisms. This
19 model also included a clearance pathway to the tracheobronchial lymph nodes. The long-
20 term clearance of particles by either physical transport processes or by dissolution-absorption
21 processes are described by the same clearance half-tune.
22 A substantial increase in knowledge about the effects of particle size on the deposition
23 of inhaled particles occurred since the publication of the TGLM report (Morrow et al.,
24 1966). This new information is reflected in the latest ICRP model (IRCP66, 1994). This
25 new ICRP model considers the respiratory tract as four anatomical regions. The extrathoracic
26 (ET) region is divided into two sub-regions: the anterior nasal airways, which clear only by
27 extrinsic processes such as nose blowing, defined as ETj, and the posterior nasal passages,
28 pharynx, mouth and larynx defined as ET2, which clears to the gastrointestinal tract via a
29 combination of mucociliary action and fluid flow. The airways within the lungs are
30 comprised of the bronchial (BB) and bronchiolar (bb) regions, which combined are equivalent
31 to the Tracheobronchial (TB) region described in Table 10-4. The TB region was divided in
April 1995 10-121 DRAFT-DO NOT QUOTE OR CITE
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1 the ICRP model to meet the need for calculating radiation doses to the bronchi and
2 bronchiolar tissues separately because of possible great differences in doses to these tissues
3 and apparent differences in radiation sensitivity. The gas-exchange tissues are defined as the
4 alveolar-interstitial (AI) region, which is exactly comparable to the pulmonary region or A
5 region (see Tables 10-2 and 10-4). There are two lymph node regions; LNET drains the
6 extrathoracic region and LNTH drains the BB, bb, and AI regions. Deposition in the four
7 anatomical regions (ET, BB, bb, and AI) is given as a function of particle size covering five
8 orders of magnitude, and two different types of particle size parameters are used. The
9 activity median thermodynamic diameter (AMTD) is used to describe the deposition of
10 particles ranging in size from 0.0005 to 1.0 micrometer; the AMAD is used to describe
11 deposition for the size range of 0.1 to 100 micrometer. The model applies to hygroscopic
12 particles by estimating particle growth in each region during inhalation. Reference values of
13 regional deposition are provided, and guidance is given for extrapolating to specific
14 individuals and populations under different levels of activity. Deposition is expressed as a
15 fraction of the number or activity of particles of a given size that is present in a volume of
16 ambient air before inspiration, and activity is assumed to be log-normally distributed as a
17 function of particle size for a typical particle density of 3 g/cm3 and dynamic shape factor of
18 1.5, although particle density and shape factor are included as variables in the deposition
19 calculations. As discussed in Section 10.5, the 1994 ICRP model includes consideration of
20 particle inhalability, which is a measure of the degree to which particles can enter the
21 respiratory tract and be available for deposition. After deposition occurs in a given region,
22 two different clearance processes act competitively on the deposited particles, except in the
23 ETj region where the only clearance process is extrinsic. These two processes are: particle
24 transport that includes mucociliary clearance from the respiratory tract and physical clearance
25 of particles to the regional lymph nodes, and absorption which includes movement of
26 material to blood regardless of process whether dissolution-absorption or transport of ultra
27 fine particles. It is assumed that the rates of particle clearance are the same for all types of
28 particles. Rates were derived from studies with human subjects. Particle clearance from the
29 BB and bb regions includes two slow phases: (1) to account for observations of slow
30 mucociliary clearance in humans and (2) to account for observations of long term retention of
April 1995 10-122 DRAFT-DO NOT QUOTE OR CITE
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1 small fractions of deposited material in the tracheobronchial tissues of both experimental
2 animals and humans. The structure for the ICRP 1994 model is shown in Figure 10-33.
3 Absorption into blood is material specific, acts in all regions except ETj, and is
4 assumed to occur at the same rates for all regions. Absorption into blood is a two stage
5 process. The first step (dissolution) involves dissociation of the particles into a form that can
6 be absorbed into blood; the second step involves absorption of the subunits of the particles.
7 Because these processes act independently on the regionally deposited particles, each can be
8 specified separately and allowed to compete against the other processes involved in the
9 model. This approach makes it possible to use time-dependent functions to describe
10 processes such as dissolution-absorption. However, for ease of calculation it is assumed that
11 time dependent dissolution can be approximated by dividing the material into two fractions
12 with different dissolution rates: material in an initial state dissolves at a constant rate,
13 simultaneously changing to a transformed state in which it dissolves at another rate. Uptake
14 into blood is treated as instantaneous for the material immediately absorbed after dissolution.
15 Another fraction of dissolved material may be absorbed more slowly as a result of binding
16 with tissue components. The model can use observed rates of absorption for compounds for
17 which there are reliable human or experimental animal data. The absorption of other
18 compounds are specified as fast, moderate or slow. In the absence of specific information,
19 compounds are assigned to types fast, moderate or slow according to their classification as
20 D, W or Y, respectively, under the previous ICRP model. Greater attention to the transfer
21 of particles to regional lymph nodes is given in this model than in the 1979 model by
22 incorporating these clearance processes at each level in the respiratory tract, not just in the
23 AI or pulmonary region in the 1979 model. Additionally, while the new ICRP model was
24 developed primarily for use with airborne radioactive particles and gases, its use for
25 non-radioactive substances is also desirable and should be encouraged.
26 An alternative new respiratory tract dosimetry model that developed concurrently with
27 the new ICRP model is being proposed by the National Council on Radiation Protection
28 (NCRP). This model is still being developed (Phalen et al., 1991), but might be available in
29 1995. As with the new ICRP model, the proposed NCRP model considers (1) inhalability of
30 aerosols, (2) new sub-regions of the respiratory tract are considered,
April 1995 10-123 DRAFT-DO NOT QUOTE OR CITE
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O
2!
O
H
O
I
8
n
H
w
The ICRP 1994 Human Respiratory Tract Model
Anterior
Nasal
(ETJ)
Extrathoracic
Naso-
Oropharynx/
Larynx
(ET2)
Bronchi
(BB)
Bronchioles
(bb)
Alveolar
Interstitium
(Al)
Surface
L
y
m
P
in Tissue
(Airway Wall)
N
0
d
e
s
-------
1 (3) dissolution-absorption is an important aspect of the model, and (4) body size (and age)
2 are considered. The proposed NCRP model defines the respiratory tract in terms of a naso-
3 oro-pharyngo-laryngeal (NOPL) region, a tracheobronchial (TB) region, a pulmonary (P)
4 region, and the lung-associated lymph nodes (LN). As with the ICRP model, inhalability of
5 aerosol particles is considered, and deposition in the various regions of the respiratory tract
6 is modeled using methods that relate to mechanisms of inertial impaction, sedimentation, and
7 diffusion. The rates of dissolution-absorption of particles and their constituents are derived
8 from clearance data from humans and laboratory animals. The effect of body growth on
9 particle deposition is also considered in the model, but particle clearance rates are assumed to
10 be independent of age. The NCRP model does not consider the fate of inhaled materials
11 after they leave the respiratory tract. Although the proposed NCRP model describes
12 respiratory tract deposition, clearance, and dosimetry for radioactive substances inhaled by
13 humans, the model can be used for evaluating inhalation exposures to all types of particles.
14 A considerable amount of information has accumulated relevant to the biokinetics of
15 inhaled radioactive materials. The radiation associated with these materials allows relative
16 ease of analysis to determine temporal patterns for retention, distribution, and excretion of
17 inhaled radioactive particles and their constituents. Non-radioactive particles are difficult to
18 study because the particles and their chemical constituents are generally difficult to detect in
19 biological systems, tissues, and excreta. Some studies have shown that the physicochemical
20 forms and sites of deposition of chemical toxicants influence clearance rates. Also,
21 adsorption of chemicals onto particles can influence deposition patterns and alter rates of
22 dissolution-absorption of the particles and their constituents. For example, vapors that would
23 not normally reach the AI region will do so if they are adsorbed onto particles. Also,
24 adsorption onto particles might slow the rates at which chemicals can be absorbed into lung
25 tissue or the circulatory system. Amounts of inhaled material may markedly influence
26 clearance as a consequence of lung overload. The cytotoxicity and shapes of particles
27 (i.e.fibers) also influence clearance. Additionally, metabolic products of the inhaled
28 materials may cause pathology and disease states that may result in nonpredictable retention
29 and clearance patterns.
30
31
April 1995 10-125 DRAFT-DO NOT QUOTE OR CITE
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1 10.6.2 Laboratory Animals
2 Several animal models have been developed to help interpret results from specific
3 studies that involved chronic inhalation exposures to non-radioactive particles (Wolff et al.,
4 1987; Strom et al., 1988; Stober et al., 1994). These models were adapted to data from
5 studies involving high level chronic inhalation exposures in which massive lung burdens of
6 low toxicity, poorly soluble particles were accumulated and the models have not been
7 adapted to chronic exposures to low concentrations of aerosols in which lung overload does
8 not occur.
9 Snipes et al. (1983) adapted a materials balance simulation model to evaluate repeated
10 or chronic inhalation exposures. The model was described by Pritsker (1974) and uses a
11 Fortran-based numerical integration of differential equations. The integration method is a
12 fourth order, variable step-size Runge-Kutta-England routine for integrating systems of first
13 order ordinary differential equations with initial values. The model was used to describe the
14 retention and clearance of poorly soluble aerosol inhaled by mice, rats, and dogs (Snipes et
15 al., 1983) and guinea pigs (Snipes et al., 1984). A distinct advantage of this kind of model
16 is the requirement that dissolution-absorption rates are approximated as part of the modeling
17 process. The simulation model was adapted to repeated or chronic exposures using the
18 assumption that each individual exposure in a series of inhalation exposures is the same with
19 regard to deposition and clearance kinetics. The model for repeated or chronic inhalation
20 exposures therefore simply integrates the results of the individual exposures and predicts the
21 lung (and other compartment) burdens of the exposure material during the course of the
22 exposures. This model adequately accounted for the observed lung burdens of diesel exhaust
23 particles (DEP) achieved in rats over the course of a 2-year chronic inhalation exposure to
24 0.35 mg DEP/m3 (Snipes, 1989). The specific lung burdens of DEP achieved in the rats
25 during the 2-year study were about 0.4 mg DEP/g lung, which is less that the amount that is
26 generally predicted to cause lung overload. This model, and alternatives that are easily
27 adapted to inhalation exposure scenarios, appears to be useful for predicting pulmonary
28 clearance patterns for a variety of inhaled materials as long as exposure concentrations are
29 reasonably low and lung overload is not incurred.
30
31
April 1995 10-126 DRAFT-DO NOT QUOTE OR CITE
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1 10.6.3 Species Similarities and Differences
2 Rates for particle translocation from the A region to tracheal lymph nodes (TLNs)
3 appear to vary considerably among species. Rats and mice have particle translocation rates
4 from the A region to TLNs that are quite different from those of guinea pigs, dogs, and
5 possibly humans (Snipes et al., 1983; 1984). Translocation from the A region to TLNs
6 begins soon after an acute inhalation exposure. However, after a few days the transport of
7 particles from the A region to TLNs appears to be negligible in mice and rats (Snipes et al.,
8 1983), but continues at a constant rate in guinea pigs and dogs (Snipes et al., 1983; 1984).
9 No experimental information is available about the rates of translocation of particles from the
10 A region to TLNs in humans. However, data for amounts of particles accumulated in the
11 lungs of humans exposed repeatedly to dusty environments (Stober et al., 1967; Carlberg et
12 al., 1971; Mclnroy et al., 1976; Cottier et al., 1987) suggest that poorly soluble particles
13 accumulate in TLNs of humans at rates that may be comparable to those observed for guinea
14 pigs, dogs, and monkeys. However, the ICRP evaluated the translocation from lung to
15 TLNs and concluded that the rate for humans could be represented as 2 X 10"5/day, i.e.,
16 lower than the rate for dogs and monkey by approximately a factor of ten.
17 Physical movement of particles from the A region to the TLNs affords the opportunity
18 to transport particles out of the lung, but the result is to sequester, or trap the particles in
19 what is generally perceived to be a dead-end compartment. Because the TLNs represent
20 traps for particles cleared from the lung, particles can accumulate to high concentrations in
21 the TLNs. Thomas (1968, 1972) discussed the implications of particle translocation from the
22 A region to TLNs when the particles contain specific radionuclides, but he presented
23 information that is relevant to all types of particles. Translocation of particles from the A
24 region to the TLNs results in concentrations of particles in the lymph nodes that can be more
25 than 2 orders of magnitude higher than concentrations in the lung. The implications of this
26 consequence of inhalation exposures has not been fully evaluated but may have important
27 implications for immunological responses in humans exposed to specific kinds of aerosols.
28 Many measurements of alveolar retention and clearance have been conducted on
29 humans and a variety of laboratory animal species. In some cases, at least two laboratory
30 animal species were exposed to the same aerosolized material, so direct comparisons among
31 species are possible. Few human inhalation exposures to the same materials as used for the
April 1995 10-127 DRAFT-DO NOT QUOTE OR CITE
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1 animal studies have occurred, so only a limited number of direct comparisons are possible
2 between laboratory animals and humans.
3 Table 10-14 contains a summary of selected results for pulmonary retention of inhaled
4 materials after single inhalation exposures to small masses of poorly soluble particles.
5 Studies of less than about 3 mo duration were not included. The variability in these results
6 was caused by several factors. In many cases, the reported results did not allow division of
7 the pulmonary burden between short- and long-term clearance. Also, for most studies,
8 dissolution-absorption of the exposure materials were not known or were not reported. The
9 broad range of particle sizes would have influenced deposition patterns, and
10 dissolution-absorption rates, but probably not physical clearance of particles from the A
11 region.
12 The information shown in Table 10-14 was used to approximate biological clearance
13 rates for particles inhaled by the species listed in Table 10-15. In addition, approximations
14 are included for the fractions of pulmonary burdens initially deposited in the A region that
15 were subjected to short- or long-term clearance. These trends clearly will not apply to all
16 types of inhaled particles. For example, in some cases, deposition and clearance may be
17 influenced by the physicochemical and/or biological characteristics of the inhaled material.
18 Further, the generalizations that led to Table 10-15 allow comparisons for the consequences
19 of chronic inhalation exposures among these animal species and humans that might not
20 otherwise be possible.
21 The mathematical expressions for curve fits to data depend on the study duration. The
22 values for percent initial alveolar burden (% IAB) versus time in the following table were
23 obtained by simulating lung retention of poorly soluble particles in the rat using the physical
24 clearance rates from Table 10-15. Two-component exponential curve fits were next made for
25 % IAB versus time using the model results for days 1 to 150, 1 to 300, and 1 to 730. As
26 indicated Table 10-16, the curve fit parameters for the data for days 1 to 150 agree well with
27 the expectations of individuals who are familiar with the results of relatively short-term lung
28 clearance studies.
29 Physical clearance patterns for alveolar burdens of particles are similar for guinea pigs,
30 monkeys, dogs, and humans. For these species, about 20-30% of the initial burden of
31 particles clears with a half-time on the order of 1 mo, the balance clears with a half-time of
April 1995 10-128 DRAFT-DO NOT QUOTE OR CITE
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2
TABLE 10-14. COMPARATIVE PULMONARY RETENTION PARAMETERS FOR POORLY SOLUBLE PARTICLES
INHALED BY LABORATORY ANIMALS AND HUMANS
o
i—»
K>
H
6
O
O
O
a
o
o
H
W
Species
Mouse
Hamster
Rat
Guinea Pig
Dog
Aerosol
Matrix
FAP0
FAP
FAP
Ru Oxide
Pu Oxide
FAP
Diesel soot
FAP
FAP
FAP
FAP
FAP
FAP
Fibers
Latex
Pu Oxide
Pu Oxide
U308
Co3O4
FAP
Diesel soot
Latex
Coal dust
Coal dust
Ce Oxide
Particle Sizea
Mm
0.7
1.5
2.8
0.38
0.2
1.2
0.12
1.25
0.7
1.5
2.8
1.2
1.4
1.2-2.3
3.0
<1.0
2.5
= 1-2
2.69
2.0
0.12
3.0
2.4
1.9
0.09-1.4
Measure
AMADd
AMAD
AMAD
CMDe
CMD
CMD
MMADf
CMD
AMAD
AMAD
AMAD
AMAD
AMAD
AMAD
CMD
CMD
AMAD
CMD
MMAD
AMAD
MMAD
CMD
MMAD
MMAD
MMD8
PI
0.93
0.93
0.93
0.88
0.86
0.73
0.37
0.62
0.91
0.91
0.91
0.83
0.76
0.39
0.20
0.75
0.67
0.70
0.22
Alveolar Burden"
T^d)
34
35
36
28
20
50
6
20
34
35
36
33
26
18
20
30
20
19
29
P2
0.07
0.07
0.07
0.12
0.14
0.27
0.63
0.38
0.09
0.09
0.09
0.17
0.24
1.00
0.61
0.80
0.25
0.33
0.30
0.78
1.00
1.00
1.00
1.00
1.00
T2(d)
146
171
201
230
460
220
80
180
173
210
258
310
210
46-76
63
180
250
500
125
385
>2,000
83
1,000
= 700
>570
Study
Duration
(days)
850
850
850
490
525
463
330
492
850
850
850
365
180
101-171
190
350
800
768
180
1100
432
190
160
301-392
140
References
Snipes et al. (1983)
Snipes et al. (1983)
Snipes et al. (1983)
Bair (1961)
Bair (1961)
Bailey et al. (1985a)
Lee et al. (1983)
Bailey et al. (1985b)
Snipes et al. (1983)
Snipes et al. (1983)
Snipes et al. (1983)
Finch et al. (1994)
Finch et al. (1995)
Morgan et al. (1977)
Snipes et al. (1988)
Langham (1956)
Sanders et al. (1976)
Galibin and Parfenov (1971)
Kreyling et al. (1993)
Snipes et al. (1984)
Lee et al. (1983)
Snipes et al. (1988)
Gibb et al. (1975)
Morrow and Yuile (1982)
Stuart et al. (1964)
-------
2
TABLE 10-14 (cont'd). COMPARATIVE RETENTION RETENTION PARAMETERS FOR POORLY SOLUBLE
PARTICLES INHALED BY LABORATORY ANIMALS AND HUMANS
Species
Dog, cont'd
i— '
o
I
o
O
|
H Monkey
6
O
Q Human
H
O
o
a
o
n
H- 1
H
W
Aerosol
Matrix
FAP
FAP
FAP
FAP
FAP
Nb Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Pu Oxide
Tantalum
U308
Zr Oxide
Pu Oxide
Pu Oxide
FAP
FAP
Latex
Latex
Pu Oxide
Graphite & PuO2
Pu Oxide
Particle Size
pm
2.1-2.3
0.7
1.5
2.8
2.01
1.6-2.5
1-5
4.3
1.1-4.9
0.1-0.65
0.72
1.4
2.8
4.3
4.0
0.3
2.0
2.06
1.6
1
4
3.6
5
0.3
6
<4-5
Measure
AMAD
AMAD
AMAD
AMAD
AMAD
AMAD
CMD
MMD
MMAD
CMD
AMAD
AMAD
AMAD
MMD
AMAD
CMD
AMAD
CMAD
AMAD
CMD
CMD
CMD
CMD
MMD
AMAD
CMD
PI
0.09
0.15
0.15
0.15
0.05
0.10
0.10
0.32
0.22
0.50
0.40
0.47
0.14
0.27
0.27
0.42
Alveolar Burden"
Tj(d)
13
20
21
21
-— 1
200
3.9
87
32
20
1.9
4.5
40
50
30
0.5
P2
0.91
0.85
0.85
0.85
0.95
1.00
1.00
1.00
0.90
0.90
0.68
0.78
0.50
0.60
0.53
1.0
1.0
1.0
0.86
0.73
0.73
0.58
1.00
1.00
1.00
T2(d)
440
257
341
485
910
>300
1,500
300
400
1,000
680
1,400
1,800
1,600
860
120
340
500-900
770-1,100
350
670
296
150-300
240
240-290
1,000
Study
Duration
(days)
181
850
850
850
1,000
128
280
300
468
=4,000
730
730
730
270
155
127
128
200
990
372-533
372-533
=480
160
300
566
427
References
Boecker and McClellan, (1968)
Snipes et al. (1983)
Snipes et al. (1983)
Snipes et al. (1983)
Kreyling et al. (1988)
Cuddihy (1978)
Bair (1961)
Bair et al. (1962)
Morrow et al. (1967)
Park et al. (1972)
Guilmette et al. (1984)
Guilmette et al. (1984)
Guilmette et al. (1984)
Bair and McClanahan (1961)
Bianco et al. (1974)
Fish (1961)
Waligora (1971)
Nolibe et al. (1977)
LaBauve et al. (1980)
Bailey et al. (1985a)
Bailey et al. (1985a)
Bohning et al. (1982)
Booker et al. (1967)
Johnson et al. (1972)
Ramsden et al. (1970)
Newton (1968)
-------
2
(j\
TABLE 10-14 (cont'd). COMPARATIVE ALVEOLAR RETENTION PARAMETERS FOR POORLY SOLUBLE
PARTICLES INHALED BY LABORATORY ANIMALS AND HUMANS
Species
Human, cont'd
Aerosol
Matrix
Th Oxide
Teflon
Zr Oxide
Particle Size Alveolar Burdenb
fim
<4-5
4.1
2.0
Measure Pl Tt(d)
CMD
CMD 0.30 4.5-45
AMAD
P2
1.00
0.70
1.00
T2(d)
300-400
200-2,500
224
Study
Durantion
(days)
427
300
261
References
Newton (1968)
Philipson et al. (1985)
Waligora (1971)
"Some aerosols were monodisperse, but most were polydisperse, with geometric standard deviations in the range of 1.5 to 4.
bPulmonary burden = Pj-e"0" 2)t/Ti + Pj-e"0" 2)t/r2, where Pj and P2 are fractions constrained to total 1.00, Tt and T2 equal retention half-times in (d), and
t equals days after exposure. Retention half-times are approximations and are the net result of dissolution-absorption and physical clearance
processes. In some examples, the original data were subjected to a computer curve-fit procedure to derive the values for Pj and Tj presented in this table.
CFAP = fused aluminosilicate particles.
dAMAD = activity median aerodynamic diameter.
eCMD = count median diameter.
fMMAD = mass median aerodynamic diameter.
gMMD = mass median diameter.
H
6
o
z
s
o
c
o
H
w
i
n
i—i
H
W
-------
TABLE 10-15. AVERAGE PULMONARY RETENTION PARAMETERS
FOR POORLY SOLUBLE PARTICLES INHALED BY SELECTED
LABORATORY ANIMAL SPECIES AND HUMANS
Alveolar Retention Parameters3
Species
Mouse
Rat, Syrian Hamster
Guinea Pig
Monkey, Dog, Human
PI
0.9
0.9
0.2
0.3
TI
30
25
29
30
P2
0.1
0.1
0.8
0.7
T2
240
210
570
700
"Alveolar burden (fraction of initial deposition) =
PI exp(-ln 2)t/Tl +p2eXp(-ln2)t/T2)
where:
P! and P2 = fractions of alveolar burden in fast and slow-clearing components;
I, and T2 = retention half-times (days) for Pj and P2; and
t = time in days after an acute inhalation exposure.
1 several hundred days. Mice, Syrian hamsters, and rats clear about 90% of the deposited
2 particles with a half-time of about 1 month and 10% with a half-time greater than 100 days.
3 The relative division of the alveolar burden between short-term and long-term clearance
4 represents a significant difference between most rodents and larger mammals and has
5 considerable impact on long-term patterns for retention of material acutely inhaled, as well as
6 for accumulation patterns for materials inhaled in repeated exposures.
7
8 10.6.4 Models to Estimate Retained Dose
9 Models have routinely been used to express retained dose in terms of temporal patterns
10 for pulmonary retention of acutely inhaled materials. Available information for a variety of
11 mammalian species and humans can be used to predict deposition patterns in the respiratory
12 tract for inhalable aerosols with reasonable degrees of accuracy. Additionally, as indicated
13 above, alveolar clearance data for mammalian species commonly used in inhalation studies
14 are available from numerous experiments that involved small amounts of inhaled radioactive
15 particles. The amounts of particles inhaled in those studies were small and can be presumed
16 to result in clearance patterns characteristic of the species unless radiation damage was a
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TABLE 10-16. PHYSICAL CLEARANCE RATES
Days
1
7
14
28
35
42
49
56
63
70
100
150
200
250
300
400
500
600
730
% IAB Pj T! P2 T2
96.96
81.21
66.89
47.00
40.03
34.43
29.87
26.14
23.06
20.49
13.26
7.80 71.6 18.4 29.4 78.3
5.39
4.10
3.30 84.4 22.0 15.6 131
2.36
1.78
1.37
0.99 91.0 25.6 9.0 221
1 confounding factor, which was probably not the case except where acute effects were an
2 experimental objective.
3 A very important factor in using models to predict retention patterns in laboratory
4 animals or humans is the dissolution-absorption rate of the inhaled material. Factors that
5 affect the dissolution of materials or leaching of their constituents in physiological fluids,
6 then absorption of their constituents are not fully understood. Solubility is known to be
7 influenced by the surface-to-volume ratio and other surface properties of particles (Mercer,
8 1967; Morrow, 1973). The rates at which dissolution and absorption processes occur are
9 influenced by factors that include chemical composition of the material. Temperature history
10 of materials is an important consideration for some metal oxides. For example, in controlled
11 laboratory environments, the solubility of oxides usually decreases when the oxides are
12 produced at high temperatures, which generally results in compact particles having small
13 surface-to-volume ratios. It is sometimes possible to accurately predict dissolution-absorption
14 characteristics of materials based on physical/chemical considerations. However, predictions
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1 for in vivo dissolution-absorption rates for most materials, especially if they contain
2 multivalent cations or anions, should be confirmed experimentally.
3 Phagocytic cells, primarily macrophages, clearly play a role in dissolution-absorption of
4 particles retained in the respiratory tract (Kreyling, 1992). Some particles dissolve within
5 the phagosomes due to the acidic milieu in those organelles (Lundborg et al., 1984, 1985),
6 but the dissolved material may remain associated with the phagosomes or other organelles in
7 the macrophage rather than diffuse out of the macrophage to be absorbed and transported
8 elsewhere (Cuddihy, 1984). Examples of delayed absorption of presumably soluble inorganic
9 materials are beryllium (Reeves and Vorwald, 1967) and americium (Mewhinney and
10 Griffith, 1983). This same phenomenon has been reported for organic materials. For
11 example, covalent binding of benzo(a)pyrene or metabolites to cellular macromolecules
12 resulted in an increased pulmonary retention tune for that compound after inhalation
13 exposures of rats (Medinsky and Kampcik, 1985). Certain chemical dyes are also retained in
14 the lung (Medinsky et al., 1986), where they may dissolve and become associated with lipids
15 or react with other constituents of lung tissue. Understanding these phenomena and
16 recognizing species similarities and differences are important for evaluating alveolar retention
17 and clearance processes and interpreting results of inhalation studies.
18 In one study related to the issue of species differences in dissolution-absorption,
19 Oberdorster et al. (1987) evaluated clearance of 109Cd from the lungs of rats and monkeys
20 after inhalation of 109Cd-labeled aerosols of CdCl2 and CdO. The inhaled Cd was cleared 10
21 times faster from the lungs of the rats than from the lungs of monkeys. Cadmium in the
22 lungs of mammalian species is probably bound to metallothionein, and these differences in
23 rates of Cd clearance appear to be the result of species differences in metallothionein
24 metabolism. Bailey et al. (1989) conducted a study that included an interspecies comparison
25 of the translocation of 57Co from the A region to blood after inhalation of 57Co3O4. The
26 results of this multi-species study suggest that mammalian species demonstrate considerable
27 variability with regard to rates of dissolution of particles retained in lung tissue, degree of
28 binding of solubilized materials with constituents of lung tissue, and rates of absorption into
29 the circulatory system.
30 Dissolution-absorption of fibers has been the subject of several studies (Morgan et al.,
31 1982; Johnson et al., 1984; Le Bouffant et al., 1984, 1987; Hammad, 1984; Hammad et al.,
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1 1988). Solubility of fibers in rat lungs, which was determined on the basis of changes in the
2 size distributions of the fibers over time, was dependent on both fiber size and composition.
3 Morgan et al. (1982) attributed the dependency of dissolution on fiber length to the
4 differences in pH encountered by the fibers. The shorter fibers retained within macrophages
5 were presumed to be exposed to a lower pH than nonphagocytized fibers in extracellular
6 fluid. These results indicate that physical and chemical attributes of the fibers, as well as
7 retention sites (intracellular versus extracellular) are important factors in processes that
8 dissolve or etch them. Additionally, most fibers found in lymph nodes were less than 10 /mi
9 long and present in macrophages as single fibers (Le Bouffant et al., 1984, 1987). This was
10 a clear demonstration that biological action in vivo reduced the more labile types of fibers to
11 sizes which had biokinetics resembling moderately soluble particles and showed that the
12 subunits of fibers could be physically translocated to TLNs.
13 Dissolution-absorption of materials in the respiratory tract is clearly dependent on the
14 chemical and physical attributes of the material. While it is possible to predict rates of
15 dissolution-absorption, it is prudent to experimentally determine this important clearance
16 parameter to understand the importance of this clearance process for the lung, TLNs, and
17 other body organs that might receive particles or fibers, or their constituents which enter the
18 circulatory system from the lung.
19
20 10.6.4.1 Extrathoracic and Conducting Airways
21 Insufficient data are available to adequately model long-term retention of particles
22 deposited in the conducting airways of any mammalian species. It is probable that some
23 particles that deposit in the head airways and TB region during an inhalation exposure are
24 retained for long times and may represent significant dosimetry concerns. Additionally,
25 some of the particles that are cleared from the A region via the mucociliary transport
26 pathway may become trapped in the TB epithelium during their transit through the airways.
27 Additional research must be done to provide the information needed to properly evaluate
28 retention of particles in conducting airways.
29 Based on the results of longitudinal scans of dogs that inhaled promethium oxide
30 particles, Stuart (1966) concluded that particles were retained for relatively long times in the
31 heads of the dogs. A study by Snipes et al. (1983) included mice, rats, and dogs exposed by
April 1995 10_i35 DRAFT-DO NOT QUOTE OR CITE
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1 inhalation to monodisperse or poly disperse 134Cs-labeled fused aluminosilicate particles. In
2 all three species, 0.001 to 1% of the initial internally deposited burden of particles was
3 retained in the head airways and was removed only by dissolution-absorption.
4 Autoradiography revealed that retained particles were in close proximity to the basement
5 membrane of nasal airway epithelium. In another study by Snipes et al. (1988), 3-, 9-, and
6 15-/mi latex microspheres were inhaled by rats and guinea pigs. About 1 and 0.1% of all
7 three sizes of microspheres were retained in the head airways of the rats and guinea pigs,
8 respectively. For rats, the 9- and 15-pim microspheres cleared with half-times of 23 days;
9 for guinea pigs, the same size microspheres cleared with half-times of about 9 days. The
10 3-/xm microspheres were cleared from the head airways of the rats and guinea pigs with
11 biological half-times of 173 and 346 days, respectively. The smaller particles are apparently
12 more likely to penetrate the epithelium and reach long-term retention sites.
13 Whaley et al. (1986) studied retention and clearance of radiolabeled, 3-/*m polystyrene
14 latex particles instilled onto the epithelium of the maxillary and ethmoid turbinates of Beagle
15 dogs. Retention of the particles at both sites after 30 days was about 0.1% of the amount
16 initially deposited. Autoradiographs of turbinate tissue indicated that the particles were
17 retained in the epithelial submucosa of both regions.
18 It is also generally concluded that most inhaled particles that deposit in the TB region
19 clear within hours or days. However, results from a number of studies in recent years
20 challenge this belief. These studies have demonstrated that small portions of the particles
21 that deposit in, or are cleared through, the TB region are retained with half-times on the
22 order of weeks or months. Patrick and Stirling (1977) noted that about 1% of barium sulfate
23 particles instilled intratracheally into rats remained in the bronchial tissue for at least 30
24 days. In a followup study, Stirling and Patrick (1980) used autoradiography to demonstrate
25 the temporal retention patterns for some of the retained 133BaS04 particles in TB airways.
26 The particles were retained within macrophages in the tracheal wall for at least 7 days after
27 intratracheal instillation of 133BaS04. By two h after instillation, some of the particles were
28 buried in the tracheal wall. After 24 h, when most of the initial deposition of particles had
29 cleared, 74% of 133BaSO4 particles located by autoradiography were in macrophages
30 proximate to the basement membrane. After 7 days, practically all of the remaining particles
31 were incorporated into the walls of the airways. The authors did not determine the
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1 mechanisms by which the particles were moved into the airway epithelium. It is possible
2 that the particles were phagocytized by macrophages and transported into the airway
3 epithelium. Another possibility is direct uptake by epithelial cells of the airways. It is also
4 probable that intratracheal instillation procedures perturb airway epithelium and influence the
5 results of these kinds of studies.
6 Gore and Thorne (1977) exposed rats by inhalation to polydisperse aerosols of UO2.
7 At 2, 4, 7, and 35 days after inhalation of the UO2, autoradiography was used to determine
8 the locations of particles retained in the TB and A regions. The authors did not report seeing
9 particles of UO2 retained in the airways, but did note two phases of clearance. The first
10 phase was associated with a clearance half-time of 1.4 days, the second phase with a
11 clearance half-time of about 16 days. The faster clearance was presumably associated with
12 particles deposited on the conducting airways during the inhalation exposure; the longer-term
13 clearance was associated with clearance of UO2 particles from the A region. In a separate
14 study, Gore and Patrick (1978) evaluated the distribution of UO2 particles in the trachea and
15 bronchi of rats for up to 14 days after inhalation of aerosols similar to those used by Gore
16 and Thorne (1977). Retention of UO2 at airway bifurcations was noted, as was retention of
17 particles in the trachea.
18 In another study, Gore and Patrick (1982) also compared the retention sites of inhaled
19 UO2 particles and intratracheally instilled barium sulphate particles. Both types of particles
20 were found in macrophages at sites near the basement membrane of the airways of the TB
21 region. The macrophages appeared to have engulfed the particles in the airways, then passed
22 through the airway epithelium and remained in the vicinity of the basement membrane.
23 About 4% of the UO2 in lungs of rats was associated with intrapulmonary airways (Gore,
24 1983; Patrick, 1983). Watson and Brain (1979) observed similar results with aerosols of
25 gold colloid and iron oxide. Both types of particles were found in bronchial epithelium, but
26 more of the iron oxide was observed, suggesting a possible particle size effect, or a
27 relationship between the process of material uptake and chemical composition of the material.
28 Both types of particles were found in bronchial epithelial cells, but neither gold nor iron
29 oxide particles were seen in interstitial macrophages.
30 In a recent inhalation study, Briant and Sanders (1987) exposed rats to 0.7 /im AM AD
31 chain-aggregate aerosols of U-Pu. These authors observed retained particles of U-Pu in the
April 1995 10-137 DRAFT-DO NOT QUOTE OR CITE
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1 larynx, trachea, carina, and bronchial airways throughout the course of their 84-day study.
2 The amounts retained varied, but were at any time approximately 1% of the concurrent
3 pulmonary burden. The pulmonary burden of U-Pu cleared with a biological half-tune of
4 100 days, and the relative amounts of U-Pu in the airways suggested comparable particle
5 clearance rates from the airways. Particles of U-Pu retained in the airways were located in
6 epithelial cells.
7 Stahlhofen et al. (1981, 1986) conducted inhalation studies with humans to directly
8 assess deposition and retention of poorly soluble particles that deposit in the TB region by
9 inhalation. Human subjects inhaled small volumes of aerosols using procedures that
10 theoretically allowed deposition to occur at specific depths in the TB region, but not in the A
11 region. Results of those studies suggested that as much as 50% of the particles that
12 deposited in the TB region clear slowly, presumably because they become incorporated into
13 the airway epithelium. Smaldone et al. (1988) reported the results from gamma camera
14 imaging analyses of aerosol retention in normal and diseased human subjects, and also
15 suggested that particles deposited on central airways of the human lung do not completely
16 clear within 24 h. There have also been a few reports indicating that poorly soluble particles
17 associated with cigarette smoke are retained in the epithelium of the tracheobronchial tree of
18 humans (Little et al., 1965; Radford and Martell, 1977; Cohen et al., 1988). The
19 cumulative results of these studies strongly suggest that a portion of particles that deposit on
20 the conducting airways can be retained for long periods of time, or indefinitely.
21 Long-term retention and clearance patterns for radioactive particles that deposit in the
22 head airways and TB region must be thoroughly evaluated because of their implications for
23 respiratory tract dosimetry and risk assessment (James et al., 1991; Johnson and Milencoff,
24 1989; Roy, 1989; ICRP, 1994). Similar concerns exist for non-radioactive particles that
25 might be cytotoxic or elicit inflammatory, allergic, or immune responses at or near retention
26 sites in conducting airways.
27
28 10.6.4.2 Alveolar Region
29 Model projections are possible for the A region using the cumulative information in the
30 scientific literature relevant to deposition, retention, and clearance of inhaled particles.
31 Table 10-17 summarizes reasonable approximations for physical pulmonary clearance
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TABLE 10-17. PHYSICAL CLEARANCE RATES8 FOR MODELING
ALVEOLAR CLEARANCE OF PARTICLES INHALED BY HUMANS
AND SELECTED MAMMALIAN SPECIES
Clearance via Mucociliary Clearance to Thoracic
Species Transport Pathway Lymph Nodes
Mouseb 0.023 exp-°-008t + 0.0013 0.0007 exp-°-5t
Ratb, Syrian Hamster0 0.028 exp'0-011 + 0.0018 0.0007 exp-°-5t
Guinea Pigb 0.007 exp-°-03t + 0.0004 0.00004
Monkeyd, Dogb 0.008 exp-°-022t + 0.0001 0.0002
"Fraction of existing alveolar burden physically cleared per day.
bAdapted from Snipes (1989)
Clearance rates assumed to be the same as for rats.
dClearance rates assumed to be the same as for dogs.
1 parameters for humans and six laboratory animal species. Alveolar clearance curves
2 produced using the parameters in Table 10-17 agree with curves produced using the
3 parameters in Table 10-15. An advantage to using the parameters in Table 10-17 is that they
4 separate physical clearance from the A region into its two components, physical clearance via
5 the mucociliary clearance pathway to the GI tract and clearance to TLNs. To model the
6 pulmonary biokinetics of a specific type of particle, the physical clearance parameters in
7 Table 10-17 are used in conjunction with a dissolution-absorption parameter to derive rates
8 for effective clearance from the A region.
9
10
11 10.7 APPLICATION OF DOSIMETRY MODELS TO DOSE-RESPONSE
12 ASSESSMENT
13 As discussed in the introduction of this chapter, objectives of dosimetry modeling for
14 this effort included an attempt to ascertain whether or not such modeling can provide insight
15 into the discrepancies between the epidemiologic and laboratory animal data, to identify
16 plausible dose metrics of relevance to the available health endpoints, and to identify
17 modifying factors that may enhance susceptibility to inhaled particles. In order to
18 accomplish these objectives, this section presents an application of dosimetry modeling to
19 data typically available from the epidemiologic and laboratory animal studies. Choice of a
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1 dosimetry model for humans and laboratory animals, respectively, is discussed and these
2 models are used to simulate deposition and retained doses of various exposures. Different
3 dose metrics and their relevance to observed health endpoints are also discussed.
4
5 10.7.1 Dosimetry Model Selection
6 Available deposition models for humans and laboratory animals were presented in
7 Section 10.5.1 and 10.5.2, respectively. Clearance models, required to calculate retained
8 doses, were discussed in Section 10.6.
9
10 Human Model
11 The semi-empirical compartmental model of the International Commission on
12 Radiological Protection (ICRP66, 1994) was chosen and used to model the dosimetry of
13 inhaled particles in humans (Sections 10.7.4 and 10.7.5 below). A distinct advantage of this
14 model is that it incorporates both deposition and clearance mechansisms so that both
15 deposited and retained doses can be calculated. LUDEP® software version 1.1 was used to
16 run the ICRP 1994 model simulations (National Radiological Protection Board, 1994).
17 Although the theoretical models described in Section 10.5 might allow prediction to
18 more localized regions of the respiratory tract, information about the dimensions of the
19 numerous gross and microscopic structures of the respiratory tract are extremely limited.
20 Experimental data are still available only for the adult Caucasian male, and for a limited
21 range of particle sizes (dae from about 1 pm to 10 /zm), making validation of theoretical
22 models also limited. For these reasons, the semi-empirical approach taken for development
23 by the ICRP was viewed as advantageous. The parametric analysis of regional lung
24 desposition, developed by Rudolf et al. (1986, 1990) and described in Section 10.5, was used
25 to represent the results of complex theoretical modeling by relatively simple algebraic
26 approximations. A theoretical model of gas transport and particle deposition (Egan et al.,
27 1989) was applied to apportion the subdivision of particle deposition among the lower
28 respiratory tract regions (BB, bb, Al — see Section 10.6), and to quantify the effects of a
29 lung size and breathing rate. The structure of the respiratory tract is represented explicitly
30 by a morphometric anatomical model as described in Table 10-4 and Figure 10-4. The ICRP
31 model reasonably describes the experimental data relating total thoracic deposition to particle
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1 size and breathing behavior. The model also succeeds in simulating the variation of regional
2 deposition with particle size and breathing pattern that was inferred by Stahlhofen et al.
3 (1980,1983) from their measurements of thoracic depostion and retention. In common with
4 earlier theoretical models of Yeh and Schum (1980) and Yu and Diu (1982), the ICRP 1994
5 model predicts significantly less thoracic deposition for particles in the range of d^ from 1
6 fim to 5 nm than the median values reported by Lippmann (1977) and Chan and Lippmann
7 (1980). These data are crucial since they represent the largest group of experimental subjects
8 studied to date. However, as described in detail elsewhere (ICRP66, 1994), when allowance
9 is made for the hygroscopic growth within the lungs of the paniculate matter used in the
10 New York University studies, these key experimental measurements are also found to support
11 the ICRP deposition model. The problem of time-dependent functions to describe clearance
12 from the various regions in the respiratory tract was overcome by using a combination of
13 compartments. Clearance from each region by three routes (absorption into blood, transport
14 to GI tract, and transport to lymphatics) is accomplished by pathways with assigned rate
15 constants.
16
17 Laboratory Animal Model
18 The particle dosimetry model of Menache et al. (1995a) was chosen to calculate
19 deposited dose estimates for laboratory animal species (U.S. EPA, 1994). Attributes of the
20 model that were viewed as especially advantageous for this exercise included the detailed
21 measurements made in all tissues that served as the source of deposition data (Raabe et al.,
22 1988); that the deposition data were available in unanesthetized, freely breathing animals of
23 five species under the same exposure conditions; and that inhalability was accounted for and
24 used to adjust the logistic function to describe deposition efficiency. This model represents a
25 revised version (Miller et al., 1988; Jarabek, et al., 1989, 1990) that has been useful to
26 develop inhalation reference concentration (RfC) values for dose-response assessment of air
27 toxics (U.S. EPA, 1994). The same approach will be used to calculate deposited doses as
28 discussed following in greater detail Section 10.7.4. For calculation of retained doses, the
29 simulation model based on Pritsker (1974) and described in Section 10.6 was used. This
30 clearance model was applied to output of the Menache et al. (1995a) deposition model in
31 order to calculate retained dose as discussed following in Section 10.7.5.
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1 10.7.2 Choice of Dose Metrics
2 As discussed in the preceding sections, inhaled dose, especially to different regions or
3 locations within the respiratory tract, is not necessarily related linearly to the exposure
4 concentration. For this reason, an internal dose to characterize the dose-response
5 relationship of PM is desired. In general, the objective is to provide a metric that is
6 mechanistically-motivated by the observed response. For example, alveolar effects could be
7 characterized by deposited mass, mass per regional surface area, mass per alveolus, or mass
8 per alveolar macrophage depending on the putative pathogenesis of the particles in question.
9 As shown in Figures 10-2 and 10-3, the smaller size fractions of aerosols are associated with
10 greater amounts of particles when characterized by surface area or by number rather than by
11 mass. That is, concentrations in this region are very small by mass but extremely high by
12 number. The need to consider this is accentuated when the high deposition of small particles
13 in the lower respiratory tract is also factored. Miller et al., (1995) recently investigated
14 differences in interspecies particle dosimetry. A summary table of this investigation is
15 provided as Table 10-18 and supports the conclusion that dose metrics based on particle
16 number per various anatomical normalizing factors indicate a need to examine the role of
17 fine particles in eliciting morbidity and mortality, particularly in patients with compromised
18 lung status (Miller et al., 1995). Anderson et al. (1990) have shown that the deposition of
19 ultrafine particles in patients with COPD is greater than that in healthy people. For this
20 external review draft, particle mass burdens have been selected as the dose metric.
21 Application of modeling to calculated number and surface area metrics are under
22 consideration.
23 The health effects data include effects that could be characterized as either "acute"
24 (e.g., mortality) or "chronic" (e.g., morbidity or laboratory animal pathology after two-year
25 biossays). Dose may be accurately described by particle deposition alone if the particles
26 exert their primary action on the surface contacted (Dahl et al., 1991), i.e., deposited dose
27 may be an appropriate metric for acute effects. An alternative to consider is dose rate
28 (jLtg/min) per unit surface area because insoluble particles deposit and clear along the surface
29 of the respiratory tract. Depending on the availability of morphometric information, other
30 normalizing factors that could be explored include those listed in Table 10-18.
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TABLE 10-18. SPECIES COMPARISONS BY MILLER ET AL. (1995) OF VARIOUS DOSE METRICS AS A
FUNCTION OF PARTICLE SIZE FOR 24 H EXPOSURES TO 150 /ig/m3
vo Human Lung Status
u\
i— »
o
i— »
O
£
H
6
0
o
H
O
o
H
W
O
o
H
w
Particle Size Dose Metric
Mass/Unit Area
0.1 pun No.b Deposited
No. /Unit Surface Area
No./Ventilatory Unit
No. /Alveolus0
No . /Macrophagec
1 pan Mass/Unit Area
No. Deposited
No. /Unit Surface Area
No./Ventilatory Unit
No. /Alveolus0
No./Macrophage°
5 pirn Mass/Unit Area
No. Deposited
No. /Unit Surface Area
No./Ventilatory Unit
No. /Alveolus0
No . /Macrophage0
aRat data values adjusted for inhalability.
bNo. = Number of particles.
Intervals for these dose metrics and ratios reflect the
the data of Yet et al. (1979) and Mercer et al. (1994)
data of Mercer et al. (1994).
dNot calculated.
Rata
3.74-3.76 X 10'3
1.2 x 1010
7.1 X 106
4.9 X 106
303-598
262-399
1.1-1.2 X 10'3
3.5 x 106
2,130
1,470
0.12-0.18
0.08-0.12
2.8-4.4 x 10-4
7.1 X 103
4
3
0.0002
0.0002
Normal
5.0 x 10-4
5.9 x 1011
9.5 x 105
1.8 x 107
1,190-1,930
100-61
2.8 x WA
3.3 x 106
532
9,910
0.07-1.1
0.06-0.09
9.1 x 104
8.5 X 106
14
260
0.02-0.03
0.001-0.002
Compromised
NCd
4.3 x 1011
2.8 x 106
5.3 x 107
3,570-5,790
298-482
NCd
2.4 X 108
1,590
29,700
2.0-3.3
0.2-0.3
NCd
6.4 X 106
42
780
0.05-0.09
0.004-0.007
Ratio:
Normal
0.13
49
0.1
4
2-5
0.3-0.6
0.23-0.25
92
0.3
7
4-9
0.5-1.2
2.09-3.23
1,195
3.2
88
49-120
6-15
Human/Rat
Compromised
NCd
37
0.4
11
6-15
0.8-1.8
NCd
69
0.8
20
11-28
1.4-3.5
NCd
897
9.7
263
145-359
18-45
range of values for the number of alveoli. Lower and upper interval values for the rat correspond to using
and for humans Mercer et al. (1994) and Weibel (1963), respectively. Lower dose ratios reflect using the
-------
1 Some of the human parameter values used in the ICRP model (ICRP66, 1994) and the
2 LUDEP® software are provided in Table 10-19. Surface area values were derived by the
3 ICRP based on the morphometry provided previously in Table 10-4. LUDEP® allows
4 simulations of either normal augmenter or mouth breather adult male humans. The
5 proportion of nasal airflow for these two types of breathing at different levels of activity
6 were previously provided in Figure 10-26 and Table 10-11 in Section 10.5. The levels of
7 activity to apportion nasal airflow are the same as those used to construct the three different
8 activity patterns (general population; worker, light work; and worker, heavy work) shown in
9 Table 10-19.
10 The broad spectrum of mammals used in inhalation toxicology research have body
11 weights ranging upwards from a few grams to hundreds of kg; these mammals also exhibit a
12 broad range of respiratory parameters. Table 10-20 lists body weights, lung weights,
13 respiratory minute ventilation and respiratory tract region surface areas for six laboratory
14 animal species. Lung weights and ventilation parameters are important variables for
15 inhalation toxicology because these parameters dictate the amounts of inhaled materials
16 potentially deposited in the lung, as well as the specific alveolar burdens (mass of particles/g
17 lung) that will result from inhalation exposures. The inverse relationship between body size
18 and metabolic rate is demonstrated by the values for respiratory minute ventilation and body
19 weight or lung tissue volume. For example, liters of air inhaled per minute per gram of lung
20 is about 20 times higher for resting mice than for resting humans, which is an important
21 factor to consider relative to potential amounts of aerosol deposited in the respiratory tract
22 per unit of tune during inhalation exposures.
23 For deposited doses, a dose expression with normalizing factors can be calculated as the
24 regional deposited dose (RDDr) can be calculated as
RDDr = 10"3 x q x VE X Fr, (10-45)
25 where:
26 RDDr = dose deposited in region r, /-ig/min,
27 Cj = concentration, /xg/m3,
28 VE = minute ventilation (L/min),
29 Fr = fractional deposition in region r.
April 1995 10-144 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-19. HUMAN MODEL PARAMETER VALUES
TABLE 10-19(a). BODY WEIGHT AND RESPIRATORY TRACT REGION SURFACE AREAS
Respiratory Tract Surface Areas
Body Weight (kg)
Lung Weight (g)
ET (cm)
TB (cm)
A(m)
73.0
1,100
470
2,690
54.0
TABLE 10-19(b). HUMAN ACTIVITY PATTERNS AND ASSOCIATED RESPIRATORY MINUTE VENTILATION.
Activity
Pattern
Sleeping
(.45 m3/h)
Sitting
(.54 m3/h)
Activity Light
(1.5 m3/h)
Activity Heavy
(3.0 m3/h)
Total/Day
Hours Total
Hours Total Hours Total m3 Hours Total m3 Hours Total
m
m
ft
O
O
o
H
O
e!
O
H
M
g
O
Adult male,
general
population
Adult male,
light work
Adult male,
heavy work
8
8
8
3.6
3.6
3.6
4.32
6.5 3.5
2.16
12
8.5 12.75
0
10
15
0
24
24
24
19.9
22.85
26.76
alnternationai Commission on Radiological Protection (ICRP66, 1994).
-------
TABLE 10-20. BODY WEIGHTS, LUNG WEIGHTS, RESPIRATORY MINUTE VENTILATION AND RESPIRATORY
TRACT REGION SURFACE AREA FOR SELECTED LABORATORY ANIMAL SPECIES
Species
Mouse (B6C3F1)
Syrian Hamster
Rat (F344)
Guinea Pig
Monkey
Dog
Minute
Body Weight Lung Weight Ventilation -
(kg) (g) (L/min)
0.037a
0.134a
0.380"
0.890"
2.45C
12.6C
0.43b
1.54b
4.34b
10. lb
27.4b
139b
0.044a
0.0573
0.253a
0.286a
0.776b
2.88b
Respiratory Region Surface Area
ET (cm2)
3a
14a
15a
30s1
NAd
NAd
TB (cm2)
3.5a
20.0a
22.5a
2003
NAd
NAd
A(m2)
0.05a
0.30s1
0.34a
0.90s
4.2e
41e
aU.S. Environmental Protection Agency (1994; 1988a). Default values for males in chronic bioassays.
bStahl, 1967: lung weight in g = 11.3 • (kg BW)°"; minute ventilation = 379 • (kg BW)°-8.
cPhalen (1984).
dNot available.
'Scaled from results of dogs and baboons in Crapo et al. (1983).
-------
1 If the RDD in animals is expressed relative to humans, the resultant ratio can be used
2 as a multiplicative factor to adjust an inhalation paniculate exposure in an experimental
3 species to a predicted human equivalent concentration (HEC) that would be expected to be
4 associated with the same dose delivered to the r* region of the respiratory tract. This
5 regional deposited dose ratio (RDDRr) can be calculated as a series of ratios
6
= >< CJ)A x (Normalizing Factor)H x (VE>A x (F^
(1(T3 x Cj)H (Normalizing Factor)A (VE)H (Fr)H
7
8 For the purposes of calculating the RDDR,., the exposure concentration for the laboratory
9 animal (A) and human (H) are assumed to be the same because it is assumed that the
10 observed effect in the laboratory animal is relevant to human health risk. The RDDR,. is
1 1 used as a factor to adjust for interspecies differences in delivered dose under the same
12 exposure scenario. The first term in Equation 10-46, therefore, equals one and will not be
13 discussed further. The last term, the ratio of deposition fractions in a given respiratory
14 region, (Fr), is calculated using the respective human and laboratory animal dosimetry
15 models.
16 The dosimetric adjustment of laboratory animal exposures to an HEC by the application
17 of the RDDRr has been used in derivation of inhalation RfC estimates. The inhalation RfC is
18 defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a
19 continuous inhalation exposure to the human population (including sensitive subgroup's) that
20 is likely to be without appreciable risk of deleterious noncancer health effects during a
21 lifetime (U.S. EPA, 1994). As such, it represents an estimate of dose-response used for
22 assessment of chemicals known as air toxics. A similar approach to the data on PM is
23 appropriate. An HEC would be calculated by
24
25 HEC (,xg/m3) = NOAEL[ADJ] (/tg/m3) X RDDRr, (10-47)
26
27
28 where the NOAEL[ADJ] is the no-observed-adverse-effect level (or other effect level) of the
29 laboratory animal study; this level, if from an intermittent exposure regimen, is often
April 1995 10-i47 DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
adjusted for the number of hours per day and days per week (#/24 x #/7) in order to a
continuous exposure.
Because the ICRP model utilizes an activity pattern, however, Equation 10-46 must be
modified to account for the fraction of time spent at each different ventilation rate
corresponding to different activity levels
RDDRr
IACT1
tmxVF xFr +tmxVE xFr + ...+trnlxVE xFr
UJ b r W C r lnJ E r
(10-48)
H[l]
H[2J
rH[n]
where t^ is the fractional tune spent breathing minute volume [i],
=1, and
a = lizing Factor)H x v p
(Normalizing Factor)A A r*
(1Q_49)
(10.50)
where VDF is a daily ventilation rate (L/min x 1440 min/day). It should be noted that the
A
human denominator is the fractional deposition value output from the ICRP model
simulations using the LUDEP® software using an activity pattern.
Although clearance is dependent on the site of initial deposition, calculation of retained
dose is probably more appropriate for assessing chronic heatlh effects. Again, different
normalizing factors such as retained mass per region, retained mass per surface area, or
retained mass per other available morphometric information may be worthwhile to explore.
The regional retained dose ratio RRDRr for interspecies dosimetric adjustment is calculated
as a series of five ratios
RRDR - (10"3xCi)A x
r -
where:
RRDR,. = relative fig of particles retained in region, r;
Ci = exposure atmosphere concentration, /xg/m3;
(Normalizing Factor)H
(Normalizing Factor)A
, (VE>A ,
(VE)H
, (Fr>A ,
(Fr)H)
, (AI^A
(AIt)H
(10-51)
April 1995
10-148 DRAFT-DO NOT QUOTE OR CITE
-------
1 Normalizing Factor = lung weight in grams;
2 VE = minute ventilation (L/min);
3 Fr = fractional aerosol deposition in region r;
4 (AIt) = relative accumulated alveolar interstitial burden of particles as a function of time
5 from the start of a chronic exposure.
6 Again, since the ICRP model allows simulation of an activity pattern, Equation 10-51
7 must be adjusted to account for the fraction of time spent at each different ventilation rate
8 corresponding to different activity levels.
9
x VEH[I] x FrH[1] x (AIt)H[1] x t[2]xVEH(2] x FrHp] x (AIt)H[2]
RRDR,
+ - + V] x VEHW x (AIt)H[n]
10 (10-52)
11
12 where t ffl is the fractional time spent breathing at minute ventilation [i],
ttll+t[2]+ • • -+tM = ^md
13
(NormalizingFactorr)
a = _ ^ X (VDE)A X (Fr)A X (AL)A ,
(NormalizingFactor) E A A l A
14
15 and VDE is a daily average ventilation rate (L/min x 1440 min/day).
A
16 The relative accumulated alveolar interstitial burden of particles as a function of time
17 from the start of a chronic exposure must be calculated for specific exposure scenarios to
18 account for species differences in clearance, as well as the dissolution-absorption
19 characteristics of the inhaled particles. This ratio is not a constant and must be calculated for
20 the chronic exposure tune of interest. Physical clearance functions and dissolution-absorption
21 rates for particles deposited in the A region are used to integrate daily deposition and
22 clearance over the chronic exposure time period of interest. The equations for laboratory
23 animals are derived using the information in Table 10-17. Physical clearance parameters for
April 1995 10-149 DRAFT-DO NOT QUOTE OR CITE
-------
1 humans are in the ICRP model (ICRP66, 1994) and the calculation of A burden for humans
2 can be made using LUDEP®.
3 It should also be stated that calculating these ratios (either deposited or retained)
4 depends on particle diameter (MMAD) and distribution (ag) but not on aerosol concentration,
5 i.e., it assumes no altered deposition or clearance due to exposure concentration or chemical-
6 specific toxicity.
7
8 10.7.3 Choice of Exposure Metrics
9 Human Exposure Data
10 Ambient exposure data provided elsewhere in the document were chosen to represent
11 typical human exposures. Three different aerosols were chosen. Additional information on
12 the characterization of each of these aerosols can be found in Chapter 3.
13 The first is the trimodal aerosol shown in Figure 10-34. Table 10-21 shows the
14 cumulative distribution of particles, based on the count diameter (dj, surface diameter (ds),
15 mass diameter (d), or aerodynamic diameter (dae). Recall from Section 10.2 that the 50%
16 size cut for each of these diameters would be the respective median diameter of the
17 distribution, i.e., the 50% size-cut diameter of the dae is the MMAD. Table 10-22 shows a
18 distribution of the particles from Figure 10-34 and Table 10-21 into arbitrary size fractions
19 (assuming the modes were distributed lognormally) and containing 1, 4, 5 or 10% of each
20 mass median size distribution.
21 The two aerosols depicted in Figure 10-35, panels A and B, for Philadelphia and
22 Phoenix respectively, were also chosen and treated similarly. Table 10-23 shows the
23 cumulative distribution of particles, based on the count diameter (d<,), surface diameter (ds),
24 mass diameter (d), or aerodynamic diameter (dae). Recall from Section 10.2 that the 50%
25 size cut for each of these diamters would be the respective median diamter of the
26 distribution, e.g., the 50% size-cut diameter of the dae is the MMAD. Table 10-24 shows a
27 distribution of the particles from Figure 10-35(a) and Table 10-23 into arbitrary size fractions
28 (assuming the modes were distributed lognormally) and containing 1, 4, 5 or 10% of each
29 mass median size distribution. Tables 10-25 and 10-26 are analogous to Tables 10-23 and
30 10-24 but show the data for Phoenix (Figure 10-35b).
April 1995 10-150 DRAFT-DO NOT QUOTE OR CITE
-------
Electrical aerosol analyzer
0.002
0.01
100
DP (\im)
Figure 10-34. An example of histogram display and fitting to log-normal functions for
particle-counting size distribution data. Instruments used and the range
covered by each are shown. Counts are combined into reasonably-sized
bins and displayed. Lognormal functions, fitted to the data, are shown
with geometric mean sizes (MMD) of each mode and the width (og) of
each mode. Data taken from a study of fine sulfate and other particles
generated by catalyst equipped cars as part of a cooperative study by
EPA and General Motors Corporation. Note the clear separation of the
nuclei mode (MMD = 0.018 urn), the accumulation mode (MMD = 0.21
jim) and coarse mode (MMD = 4.9 jon). Fine particles, as defined by
Whitby (1988), include the nuclei and accumulation mode.
Source: Wilson et al., 1977.
1
2
3
4
The last aerosol chosen to represent ambient human exposures is that shown in
Figure 10-36. Tables 10-27 and 10-28 show the cumulative distributions and recalculated
distribution (using assignment into arbitrary size fractions and based on assuming that the
mode was distributed lognormally) for these data.
April 1995
10-151 DRAFT-DO NOT QUOTE OR CITE
-------
> TABLE 10-21. DISTRIBUTION OF PARTICLE SIZES IN A TRIMODAL POLYDISPERSE AEROSOL DEFINED IN
B FIGURE 10-34. THE TABULATED NUMBERS REPRESENT THE UPPER SIZE LIMIT FOR EACH PARTICLE SIZE
~ INTERVAL BASED ON THE COUNT MEDIAN DISTRIBUTION (dc), SURFACE MEDIAN DISTRIBUTION (dg), MASS
g MEDIAN DISTRIBUTION (d), OR MASS MEDIAN AERODYNAMIC EQUIVALENT SIZE DISTRIBUTION (dae)a
Percent of Particles Smaller Than Size Cut
*— ^
0
h— *
to
0
?
*D
H
6
^
o
H
0
a
o
H
w
o
n
en
Aerosol Mode Particle Parameter, jim
Nuclei5 dc
dg
d
dae
Accumulation0 dc
dg
d
dae
Coarsed dc
dg
d
dae
1 5 10
0.0031 0.0043 0.0051
0.0048 0.0067 0.0079
0.0060 0.0083 0.010
0.044 0.051 0.056
0.019 0.028 0.034
0.038 0.057 0.069
0.053 0.080 0.097
0.127 0.162 0.183
0.346 0.534 0.673
0.757 1.17 1.47
1.12 1.73 2.18
1.78 2.68 3.35
aValues for dae were calculated using Equations 5 and 7 of Raabe (1972)
= d(p[l + a + /3e-w2X))(2X/d])0-5 where a ~ 1.26, 0 - 0.45; 7 - 0
bMass median diameter (MMD) = 0.018
CMMD = 0.21 pm; ag = 1.8; density, p
dMMD = 4.9 fj,m; ag = 1.87; density, p
20
0.0062
0.0096
0.012
0.062
0.046
0.091
0.129
0.220
0.880
1.93
2.85
4.35
, which
30
0.0072
0.011
0.014
0.067
0.055
0.109
0.154
0.248
1.08
2.37
3.50
5.31
include a slip
40
0.0082
0.013
0.016
0.072
0.064
0.127
0.180
0.278
1.28
2.80
4.15
6.28
50 60
0.0093 0.010
0.014 0.016
0.018 0.020
0.076 0.081
0.074 0.087
0.149 0.173
0.210 0.245
0.311 0.350
1.51 1.79
3.31 3.92
4.90 5.80
7.39 8.72
70
0.012
0.018
0.023
0.087
0.103
0.205
0.290
0.400
2.41
5.27
7.80
11.7
80
0.014
0.022
0.027
0.095
0.124
0.248
0.350
0.466
2.56
5.61
8.30
12.4
correction factor and particle density to
.0650 /un for air at 21 °C at
/im; geometric standard deviation (ag)
= 1.2 g/cm3.
= 2.2 g/cm3.
= 1.6; density, (p)
sea level.
= 1.4 g/cm3.
90
0.017
0.026
0.033
0.106
0.160
0.319
0.450
0.576
3.40
7.43
11.0
16.4
95
0.020
0.031
0.039
0.116
0.199
0.396
0.560
0.698
4.32
9.46
14.0
20.9
99
0.028
0.043
0.054
0.139
0.294
0.588
0.830
0.995
6.48
14.2
21.0
31.3
calculate d.^ from d: (
-------
£ TABLE 10-22. DISTRIBUTION OF PARTICLE
»-1
h-»-
§
L»
FIGURE 10-34. EACH INDIVIDUAL MODE OF
SIZE FRACTIONS CONTAINING
THE PERCENT OF TOTAL AEROSOL
1,4,5
MASS
MASS IN A TRIMODAL POLYDISPERSE AEROSOL DEFINED IN
THE TRIMODAL AEROSOL WAS SEPARATED
INTO ARBITRARY
, OR 10% OF EACH MASS MEDIAN SIZE DISTRIBUTION.
IN EACH SIZE FRACTION WAS CALCULATED BASED ON THE
KNOWLEDGE THAT 15.6% OF THE TOTAL MASS WAS IN
"ACCUMULATION MODE, " AND 45.7% IN
9
Ul
D
£
6
O
O
H
O
^
H
O
O
H
W
Mode Percent of Mode Percent of
Nucleia 1
4
5
10
10
10
10
10
10
10
10
5
4
1
Accumulation1" 1
4
5
10
10
10
10
10
Trimodal
0.156
0.624
0.780
1.560
1.560
1.560
1.560
1.560
1.560
1.560
1.560
0.780
0.624
0.156
0.385
1.544
1.925
3.850
3.850
3.850
3.850
3.850
Aerosol dc
0.0031
0.0043
0.0051
0.0062
0.0072
0.0082
0.0093
0.010
0.012
0.014
0.017
0.020
0.028
0.103
0.019
0.028
0.034
0.046
0.055
0.064
0.074
0.087
THE "NUCLEI
THE "COARSE
Particle Size
dg
0.0048
0.0067
0.0079
0.0096
0.011
0.013
0.014
0.016
0.018
0.022
0.026
0.031
0.043
0.160
0.038
0.057
0.069
0.091
0.109
0.127
0.149
0.173
MODE," 38
MODE"
Interval Cutoff
d
0.0060
0.0083
0.0099
0.012
0.014
0.016
0.018
0.020
0.023
0.027
0.033
0.039
0.054
0.200
0.053
0.080
0.097
0.129
0.154
0.180
0.210
0.245
.7% IN THE
dae
0.044
0.051
0.056
0.062
0.067
0.072
0.076
0.081
0.087
0.095
0.105
0.116
0.139
0.324
0.127
0.162
0.183
0.220
0.248
0.278
0.311
0.350
-------
£ TABLE 10-22 (cont'd). DISTRIBUTION OF PARTICLE MASS IN A TRIMODAL POLYDISPERSE AEROSOL
3. DEFINED IN FIGURE 10-34. EACH INDIVIDUAL MODE OF THE TRIMODAL AEROSOL WAS SEPARATED INTO
~ ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH MASS MEDIAN SIZE DISTRIBUTION.
8 THE PERCENT OF TOTAL AEROSOL MASS IN EACH SIZE FRACTION WAS CALCULATED BASED ON THE
KNOWLEDGE THAT 15.6% OF THE TOTAL MASS WAS IN THE "NUCLEI MODE," 38.7% IN THE
"ACCUMULATION MODE, " AND 45.7% IN THE "COARSE MODE"
Particle Size Interval Cutoff
Mode
5 Coarse0
1
»— *
•^
O
TI
H
o
0
^
s
0
s
a
Percent of Mode
10
10
10
5
4
1
1
4
5
10
10
10
10
10
10
10
10
5
4
1
Percent of Trimodal Aerosol
3.850
3.850
3.850
1.925
1.544
0.385
0.457
1.828
2.285
4.570
4.570
4.570
4.570
4.570
4.570
4.570
4.570
2.285
1.828
0.457
dc
0.103
0.124
0.160
0.199
0.294
1.06
0.346
0.534
0.673
0.880
1.08
1.28
1.51
1.79
2.41
2.56
3.40
4.32
6.48
24.7
dg
0.205
0.248
0.319
0.396
0.588
2.12
0.757
1.17
1.47
1.93
2.37
2.80
3.31
3.92
5.27
5.61
7.43
9.46
14.2
54.1
d
0.290
0.350
0.450
0.560
0.830
3.00
1.12
1.73
2.18
2.85
3.50
4.15
4.90
5.80
7.80
8.30
11.0
14.0
21.0
80.0
dae
0.400
0.466
0.576
0.698
0.995
3.37
1.78
2.68
3.35
4.35
5.31
6.28
7.39
8.72
11.7
12.4
16.4
20.9
31.3
119
?& "Mass median diameter (MMD) = 0.018 /an; geometric standard deviation (a.) = 1.6; density, p — 1.4 g/cm3
Q bMMD = 0.21 /an; ag = 1.8; density, p = 1.2 g/cm3.
H CMMD = 4.9 /an; a. =1.87; density, p = 2.2 g/cm3.
W B
-------
90.0
E
a.
N^
Q.
Q
S
45.0
Q.
Q
I
2
90.0
45.0'
Philadelphia-WRAC
Mode MMD
1 0.436
2 2.20
3 28.8
1.0 10.0
Aerodynamic Diameter, Dp (|im)
100.0
Phoenix-WRAC
Mode MMD
-------
c;
Lft
TABLE 10-23. DISTRIBUTION OF PARTICLE SIZES IN A TRIMODAL POLYDISPERSE AEROSOL FOR
PHILADELPHIA DEFINED IN FIGURE 10-35(a). THE TABULATED NUMBERS REPRESENT THE UPPER SIZE
LIMIT FOR EACH PARTICLE SIZE INTERVAL BASED ON THE COUNT MEDIAN DISTRIBUTION (dc), SURFACE
MEDIAN DISTRIBUTION (d ), MASS MEDIAN DISTRIBUTION (d), OR MASS MEDIAN AERODYNAMIC
EQUIVALENT SIZE DISTRIBUTION (dae)a
Percent of Particles Smaller Than Size Cut
9
i— *
cr\
O
6
O
O
H
O
1
§
n
H
W
Aerosol Mode Particle Parameter, /*m
Accumulation11 dc
dg
d
dae
Intermodalc dc
dg
d
dae
Coarsed dc
dg
d
dae
1 5
0.100 0.132
0.140 0.186
0.166 0.220
0.273 0.335
1.45 1.61
1.52 1.68
1.55 1.72
1.86 2.05
0.802 1.37
2.62 4.48
4.75 8.10
5.51 9.33
10
0.153
0.215
0.255
0.376
1.69
1.77
1.81
2.16
1.79
5.86
10.6
12.2
20
0.183
0.257
0.305
0.433
1.82
1.90
1.94
2.30
2.53
8.29
15.0
17.2
30
0.207
0.291
0.345
0.479
1.91
2.00
2.04
2.42
3.24
10.6
19.2
22.0
40 50
0.231 0.262
0.325 0.368
0.385 0.436
0.525 0.584
1.98 2.05
2.07 2.15
2.12 2.20
2.51 2.60
4.00 4.86
13.1 15.9
23.7 28.8
27.1 32.9
60 70
0.287 0.320
0.403 0.449
0.478 0.532
0.632 0.694
2.14 2.24
2.24 2.34
2.29 2.39
2.70 2.82
5.94 7.34
19.5 24.0
35.2 43.5
40.2 49.7
80
0.362
0.509
0.603
0.776
2.34
2.45
2.50
2.94
9.37
30.7
55.5
63.4
90
0.434
0.609
0.722
0.912
2.51
2.62
2.68
3.15
13.3
43.7
79.0
90.2
95
0.503
0.707
0.838
1.04
2.64
2.76
2.82
3.31
17.6
57.5
104
119
aValues for dae were calculated using Equations 5 and 7 of Raabe (1972), which include a slip correction factor and particle density to calculate dae
= d(p[l + a + |3e-
-------
£ TABLE 10-24. DISTRIBUTION OF PARTICLE MASS IN A TRIMODAL POLYDISPERSE AEROSOL FOR
a PHILADELPHIA DEFINED IN FIGURE 10-35(a). EACH INDIVIDUAL MODE OF THE TRIMODAL AEROSOL WAS
£ SEPARATED INTO ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH MASS MEDIAN
% SIZE DISTRIBUTION. THE PERCENT OF TOTAL AEROSOL MASS IN EACH SIZE FRACTION WAS
CALCULATED BASED ON THE KNOWLEDGE THAT 48.2% OF THE TOTAL MASS WAS IN THE
"ACCUMULATION MODE," 7.4% IN THE "INTERMODAL MODE," AND 44.3% IN THE "COARSE MODE"
Mode
Accumulation3
t— »
9
5
O
£
.L Intermodalb
O
1
€
a
o
90'
n
Particle Size Interval Cutoff
Percent of Mode
1
4
5
10
10
10
10
10
10
10
10
5
4
1
1
4
5
10
10
10
10
10
Percent of Trimodal Aerosol
0.482
1.928
2.410
4.820
4.820
4.820
4.820
4.820
4.820
4.820
4.820
2.410
1.928
0.482
0.074
0.296
0.370
0.740
0.740
0.740
0.740
0.740
dc
0.100
0.132
0.153
0.183
0.207
0.231
0.262
0.287
0.320
0.362
0.434
0.503
0.667
1.80
1.45
1.61
1.69
1.82
1.91
1.98
2.06
2.14
dg
0.140
0.185
0.215
0.257
0.291
0.325
0.368
0.403
0.449
0.509
0.609
0.707
0.937
2.53
1.52
1.68
1.77
1.90
2.00
2.07
2.15
2.24
d
0.166
0.220
0.255
0.305
0.345
0.385
0.436
0.478
0.532
0.603
0.722
0.838
1.11
3.00
1.55
1.72
1.81
1.94
2.04
2.12
2.20
2.29
dae
0.273
0.335
0.376
0.433
0.479
0.525
0.583
0.632
0.694
0.776
0.912
1.04
1.36
3.51
1.86
2.05
2.16
2.30
2.42
2.51
2.60
2.70
-------
a
O
H-1
S
TABLE 10-24 (cont'd). DISTRIBUTION OF PARTICLE MASS IN A TRIMODAL POLYDISPERSE AEROSOL FOR
PHILADELPHIA DEFINED IN FIGURE 10-35(a). EACH INDIVIDUAL MODE OF THE TRIMODAL AEROSOL WAS
SEPARATED INTO ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH MASS MEDIAN
SIZE DISTRIBUTION. THE PERCENT OF TOTAL AEROSOL MASS IN EACH SIZE FRACTION WAS
CALCULATED BASED ON THE KNOWLEDGE THAT 48.2% OF THE TOTAL MASS WAS IN THE
"ACCUMULATION MODE," 7.4% IN THE "INTERMODAL MODE," AND 44.3% IN THE "COARSE MODE"
Mode
t_L Coarse0
0
h-*
oo
O
&
V
6
o
5£
O
H
O
c|
Percent of Mode
10
10
10
5
4
1
1
4
5
10
10
10
10
10
10
10
10
5
4
1
Percent of Trimodal Aerosol
0.740
0.740
0.740
0.370
0.296
0.074
0.443
1.772
2.215
4.430
4.430
4.430
4.430
4.430
4.430
4.430
4.430
2.215
1.772
0.443
dc
2.24
2.34
2.51
2.64
2.92
4.21
0.802
1.37
1.79
2.53
3.24
4.00
4.86
5.94
7.34
9.37
13.3
17.6
29.5
118
Particle Size
dg
2.34
2.45
2.62
2.76
3.05
4.40
2.62
4.48
5.86
8.29
10.6
13.1
15.9
19.5
24.0
30.7
43.7
57.5
96.7
387
Interval Cutoff
d
2.39
2.50
2.68
2.82
3.12
4.50
4.75
8.10
10.6
15.0
19.2
23.7
28.8
35.2
43.5
55.5
79.0
104
175
700
dae
2.82
2.94
3.15
3.31
3.65
5.22
5.51
9.33
12.2
17.2
22.0
27.1
32.9
40.2
49.7
63.4
90.2
119
200
798
aMass median diameter (MMD) = 0.436 /tim; geometric standard deviation (ag) = 1.51; density, p = 1.3 g/cm3.
bMMD = 2.20 /mi; og = 1.16; density, p = 1.3 g/cm3.
CMMD = 28.8 /mi; ag = 2.16; density, p = 1.3 g/cm3.
-------
> TABLE 10-25. DISTRIBUTION OF PARTICLE SIZES IN A TRIMODAL POLYDISPERSE AEROSOL FOR PHOENIX
3: DEFINED IN FIGURE 10-35(b). EACH INDIVIDUAL MODE OF THE TRIMODAL AEROSOL WAS SEPARATED
~ INTO ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH SIZE DISTRIBUTION. THE
£ TABULATED NUMBERS REPRESENT THE UPPER SIZE LIMIT FOR EACH PARTICLE SIZE INTERVAL BASED
ON THE COUNT MEDIAN DISTRIBUTION (dc), SURFACE MEDIAN DISTRIBUTION (dg), MASS MEDIAN
DISTRIBUTION (d), OR MASS MEDIAN AERODYNAMIC EQUIVALENT SIZE DISTRIBUTION (dae)a
(— '
9
u«
vo
o
6
o
I
o
Aerosol Mode
Accumulation5
Intermodalc
Coarsed
Particle Parameter, /cm
dc
dg
d
dae
dc
dg
d
dae
dc
d
dae
1 5
0.039 0.053
0.057 0.076
0.069 0.092
0.177 0.210
0.108 0.169
0.246 0.384
0.372 0.580
0.584 0.857
0.063 0.127
0.516 1.05
1.48 3.00
2.03 4.02
10
0.061
0.089
0.107
0.232
0.215
0.490
0.740
1.07
0.186
1.53
4.38
5.82
Percent
20 30
0.074 0.085
0.107 0.124
0.130 0.149
0.263 0.289
0.288 0.352
0.656 0.801
0.990 1.21
1.39 1.68
0.295 0.408
2.42 3.35
6.95 9.60
9.17 12.6
of Particles Smaller Than Size Cut
40 50
0.096 0.107
0.139 0.156
0.168 0.188
0.314 0.341
0.418 0.494
0.954 1.13
1.44 1.70
1.98 2.32
0.540 0.697
4.43 5.72
12.7 16.4
16.7 21.5
60 70
0.120 0.134
0.174 0.195
0.210 0.235
0.370 0.403
0.581 0.694
1.32 1.58
2.00 2.39
2.71 3.22
0.914 1.21
7.50 9.95
21.5 28.5
28.1 37.3
80
0.154
0.224
0.270
0.449
0.851
1.94
2.93
3.93
1.69
13.9
39.8
52.0
90
0.187
0.272
0.328
0.526
1.13
2.58
3.90
5.19
2.68
22.0
63.0
82.2
95
0.219
0.318
0.383
0.598
1.44
3.28
4.95
6.56
3.44
28.3
81.0
106
"Values for dae were calculated using Equations 5 and 7 of Raabe (1972), which include a slip correction factor and particle density to calculate dae
= d(p[l + a + jSe^^X/d])0-5 where a ~ 1.26, 0 ~ 0.45; 7 ~ 0.0650 /tin for air at 21 °C at sea level.
bMass median diameter (MMD) = 0.188 /tm; geometric standard deviation (ag) = 1.54; density, (p) = 1.7 g/cm3.
CMMD = 1.70 /tm; ag = 1.90; density, p = 1.7 g/cm3.
dMMD = 16.4 /tm; ag = 2.79; density, p = 1.7 g/cm3.
99
0.329
0.477
0.575
0.850
2.24
5.10
7.70
10.1
7.86
64.6
185
241
from d: d.
O
n
-------
8
TABLE 10-26. DISTRIBUTION OF PARTICLE MASS IN A TRIMODAL POLYDISPERSE AEROSOL DEFINED FOR
PHOENIX IN FIGURE 10-35(b). EACH INDIVIDUAL MODE OF THE TRIMODAL AEROSOL
WAS SEPARATED INTO ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH SIZE
DISTRIBUTION. THE PERCENT OF TOTAL AEROSOL MASS IN EACH SIZE FRACTION WAS CALCULATED
BASED ON THE KNOWLEDGE THAT 22.4% OF THE TOTAL MASS WAS IN THE "ACCUMULATION MODE",
13.8% IN THE "INTERMODAL MODE," AND 63.9% IN THE "COARSE MODE"
Particle Size Interval Cutoff
Mode
Accumulation3
0
H->
s
o
£
3
O Intermodalb
2;
^
O
c
o
H
W
0
p— 1
H
W
Percent of Mode
1
4
5
10
10
10
10
10
10
10
10
5
4
1
1
4
5
10
10
10
10
10
Percent of Trimodal Aerosol
0.224
0.896
1.120
2.240
2.240
2.240
2.240
2.240
2.240
2.240
2.240
1.120
0.896
0.224
0.138
0.552
0.690
1.380
1.380
1.380
1.380
1.380
dc
0.039
0.053
0.061
0.074
0.085
0.096
0.107
0.120
0.134
0.154
0.187
0.219
0.329
0.857
0.108
0.169
0.215
0.288
0.352
0.418
0.494
0.581
dg
0.057
0.076
0.089
0.108
0.124
0.139
0.156
0.174
0.195
0.224
0.272
0.318
0.477
1.24
0.246
0.384
0.490
0.656
0.801
0.954
1.13
1.32
d
0.069
0.092
0.107
0.130
0.149
0.168
0.188
0.210
0.235
0.270
0.328
0.383
0.575
1.50
0.372
0.580
0.740
0.990
1.21
1.44
1.70
2.00
dae
0.177
0.210
0.232
0.263
0.289
0.314
0.341
0.370
0.403
0.449
0.526
0.598
0.850
2.06
0.584
0.857
1.07
1.39
1.68
1.98
2.32
2.71
-------
TABLE 10-26 (cont'd). DISTRIBUTION OF PARTICLE MASS IN A TRTMODAL POLYDISPERSE AEROSOL
DEFINED FOR PHOENIX IN FIGURE 10-35(b). EACH INDIVIDUAL MODE OF THE TRTMODAL AEROSOL
WAS SEPARATED INTO ARBITRARY SIZE FRACTIONS CONTAINING 1, 4, 5, OR 10% OF EACH SIZE
DISTRIBUTION. THE PERCENT OF TOTAL AEROSOL MASS IN EACH SIZE FRACTION WAS CALCULATED
BASED ON THE KNOWLEDGE THAT 22.4% OF THE TOTAL MASS WAS IN THE "ACCUMULATION MODE",
13.8% IN THE "INTERMODAL MODE," AND 63.9% IN THE "COARSE MODE"
o
ON
O
C
T1
b
o
o
o
c
o
H
W
Mode Percent of Mode
10
10
10
5
4
1
Coarse0 1
4
5
10
10
10
10
10
10
10
10
5
4
1
aMass median diameter (MMD) = 0. 188 /*m;
bMMD = 1.70 /tm;
-------
0)
CT
0)
35
30
25
20
15
10
5
0
Summer All Sites SOj •
(a)
0.1
1
Aerodynamic Mode Diameter (urn)
10
400
300
O 200
§> 100
0 -
Summer All Sites SO* -
(b)
0.1 1
Aerodynamic Mode Diameter
10
Figure 10-36. Data from the South Coast Air Quality Study (John et al., 1990). Plots
show (a) frequency of sulfate modes of various sizes as a function of
mode mass mean diameter (MMD) and (b) average sulfate mode
concentration as a function of mode MMD. Note that although there are
only a few instances when the MMD is near 1.0 /on diameter may be due
to collection of fog droplets containing sulfate or reaction of SO2 in liquid
droplets of NaCl due to NaCl sea spray droplets in which SO2 has
dissolved and reacted to form sulfate and release HC1 gas.
April 1995
10-162 DRAFT-DO NOT QUOTE OR CITE
-------
> TABLE 10-27. DISTRIBUTION OF PARTICLE SIZES IN A POLYDISPERSE AEROSOL FOR LOS ANGELES IN
2 FIGURE 10-36(b). THE TABULATED NUMBERS REPRESENT THE UPPER SIZE LIMIT FOR EACH PARTICLE
£ SIZE INTERVAL BASED ON THE COUNT MEDIAN DISTRIBUTION (dc), SURFACE MEDIAN DISTRIBUTION (dg),
S MASS MEDIAN DISTRIBUTION (d), OR MASS MEDIAN AERODYNAMIC EQUIVALENT SIZE DISTRIBUTION (dae)a
O
O
2
O
H
O
C
1
§
n
Percent of
Aerosol Mode
Nuclei5
Particle Parameter, jtm
dc
dg
d
dae
1
0.063
0.125
0.177
0.263
5
0.108
0.215
0.304
0.397
10
0.134
0.268
0.378
0.476
20
0.174
0.347
0.490
0.594
30
0.209
0.418
0.590
0.700
Particles Smaller Than Size
40
0.245
0.488
0.690
0.805
50
0.284
0.566
0.800
0.921
60
0.333
0.664
0.938
1.07
Cut
70
0.390
0.779
1.10
1.24
80
0.468
0.934
1.32
1.47
90
0.614
1.22
1.73
1.90
95
0.752
1.50
2.12
2.31
99
1.12
2.23
3.15
3.39
aValues for dae were calculated using Equations 5 and 7 of Raabe (1972), which include a slip correction factor and particle density to calculate dae from d: dae
= d(p[l + a + /3e-^/2X))(2X/d])°-5 where a - 1.26, 0 ~ 0.45; y ~ 0.0650 urn for air at 21 °C at sea level.
bMass median diameter (MMD) = 0.8 jim; geometric standard deviation (ag) = 1.8; density, (p) = 1.1 g/cm3.
-------
TABLE 10-28. DISTRIBUTION OF PARTICLE MASS IN A POLYDISPERSE
AEROSOL FOR LOS ANGELES DEFINED IN FIGURE 10-36(b). THE AEROSOL
WAS SEPARATED INTO ARBITRARY SIZE FRACTIONS CONTAINING
1, 4, 5, OR 10% OF THE SIZE DISTRIBUTION
Particle Size Interval Cutoff
Aerosol Percent of Aerosol
LA-WETa 1
4
5
10
10
10
10
10
10
10
10
5
4
1
dc
0.063
0.108
0.134
0.174
0.209
0.245
0.284
0.333
0.390
0.468
0.614
0.752
1.12
3.55
dg
0.125
0.215
0.268
0.347
0.418
0.488
0.566
0.664
0.779
0.934
1.22
1.50
2.23
7.08
d
0.177
0.304
0.378
0.490
0.590
0.690
0.800
0.938
1.10
1.32
1.73
2.12
3.15
10.0
dae
0.263
0.397
0.476
0.594
0.700
0.805
0.921
1.07
1.24
1.47
1.90
2.31
3.39
10.6
"Mass median diameter (MMD) = 0.8 ^m; geometric standard deviation (a.) = 1.8; density, p = 1.1 g/cm3.
1 region into compartments, ET1 and ET2. The ICRP model also divides the TB region into
2 two compartments, the bronchi (BB) and bronchiole (bb). The alveolar interstitial (AI)
3 compartment is equivalent to the A region. When compared to the laboratory animal data,
4 deposition fractions for ET1 and ET2 were summed to calculate ET deposition. Likewise,
5 the BB and bb deposition fractions were summed to calculate the TB fraction.
6
7 Human Deposition Estimates
8 Tables 10-29 through 10-35 present the regional deposition fractions (% deposition) and
9 regional deposited particle mass (ug) for each of the three ambient human exposure aerosols
10 depicted in Figures 10-34, 10-35(a) (Philadelphia), 10-35(b) (Phoenix), and 10-36 (Los
11 Angeles). Data are shown for normal augmenters (Tables 10-29, 10-31, 10-33, and 10-35)
12 versus mouth breathers (Tables 10-30, 10-32, 10-34, and 10-35) for three different activity
13 patterns.
April 1995
10-164 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-29. DAILY MASS DEPOSITION OF PARTICLES FROM AEROSOL IN FIGURE 10-34 IN THE
RESPIRATORY TRACT OF "NORMAL AUGMENTER" ADULT MALE HUMANS EXPOSED AT 50 jig PARTICLES/m3
ON
L/l
o
o
z
o
H
O
§
w
g
o
Trimodal Aerosol Modes3
Activity Pattern
General
population13
Workers, light
workc
Workers, heavy
workd
Region of
Respiratory
Tract
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
Nuclei
Percent
Deposition
2.27
2.34
0.86
5.64
21.96
33.06
2.11
2.32
0.80
5.28
21.75
32.26
2.00
2.29
0.74
4.94
21.56
31.53
Mode
Mass of
Particles
164.77
187.48
7.78
5.74
17.98
383.75
178.36
219.38
15.89
6.95
19.91
440.49
201.11
260.97
24.21
8.01
21.77
516.07
"Nuclei mode MMAD = 0.076 /an, ag = 1.6, density = 1.4g/cm3, 15.6% of the aerosol mass; accumulation mode MMAD = 0.311 /tin, ag = 1.8, density = 1.2 g/cm3, 38.7% of the aerosol mass;
coarse mode MMAD = 7.39 pm,
-------
TABLE 10-30. DAILY MASS DEPOSITION OF PARTICLES FROM AEROSOL IN FIGURE 10-34 IN THE
RESPIRATORY TRACT OF "MOUTH BREATHER" ADULT MALE HUMANS EXPOSED AT 50 ng PARTICLES/m3
8
o
o
O
C!
O
H
W
S
O
h— I
H
W
Trimodal Aerosol Modes3
Activity Pattern
General
population13
Workers, light
workc
Workers, heavy
workd
Region of
Respiratory
Tract
ET,
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ET!
ET2
BB
bb
AI
Total
Nuclei
Percent
Deposition
1.27
2.41
0.86
5.68
22.10
32.32
1.17
2.38
0.80
5.30
21.89
31.54
1.08
2.35
0.74
4.96
21.71
30.84
Mode
Mass of
Particles
(Mg)
1.97
3.74
1.34
8.83
34.34
50.22
2.09
4.25
1.43
9.45
39.05
56.27
2.25
4.91
1.54
10.35
45.31
64.36
Accumulation
Percent
Deposition
0.94
1.26
0.44
1.90
8.68
13.22
0.92
1.28
0.44
1.76
8.51
12.91
0.89
1.28
0.46
1.64
8.35
12.62
Mode
Mass of
Particles
tm, ag = 1.8, density =1.2 g/cm3, 38.7% of the aerosol mass;
coarse mode MMAD = 7.39 pm, ag = 1.87, density = 2.2 g/cm3, 45.7% of the aerosol mass (see Tables 10-21 and 10-22).
bAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10-19).
'Average for 24 h, as derived from ICRP-66 (1974): for 33.3% sleep, 27.1% sitting, 35.4% light exercise, 4.2% heavy exercise. (See Table 10-19).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, 41.7% light exercise, 8.3% heavy exercise. (See Table 10-19).
-------
VO
O
H
O
G
3
w
§
O
TABLE 10-31. DAILY MASS DEPOSITION OF PARTICLES FROM PHILADELPHIA AEROSOL IN FIGURE 10-35(a)
IN THE RESPIRATORY TRACT OF "NORMAL AUGMENTER" ADULT MALE HUMANS EXPOSED AT 50 /tg PARTICLES/m3
Trimodal Aerosol Modes3
Activity Pattern
General
population15
Workers, light
work0
Workers, heavy
workd
Region of
Respiratory
Tract
ET,
ET2
BB
bb
AI
Total
ET,
ET2
BB
bb
AI
Total
ET,
ET2
BB
bb
AI
Total
Accumulation
Percent
Deposition
4.05
3.94
0.38
1.44
7.73
17.54
3.97
3.94
0.42
1.34
7.57
17.24
4.02
4.05
0.44
1.24
7.40
17.15
Mode
Mass of
Particles
<0g)
19.44
18.91
1.82
6.91
37.11
84.19
21.88
21.72
2.31
7.39
41.72
95.02
25.93
26.12
2.84
8.00
47.72
110.61
Intermodal
Percent
Deposition
25.34
35.64
2.07
2.51
15.37
80.93
24.36
34.99
3.16
2.54
15.17
80.22
24.09
35.22
3.96
2.50
14.64
80.41
Mode
Mass of
Particles
(Mg)
18.68
26.27
1.53
1.85
11.33
59.66
20.61
29.61
2.67
2.15
12.84
67.88
23.85
34.87
3.92
2.48
14.50
79.62
Coarse
Percent
Deposition
29.34
30.24
0.40
0.15
0.26
60.39
27.45
31.94
0.62
0.14
0.24
60.39
26.18
33.12
0.76
0.13
0.22
60.41
Mode
Mass of
Particles
to)
129.46
133.43
1.76
0.66
1.15
266.46
139.05
161.80
3.14
0.71
1.22
305.92
155.18
196.31
4.50
0.77
1.30
358.06
"Accumulation mode MMAD = 0.436 /an, ag = 1.51, density =1.3 g/cm3, 48.2% of the aerosol mass; intermodal mode MMAD = 2.20 /an, ag =
mass; coarse mode MMAD = 28.8 /an,
-------
TABLE 10-32. DAILY MASS DEPOSITION OF PARTICLES FROM PHILADELPHIA AEROSOL IN FIGURE 10-35(a)
IN THE RESPIRATORY TRACT OF "MOUTH BREATHER" ADULT MALE HUMANS EXPOSED AT 50 |tg PARTICLES/m3
9
t—*
OO
O
o
2
o
H
O
Trimodal Aerosol Modes3
Activity Pattern
General
population15
Workers, light
workc
Workers, heavy
workd
Region of
Respiratory
Tract
ET]
ET2
BB
bb
AI
Total
ETJ
ET2
BB
bb
AI
Total
ET,
ET2
BB
bb
AI
Total
Accumulation
Percent
Deposition
1.07
1.26
0.40
1.48
8.04
12.25
1.06
1.29
0.44
1.38
7.86
12.03
1.05
1.31
0.46
1.28
7.70
11.80
Mode
Mass of
Particles
Otg)
5.14
6.05
1.92
7.11
38.60
58.82
5.84
7.11
2.43
7.61
43.32
66.31
6.77
8.45
2.97
8.25
49.66
76.10
Intermodal
Percent
Deposition
8.95
14.12
4.17
4.10
25.31
56.65
8.66
14.46
5.42
4.08
24.59
57.21
8.38
14.72
6.42
4.03
23.99
57.54
Mode
Mass of
Particles
0*g)
6.60
10.41
3.07
3.02
18.65
41.75
7.33
12.24
4.59
3.45
20.81
48.42
8.30
14.57
6.36
3.99
23.76
56.98
Coarse
Percent
Deposition
14.87
41.19
2.49
0.56
0.85
59.96
13.78
42.39
2.59
0.51
0.76
60.03
12.74
43.52
2.69
0.45
0.68
60.08
Mode
Mass of
Particles
-------
9
»—»
ON
TABLE 10-33. DAILY MASS DEPOSITION OF PARTICLES FROM PHOENIX AEROSOL IN FIGURE 10-35(b)
IN THE RESPIRATORY TRACT OF "NORMAL AUGMENTER" ADULT MALE HUMANS EXPOSED AT 50 /ig PARTICLES/m3
Trimodal Aerosol Modes3
Activity Pattern
General
population15
Workers, light
workc
Workers, heavy
workd
Region of
Respiratory
Tract
ETj
ET2
BB
bb
AI
Total
ETt
ET2
BB
bb
AI
Total
ET!
ET2
BB
bb
AI
Total
Accumulation
Percent
Deposition
1.76
1.62
0.54
3.08
11.87
18.87
1.66
1.61
0.50
2.86
11.68
18.31
1.62
1.61
0.46
2.66
11.50
17.85
Mode
Mass of
Particles
(Mg)
3.93
3.61
1.20
6.87
26.48
42.09
4.25
4.12
1.28
7.33
29.92
46.90
4.86
4.83
1.38
7.97
34.47
53.51
Intermodal
Percent
Deposition
21.09
27.60
1.56
1.97
12.54
64.76
20.29
27.25
2.44
1.98
12.33
64.29
20.07
27.51
3.08
1.92
11.91
64.49
Mode
Mass of
Particles
0*g)
28.99
37.94
2.14
2.71
17.24
89.02
32.02
43.00
3.85
3.12
19.46
101.45
37.06
50.80
5.69
3.55
21.99
119.09
Coarse
Percent
Deposition
31.77
34.28
0.91
0.58
1.87
69.41
29.83
35.62
1.53
0.60
1.80
69.38
28.59
36.62
1.96
0.58
1.69
69.44
Mode
Mass of
Particles
(Mg)
202.20
218.17
5.79
3.69
11.90
441.75
217.97
260.27
11.18
4.38
13.15
506.95
244.44
313.09
16.76
4.96
14.45
593.70
"Accumulation mode MMAD = 0.188 pm, ag = 1.54, density = 1.7g/cm3, 22.4% of the aerosol mass; intermodal mode MMAD = 1.70/on,
-------
TABLE 10-34. DAILY MASS DEPOSITION OF PARTICLES FROM PHOENIX AEROSOL IN FIGURE 10-35(b)
IN THE RESPIRATORY TRACT OF "MOUTH BREATHER" ADULT MALE HUMANS EXPOSED AT 50 /tg PARTICLES/m3-
o
1-^
o
H
6
o
25
O
H
O
d
3
Trimodal Aerosol Modes3
Activity Pattern
General
population1"
Workers, light
workc
Workers, heavy
work4
Region of
Respiratory
Tract
ETt
ET2
BB
bb
AI
Total
ETi
ET2
BB
bb
AI
Total
ETi
ET2
BB
bb
AI
Total
Accumulation
Percent
Deposition
0.81
1.41
0.54
3.08
11.94
17.78
0.75
1.39
0.50
2.88
11.74
17.26
0.70
1.38
0.46
2.68
11.56
16.78
Mode
Mass of
Particles
G»g)
1.81
3.15
1.20
6.87
26.64
39.67
1.92
3.56
1.28
7.38
30.07
44.21
2.10
4.14
1.38
8.03
34.65
50.30
Intermodal
Percent
Deposition
7.45
12.21
3.73
3.39
19.43
46.21
7.19
12.55
4.69
3.32
18.80
46.55
6.94
12.81
5.49
3.25
18.27
46.76
Mode
Mass of
Particles
G*g)
10.24
16.78
5.13
4.66
26.71
63.72
11.35
19.80
7.40
5.24
29.67
73.46
12.81
23.65
10.14
6.00
33.73
86.33
Coarse
Percent
Deposition
15.41
39.98
4.88
1.87
4.65
66.79
14.35
41.20
5.37
1.76
4.31
66.99
13.34
42.32
5.82
1.65
4.02
67.15
Mode
Mass of
Particles
-------
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April 1995
10-171 DRAFT-DO NOT QUOTE OR CITE
-------
1 As expected from experimental studies, these simulations predict different deposition
2 fractions for mouth breathing versus nasal breathing. This is most noticeable for deposition
3 of the intermodal and coarse modes of the Philadelphia and Phoenix aerosols (depicted in
4 Figures 10-35a and 10-35b), which showed significant increases in BB and AI deposition
5 fractions. The MM AD for the intermodal and coarse modes were 2.6 and 27.1, respectively
6 for the Philadelphia aerosol and 2.32 and 21.5 for the Phoenix aerosol. The accumulation
7 mode was less effected by mouth breathing as would be anticipated for these smaller
8 MMADs.
9 Activity pattern influenced the deposition fractions greatly. Again the influence was
10 more significant for the intermodal and coarse modes. A noticeable increase in both BB and
11 AI deposition occurred with percent changes of increased deposition ranging from 60 to
12 500%. Differences were also apparent in the nuclei and accumulation modes. For the
13 aerosol depicted in Figure 10-34, the nuclei mode (MMAD = .076 /im) deposition fractions
14 decreased in the BB, bb, and AI regions with the heavy work activity pattern compared to
15 that for the general population. For the Philadelphia aerosol, deposition of the accumulation
16 mode (MMAD = .584 /*m) increased in the BB region but decreased in the bb and AI
17 regions with the heavy work activity pattern. For the Phoenix aerosol, deposition of the
18 accumulation mode (MMAD = .341 /*m) decreased for all three lower respiratory
19 compartments (BB, bb, and AI) with the heavy work activity pattern.
20 Differences among the aerosols were also apparent and reflected the differences in the
21 MMAD values and percent mass of each mode. Table 10-36 presents summary data for each
22 of the three chosen ambient aerosols. To better understand the deposition differences for
23 each mode, however, the previous Tables 10-29 through 10-35 should also be consulted.
24
25 Laboratory Animal Deposition Estimates
26 Tables 10-37 through 10-42 provide the deposition fractions of various particle sizes
27 (MMAD) for either a relatively monodisperse (ag = 1.3) versus a more polydisperse (ag =
28 2.4) distribution in four different laboratory animal species. Deposition fractions of these
29 aerosols for an adult male human normal augmenter and mouth breather with a general
30 population activity pattern were calculated using the ICRP model. Deposition fraction for
31 each respiratory tract region are presented: ET in Tables 10-37 and 10-38; TB in
April 1995 10-172 DRAFT-DO NOT QUOTE OR CITE
-------
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April 1995
10-173 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-37. EXTRATHORACIC DEPOSITION FRACTIONS OF INHALED
MONODISPERSE AEROSOLS (a =1.3) IN VARIOUS LABORATORY SPECIES AND
HUMAN "NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
0.5
0.6
0.7
0.8
0.9
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
Normal
Augmenter
0.0868
0.1203
0.1569
0.1953
0.2343
0.2728
0.4431
0.5661
0.6511
0.711
0.7541
0.7854
0.8079
0.8235
0.8337
0.8392
0.8411
0.84
0.8364
0.8304
0.8237
0.8153
0.8062
0.7963
Mouth
Breather
0.0236
0.0307
0.0397
0.05
0.0614
0.0736
0.141
0.2085
0.2704
0.3259
0.3754
0.4201
0.4601
0.4958
0.5274
0.5551
0.5789
0.5989
0.6156
0.6291
0.6397
0.6478
0.6536
0.6575
Rat
0.008
0.019
0.039
0.071
0.117
0.178
0.554
0.737
0.77
0.757
0.731
0.702
0.673
0.645
0.619
0.594
0.57
0.548
0.527
0.507
0.489
0.471
0.455
0.439
Mouse
0.161
0.211
0.26
0.308
0.353
0.394
0.544
0.621
0.653
0.661
0.655
0.642
0.626
0.607
0.587
0.568
0.548
0.53
0.511
0.494
0.477
0.461
0.446
0.432
Hamster Guinea Pig
0.042
0.07
0.106
0.149
0.198
0.251
0.497
0.639
0.695
0.706
0.697
0.679
0.657
0.634
0.61
0.587
0.565
0.544
0.524
0.505
0.487
0.47
0.453
0.438
0.141
0.166
0.189
0.211
0.231
0.25
0.326
0.377
0.41
0.43
0.442
0.447
0.448
0.445
0.44
0.434
0.426
0.418
0.409
0.4
0.391
0.382
0.372
0.363
1 Tables 10-39 and 10-40; and A in Tables 10-41 and 10-42. These regional deposition
2 fractions are shown plotted in Figures 10-37, 10-38, and 10-39, respectively. The top panel
3 in each figure represents the deposition fractions for the relatively monodisperse aerosol (ag
4 =1.3) and the bottom panel represents the more polysdisperse aerosol (ag = 2.4). Note
5 that the y-axis scale changes from one panel to the other and from figure to figure.
April 1995
10-174 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-38. EXTRATHORACIC DEPOSITION FRACTIONS OF INHALED
POLYDISPERSE AEROSOLS (a =2.4) IN VARIOUS LABORATORY SPECIES AND
HUMAN "NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
0.5
0.6
0.7
0.8
0.9
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
Normal
Augmenter
0.1638
0.1997
0.234
0.2666
0.2971
0.3257
0.4419
0.5238
0.5822
0.6244
0.6551
0.6775
0.6937
0.7053
0.7133
0.7187
0.722
0.7237
0.7241
0.7235
0.7221
0.7202
0.7177
0.7148
Mouth
Breather
0.0566
0.0698
0.0837
0.0978
0.112
0.1261
0.1925
0.2499
0.2985
0.3395
0.3741
0.4035
0.4284
0.4496
0.4678
0.4833
0.4966
0.5081
0.5179
0.5263
0.5337
0.5399
0.5453
0.5499
Rat
0.127
0.166
0.204
0.24
0.274
0.304
0.421
0.489
0.528
0.547
0.555
0.555
0.551
0.543
0.534
0.524
0.513
0.501
0.49
0.478
0.467
0.456
0.445
0.435
Mouse
0.224
0.263
0.297
0.328
0.354
0.378
0.459
0.501
0.523
0.532
0.533
0.529
0.523
0.515
0.505
0.495
0.485
0.475
0.464
0.454
0.444
0.434
0.424
0.415
Hamster Guinea Pig
0.144
0.182
0.218
0.251
0.281
0.309
0.412
0.472
0.506
0.524
0.532
0.533
0.529
0.523
0.515
0.506
0.496
0.486
0.475
0.465
0.455
0.445
0.435
0.425
0.166
0.188
0.207
0.225
0.24
0.254
0.305
0.336
0.354
0.365
0.371
0.373
0.374
0.372
0.369
0.365
0.361
0.356
0.352
0.346
0.341
0.336
0.33
0.325
1 As discussed in Section 10.5, polydisperity tends to blund or smear the regional
2 deposition across the range of particles. The interspecies differences in fractional deposition
3 are readily apparent from these figures. The data in Tables 10-37 through 10-42 or from
4 Figures 10-37 through 10-39 can be used to calculate the fractional deposition term, i.e.,
5 Fr(A)/Fr(H) in Equation 10-51 in order to calculate an RDDRj.
April 1995
10-175 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-39. TRACHEOBRONCHIAL DEPOSITION FRACTIONS OF INHALED
MONODISPERSE AEROSOLS ( 2.5 /*m for ag = 1.3), the laboratory animal species have very litte deposition
April 1995
10-176 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-40. TRACHEOBRONCHIAL DEPOSITION FRACTIONS OF INHALED
POLYDISPERSE AEROSOLS (a=2.4) IN VARIOUS LABORATORY SPECIES AND
HUMAN "NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
0.5
0.6
0.7
0.8
0.9
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
Normal
Augmenter
0.026
0.0258
0.0263
0.0268
0.0276
0.0284
0.0322
0.0348
0.036
0.0363
0.036
0.0352
0.0345
0.0333
0.0322
0.0311
0.03
0.0288
0.0276
0.0266
0.0255
0.0244
0.0235
0.0225
Mouth
Breather
0.0319
0.0342
0.0374
0.0409
0.0448
0.0488
0.0681
0.0838
0.0957
0.1042
0.1099
0.1137
0.1156
0.1165
0.1163
0.1155
0.114
0.1123
0.1103
0.1079
0.1055
0.1029
0.1003
0.0977
Rat
0.06
0.062
0.062
0.061
0.06
0.058
0.048
0.039
0.031
0.025
0.021
0.017
0.014
0.012
0.01
0.008
0.007
0.006
0.005
0.005
0.004
0.004
0.003
0.003
Mouse
0.055
0.059
0.061
0.063
0.064
0.065
0.063
0.058
0.053
0.048
0.043
0.039
0.036
0.032
0.03
0.027
0.025
0.023
0.021
0.02
0.018
0.017
0.016
0.015
Hamster Guinea Pig
0.051
0.055
0.057
0.058
0.058
0.058
0.054
0.047
0.041
0.035
0.031
0.027
0.023
0.02
0.018
0.016
0.014
0.013
0.011
0.01
0.009
0.008
0.008
0.007
0.045
0.045
0.045
0.045
0.045
0.045
0.042
0.04
0.037
0.034
0.032
0.03
0.028
0.026
0.025
0.023
0.021
0.02
0.019
0.018
0.017
0.016
0.016
1 due to the lack of inhalability of these particle diameters. This may help to explain why
2 larger exposure concentrations have exhibited little effect in some bioassays.
3 The information in Tables 10-37 through 10-42 and depicted in Figures 10-37 through
4 10-39, can be used to calculate the deposition fraction term in Equation 10-48. The average
5 ventilation rates and parameters such as surface area to use for normalizing factors for
6 laboratory animals are found in Table 10-20. Respiratory tract region surface areas for
April 1995
10-177 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 10-41. ALVEOLAR DEPOSITION FRACTIONS OF INHALED
MONODISPERSE AEROSOLS (a =1.3) IN VARIOUS LABORATORY SPECIES AND
HUMAN "NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
0.5
0.6
0.7
0.8
0.9
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
Normal
Augmenter
0.0769
0.0842
0.093
0.1023
0.1112
0.1194
0.1459
0.1504
0.1415
0.1262
0.1089
0.092
0.0767
0.0634
0.052
0.0425
0.0347
0.0283
0.023
0.0187
0.0153
0.0124
0.0102
0.0083
Mouth
Breather
0.0799
0.0892
0.1008
0.1135
0.1267
0.1398
0.198
0.2368
0.2556
0.2576
0.2475
0.2295
0.2071
0.183
0.159
0.1364
0.1158
0.0975
0.0815
0.0679
0.0563
0.0466
0.0384
0.0317
Rat
0.005
0.011
0.02
0.032
0.046
0.063
0.099
0.056
0.024
0.011
0.005
0.002
0.001
0.001
0
0
0
0
0
0
0
0
0
0
Mouse
0.083
0.094
0.102
0.107
0.11
0.11
0.094
0.071
0.052
0.038
0.028
0.021
0.016
0.012
0.009
0.007
0.006
0.005
0.004
0.003
0.002
0.002
0.002
0.001
Hamster Guinea Pig
0.03
0.05
0.072
0.097
0.121
0.142
0.166
0.113
0.066
0.038
0.023
0.014
0.009
0.006
0.004
0.003
0.002
0.001
0.001
0.001
0.001
0
0
0
0.279
0.259
0.242
0.227
0.213
0.201
0.154
0.122
0.099
0.081
0.068
0.058
0.049
0.042
0.037
0.032
0.029
0.025
0.023
0.02
0.018
0.016
0.015
0.014
1 humans are found in Table 10-19. The human male adult general population activity pattern
2 in Table 10-20 corresponds to 19.9 m3/day. This is the average ventilation rate that was
3 used to run the LUDEP* simulations and would be used in the denominator of
4 Equation 10-48. The normal augmenter or mouth breather deposition fractions found in
5 Tables 10-37 through 10-42 represents the sum of the FrH factors in the denominator of the
April 1995
10-178 DRAFT-DO NOT QUOTE OR CITE
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TABLE 10-42. ALVEOLAR DEPOSITION FRACTIONS OF INHALED
POLYDISPERSE AEROSOLS (a =2.4) IN VARIOUS LABORATORY SPECIES AND
HUMAN "NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
0.5
0.6
0.7
0.8
0.9
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
Normal
Augmenter
0.1041
0.1047
0.1061
0.1078
0.1093
0.1105
0.1124
0.1089
0.1028
0.0957
0.0885
0.0815
0.0749
0.0689
0.0634
0.0583
0.0538
0.0496
0.0459
0.0424
0.0393
0.0365
0.034
0.0316
Mouth
Breather
0.1195
0.1252
0.1317
0.1384
0.1447
0.1506
0.1709
0.179
0.1794
0.1753
0.1687
0.1608
0.1523
0.1438
0.1354
0.1273
0.1196
0.1123
0.1055
0.0991
0.0932
0.0876
0.0824
0.0776
Rat
0.022
0.026
0.3
0.033
0.035
0.036
0.038
0.035
0.031
0.027
0.023
0.02
0.017
0.015
0.013
0.011
0.01
0.009
0.008
0.007
0.006
0.005
0.005
0.004
Mouse
0.07
0.073
0.075
0.076
0.077
0.076
0.07
0.061
0.053
0.046
0.04
0.035
0.031
0.027
0.024
0.022
0.02
0.018
0.016
0.014
0.013
0.012
0.011
0.01
Hamster Guinea Pig
0.054
0.062
0.069
0.074
0.078
0.08
0.082
0.075
0.067
0.058
0.051
0.044
0.039
0.034
0.03
0.026
0.023
0.021
0.018
0.016
0.015
0.013
0.012
0.011
0.273
0.254
0.238
0.224
0.212
0.201
0.16
0.133
0.113
0.097
0.085
0.076
0.068
0.061
0.055
0.05
0.046
0.042
0.039
0.036
0.034
0.032
0.03
0.028
1 expression found in Equation 10-48. Likewise, the deposition fractions for the various
2 species represent the FrA factor.
3 If Equation 10-48 is used to calculate deposited dose with the tracheobronchial surface
4 area as the normalizing factor, a RDDRTB[ACT] of 9.39 is calculated for a rat exposed to an
5 aerosol with a 0.5 /mi MMAD and ag of 1.3. The RDDRTB[ACT] calculated for the guinea
6 pig exposed to the same aerosol is 0.79. This factor could be used to adjust an exposure
April 1995
10-179 DRAFT-DO NOT QUOTE OR CITE
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o
1
c
o
0.8
0.6
CO
§. 0.4
Q
Li
0.2
4 6
MMAD (urn)
8
10
Nose
Mouth
Rat
Mouse
Hamster
Guinea Pig
0.8
§ 0.6
I
I 0.4
'w
a
0.2
og = 2.4
4 6
MMAD (urn)
8
10
Nose
Mouth
Rat
Mouse
Hamster
Guinea Pig
Figure 10-37. Predicted extrathoracic deposition fractions versus MMAD of inhaled
monodisperse (
-------
3.
TB Deposition Fraction
o o o o o
§P ^
-* ro
TB Deposition Fraction
g §
s
01
p
K>
9
t— *•
OO
RAFT
s
o
w
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n
I
00
ro -
>
D
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3
oo
v-k-
Q
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O
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2
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I
ADE Deposition Fraction
ADE Deposition Fraction
Ui
o
Ol
-•• Ol
ro
ro
01
p
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o
en
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'-1 01
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00
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S 33 2
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CO
-------
1 concentration to a human equivalent concentration using Equation 10-47. To illustrate, if a
2 rat exhibited tracheobronchial effects when exposed to this aerosol at 100 /xg/m3, the
3 predicted HEC would be 939 pig/m3. This HEC would result in a similar tracheobronchial
4 deposited dose and thereby a similar effect in humans, assuming species sensitivity to a given
5 dose is equal. The HEC calculated from the guinea pig would be 79 /ig/m3. For an alveolar
6 effect, the RDDRA[ACT] would be calculated. The RDDRA[ACT] for rat and guinea pigs is
7 0.19 and 4.5, respectively. Thus, although the two laboratory species were exposed to the
8 same aerosol and same concentration, each received a very different deposited dose and when
9 normalized for differences in surface areas, results in very different HEC values. Thus,
10 taking into account species differences in dosimetry is necessary before comparing effective
11 concentrations when interpreting toxicity data.
12 The impact of particle diameter and distribution as illustrated in Figures 10-37 through
13 10-39 is also reflected in calculated RDDRr[ACT] values. For an aerosol with a 2.55 /mi
14 MM AD and ag of 2.4, the RDDRTB[ACT] is 1.88 and 0.29 for the rat and guinea pig,
15 respectively. The RDDRA[ACT] for this aerosol is 0.88 and 1.36 for rat and guinea pig,
16 respectively.
17
18 10.7.5 Retained Dose Estimations
19 An important issue in inhalation toxicology is the relationship between repeated or
20 chronic inhalation exposures and the resulting alveolar burdens of exposure material achieved
21 in the human lung versus the lungs of laboratory animal species. It is generally assumed that
22 the magnitude of the alveolar burden of particles produced during an inhalation exposure is
23 an important determinant of biological responses to the inhaled particles. Therefore,
24 understanding the basis for differences among species in alveolar burdens that will result
25 from well-defined inhalation exposures will provide investigators with a better understanding
26 of alveolar burdens that would result from exposures of various mammalian species to the
27 same aerosol. Alternatively, the exposure conditions could be tailored for each species to
28 produce desired alveolar burdens of particles.
29 Predictable deposition, retention, and clearance patterns are possible for acute inhalation
30 exposures of laboratory animal species and humans. Repeated exposures also occur for
31 humans and are used routinely in laboratory animals to study the inhalation toxicology of a
April 1995 10-183 DRAFT-DO NOT QUOTE OR CITE
-------
1 broad spectrum of potentially hazardous particulates. The predicted biokinetics of particles
2 acutely inhaled can be readily extrapolated to repeated exposures. However, the predictions
3 become increasingly questionable as exposure conditions deviate away from those used for
4 acute inhalation exposures. The following predictions for repeated inhalation exposures are
5 therefore intended to be comparative, rather than absolute, and were made using the
6 assumption that physical clearance parameters for the A region are the same for acute and
7 repeated inhalation exposures.
8 Deposition data for two different aerosols, one with an MM AD of 0.5 and ag of 1.3,
9 the other with an MM AD of 2.55 and a ag = 2.4 were chosen to calculate total alveolar
10 retention (Table 10-43). The aerosol with an MM AD of 0.5 um and ag of 1.3 was chosen as
11 the smallest particle diameter for which the laboratory animal dosimetry model calculates
12 fractional deposition and to represent a relatively monodisperse distribution. The aerosol
13 with an MMAD of 2.55 um and a ag of 2.4 was chosen to approximate a hypothetical PM10
14 aerosol in which the PM2.5 to PM10 sample size cut ratio is 0.6 (Dockery and Pope).
15 Table 10-44 summarizes the common and specific parameters used for predicting
16 alveolar burdens for exposures of humans and six laboratory animal species of the two
17 different aerosols at a concentration of 50 fig particles/m3. Exposures were assumed to take
18 place 24 h/day at the average minute respiratory ventilation and deposition fractions
19 presented in Tables 10-20, 10-41, and 10-42. Daily alveolar deposition was expressed in
20 units of fig particles/g lung to normalize deposition rates among the species. Particle
21 dissolution-absorption rates were varied; half-times of 10, 100, and 1000 days were used to
22 simulate particles that are relatively soluble, moderately soluble, and poorly soluble. The A
23 clearance parameters used for predicting the results of repeated exposures were the same as
24 the ones used for predicting the consequences of acute inhalation exposures, and are given-in
25 Table 10-17. The clearance parameters as recommended by the ICRP (ICRP66, 1994) were
26 used in the human model LUDEP* version 1.1 software.
27 Tables 10-45, 10-46, and 10-47 show the calculated alveolar particle burdens of the 0.5
28 um MMAD (ag = 1.3) aerosol in various laboratory animal species and an adult human
29 normal augmenter for a general population activity pattern, assuming a particle dissolution-
30 absorption half-time of 10, 100, and 1,000 days, respectively. Tables 10-48, 10-49, and
31 10-50 show the analogous calculated alveolar particle burdens for the 2.55 um MMAD (ag =
April 1995 10-184 DRAFT-DO NOT QUOTE OR CITE
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p
h—'
ex
H
6
O
O
H
s
w
s
n
TABLE 10-43. FRACTION OF INHALED PARTICLES DEPOSITED IN THE ALVEOLAR INTERSTITIAL REGION
OF THE RESPIRATORY TRACT FOR SELECTED MAMMALIAN SPECIES AND ADULT MALE HUMANS
Fraction of Aerosol Deposited in Alveolar Interstitial Region
Aerosol Parameters
0.5 fun MMAD, ag = 1
2.55 ^m MMAD, ag =
.3
2.4
Mouse3
0.083
0.053
Syrian Hamster3
0.030
0.067
Rat3
0.005
0.031
Guinea Pig3
0.279
0.113
Monkey and Dogb
0.140
0.099
Human0
0.077
0.102
3Values calculated using specified laboratory animal model (U.S. Environmental Protection Agency, 1994; Menache et al., 1995)
bAdapted from Snipes (1989).
cFrom (ICRP 66, 1994) average for general population activity pattern (8 h sleeping, 8 h sitting, and 8 h light activity) for adult male
"normal augmenter" (see Table 10-18).
-------
TABLE 10-44. SUMMARY OF COMMON AND SPECIFIC INHALATION
EXPOSURE PARAMETERS USED FOR PREDICTING ALVEOLAR BURDENS OF
PARTICLES INHALED BY MICE, RATS, SYRIAN HAMSTERS, GUINEA
PIGS, MONKEYS, DOGS,AND HUMANS
A. Common Parameters:
Exposure atmosphere 50 /jg/rn3
Particle MMAD, ag 0.5 jum, 1.3; or 2.55 urn, 2.4
Particle dissolution-absorption half-time 10, 100, or 1,000 days
Chronic inhalation exposure pattern 24 h/day; 7 days/week
Duration of continuous exposure 4, 13, or 104 week
B. Specific Parameters: (Particle deposition rates in the alveolar region; data calculated
using information in Tables 10-19 10-20, 10-41, and 10-42
Species
Mouse
Syrian Hamster
Rat
Guinea pig
Monkey
Dog
Human3
Daily Deposition
of 0.5 /im MMAD, ag =
1.3 aerosol (/*g)
0.263
0.123
0.091
5.75
7.82
29.03
76.69
Daily Deposition
of 2.55 jwm MMAD,
-------
Vi
a
w
u ft
^
rfr 05 bo 5b ON 25 O O
CU
i
C/3
J
O
" »r
Q \b '-i cK r-" «S Q O\ t^ oo co po qo
- =
a I
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ta EU
^ I
o'ooooooooooo
go"
3
I jj
2o -S^QN^^^^OQ
r \ NN _
O O O »™^ »~i
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o,
J a
Q g
^HO«oo
April 1995
10-187 DRAFT-DO NOT QUOTE OR CITE
-------
s
o
I
« ss
o
3 r- i-i oo ^H _
«n o\ TT oo
3Z
Q
SP
AH
J
tS 8
gcS '8.
Q ^ nj p >n o\ co >S 60 ^H in vo r- o\
^^ ^5 C5 *™^ ^^ ^^ C^ C^ C**4 C^l C^
3 O
II
'(/3 3oO'-i'-in o «n
8
April 1995
10-188 DRAFT-DO NOT QUOTE OR CITE
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a.
TABLE 10-47. ALVEOLAR PARTICLE
PARTICLE DISSOLUTION
BURDENS (ug) OF 0.5 jim MMAD AEROSOL ASSUMING
ABSORPTION HALF— TIME OF 1,000 DAYS.
!g Species
i— i
9
00
DRAFT-DO
O
H
O
H
m
§
n
si
Days
1
7
14
21
28
35
50
75
91
100
150
200
300
400
500
600
700
730
Mouse
0.163
1.041
1.884
2.574
3.143
3.615
4.385
5.198
5.533
5.680
6.180
6.412
6.601
6.667
6.693
6.704
6.709
6.710
Hamster
0.265
1.669
2.977
4.016
4.850
5.526
6.599
7.689
8.126
8.316
8.960
9.260
9.511
9.600
9.635
9.649
9.655
9.656
Rat
0.544
3.429
6.117
8.250
9.963
11.353
13.557
15.797
16.694
17.085
18.408
19.025
19.539
19.721
19.793
19.823
19.835
19.837
Guinea Pig
2.294
15.416
29.491
42.440
54.424
65.570
87.068
117.145
133.399
141.683
178.656
204.110
233.865
248.101
254.913
258.174
259.734
260.018
Dog
20.221
135.498
258.316
370.403
473.292
568.216
749.162
997.162
1130.214
1197.277
1494.147
1697.533
1936.410
2052.134
2108.282
2135.530
2148.758
2151.188
Monkey Human
5.448 101.325
36.505 681.370
69.594 1306.140
99.792 1872.134
127.513 2394.590
153.085 2884.393
201.836 3798.690
268.816 5039.523
304.497 5692.593
322.565 6019.128
402.546 7423.229
457.341 8359.297
521.699 9404.209
552.875 9883.128
568.003 10111.700
575.345 10209.660
578.908 10253.200
579.562 10264.080
-------
I
Ul
o
i
o
6
o
1
o
o
3
TABLE 10-48. ALVEOLAR PARTICLE BURDENS (ug) OF 2.55 /tm MMAD AEROSOL ASSUMING
PARTICLE DISSOLUTION-ABSORPTION HALF-TIME OF 10 DAYS.
Days
1
7
14
21
28
35
50
75
91
100
150
200
Mouse
0.153
0.823
1.255
1.483
1.604
1.669
1.725
1.744
1.746
1.746
1.747
1.747
Hamster
0.249
1.322
1.992
2.335
2.513
2.607
2.685
2.710
2.713
2.714
2.714
2.714
Rat
0.511
2.717
4.092
4.797
5.163
5.355
5.516
5.568
5.574
5.575
5.576
5.576
Species
Guinea Pig
2.155
12.147
19.312
23.570
26.117
21 Ml
29.189
29.859
29.953
29.974
29.997
29.998
Dog
18.998
106.789
169.327
206.201
228.071
241.108
254.098
259.652
260.415
260.586
260.774
260.780
Monkey
5.118
28.771
45.619
55.554
61.446
64.958
68.458
69.954
70.160
70.206
70.257
70.258
Human
98.178
554.021
880.556
1074.300
1186.411
1262.602
1327.909
1349.678
1360.563
1360.563
1360.563
1360.563
n
-------
3.
TABLE 10-49. ALVEOLAR PARTICLE BURDENS (ug) OF 2.55 urn MMAD AEROSOL ASSUMING PARTICLE
DISSOLUTION— ABSORPTION HALF— TIME OF 100 DAYS.
i
p— *
9
i— >
O
!>
i
o
o
g
o
a
o
H
m
i
Days
1
7
14
21
28
35
50
75
91
100
150
200
300
400
500
600
700
730
Mouse
0.256
1.669
3.083
4.290
5.330
6.232
7.805
9.678
10.558
10.976
12.661
13.731
15.085
15.970
16.626
17.140
17.553
17.661
Hamster
0.119
0.765
1.391
1.910
2.346
2.715
3.340
4.058
4.386
4.541
5.160
5.555
6.068
6.410
6.661
6.854
7.002
7.040
Rat
0.088
0.566
1.029
1.413
1.735
2.008
2.471
3.001
3.244
3.358
3.816
4.109
4.488
4.741
4.927
5.069
5.179
5.207
Species
Guinea Pig
5.699
39.010
76.220
111.979
146.550
180.139
249.492
359.296
426.805
464.016
662.547
849.273
1192.050
1498.060
1771.281
2015.240
2233.069
2293.754
Dog
28.772
196.386
382.346
559.632
729.638
893.479
1227.773
1747.511
2062.527
2235.077
3147.853
4002.444
5579.528
7005.263
8295.952
9464.616
10522.820
10820.340
Monkey
7.753
52.916
103.023
150.792
196.601
240.746
330.822
470.863
555.745
602.237
848.183
1078.449
1503.390
1887.541
2235.325
2550.219
2835.362
2915.512
Human
76.665
525.888
1027.125
1503.711
1963.863
2407.581
3311.451
4691.907
5513.607
5965.542
8299.170
10353.420
14051.070
17173.530
19885.140
22185.900
24157.980
24733.170
-------
3.
TABLE 10-50. ALVEOLAR PARTICLE
PARTICLE DISSOLUTION
BURDENS (ug) OF 2.55 /on MMAD AEROSOL ASSUMING
—ABSORPTION HALF—TIME OF 1,000 DAYS.
t— *
^g Species
9
s
O
?
i
O
o
25
O
H
O
d
o
H
W
0
?d
O
Days
1
7
14
21
28
35
50
75
91
100
150
200
300
400
500
600
700
730
Mouse
0
1
1
2
3
3
4
6
6
7
8
8
9
10
10
10
11
11
.164
.066
.969
.741
.405
.981
.986
.182
.744
.011
.088
.771
.636
.201
.620
.949
.212
.281
Hamster
0.267
1.710
3.110
4.271
5.245
6.070
7.469
9.073
9.807
10.153
11.537
12.421
13.568
14.332
14.895
15.325
15.657
15.741
Rat
0.548
3.513
6.389
8.774
10.775
12.471
15.345
18.640
20.148
20.589
23.702
25.519
27.874
29.444
30.600
31.483
32.166
32.339
Guinea Pig
2
15
30
45
59
72
101
145
172
187
268
343
482
606
717
816
904
929
.308
.801
.873
.357
.360
.965
.057
.533
.878
.950
.365
.998
.840
.789
.457
.273
.505
.085
Dog
20
138
270
395
515
631
868
1235
1458
1580
2226
2830
3945
4953
5866
6693
7441
7651
.347
.881
.388
.762
.986
.852
.258
.807
.580
.605
.103
.453
.738
.990
.741
.198
.539
.941
Monkey
5.482
37.417
72.847
106.624
139.015
170.230
233.922
332.945
392.964
425.838
599.746
762.566
1063.038
1334.670
1580.586
1803.245
2004.869
2061.542
Human
101.552
696.608
1360.563
1991.864
2601.396
3189.158
4386.454
6215.049
7303.500
7902.147
10993.34
13714.47
18612.49
22748.61
26340.49
29388.15
32000.43
32762.34
-------
1 change with time and the accumulated A burdens would consist of the more persistent types
2 of particles or constituents of particles present in ambient aerosols. The more soluble, and
3 perhaps more toxic, constituents of the aerosols will be rapidly absorbed into the circulatory
4 system, metabolized, excreted, or redeposited in body organs.
5 Species differences are more apparent for the smaller diameter and more monodisperse
6 particle aerosol (0.5 urn MM AD, ag = 1.3) than for the larger diameter and more
7 polydisperse particle aerosol (2.55 um MM AD, ag = 2.4). At the longer dissolution-
8 absorption half-times, more disparity occurs between hamsters and humans, while the mouse
9 moves into closer proximity. Notably, the rat remains at lower alveolar particle burdens
10 than the humans at all dissolution-absorption half-times.
11 A different relationship of alveolar particle burdens among species is evident in
12 Figures 10-43, 10-44, and 10-45 for the larger diameter and more polydisperse aerosol (2.55
13 um MM AD, ag = 2.4). At short dissolution-absorption half-times, the rat and human have
14 very similar alveolar particle burdens, with the rat having a slightly greater burden at an
15 assumed dissolution-absorpton half-time of 10-days. At an assumed dissolution-absorption
16 half-time of 100 days, both the hamster and rat have alveolar particle burdens that are less
17 than that of humans. By 1000 days, the mouse alveolar particle burden is similar to but
18 lower than the human burden and the rat and hamster burdens are considerably lower. The
19 remaining species (monkey, dog, and and guinea pig), change relationships of alveolar
20 particle burdens relative to each other but have consistently higher burdens than do humans
21 across the assumed dissolution-absorption half-times.
22 Data in Tables 10-45, 10-46, and 10-47 were used together with the data in
23 Table 10-20 to calculate the ug of particles per gram of lung tissue for each aerosol at each
24 of the assumed particle dissolution-absorption half-life times. Figures 10-40, 10-41, and
25 10-42 show the alveolar particle burdens normalized to lung tissue weight (ug particles per g
26 lung tissue) for the 0.5 um MM AD (ag = 1.3) aerosol assuming particle dissolution-
27 absorption half-times of 10, 100, and 1,000 days, respectively. Figures 10-43, 10-44, and
28 10-45 show the alveolar particle burdens normalized to lung tissue weight (ug particles per g
29 lung tissue) for the 2.55 um MM AD (ag = 2.4) aerosol assuming particle dissolution-
30 absorption half-times of 10, 100, and 1,000 days, respectively.
April 1995 10-193 DRAFT-DO NOT QUOTE OR CITE
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Guinea Pig
Monkey
Human
Mouse
Dog
Hamster
Rat
I l I I I l I
0 100 200 300 400 500 600 700
Days of Exposure
Figure 10-40. Predicted retained alveolar dose (ug/g lung) for 0.5 ion MMAD
monodisperse (
-------
1,0003
100
200 300 400
Days of Exposure
500
600
700
Figure 10-42. Predicted retained alveolar dose (ug/g lung) for 0.5 /im MMAD
monodisperse (ag = 1.3) aerosol assuming a dissolution-absorption half-
time of 1,000 days.
"~ Mouse
Guinea Pig
" Monkey Dog
Hamster
Rat
Human
—I—
100
—I 1 1—
200 300 400
Days of Exposure
500
600
700
Figure 10-43. Predicted retained alveolar dose (ug/g lung) for 2.55 jon MMAD
polydisperse aerosol (
-------
100n
100
200 300 400
Days of Exposure
500
600
700
Figure 10-44. Predicted retained alveolar dose (ug/g lung) for 2.55 fim MMAD
polydisperse aerosol (ag = 2.4) assuming a dissolution-absorption
half-time of 100 days.
1,0003
o>
300 400
Days of Exposure
500
600
700
Figure 10-45. Predicted retained alveolar dose (ug/g lung) for 2.55 /tin MMAD
polydisperse aerosol (ag = 2.4) assuming a dissolution-absorption
half-time of 1,000 days.
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1 Figures 10-46, 10-47, and 10-48 show the alveolar retained dose ratios for both
2 aerosols and assuming particle dissolution-absorption half-times of 10, 100, and 1,000 days,
3 respectively. Dose was normalized to lung tissue weight (ug particles per g lung tissue).
4 These ratios could be calculated using Equation 10-52. Tables 10-45 through 10-50 provide
5 the (AIt) term. Tables 10-37 through 10-42 provide the (Fr) term. Normalizing factor data
6 and ventilation rates for laboratory humans and laboratory animals are provided in
7 Tables 10-19 and 10-20, respectively. These figures present the RRDRA[ACT] values that
8 would be applied to a given concentration to calculate an HEC for each of seven species for
9 these simulated continuous exposures. It is apparent that a substantial range of exposure
10 concentrations would be required to produce the same specific A burdens in these
11 mammalian species, and the exposure concentrations depend on the exposure protocol, or
12 study duration. These results demonstrate the importance of understanding respiratory,
13 deposition, and physical clearance parameters of humans and laboratory animals, as well as
14 the dissolution-absorption characteristics of the inhaled particles. This combination of factors
15 results in significant species differences in A accumulation patterns of inhaled particles
16 during the course repeated or chronic exposures which must be considered in experiments
17 designed to achieve equivalent alveolar burdens, or in evaluating the results of inhalation
18 exposures of different mammalian species to the same aerosolized test materials.
19 These retained dose ratios are different than those predicted for deposited dose,
20 reflecting both a difference in normalizing factor as well as differences in clearance rates and
21 the dissolution-absorption characteristics of the inhaled particles. To illustrate, the predicted
22 alveolar deposited dose ratio for the aerosol with a 0.5 pm MM AD and a of 1.3 was 9.39
23 and 0.79 for the rat and guinea pig, respectively (see Section 10.7.4). If a dissolution-
24 absorption half-time of 10 days is assumed for the same aerosol, the alveolar retained dose
25 ratio is 0.22 and 7.84 for the rat and guinea pig, respectively. Assuming a more insoluble
26 aerosol with a dissolution-half-time of 1,000 days results in a ratio of 0.49 and 2.76 for the
27 rat and guinea pig, respectively. Again, this emphasizes the importance of understanding
28 interspecies dosimetry and also of choosing a dose metric that is appropriate for the health
29 effect or endpoint of interest since the magnitude and direction of interspecies differences
30 also depends on the normalizing factors chosen.
April 1995 10-197 DRAFT-DO NOT QUOTE OR CITE
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11-
10-
9-
8-
o
* 7-
cc '
0
(0
o
OB-
T3
0
C
* *
0 O~
CC
0 4~
3-
2-
1-
o-
0
0.5 jim MMAD, a, = 1.3
a
O CC nm RJIIlJIAr^ O >1
— t.oo |im MMAU, Og — 2.4
Guinea Pig
\
\ Mou.se
Monkey
V
Mouse
Dog
Guinea Pig
Monkey
V Dog
\^ Hamster
— _
Hamster
i i i
1 00 200 300
Rat
Rat
i i i i i
400 500 600 700 800
Days of Exposure
Figure 10-46. Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 /tm MMAD monodisperse (ag = 1.3) and
2.55 jtm MMAD polydisperse (ag = 2.4) aerosols assuming a
dissolution-absorption half-time of 10 days.
April 1995
10-198 DRAFT-DO NOT QUOTE OR CITE
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0.5 urn MMAD, og =1.3
2.55 urn MMAD, og = 2.4
0 100 200 300 400 500 600 700 800
Days of Exposure
Figure 10-47. Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 jon MMAD monodisperse (ag = 1.3) and
2.55 urn MMAD polydisperse (ag = 2.4) aerosols assuming a
dissolution-absorption half-time of 100 days.
April 1995
10-199 DRAFT-DO NOT QUOTE OR CITE
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11-
10-
9-
8-
o
'•S-7-
0.5 urn MMAD, og -1.3
2.55 urn MMAD, og - 2.4
Guinea Pig
Guinea Pi
Monke
^_^——^—
ouse
i r
100 200
300 400 500
Days of Exposure
600 700 800
Figure 10-48. Predicted alveolar region retained dose ratios in various laboratory
animals versus humans of 0.5 jtm MMAD monodisperse (ag = 1.3) and
2.55 nm MMAD polydisperse (ag = 2.4) aerosols assuming a
dissolution-absorption half-time of 1,000 days.
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1 10.7.6 Summary
2 The dosimetry modeling exercise in this section has emphasized the importance of
3 accounting for major determinants of particle deposition and clearance in order to calculate
4 inhaled doses (either deposited or retained) that account for both within species and
5 interspecies differences. For example, mouth breathing alters the deposition fraction of
6 typical ambient aerosols in the tracheobronchial and alveolar regions when compared to nasal
7 breathing. The differences in deposition between activity patterns emphasizes the need to
8 take into account differences in ventilation rate and morphometry between the genders and at
9 different ages. Since the LUDEP® version 1.1 software only allows simulation for adult
10 male humans, these calculations await the next version. The ICRP has demonstrated
11 differences between children of 1 year and adults across particles ranging from AMTD to
12 AM AD of approximately 2.5-fold in the BB region and 2-fold in the alveolar region ICRP66,
13 1994). Differences in ventilation and morphometry as a consequence of disease can also be
14 expected.
15 The various species used in inhalation toxicology studies that serve as the basis for
16 exposure-dose-response assessment do not receive identical doses in a comparable respiratory
17 tract region when exposed to the same aerosol. Such interspecies differences are important
18 because the adverse toxic effect is likely more related to the quantitative pattern of deposition
19 within the respiratory tract than to the exposure concentration; this pattern determines not
20 only the initial respiratory tract tissue dose but also the specific pathways by which the
21 inhaled material is cleared and redistributed. Thus, accounting for differences in dosimetry
22 can change the apparent effect levels among species. To illustrate, for the same aerosol of
23 0.5 um MM AD and aB of 1.3 at an exposure concentration of 100 /ig/m3, using deposition
&
24 normalized to surface area for an effect observed in the tracheobronchial region, a human
25 equivalent exposure concentration would be 939 /ig/m3 and 79 ^ig/m3 based on rat versus
26 guinea pig, respectively. This assumes the same sensitivity in humans to the deposited dose
27 per surface area as in the rat or guinea pig. However, for chronic exposures to the same
28 aerosol at the same concentration (100 /zg/m3), assuming it is relatively insoluble (i.e.,
29 assuming a dissolution-absorption half-time of 1,000 days), and based on a particle burden
30 per gram of lung tissue, a human equivalent exposure concentration would be predicted as 22
31 Mg/m3 or 784 /ng/m3 based on the rat and guinea pig, respectively.
April 1995 10-201 DRAFT-DO NOT QUOTE OR CITE
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1 These examples show that relevance of a particular animal model should be considered
2 together with dosimetry and the appropriateness of the metric for a given health endpoint. In
3 general, the objective should be to provide a metric that may is mechanistically-motivated by
4 the observed health effect of interest for extrapolation.
5 Smaller particle diameters have shown higher mass burdens of particle deposition in the
6 TB region and of retained particle burden in the A region. This calls attention to the need
7 for additional calculations based on particle number or surface area burdens. Considering
8 that the bronchiolar region of the lung has a much smaller surface area than the alveolar
9 region (factor of «170) the deposition of numbers of particles/unit surface area is =50
10 times higher in the bronchiolar region versus the alveolar region. This could indicate that
11 the target site for reactive small particles may be the bronchiolar region, where subsequent
12 particle-induced reactions may lead to impairment of breathing, thereby increasing symptoms
13 which already may be present in persons with a compromised respiratory system like in
14 COPD patients.
15 Dosimetry modeling can address important mechanistic factors of particle deposition
16 and clearance including the aerosol particle diameter and distribution, intra and interspecies
17 differences in deposition as as function of ventilation and morphometry, and intra and
18 interspecies differences in clearance rates. Use of dosimetry modeling and judicious choice
19 of appropriate dose metrics should be used to interpret the observed health effects data
20 related to PM10 exposures. Predictions in this chapter were based on the use of mass as the
21 exposure metric. Recent data suggest that particle number, or possibly particle surface area,
22 may be a more appropriate exposure metric because the fine mode aerosols are small in mass
23 but have extremely high concentrations of particle numbers. Also, normalizing factors such
24 as number of alveoli or number of macrophages may be more appropriate for certain
25 pathogenesis mechanisms. Creating these dose metrics for various species will depend on the
26 availability of morphometric information.
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28 32: 91-104.
29
30 Yeates, D. B.; Aspin, N.; Levison, H.; Jones, M. T.; Bryan, A. C. (1975) Mucociliary tracheal transport rates
31 in man. J. Appl. Physiol. 19: 487-495.
32
33 Yeates, D. B.; Gerrity, T. R.; Garrard, C. S. (1981a) Particle deposition and clearance in the bronchial tree.
34 Ann. Biomed. Eng. 9: 577-592.
35
36 Yeates, D. B.; Pitt, B. R.; Spektor, D. M.; Karron, G. A.; Albert, R. E. (1981b) Coordination of mucociliary
37 transport in human trachea and intrapulmonary airways. J. Appl. Physiol.: Respir. Environ. Exercise
38 Physiol. 51: 1057-1064.
39
40 Yeh, H.-C.; Schum, G. M. (1980) Models of human lung airways and their application to inhaled particle
41 deposition. Bull. Math. Biol. 42: 461-480.
42
43 Yeh, H. C.; Zhuang, Y.; Chang, I. Y. (1993) Mathematical model of particle deposition from inhaled
44 polydisperse aerosols. In: Nikula, K. J.; Belinsky, S. A.; Bradley, P. L., eds. Inhalation Toxicology
45 Research Institute annual report 1992—1993. Albuquerque, NM: U.S. Department of Energy, Lovelace
46 Biomedical and Environmental Research Institute; pp. 127-129; report no. ITRI-140. Available from:
47 NTIS, Springfield, VA; AD-A277 924/7/XAB.
48
49 Yu, C. P. (1978) Exact analysis of aerosol deposition during steady breathing. Powder Technol. 21: 55-62.
50
51 Yu, C. P. (1985) Theories of electrostatic lung deposition of inhaled aerosols. Ann. Occup. Hyg. 29: 219-227.
52
53 Yu, C. P.; Asgharian, B. (1993) Mathematical models of fiber deposition in the lung. In: Warheit, D. B., ed.
54 Fiber toxicology. San Diego, CA: Academic Press, Inc.; pp. 73-98.
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1 Yu, C. P.; Diu, C. K. (1982a) A comparative study of aerosol deposition in different lung models. Am. Ind.
2 Hyg. Assoc. J. 43: 54-65.
3
4 Yu, C. P.; Diu, C. K. (1982b) A probabilistic model for intersubject deposition variability of inhaled particles.
5 Aerosol Sci. Technol. 1: 355-362.
6
7 Yu, C. P.; Diu, C. K. (1983) Total and regional deposition of inhaled aerosols in humans. J. Aerosol Sci.
8 5: 599-609.
9
10 Yu, C. P.; Xu, G. B. (1987) Predicted deposition of diesel particles in young humans. J. Aerosol Sci.
11 18:419-429.
12
13 Yu, C. P.; Liu, C. S.; Taulbee, D. B. (1977) Simultaneous diffusion and sedimentation of aerosols in
14 a horizontal cylinder. J. Aerosol Sci. 8: 309-316.
15
16 Yu, C. P.; Nicolaides, P.; Soong, T. T. (1979) Effect of random airway sizes on aerosol deposition. Am. Ind.
17 Hyg. Assoc. J. 40: 999-1005.
18
19 Yu, C. P.; Diu, C. K.; Soong, T. T. (1981) Statistical analysis of aerosol deposition in nose and mouth. Am.
20 Ind. Hyg. Assoc. J. 42: 726-733.
21
22 Yu, C. P.; Chen, Y. K.; Morrow, P. E. (1989) An analysis of alveolar macrophage mobility kinetics at dust
23 overloading of the lungs. Fundam. Appl. Toxicol. 13: 452-459.
24
25 Yu, C. P.; Yoon, K. J.; Chen, Y. K. (1991) Retention modeling of diesel exhaust particles in rats and humans.
26 J. Aerosol Med. 4: 79-115.
27
28 Yu, C. P.; Zhang, L.; Becquemin, M. H.; Roy, M.; Bouchikhi, A. (1992) Algebraic modeling of total and
29 regional deposition of inhaled particles in the human lung of various ages. J. Aerosol Sci. 23: 73-79.
30
31 Zeltner, T. B.; Sweeney, T. D.; Skoraik, W. A.; Feldman, H. A.; Brain, J. D. (1991) Retention and clearance
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33
34 Zhang, L.; Yu, C. P. (1993) Empirical equations for nasal deposition of inhaled particles in small laboratory
35 animals and humans. Aerosol Sci. Technol. 19: 51-56.
36
37 Zwicker, G. M.; Filipy, R. E.; Park, J. F.; Loscutoff, S. M.; Ragan, H. A.; Stevens, D. L. (1978) Clinical and
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i 11. TOXICOLOGICAL STUDIES OF
2 PARTICULATE MATTER
3
4
5 11.1 INTRODUCTION
6 This chapter reviews the results of exposure to PM in controlled human clinical studies,
7 selected occupational studies, and animal toxicology studies. It focuses on those studies
8 published since the 1982 PM Criteria Document (CD) (U.S. Environmental Protection
9 Agency, 1982), which was the last PM CD to describe animal toxicology studies.
10 Paniculate matter is a broad term that encompasses thousands of chemical species,
11 many of which have not been investigated in controlled animal or human studies. However,
12 even a full discussion of all the types of particles that have been studied is well beyond the
13 scope of this chapter. Thus, criteria were used to select topics for presentation. High
14 priority was placed on studies that (1) may elucidate or extend knowledge of the health
15 effects of large portions of PM (e.g., sulfates, carbon), (2) that may contribute to enhanced
16 understanding of the epidemiological studies (e.g., real-world particles; "surrogate" particles,
17 defined as particles with low inherent toxicity that may cause effects due to their generic
18 nature as a particle, such as their ultrafine size), or (3) that are ubiquitous. Although the
19 latter is a criterion from the Clear Air Act, such widespread exposures also serve to increase
20 public health interest. From these criteria, full summaries of acid aerosols, ultrafine
21 particles, real-world particles, and "surrogate" particles are provided. Diesel exhaust
22 particles generally fit the criteria, but because they are described in great detail elsewhere
23 (U.S. Environmental Protection Agency, 1994), they are only summarized briefly here.
24 Likewise, silica (U.S. Environmental Protection Agency, 1994) is only briefly presented.
25 Diesel particles also differ from other particles in this classification because they are
26 regulated pursuant to mobile source sections of the Clear Air Act (g/mi emission standards),
27 although there is still a relationship of these regulations to the PM10 standard. Medium
28 priority was placed on particles with high inherent toxicity that are of concern primarily
29 because of point source emissions and more local exposures (as contrasted to ubiquitous
30 pollutants). Metals having air concentrations greater than 1 ng/m3 were placed in this class.
31 Asbestos was also put in this class. The health effects of particles in this prioritization class
April 1995 11-1 DRAFT-DO NOT QUOTE OR CITE
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1 are summarized far more briefly here. It must be emphasized that this prioritization is not
2 related to a judgement or decision about potency or health risk. For example, it should not
3 be inferred that on an individual exposure basis, a "high priority" particle is of more inherent
4 health concern than a "medium priority" particle. The split is primarily related to regulatory
5 issues. The Clean Air Act requires a criteria document for criteria pollutants. Except for
6 lead, individual metals are not criteria pollutants. Rather, they are regulated as hazardous air
7 pollutants under the Clean Air Act. Thus, their inclusion here is only intended to be
8 generally instructive because they can be part of the complex mixture of PM in the ambient
9 air.
10 As noted above, lead is a criteria air pollutant, also regulated, like paniculate matter,
11 under Sections 108 and 109 of the Clean Air Act. Earlier extensive evaluations in Air
12 Quality Criteria for Lead (U.S. Environmental Protection Agency, 1977) led to setting of the
13 current National Ambient Air Quality Standard (primary as well as secondary) for lead at
14 1.5 jug/m3 on a quarterly average basis (Federal Register, 1978 [PB-1910]). Subsequent to
15 promulgation of that standard, the U.S. Environmental Protection Agency issued a revised
16 Air Quality Criteria for Lead (1986) and a Supplement (U.S. Environmental Protection
17 Agency, 1990). These and other such assessments found blood lead levels of 10 jug/dl in
18 young children and women of child bearing age (due to risk to the fetus in utero) to be
19 associated with unacceptable risk of slowed prenatal and postnatal growth and
20 neuropsychological development. Air levels below 0.50 to 0.75 /xg/m3 lead have been
21 proposed as adequate to protect against such risk (World Health Organization, 1987).
22 Typical ambient air levels of lead in U.S. urban areas almost invariably now fall below
23 0.10 to 0.25 jug/m3. The reader is referred to the above-noted air quality criteria
24 documents/supplement and Federal Register notices concerning the lead National Ambient
25 Air Quality Standard for detailed information on particulate lead health effects.
26 Mixtures are important to understand because people are not exposed to single air
27 pollutants, and the risks of the mixture can be different from those of the individual
28 chemical. Little is known about mixtures, however. Most mixture studies involve two
29 pollutants only. A significant exception to this is the body of work on the mutagenicity and
30 carcinogenicity of particle-bound organics, which is also briefly summarized here, and on
31 diesel emissions
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1 The different nature of the data bases also influences the structure of the chapter. For
2 example, community epidemiology studies that sought associations with some type of PM
3 metric are described in Chapter 12 to permit full portrayal and integrated evaluation of the
4 results. For the metals and diesel particles, included to reach a different goal,
5 epidemiological studies are included here in Chapter 11 to facilitate a full hazard
6 identification, and as appropriate, exposure-response information. Besides the summary of
7 the effects portion of the literature, this chapter also attempts to identify and characterize key
8 factors that may have significant influences on the health effects of PM.
9 Most of the investigations reported herein were conducted with animals, raising the
10 question of their quantitative extrapolation to humans. Of the dosimetric and species
11 sensitivity aspects of extrapolation, most is known about the former, which is presented in
12 Chapter 10. Both Chapters 10 and 11 must be jointly considered for interpretation. For
13 example, was one aerosol more toxic than another because it had a greater deposition in a
14 sensitive lung target site or because it had higher potency?
15 Most of the animal toxicological and occupational epidemiological studies summarized
16 here used very high particulate concentrations, relative to ambient, even when animal-to-
17 human dosimetric differences are considered. This raises a question about the relevance of,
18 for example, a rat study at 5,000 /jg/m3 in terms of direct extrapolation to humans in
19 ambient exposure scenarios. In spite of these difficulties, the array of animal studies does
20 illustrate certain toxicological principles for particles. To identify but a few here, the data
21 base clearly shows that the site of respiratory tract deposition (and hence particle size) clearly
22 influences the health outcome and that toxicity is dependent on the chemical species (e.g.,
23 cadmium is different from sulfuric acid, and cadmium chloride is different from cadmium
24 oxide).
25
26
27 11.2 ACIDIC SULFATE PARTICLES
28 11.2.1 Controlled Human Exposure Studies of Acid Aerosols
29 11.2.1.1 Introduction
30 Human clinical exposure studies utilize controlled laboratory conditions to test
31 responses to atmospheric pollutants. Advantages include the opportunity to study the species
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1 of interest, humans, and the ability to carefully control the atmosphere with regard to
2 pollutant concentration, aerosol characteristics, temperature, and relative humidity.
3 Concentrations can be varied while other conditions are held constant to determine
4 exposure-response relationships. Mixtures of pollutants or sequential exposures to different
5 pollutants can be used to elucidate interactions.
6 Methods of inhalation used in clinical studies include mouthpiece, face mask,
7 head-dome, and environmental chamber. Breathing through a mouthpiece alters breathing
8 patterns, and bypasses the normal filtering and humidifying role of the nasal passages,
9 thereby increasing delivery of particles to the lower airways. Environmental chamber and
10 head-dome exposures allow the assessment of shifts between nasal and oral-nasal breathing
11 that normally occur with exercise.
12 Several factors limit the utility of human clinical studies. To meet legal and ethical
13 requirements, exposures must be without significant harm. Studies are typically limited to
14 short-term exposures, since long-term exposures are impractical, and may be more likely to
15 cause harm. Sample sizes are small, and therefore may not be representative of populations
16 at risk. Finally, individuals likely to be at greatest risk (i.e., the very young and very old,
17 those with severe obstructive lung disease, or combined heart and lung disease) have not
18 been studied. The data from human clinical studies should therefore be used together with
19 information from animal exposure studies, epidemiologic studies, and in vitro exposure
20 studies, in the process of health assessment.
21 The endpoints most commonly measured in human clinical studies are symptoms and
22 pulmonary function tests. The latter are well standardized, and their use in these studies has
23 been reviewed (Utell et al., 1993). Effects in clinical studies can be directly compared to
24 acute changes in field studies, as has been done extensively in studies of ozone health effects
25 (U.S. Environmental Protection Agency, 1995).
26 Airway responsiveness is another endpoint commonly measured in human clinical
27 studies. This test measures changes in lung function in response to pharmacologic
28 bronchoconstricting agents, typically methacholine, carbachol, or histamine (see also
29 Section 11.2.4). A dose-response curve is obtained for the agent, and airway responsiveness
30 is expressed as the dose of the bronchoconstricting agent resulting in a specific change in
31 lung function: e.g., the PD20 is the provocative dose resulting in a 20% fall in forced
April 1995 11-4 DRAFT-DO NOT QUOTE OR CITE
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1 expiratory volume in 1 sec (FEVj). Individuals with asthma almost always have
2 hyperresponsive airways, with a PD20 well below the normal range. Increase in airway
3 reactivity in response to pollutant exposure could reflect airway inflammation or edema.
4 However, smaller airway caliber as a consequence of the exposure will also increase
5 measured responsiveness because of factors related to airways geometry. It is therefore
6 important to measure responsiveness at a time when spirometric function has returned to
7 baseline. Likewise, performing airway challenge testing prior to pollutant exposure may
8 alter subsequent lung function responses to the pollutant by changing the baseline airways
9 caliber. Differences among laboratories in the protocols and provocative agents used for
10 airway challenge make comparison of experimental results problematic.
11 Endpoints in human clinical studies have extended beyond measures of air flow and
12 lung volume. Mucocilary clearance is measured using inhaled radio-labelled aerosols. As
13 reviewed in the Acid Aerosols Issue Paper (U.S. Environmental Protection Agency, 1989),
14 exposure to acid aerosols alters mucociliary clearance in humans as well as in several animal
15 species. Within the past decade, fiberoptic bronchoscopy has been used to sample the lower
16 respiratory tract in healthy volunteers exposed to pollutants. Cells that populate the alveolar
17 space, including alveolar macrophages (AM), lymphocytes, and polymorphonuclear
18 leukocytes (PMN), can be recovered by bronchoalveolar lavage (BAL); bronchial epithelial
19 cells can be sampled using bronchial brushing and endobronchial biopsies. Nasal lavage can
20 be used to quantitate inflammation in the nose.
21 Features of experimental design of particular importance with regard to human clinical
22 studies are method of exposure, exercise, and selection of control exposures. Exposure by
23 mouthpiece reduces humidification of inhaled air that normally occurs in the nasal passages;
24 entry of incompletely humidified air into the airways may cause bronchoconstriction in
25 asthmatic subjects. Exercise plays an important role in enhancing pollutant effects by
26 causing a change from nasal to oral-nasal breathing, hence decreasing upper airways
27 deposition, and by increasing pollutant dose through increased VE.
28 Selection of control exposures is of particular importance. Typically, each subject
29 serves as his/her own control to reduce intersubject variability. The control atmosphere
30 depends on the study objectives, and may consist of clean air, or, when acidic aerosols are
31 being tested, a neutral aerosol, such as sodium chloride (NaCl), to distinguish non-specific
April 1995 H_5 DRAFT-DO NOT QUOTE OR CITE
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1 effects of the aerosol from pollutant or hydrogen ion (H+) effects. It is important that
2 control exposures be performed under similar conditions of temperature, relative humidity,
3 VE, and time of day; that control and pollutant exposure be separated by sufficient time to
4 avoid carry-over effects; and that the order of the exposures be randomized among the study
5 group. Investigators and subjects should be blinded to exposure atmospheres to the extent
6 possible.
7 The majority of human clinical studies have focused on the pulmonary function effects
8 of exposure to acid aerosols. These studies will therefore be summarized separately, first
9 reviewing studies of effects on healthy subjects, followed by subjects with asthma.
10 Subsequent sections will deal with effects other than lung function, and with studies of
11 particulate pollutants other than acid aerosols. Within each section, studies will generally be
12 reviewed in chronological order. Table 11-1 summarizes, in alphabetical order by author,
13 controlled clinical studies of particle exposure published since 1988.
14 Human exposure studies of the effects of acid aerosols were reviewed in the Acid
15 Aerosols Issue Paper (U.S. Environmental Protection Agency, 1989). That review reached
16 the following conclusions:
17
18 1) In healthy subjects, no effects on spirometry have been observed after exposure
19 to concentrations of H2SO4 less than 500 /xg/m3, and no consistent effects have
20 been observed at levels up to 1,000 /xg/m3 with exposure durations up to 4 h.
21 Studies of a variety of other sulfate and nitrate aerosols have similarly
22 demonstrated an absence of spirometric effects on healthy subjects.
23 2) Combinations of sulfates with ozone or SO2 have not demonstrated synergistic
24 or interactive effects.
25 3) Asthmatic subjects experience modest bronchoconstriction after exposure to
26 =400 to 1000 jug/m3 H2SO4, and small decrements in spirometry have been
27 observed in adolescent asthmatics at concentrations as low as 68 /ig/m3 for
28 30 min.
29 4) Some studies suggest that delayed effects may occur in healthy and asthmatic
30 subjects following exposure to H2SO4.
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TABLE 11-1. CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Anderson et
al. (1992)
Aris et al.
(1990)
Aris et al.
(1991a)
Aris et al.
(1991b)
Subjects
15 healthy
15 asthmatic
18 to 45 years
19 asthmatic
20 to 40 years
10 healthy
nonsmokers 21
to 31 years
ozone sensitive
18 asthmatics
23 to 37 years
Exposures' MMAD2 OSD3
fan urn
1): air
2): H2SO4 = 100 /tg/m3 1.0 2
3): carbon black
=200 /ig/m3
4): acid-coated carbon
with = 100 ng/m3 H2SO4
Mouthpiece study:
HMSA5 0 to 1000 (*M +
H2SO4 50 /*M vs H2SO4 50
/*M
Chamber study: _
HMSA 1 mM + H2SO4
5 mM vs H2SO4 5 mM
HNO3 0.5 mg/m3 or H2O, or =6
air followed by ozone 0.2
ppm
Mouthpiece study:
H2SO4 vs NaCl, =3 mg/m3 0.4 vs =6
with varying particle size,
osmolarity, relative humidity
Chamber study: H2SO4 vs
NaCl fog, 0.96 to 1 .4 mg/m3 6
with varying water content
Duration Exercise Temp
•c
60 min. VE = 50 22
L/min
100 Won
cycle
1 h =25
2 h 50 min of 22
each h
J 11
40 L/min
22
16 min With &
without _ - ,
exercise.
1 h 100 W on
cycle =27
RH4 Symptoms
%
50 Healthy subjects
more
symptomatic in
air.
100 HMSA did not
increase
symptoms in
comparison with
H2SO4 alone.
100 No effects of
fog exposure
50
No effects
<10 vs
100
Lung Function Other Effects
Largest No change in
decrements in airway
FVC with air responsiveness
exposure.
No effects on
SRaw6
No direct effects No change in
of fog exposures, airway
_ responsiveness
Greatest r
decrements when
ozone preceded
by air.
Increases in SRaw
with low RH
conditions; no
pollutant-related
effects
Comments
Smoking
status of
subjects not
stated.
Fog may
have
reduced
ozone
effects on
lung
function.
Postulated
that effects
seen in other
studies due
to secretions
or effects on
larynx
-------
TABLE 11-1 (CONT'D). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
oo
Ref.
Avol et al.
(1988a)
Avol et al.
(1988b)
Avol et al.
(1990)
Balmes et
al. (1988)
Subjects
21 healthy
21 asthmatic
18 to 45 years
22 healthy
22 asthmatic
18 to 45 years
32 asthmatics
8 to 16 years
12 asthmatics
responsive to
hypoosmolar
saline aerosol
25 to 41 years
Exposures MMAD1 GSD2
Air 0.85 to 2.4 to
H2SO4: 0.91 2.5
Healthy: 363,
1128, 1578
Asthmatic: 396,
999, 1,460
/ig/m3
H2O fog 9.7 to 10.7
H2SO4:
Healthy: 647,
1,100,2,193
/*g/m3
Asthmatic: 516,
1,085,2,034
pg/m3
Air
H2SO446, 127, 0.5 1.9
and 134 /
-------
I
H- 1
S
Lf»
h- >
VD
rt
TABLE 11-1 (CONT'D). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Gulp et al.
(1995)
Fine et al.
(1987b)
Fine et al.
(1987a)
Frampton et
al. (1992)
Subjects
16 healthy
20 to 39 yrs
8 asthmatics
22 to 29 yrs
10 asthmatics
22 to 34 yrs
12 healthy
20 to 39 yrs
Exposures MMAD1 GSD2 Duration Exercise
NaCl 1000 pg/m3 0.9 1.9 2h 10 min X 4
H2SO4 =40 L/min
l,000pg/m3
Mouthpiece: 5.3 to 6.2 1.6 to At rest
Buffered and 1.8
unbuffered HC1
and H2SO4 at
varying pH
Mouthpiece: 5. 6 to 6.1 1.6 to At rest
Na2SO3Oto 1.7
10 mg/ml, pH 9,
6.6, 4; buffered
acetic acid pH 4;
SO2 0.25 to 8 ppm
NaCl 1,000 pg/m3 0.9 1.9 2h 10 min X 4
H2SO4 1000 ng/m3 * 40 L/min
Temp
'C RH3 Symptoms
22 40
Cough with
inhalation of
unbuffered
pH 2 aerosols
22 40 4/12 subjects:
throat
irritation with
acid
exposure.
Lung Function
= 50% increase in
airway resistance
with buffered acid
aerosols at pH 2.
Little response to
unbuffered acids.
For Na2SO3,
broncho-constriction
greater at lower pH;
no response to acetic
acid.
No pollutant effects
Other Effects
Mucins from
bronchoscopy: no
effects on mucin
recovery or
changes in
glycoproteins
BAL findings: No
effects on cell
recovery,
lymphocyte
subsets, AM
function, fluid
Comments
Titratable acidity
important
determinant of
response to acid
aerosols.
Suggests effects
related to release
of SO2 or
bisulfite, but not
sulfite.
proteins.
Frampton et 30 healthy
al. (1995) 30 asthmatics
20 to 42 yrs
Green et al. 24 healthy
(1989) 18 to 35 yrs
NaCl or H2SO4 0.45
100 /*g/m3 0.64
followed by
ozone 0.08, 0.12,
or 0.18 ppm
Air; activated 1.4
carbon 510 jig/m3;
HCHO 3.01 ppm;
carbon 510 /tg/m3
+ HCHO 3.01
ppm
4.05 3 h 10 min X 6. 21 40
2.50 Healthy: 33 to
40 L/min;
3 h asthmatics: 31
to 36 L/min
1.8 2h 15 of each 30 22 65
min., 57 L/min
No pollutant
effects
Increased
cough with
carbon +
HCHO
Healthy subjects: no
significant effects.
Asthmatics: ozone
dose-response
following H2SO4
pre-exposure, but
not NaCl
No direct effects of
carbon. Additive
effects of carbon +
HCHO on FVC,
FEV3, peak flow;
decrements less than
5%.
-------
TABLE 11-1 (CONT'D). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
VJ
~
VO
u«
h— '
1
H- *
0
C»
'Tl
H
O
O
0
H
O
O
H
W
Ref. Subjects
Hanley et 22 asthmatics
al. (1992) 12 to 19 yrs
Koenig et 9 asthmatics with
al. (1989) exercise-induced
broncho-spasm
12 to 18 yrs
Koenig et 14 asthmatics with
al. (1992) exercise-induced
broncho-spasm
13 to 18 yrs
Koenig et 8 healthy
al. (1993) 9 asthmatic
60 to 76 yrs
Temp
Exposures MMAD1 GSD2 Duration Exercise 'C RH3
Mouthpiece: 22 65
1): Air; 40 min. 10 min
H2S04 70, 130 ;
-------
TABLE 11-1 (CONT'D). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
3.
p— >
vo
(— '
»— *
i
i—^
O
[>.
V
D
5S
s
o
H
W
O
^
O
HH
H
W
Ref. Subjects
Koenig et 28
al. (1994) asthmatics
12 to 19 yrs
Kulle et al. 20 healthy
(1986) 20 to 35 yrs
Laube et al. 7 healthy
(1993) 20 to 31 yrs
Linn et al. 22 healthy
(1989) 19 asthmatic
18 to 48 yrs
Linn et al. 15 healthy
(1994) 30 asthmatic
18 to 50 yrs
Exposures MMAD1
Mouthpiece:
Air;
ozone 0.12 ppm+NOj 0.6
0.3 ppm;
ozone 0.12 ppm+NO2
0.3 ppm+H2SO4
68 ^ig/m '
ozone 0.12 ppm+N^
0.3 ppm+HNO3
0.05 ppm
Air; activated carbon 5 17 1.5
/ig/m3; SO2 0.99 ppm;
carbon 5 17 /ig/m3 +
SO2 0.99 ppm.
Head dome:
NaCl =500/ig/m3 10.3
H2SO4 = 500 /*g/m3 10.9
H2O 20
H2S04 =2,000 ftg/m3 10
1
Air;
ozone 0.12 ppm; =0.5
H2SO4 100 pg/m3;
ozone +H2SO4
Temp
GSD2 Duration Exercise 'C RH3 Symptoms
90 min X VE 3 X 22 65 No pollutant
2 days resting effects
1.5
1.5 4h 15 minx 2, 22 60 No
35 L/min symptoms
related to
carbon
exposure
1 h 20 min 22 to 25 99 No pollutant
effects
1 h 40 to 45 =10 74 to Increased
L/min 100 total score
with larger
acid
particles.
6.5 h/dX 2 50 min X 6 21 50 Symptoms
- 2 d 29 L/min unrelated to
atmosphere
Lung Function
No pollutant effects
No direct or additive
effects of carbon
exposure
No pollutant effects
No pollutant effects
IFEV, &FVC in
ozone, similar for
healthy & asthmatic
subjects. Greater fall in
FEV! for acid+ozone
than ozone alone,
marginally significant
interaction.
Other Effects
No effects on
airway
responsiveness
Tracheal
clearance
increased
(4/4 subjects).
Outer zone
clearance
increased
(6/7 subjects).
No effects on
airway
responsiveness
No effects on
airway
reactivity
Increased
airway
responsiveness
with ozone,
marginal
further
increase with
ozone + acid
Comments
6 subjects with
moderate or
severe asthma did
not complete
protocol
4 asthmatic
subjects unable to
complete
exposures because
of symptoms.
Average subject
lost 100 ml FEVt
with ozone, 189
ml with
ozone + acid
Original findings
replicated in
13 subjects
-------
TABLE 11-1 (CONT'D). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
K>
Ref.
Morrow et al.
(1994)
Utell et al.
(1989)
Yang and
Yang (1994)
Subjects
17 asthmatic
20 to 57 yrs
17 COPD
52 to 70 yrs
15 asthmatic
19 to 50 yrs
30 healthy
25 asthmatic
23 to 48 yrs
Exposures MMAD1 GSD2
NaCl = 100 /*g/m3
H2SO4 =90/ low NH3
Mouthpiece: Bagged
polluted air,
TSP = 202 Mg/m3
Temp
Duration Exercise ' C
2 h Asthmatics: 21
10 min X 4
COPD: 7 min
X 1
30 min 10 min
VE3X
resting
30 min At rest
RH3 Symptoms Lung Function
30 No pollutant Asthmatics:
effects. IFEV, slightly
greater after acid
than after NaCl.
COPD: No
effects.
20 to 25 Greater fall in
FEV, with low
NH3(19%)than
with high NH3
(8%).
Healthy subjects:
no change
Asthmatics:
IFEV, =7%
Other Effects
Increased airway
responsiveness
in asthmatics
reported; no
allowance for
change in
airway caliber
Comments
No control
exposure
'Exposures in environmental chamber unless otherwise stated.
2Mass median aerodynamic diameter. In some studies expressed as volume median diameter; see text.
2Geometric standard deviation.
4Relative humidity.
5Hydroxymethanesulfonic acid.
'Specific airways resistance.
-------
1 5) Effects of sulfate aerosols are related to their acidity, and neutralization by oral
2 ammonia tends to mitigate these effects.
3 6) Exposure to H2SO4 at concentrations as low as 100 /xg/m3 for 60 min alters
4 mucociliary clearance.
5 7) Airway reactivity increases in healthy and asthmatic subjects following exposure
6 to 1,000 jug/m3 H2SO4 for 16 min.
7 8) Differences in estimated respiratory intake explain only a portion of the
8 differences in responses among studies.
9
10 In the five years since the publication of the Acid Aerosol Issue Paper, several of these
11 summary statements have been further confirmed. For example, recent studies confirm the
12 absence of spirometric effects following acute exposure to H2SO4 and other acid aerosols in
13 healthy subjects, at or below 1,000 /*g/m3. The observation of effects on adolescent
14 asthmatics at levels as low as 68 /ng/m3 has not been confirmed, and studies utilizing longer
15 exposures have raised further questions about the relationship between dosimetry and health
16 effects. However, additional evidence supports the conclusion that lung function effects in
17 asthmatic subject are related to hydrogen ion exposure, which is in part determined by the
18 degree of neutralization by oral ammonia. Two recent studies examining sequential exposure
19 to H2SO4 and ozone (Linn et al., 1994; Frampton et al., 1995) suggest that acid aerosols
20 may potentiate the response to ozone in some asthmatic subjects. Finally, clinical studies of
21 acid aerosols have been expanded to include endpoints associated with fiberoptic
22 bronchoscopy and BAL.
23
24 11.2.1.2 Pulmonary Function Effects Of H2SO4 In Healthy Subjects
25 Since 1988, ten studies have examined the effects of H2SO4 exposure on pulmonary
26 function in healthy subjects. Exposure levels ranged from 100 /ig/m3 to 2,000 /*g/m3, with
27 exposure durations ranging from 16 min to 6.5 h on two successive days. All of these
28 studies confirmed the findings from previous studies of an absence of spirometric effects on
29 healthy subjects. Exposures at the highest concentrations (i.e. 1,000 pig/m3 or greater) were
30 associated with mild increases in lower respiratory symptoms, especially those exposures
31 with particle sizes in the 10 to 20 /xm range.
April 1995 1143 DRAFT-DO NOT QUOTE OR CITE
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1 Two studies reported by Avol and colleagues (Avol et al., 1988a,b) examined effects of
2 1 h H2SO4 aerosol exposures in an environmental chamber. In the first study (Avol et al.,
3 1988b), 22 healthy nonsmoking subjects between the ages of 18 and 45 years, some reporting
4 allergies, were exposed for 1 h to fogs (volume median diameter (VMD) 9.7 to 10.3 /mi,
5 GSD not stated) consisting of H2O (control) or H2SO4 at 647, 1,100, and 2,193 /ig/m3.
6 Three 10-min periods of moderate exercise (46 L/min) were included. All subjects were
7 exposed to each atmosphere, separated by one week. Half the subjects received an acidic
8 gargle to reduce oral ammonia levels prior to exposure; no difference in effects was observed
9 with or without the gargle, so data were combined in the analysis. Healthy subjects
10 experienced a slight concentration-related increase in lower respiratory symptoms, but no
11 effect was found on spirometry or on airway reactivity to methacholine measured 1 h after
12 exposure.
13 A second study (Avol et al., 1988a) essentially duplicated this protocol for H2SO4
14 aerosols with a smaller particle size (MMAD = 0.85 to 0.91 /mi, geometric standard
15 deviation [GSD = 2.4 to 2.5]). Twenty-one healthy subjects, 12 with allergies by skin
16 testing, were exposed on separate occasions to air and H2SO4 aerosol at each of three
17 concentrations: 363, 1128, 1578 /^g/m3. A slight increase in cough was found at the two
18 highest concentrations of H2SO4, but no effects were found on spirometry, specific airway
19 resistance (SRaw), or airway reactivity to methacholine.
20 Linn et al. (1989) examined the effects of droplet size on 22 healthy subjects exposed
21 to nominally 2,000 /zg/m3 H2SO4 for 1 h, with three, 10-min exercise periods. Distilled
22 H2O fog served as control aerosols. Aerosol VMDs were 1, 10, and 20 /mi. Actual
23 exposure concentrations were 1,496, 2,170, and 2,503 /ig/m3. Results were similar to the
24 previous fog studies by this group, with no significant effects on lung function or airway
25 reactivity to methacholine. Total symptom scores were increased with exposure to 10 /mi
26 and 20 /mi H2SO4 particles, but not to 1 /mi.
27 Frampton et al. (1992) exposed 12 healthy nonsmokers to aerosols of NaCl (control) or
28 H2SO4 (MMAD = 0.9/rni, GSD = 1.9) at 1,175 /tg/m3 for 2 h in an environmental
29 chamber. Four 10-min exercise periods at VE of «40 L/min were included. Subjects
30 brushed their teeth and rinsed with mouthwash prior to and once during each exposure to
31 reduce oral ammonia levels. Mild throat irritation was described by 4 of 12 subjects after
April 1995 11-14 DRAFT-DO NOT QUOTE OR CITE
-------
1 acid exposure and 3 of 12 subjects after NaCl exposure. No effects on lung function were
2 found.
3 Five other recent studies (Anderson et al., 1992; Koenig et al., 1993; Laube et al.,
4 1993; Linn et al., 1994; Frampton et al., 1995) have included healthy subjects in exposures
5 to H2SO4 aerosols at levels below 1000 /zg/m3; none have shown meaningful effects on lung
6 function. Anderson et al., (1992) studied the responses of 15 healthy subjects exposed for
7 1 h in a chamber to air, 100 /*g/m3 H2SO4, 200 /ng/m3 carbon black, and carbon black
8 coated with H2SO4, (MMAD «1 /mi). Lemonade or citrus juice gargles were used to
9 reduce oral ammonia levels. Exposures containing acid were without effects on symptoms,
10 lung function, or airway reactivity. Healthy subjects were actually more symptomatic and
11 demonstrated greater increases in SRaw after air than after pollutant exposure, contrary to
12 expectation. Koenig et al, (1993) studied eight elderly subjects age 60 to 76 years exposed
13 to air, H2SO4, or ammonium sulfate at nominally 70 jug/m3 ( = 82 /ig/m3 H2SO4) for 40 min,
14 delivered by mouthpiece. No effects were found on spirometry or total respiratory
15 resistance. In a study designed to examine effects of acid fog on pulmonary clearance,
16 Laube et al., (1993) exposed seven healthy volunteers to NaCl or H2SO4 at 470 /ig/m3,
17 MMAD «11 fim, for 1 h with 20 min of exercise. Acid exposure did not alter Symptoms or
18 lung function. Two chamber studies designed to examine the effects of combined or
19 sequential exposure to acid aerosols and ozone found no direct effects of exposure to
20 =100 fjLg/m3 H2SO4 on lung function of healthy subjects, using exposure durations of
21 3 h (Frampton et al., 1995) or 6.5 h for two successive days (Linn et al., 1994). Both
22 studies included exercise and acidic mouth wash to minimize oral ammonia.
23 Thus for young, healthy adults, brief exposures to H2SO4 at mass concentrations more
24 than an order of magnitude above ambient levels do not alter lung function. Some subjects
25 report increased lower respiratory symptoms, including cough, at 1000 /*g/m3 and higher
26 levels, particularly with larger particle sizes (> 5 /mi). The elderly do not demonstrate
27 decrements in lung function at low levels of exposure ( = 82 /ig/m3). There are no data on
28 the responses to particle exposure for healthy adolescents or children.
29
30
April 1995 1M5 DRAFT-DO NOT QUOTE OR CITE
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1 11.2.1.3 Pulmonary Function Effects Of H2SO4 In Asthmatic Subjects
2 Individuals with asthma often experience bronchoconstriction in response to a variety of
3 stimuli, including exercise, cold dry air, or exposure to strong odors, smoke, and dusts.
4 Considerable individual variability exists in the nature of stimuli that provoke a response, and
5 in the degree of responsiveness. Thus, for clinical studies involving asthmatic subjects,
6 subject selection and sample size deserve particular consideration. Differences among
7 subjects may explain in part the widely differing results between laboratories studying effects
8 of acid aerosols. For example, in some studies described below, asthmatic subjects were
9 specifically selected to have exercise-induced bronchoconstriction (Koenig et al., 1989, 1992,
10 1994; Hanley et al., 1992), or responsiveness to hypo-osmolar aerosols (Balmes et al.,
11 1988). The interval for withholding medications prior to exposure differed among various
12 laboratories and different studies. In addition, the severity of asthma differed among studies;
13 severity is often difficult to compare because published information describing clinical
14 severity and baseline lung function is often incomplete. Table 11-2 lists the characteristics of
15 asthmatic subjects exposed to acid aerosols and other particles.
16 Several studies have suggested that asthmatics are more sensitive than healthy subjects
17 to effects of acid aerosols on lung function. Utell et al., (1982) found significant decrements
18 in specific airway conductance (SGaw) in asthmatic subjects exposed by mouthpiece for
19 16 min to 450 and 1,000 fig/m3 H2SO4. Moreover, exposure to neutralization products of
20 H2SO4 produced smaller decrements in function, roughly in proportion to their acidity
21 (H2S04 > NH4HS04 > NaHSO4).
22 The role of H+ in the responsiveness of asthmatics to acid aerosols was explored by
23 Fine et al. (1987b), who found that titratable acidity and chemical composition, rather than
24 pH alone, are key determinants of response in asthmatics. Eight asthmatic subjects were
25 challenged by mouthpiece for 3 min at rest, with buffered or unbuffered hydrochloric acid
26 (HC1) or H2SO4 at varying pH levels, and changes in SRaw were measured. Solutions were
27 buffered with glycine, which, by itself, was found to have no direct effect on lung function.
28 Aerosol MM AD ranged from 5.3 to 6.2 /im (GSD 1.6 to 1.8), simulating acid fogs. There
29 was no group response to unbuffered acid, even at pH 2. However, SRaw increased in
30 seven of eight subjects after inhalation of H2SO4 and glycine at pH 2, suggesting that
31 titratable acidity or available H+, rather than pH, plays a role in mediating acid fog-induced
April 1995 1M6 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-2. ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
a Subject # Age range
13 Ref. (F/M) (mean)
<•" Anderson 15 19 to 45
et al. (6/9) years
(1992) (29)
Aris et al. 19 20 to 40
(1990) (8/11) years
£ Aris et al. 18 23 to 37
H* (1991b) years
'***•*
O
£
H
6
0
o
H
O
a
o
o
o
H
M
Exposures1 Allergies
1): Air Not stated
2): H2SO4
= 100 /*g/m3
3): carbon black
=200 /tg/m3
4): acid-coated carbon
Mouthpiece study: Not stated
HMSAOto l.OOOmM
+ H2SO4 50 mM vs
H2SO4 50 mM
Chamber study:
HMSA 1 mM +
H2SO4 5 mM vs
H2SO4 5 mM
Mouthpiece study: Not stated
H2SO4 vs NaCl to test
changes hi particle
size, osmolarity (30 to
300 mOsm), relative
humidity Chamber
study: H2SO4 vs NaCl
fog with varying water
content
FEVj
Medications (% pred.)
Not stated Not stated
All but one on 82 ±20
albuterol. 3 on (SD)
inhaled steroids.
No meds 24 h
before study.
Most subjects on 79 ±23
albuterol. Several (SD)
on inhaled
steroids. No
meds 24 h before
study.
FEVj/FVC Airway
(%) Responsiveness
69±14(SD) Methacholine:
PD20 < 56
"breath-units"
Not stated Methacholme:
All responded
to <2 mg/ml
Not stated Methacholine:
All responded
to < 1 mg/ml
Exercise/ VE
Intermittent at
=50 L/min
Intermittent,
100 W on cycle
ergometer
Mouthpiece
study: with &
without
exercise.
Chamber study:
intermittent
exercise at 100
W on cycle
ergometer.
-------
y
i
*
•H
O
C/3
J
O
I
"<
fa
o
t/3
3
5
><
c«
H
U
i
J
I
w
Airwa
Respo
n< u.
edica
w
Di
2 2
sponsive
acholine
ot
ified
Hyper
b me
challen
further
acholine:
<295
li
5
ts
y
ha
eth
D
oo
Ov
P0
"dose
"
v
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2
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"8
1
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<
April 1995
11-18 DRAFT-DO NOT QUOTE OR CITE
-------
> TABLE 11-2. ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
~ Subject # Age range
£ Ref. (F/M) (mean)
<-" Fine et al. 8 22 to
(1987b) (6/8) 29 years
Fine et al. 10 22 to
(1987a) (5/5) 34 years
(26.7)
Frampton et 30 20 to
al. (1995) (20/10) 42 years
^
»— »
Hanley et 22 12 to
al. (1992) (7/15) 19 years
O
!>
3
6
0
^
O
0
ci
o
H
W
O
n
H
W
Exposures1
Mouthpiece:
Buffered and
unbuffered HC1 and
H2SO4 at varying pH
Mouthpiece: Na2SO3
0 to 10 mg/ml, pH 9,
6.6, 4; buffered
acetic acid pH 4;
SO2 0.25 to 8 ppm
NaCl or H2SO4
100 /ig/m3 followed
by
ozone 0.08, 0.12, or
0.18 ppm
Mouthpiece:
1): Air or H2SO4 70,
130 /ig/m3
2): Air or H2SO4 70
/zg/rn3, with and
without lemonade
Allergies
Not stated
Not stated
All had
positive
skin tests.
tlgEin
10.
"All had
allergic
asthma".
TlgEin 8.
Medications
6 on inhaled meds
and/or
theophylline, no
steroids. No meds
12 h before study.
7 on inhaled meds,
no steroids. No
meds 12 h before
study.
All on intermittent
or daily
bronchodilators.
None on steroids.
Meds held 24 h
before study.
All but 2 on meds,
no steroids. No
meds 4 h before
study.
FEVj FEVj/ Airway
(% pred.) FVC(%) Responsiveness
41 to 108 74±11 Methacholine:
(SD) All responded to
<3 mg/ml.
81±4(SE) 75+2(SE) Positive
carbachol
challenge if
normal
spirometry
Not stated Not stated Methacholine:
PD20 0.25 to 25
mg/ml; not
available for
3 subjects.
18 were
responsive to
exercise by
treadmill test
Exercise/ VE
At rest
At rest
10 min X 6
for each
exposure.
1): 10 min
2): 30 min
=30 L./min
-------
> TABLE 11-2
£ Ref.
<•*• Koenig
et al.
(1989)
Koenig
et al.
(1992)
Subject #
(F/M)
9
(3/6)
14
(5/9)
(CONT'D).
Age range
(mean)
12 to
18 years
13 to
18 years
. ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
Exposures1
Mouthpiece: Air
H2SO4 68 fig/m3
SO20.1 ppm
H2S04+SO2
HN03 0.05 ppm
Mouthpiece:
Air
H2SO4 35 or
70 /ig/m3
Allergies Medications
5 "allergic Not stated
asthma"
"Allergic Not stated
asthma"
FEVj FEVj/ Airway
(% pred.) FVC (%) Responsiveness
Not stated Not stated Methacholine:
All responded to
<20 rag/ml.
All had ^FEVl
>15% with
treadmill test
Not stated Not stated Methacholine:
PD20 0.25 to
25 rag/ml; not
available for
1 subject; 8 had
pos. treadmill
tests, 4 history
of exercise
Exercise/ VE
"Moderate", on
treadmill for
10 min.
Intermittent =23
L/min
responsiveness,
2 did not meet
stated criteria for
exercise
responsiveness.
O Koenig 9
£ et al. (7/2)
Jfl (1993)
o
O
H
O
H
W
O
90
0
60 to 76 Mouthpiece:
years 1): Air
2): (NH4)2SO4
=70 ftg/m3
3&4): H2SO4
=74 /tg/m3 with
and without
lemonade
Not stated All on 75
"bronchodilator
and/or anti-
inflammatory
treatment".
Steroids not
specified.
Not stated Methacholine: 10 min
PD20 < 10 mg/rol 17.5 L/min
-------
> TABLE 11-2 (CONT'D).
~ Subject #
£ Ref. (F/M)
& Koenig 28
et al. (9/19)
(1994)
Linn et al. 19
(1989) (13/6)
^
V*
I— »
o
^ Linn et al. 30
T1 (1994) (17/13)
*7
O
O
Morrow et 17
*§ al. (1994)
0
H
W
Age range
(mean)
12 to 19
years
18 to 48
years
(29)
18 to 50
years
(30)
20 to 57
years
ASTHMA SEVER!
Exposures1
Mouthpiece:
1): Air
2): ozone
0.12ppm+NO2
0.3 ppm
3): ozone
0.12ppm+NO2
0.3 ppm+H2SO4
68 /ig/m3
4): ozone 0.12
ppm+NO2 0.3
ppm+HNO3 0.05 ppm
H2O
H2SO4 =2,000 /tg/m3
1): Air
2): ozone 0.12 ppm
3): H2SO4 100 fig/m3
4): ozone+H2SO4
NaCl ~ 100 /xg/rn3
H2SO4 =90 /ig/m3
TY IN ST
Allergies
"Personal
history of
allergic
asthma"
"Some"
subjects
had history
of allergy
Some
subjects
had
positive
skin tests.
Positive
skin tests
UDIES OF ACID AERO
FEVj
Medications (% pred.)
3 on no meds, 87
rest on regular
meds. 4 on
inhaled steroids.
All on Not stated
bronchodilators
at least weekly.
No regular
steroid use. No
meds 12 h
before study.
Wide range of Not stated
medication
usage. Some on
inhaled steroids.
No meds 4 h
before study.
Requirement for Not stated
bronchodilators
>SOLS AND OTHER PAKTJ
FEV^ Airway
FVC (%) Responsiveness
Not stated Methacholine:
PD20<25mg/ml.
All but 1 responsive
to exercise by
treadmill test.
70 + 1 1 Hyperresponsiveness
(SD) based on
methacholme
PD20<38 "breath
units", exercise
responsiveness, or
bronchodilator
response.
72 Responsive to
methacholme or
exercise, or
bronchodilator
response
65+8(SD) Positive carbachol
challenge if normal
spirometry
LCLES
Exercise/ VE
Intermittent
VE3X
resting
Intermittent
40 to 45
L/min
50 min X 6
29 L/min
10 min X 4
Q
a
-------
> TABLE 11-2
*±*
to Ref.
<-" Utell et al.
(1989)
Yang and
Yang
(1994)
Subject #
(F/M)
15
25
(15/10)
(CONT'D). ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
Age range
(mean)
19 to 50
years
23 to 48
years
Exposures1 Allergies
Mouthpiece: Not stated
1): NaCl 350 /Kg/m3
2): H2SC>4
350 jig/m3 high
NH3
3): H2SO4 low NH3
Mouthpiece: All tlgE
Bagged polluted air,
TSP = 202 jtg/m3
Medications
All on intermittent or
daily bronchodilators.
None on steroids.
Meds held 24 h
before study.
No steroids. Holding
of medications not
stated.
FEVj
(% pred.)
88 ±4 (SE)
Not stated
FEVj/ Airway
FVC (%) Responsiveness
70 ±3 (SE) Positive carbachol
challenge if normal
spirometry
Not stated Hyperresponsive to
methacholine
Exercise/ VE
10 min VE
3 X resting
Rest
'Exposures in chamber unless otherwise stated.
-------
1 bronchoconstriction. Nevertheless, the response occurred at H2SO4 concentrations estimated
2 in excess of 10 mg/m3, more than an order of magnitude higher than the concentration
3 producing a response in the study of Utell et al. (1982).
4 Fine et al. (1987a) further examined the role of pH in sulfite-induced
5 bronchoconstriction in asthmatics. Ten subjects with asthma were challenged with increasing
6 concentrations of sodium sulfite (Na^O^ at three different pH levels. Challenge with
7 buffered acetic acid aerosols at pH 4 was used to control for the airway effects of acid
8 aerosols. Subjects also inhaled increasing concentrations of SO2 gas during eucapneic
9 hyperpnea. Exposures consisted of 1 min of tidal breathing on a mouthpiece at rest. Particle
10 MM AD ranged from 5.6 to 6.1 /xm. Nine of ten subjects experienced bronchoconstriction
11 with Na2SO3,with greater responses to aerosols made from solutions with lower pH. No
12 response was seen following acetic acid. The authors concluded that bronchoconstriction in
13 response to Na2SO3 aerosols may be caused by the release of SO2 gas or by bisulfite ions,
14 but not by sulfite ions and not merely by alterations of airway pH. These studies of Fine et
15 al., as pointed out by the authors, addressed potential mechanisms for bronchoconstriction in
16 response to acidic sulfates, but did not attempt to mimic the effects of environmental
17 exposures.
18 Hypo-osmolar aerosols can induce bronchoconstriction in some asthmatics. To test the
19 effects of varying osmolarity of acidic aerosols, Balmes et al. (1988) administered aerosols of
20 NaCl, H2SO4, HNO3, or H2SO4 + HNO3 to 12 asthmatic subjects via mouthpiece. All
21 solutions were prepared at an osmolarity of 30 mOsm, and delivered at doubling
22 concentrations until SRaw increased by 100%. An additional series of challenges with
23 H2SO4 at 300 mOsm was performed. The 12 subjects were selected from a group of
24 17 asthmatics on the basis of responsiveness to challenge with hypo-osmolar saline aerosol.
25 Aerosol particle size was similar to coastal fogs, with MM AD ranging from 5.3 to 6.1.
26 Delivered nebulizer output was quite high, ranging from 5.9 to approximately 87 g/m3.
27 All hypo-osmolar aerosols caused bronchoconstriction. Lower concentrations of
28 hypo-osmolar acidic aerosols were required to induce bronchoconstriction than with NaCl,
29 and there was no difference between acidic species. No bronchoconstriction occurred with
30 isosmolar H2SO4, even at maximum nebulizer output (estimated H2SO4 concentration greater
31 than 40 mg/m3). The authors concluded that acidity can potentiate bronchoconstriction
April 1995 H_23 DRAFT-DO NOT QUOTE OR CITE
-------
1 caused by hypo-osmolar aerosols. As in the studies of Fine et al. (1987a,b), these exposures
2 did not mimic environmental conditions.
3 Koenig and colleagues have studied the responses of adolescents with allergic asthma to
4 H2SO4 aerosols with particle sizes in the respirable range, and concentrations only slightly
5 above peak, worst-case ambient levels. In one study (Koenig et al., 1983), ten adolescents
6 were exposed to 110 jig/m3 H2SO4 (MMAD = 0.6 /im) by mouthpiece for a total of 40 min,
7 30 min at rest followed by 10 min of exercise. The FEV\ decreased 8% after exposure to
8 H2SO4, and 3% after a similar exposure to NaCl, a statistically significant difference. In
9 another study (Koenig et al., 1989), nine allergic adolescents were exposed to 68 jug/m3
10 H2SO4 (MMAD = 0.6 /mi) for 30 min at rest followed by 10 min of exercise (VE = 32
11 L/min). Although only five subjects were described as having "allergic asthma", all subjects
12 had exercise-induced bronchoconstriction; thus all subjects were asthmatic by generally
13 accepted criteria (Sheffer, 1991). Effects were compared with similar exposures to air, 0.1
14 ppm SO2, 68 /xg/m3 H2SO4 + 0.1 ppm SO2, and 0.05 ppm HNO3. The FEVj decreased 6%
15 after exposure to H2SO4 alone, and 4% after exposure to H2SO4 + SO2, compared to a 2%
16 decrease after air. Increases in total respiratory resistance were not significant. These
17 results were presented as preliminary findings, in that a total of 15 subjects were to be
18 studied; formal statistical comparison of H2SO4 versus air was not presented. Findings from
19 the full group of 15 subjects have not been published. These studies suggest that allergic
20 asthmatics with exercise-induced bronchoconstriction may be more sensitive to effects of
21 H2SO4 than adult asthmatics, and that small changes in lung function may be observed at
22 exposure levels below 100 /ig/m3.
23 Two studies reported by Avol et al. (1988a,b) examined effects of H2SO4 aerosols and
24 fogs on asthmatic subjects. The results for healthy subjects in these studies were described
25 in Section 11.2.1.2. In the first study, 21 adult asthmatics, 20 of whom had positive skin
26 tests to common allergens, were exposed to air or 396, 999, and 1,460 /ig/m3 H2SO4
27 (MMAD 0.85 to 0.91 pirn) for one hour with intermittent exercise. The asthmatic subjects
28 experienced concentration-related increases in lower respiratory symptoms, with some
29 persistence of symptoms at 24 h. The FEVj decreased by a mean of 0.26 L after exposure
30 to 999 /ig/m3, and 0.28 L after exposure to 1,460 /ig/m3. Results using analysis of variance
31 (ANOVA) were significant for concentration effects on change in FEVj and FVC. However,
April 1995 11-24 DRAFT-DO NOT QUOTE OR CITE
-------
1 decrements at 396 /ig/m3 were identical to those seen with air exposure. The SRaw
2 approximately doubled following exposure to both air and 396 /ig/m3 H2SO4, and
3 approximately tripled following exposure to 999 and 1,460 /
-------
1 dependence on droplet size". These more dramatic responses to acid aerosols are not
2 reflected in the mean responses, and suggest the existence of a few particularly susceptible
3 individuals. Mean responses of FEVj to acid aerosol exposure were about -21%, with
4 responses to exercise in clean air of about -12%. Some subjects experienced decreases in
5 FEVj in excess of 50%, as a result of combined exercise and acid aerosol exposure.
6 Analysis of variance found significant effects of acid x time on SRaw and FEVj. There was
7 no apparent effect of droplet size.
8 Utell et al. (1989) examined the influence of oral ammonia levels on responses to
9 H2SO4. Fifteen subjects with mild asthma inhaled H2SO4 aerosols (350 /xg/m3,
10 MMAD = 0.8 urn) via mouthpiece for 20 min at rest followed by 10 min of exercise.
11 Sodium chloride aerosol served as control. Low oral ammonia levels were achieved using a
12 lemon juice gargle and toothbrushing prior to exposure, and high levels were achieved by
13 eliminating oral hygiene and food intake for 12 h prior to exposure. These procedures
14 achieved a five-fold difference in oral ammonia levels. The FEVj decreased 19% with low
15 ammonia versus 8% with high ammonia (p< 0.001). The FEVj also decreased 8% with
16 NaCl aerosol. These findings extended the authors' previous findings (Utell et al., 1983b) of
17 decrements in SGaw following exposure to 450 /xg/m3 H2SO4, and demonstrated the
18 importance of oral ammonia in mitigating the clinical effects of submicron H2SO4 aerosols.
19 The findings of Koenig et al. (1989) in adolescent asthmatics prompted an attempt by
20 Avol and colleagues (1990) to replicate the study using a larger group of subjects.
21 Thirty-two subjects with mild asthma, aged 8 to 16 years, were exposed to 46 and 127 /ig/m3
22 H2SO4 (MMAD «0.5^im) for 30 min at rest followed by 10 min of exercise at 20 L/min/m2
23 body surface area. Subjects gargled citrus juice prior to exposure to reduce oral ammonia.
24 Bronchoconstriction occurred after exercise in all atmospheres, with no statistically
25 significant difference between clean air and acid exposures at any concentration. Because
26 these exposures were undertaken in an environmental chamber with unencumbered oral/nasal
27 breathing, in contrast to mouthpiece exposure in the Koenig studies, a subsequent study was
28 performed to examine the effects of oral breathing only. Twenty-one of these subjects were
29 therefore exposed to 134 jug/m3 H2SO4 while breathing chamber air through an open
30 mouthpiece. Again, no acid effect was found. One subject who was "unusually susceptible
31 to exercise-induced bronchospasm" also showed the largest decrements in lung function with
April 1995 H_26 DRAFT-DO NOT QUOTE OR CITE
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1 both exposures to the highest acid concentrations. It is possible that the subjects in the
2 Koenig et al. (1989) study, all of whom demonstrated exercise-induced bronchoconstriction
3 during a specific exercise challenge test, represented a more responsive subgroup of
4 adolescent asthmatics. Only 15 of the 32 subjects in the Avol et al. (1990) study were
5 known to have exercise-induced bronchoconstriction. Indeed, subsequent data from Dr.
6 Koenig's laboratory (Hanley et al., 1992) suggest exercise responsiveness is predictive of
7 H2SO4 responsiveness (see below).
8 Aris et al. (1990) examined the effects of hydroxymethanesulfonic acid (HMSA), which
9 has been identified as a component of west coast acidic fogs. They postulated that HMSA
10 might cause bronchoconstriction in asthmatics because, at the pH of airway lining fluid, it
11 dissociates into CH2O and SO2 . In the first part of the study, nine asthmatics were serially
12 challenged by mouthpiece with 0, 30, 100, 300 and 1,000 /*M HMSA in 50 /iM H2SO4
13 (MMAD = 6.1 /mi). The SRaw was measured after each challenge. These findings were
14 compared on a separate day to a similar series of exposures to 50 /xM H2SO4 alone. No
15 effect was found for HMSA on symptoms or airways resistance. An environmental chamber
16 exposure study was then performed in which 10 asthmatic subjects were exposed to 1 mM
17 HMSA + 5 mM H2SO4 for 1 h with intermittent exercise. The control was exposure to
18 5 mM H2SO4 alone. Three subjects underwent additional exposures to NaCl aerosol.
19 Particle MMAD was approximately 7 /mi. Both acid exposures slightly increased respiratory
20 symptoms, but no significant effects on SRaw were found.
21 In a subsequent series of studies, Aris et al. (1991b) examined the effects of varying
22 particle size, osmolarity, and relative humidity on airways resistance in response to H2SO4
23 aerosol. To study effects of particle size and osmolarity, 11 asthmatics inhaled five different
24 aerosols for 16 min by mouthpiece at rest: (1) H2SO4 at 300 mOsm (VMD approximately
25 6 /mi); (2) H2SO4 30 mOsm (VMD approximately 6 /mi); (3) sodium chloride 30 mOsm
26 (VMD approximately 6 pirn); (4) H2SO4 (VMD approximately 0.4 /mi); and (5) H2SO4,
27 (VMD approximately 0.4 /on). Sulfuric acid concentrations were high, at approximately
28 3 mg/m3. Airway resistance actually decreased slightly with all aerosol exposures and there
29 were no significant effects on respiratory symptoms.
30 In a second mouthpiece study, nine subjects were exposed at rest (part 1) to H2SO4 at
31 approximately 3 mg/m3, with large (VMD =6 /mi) versus small (0.3 /mi) particle size and
April 1995 H_27 DRAFT-DO NOT QUOTE OR CITE
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1 low(< 10%) versus high (100%) relative humidity. Sodium chloride aerosols under similar
2 conditions served as control. Because these exposures caused no decrements in SRaw, six
3 subjects underwent exposures to small particle, low humidity H2SO4 versus sodium chloride
4 while exercising at 40 L/min (part 2). Although SRaw increased significantly with exercise,
5 there was no difference between H2SO4 and sodium chloride exposures. These results are
6 shown in Figure 11-1. A significant increase in throat irritation was observed with the low
7 humidity, small particle H2SO4 inhalation in part 1 of this study (n=9) but was not replicated
8 in part 2 (n=6).
9 Finally, an environmental chamber exposure study was undertaken to examine effects of
10 H2SO4 fogs (VMD approximately 6 jum) with varying water content on airways resistance.
11 Ten subjects were exposed for 1 h with intermittent exercise to H2SO4 and NaCl at low
12 (0.5 /ig/m3) and high (1.8 /ig/m3) liquid water content. The mean sulfate concentrations
13 were 960 jug/m3 for low water content fogs and 1,400 /ig/m3 for high liquid water content
14 fog. Surprisingly, SRaw decreased slightly with most exposures, with no significant
15 difference among the 4 atmospheres. The authors speculated that the decrements in
16 pulmonary function following exposure to acid aerosols in previous studies may have been
17 due to increases in airway secretions or effects on the larynx rather than bronchoconstriction.
18 Responsiveness of adolescent asthmatic subjects to H2SO4 aerosols was further explored
19 by Hanley et al. (1992). Fourteen allergic asthmatics aged 12 to 19 years inhaled air or
20 H2SO4 at targeted concentrations of 70 and 130 /ig/m3, for 30 min at rest and 10 min with
21 exercise. In a second protocol, nine subjects were exposed to targeted concentrations of
22 70 /ig/m3 H2SO4, with and without drinking lemonade to reduce oral ammonia. Actual
23 exposure concentrations ranged from 51 to 176 /ig/m3 H2SO4. Exposures lasted 45 min,
24 including two 15-min exercise periods. Aerosol MMAD was 0.72 /on. For the purposes of
25 this document, mean changes in FEVj were calculated from individual subject data provided
26 in the published report. In the first protocol, FEVj fell 0.05 ± 0.08 L after air and 0.15 ±
27 0.14 L after nominal 70 /ig/m3 H2SO4. In the second protocol, FEVj fell 0.00 ± 0.23 L
28 without lemonade gargle and 0.13± 0.09 L with lemonade gargle. Results from the 22
29 subjects exposed in the two protocols were combined for the published analyses, and changes
30 in pulmonary function were regressed against H+ concentration for each subject.
31 Decrements in FEVj and FVC were statistically significant at 2 to 3 min after exposure, but
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0?
V)
LowRH
Small Particle
NaCI
LowRH
Small Particle
4,804
High RH
Large Particle
H>SO4
LowRH
Small Particle
NaCI
LowRH
Small Particle
Figure 11-1. Mean ± SEM specific airway resistance (SRaw) before and after a 16-min
exposure for (A) nine subjects who inhaled low relative-humidity (RH)
NaCI, low-RH H2SO4, and high-RH H2SO4 aerosols at rest, and (B) six
subjects who inhaled low-RH NaCI and low-RH H2SO4 aerosols during
exercise.
Source: Ariset al., 19915.
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1 not at 20 min after exposure. Changes in Vmax50 and total respiratory resistance were not
2 significantly different. The findings corresponded to a fall in FEVj of approximately
3 37 ml/jwM H+. A significant correlation was found between exercise-induced
4 bronchoconstriction, determined prior to exposure using a treadmill test, and the slope of A
5 FEVj/H"1". A similar observation linking baseline airways reactivity to H2SO4
6 responsiveness had been made previously by Utell et al., (Utell et al., 1983b).
7 Koenig et al. (1992) examined the effects of more prolonged mouthpiece exposures to
8 H2SO4. Fourteen allergic asthmatic subjects aged 13 to 18, with exercise-induced
9 bronchoconstriction, were exposed to air or 35 and 70 /-ig/m3 H2SO4, for 45 min and 90 min,
10 on separate occasions. Oral ammonia was reduced by drinking lemonade. The exposures
11 included alternate 15-min periods of exercise at three times resting VE. The largest
12 decrements in FEVj (6%) actually occurred with the shorter exposure to the lower
13 concentration of H2SO4 (35 /*g/m3). Changes following exposure to 70 /ig/m3 and following
14 90 min exposures were not significant. The authors concluded that duration of exposure did
15 not play a role in the response to H2SO4 aerosols. However, the absence of a concentration
16 response in the studies suggests that the statistical findings may be due to chance. Therefore,
17 the study does not appear to demonstrate a convincing effect of H2SO4 at these exposure
18 levels.
19 Anderson et al. (1992) included 15 asthmatic adults in a study comparing the effects of
20 exposure for 1 h to air, 100 jig/m3 H2SO4, 200 /tg/m3 carbon black particles, and acid-
21 coated carbon black. Decrements in FEVj were observed for all exposures, averaging about
22 9%. Analysis of variance for FVC showed a significant interaction of acid, carbon, and time
23 factors (p = 0.02), but the largest decrements actually occurred with air exposure.
24 In the only study of elderly asthmatics, Koenig et al. (1993) exposed nine subjects,
25 60 to 76 years of age, by mouthpiece to air, (NH4)2SO4, or 70 /ig/m3 H2SO4, with and
26 without lemonade gargle. Exposures were 30 min at rest followed by 10 min of mild
27 exercise (VE = 17.5 L/min). Greater increases in total respiratory resistance occurred
28 following H2SO4 without lemonade than following the other atmospheres, but the difference
29 between atmospheres was not significant.
30 In a study comparing effects of H2SO4 exposure in subjects with asthma and COPD,
31 Morrow et al. (1994) exposed 17 allergic asthmatic subjects in an environmental chamber to
April 1995 11-30 DRAFT-DO NOT QUOTE OR CITE
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1 90 iwg/m3 H2SO4 or NaCl (MMAD< 1 /im) for 2 h with intermittent exercise. Pulmonary
2 function was measured after each of four 10 min exercise periods, and again 24 h after
3 exposure, before and after exercise. Decrements in FEVl were consistently greater in H2SO4
4 than NaCl, although the difference was statistically significant only following the second
5 exercise period. FEV! decreased «18% after H2SO4 compared with «14% after NaCl (p
6 = 0.02). Reductions in SGaw were significantly different only following the fourth exercise
7 period (p = 0.009). No changes were found in symptoms or arterial oxygen saturation, and
8 there were no significant changes in lung function 24 h after exposure.
9 Finally, two recent studies have examined combined exposures to H2SO4 and ozone,
10 one using a combined pollutant atmosphere for 6 h per day over 2 days, (Linn et al., 1994)
11 and the other using sequential 3 h exposures to H2SO4 followed 1 day later by ozone
12 (Frampton et al., 1995). These reports will be discussed in detail in section 11.2.1.7.
13 However, neither study found any significant changes in lung function in asthmatics exposed
14 to 100 jitg/m3 H2SO4 alone.
15 In summary, asthmatic subjects appear to be more sensitive than healthy subjects to the
16 effects of acid aerosols on lung function, but the effective concentrations differ widely among
17 laboratories. Although the reasons for these differences remain largely unclear, subject
18 selection differences in neutralization of acid by NH3 may be an important factor.
19 Adolescent asthmatics may be more sensitive than adults, and may experience small
20 decrements in lung function in response to acid aerosols at exposure levels only slightly
21 above peak ambient levels. Even in studies reporting an overall absence of effects on lung
22 function, some asthmatic subjects appear to demonstrate clinically important effects.
23
24 11.2.1.4 Effects Of Acid Aerosols On Airway Responsiveness
25 Human airways may undergo bronchoconstriction in response to a variety of stimuli.
26 Airway responsiveness can be quantitated by measuring changes in expiratory flow or
27 airways resistance in response to inhalation challenge. Typically, the challenging agent is a
28 non-specific pharmacologic bronchoconstrictor such as methacholine or histamine. Other
29 agents include carbamylcholine (carbachol), cold dry air, sulfur dioxide, hypo-osmolar
30 aerosols, or exercise. In allergic subjects, airway challenge with specific allergens can be
31 performed, although the responses are variable, and late phase reactions can result in
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1 bronchoconstriction beginning 4 to 8 h after challenge and lasting 24 h or more. Although
2 many individuals with airway hyperresponsiveness do not have asthma, virtually all
3 asthmatics have airway hyperresponsiveness, possibly reflecting underlying airway
4 inflammation. Changes in clinical status are often accompanied by changes in airway
5 responsiveness. Thus alterations in airway responsiveness may be clinically significant, even
6 in the absence of direct effects on lung function. Godfrey (1993) and Weiss et al. (1993)
7 have recently reviewed airways hyperresponsiveness and its relationship to asthma. Molfino
8 et al. (1992) have provided a brief review of air pollution effects on airway responsiveness.
9 As noted in section 11.2.3, two studies (Utell et al., 1983b; Hanley et al., 1992) have
10 suggested that the degree of baseline airway responsiveness may predict responsiveness to
11 acid aerosol exposure in asthmatic subjects. This section will deal only with studies
12 examining changes in airway responsiveness with exposure to particles.
13 Despite the absence of effects on lung function in healthy subjects, Utell et al. (1983a)
14 observed, in healthy nonsmokers, an increase in airway responsiveness to carbachol
15 following exposure to 450 /ig/m3 H2SO4. The increase occurred 24 h, but not immediately,
16 after exposure. In addition, some subjects reported throat irritation between 12 and 24 h
17 after exposure to H2SO4. These findings suggested the possibility of delayed effects. These
18 investigators also observed increases in airway responsiveness among asthmatic subjects
19 following exposure to 450 and 1000 /*g/m3, but not 100 /ig/m3 H2SO4. These findings have
20 been reviewed (Utell et al., 1991).
21 Avol et al. (1988a,b) included airway responsiveness as an outcome measure in their
22 studies of healthy and asthmatic subjects exposed to varying concentrations of H2SO4. No
23 effects on responsiveness were reported, with either acidic fogs or submicron aerosols, at
24 H2SO4 concentrations as high as 2000 /ig/m3. However, airway challenge was performed
25 using only two concentrations of methacholine. This limited challenge may have been
26 insufficiently sensitive to detect small changes in airway responsiveness.
27 Using a similar 2-dose methacholine challenge protocol, Linn et al. (1989) found no
28 change in airway responsiveness of healthy subjects following exposure to 2000 /ig/m3
29 H2SO4 for 1 h, at particle sizes ranging from 1 to 20 /mi. Anderson et al. (1992), in their
30 study of responses to 100 /ig/m3 H2SO4, 200 /ig/m3 carbon black, and acid coated carbon,
31 found no effects on airway responsiveness in healthy or asthmatic subjects. In this study, a
April 1995 11-32 DRAFT-DO NOT QUOTE OR CITE
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1 conventional methacholine challenge was used, administering doubling increases in
2 methacholine concentration until FEVj decreased more than 20%.
3 In a study primarily designed to examine effects of acid fog exposure on mucociliary
4 clearance, Laube et al. (1993) examined changes in airway responsiveness to methacholine in
5 7 asthmatic subjects exposed to 500 jiig/m3 H2SO4 or NaCl (MMAD = 10 /im) for 1 h with
6 20 min of exercise. Responsiveness was measured at screening and 30 min after each
7 exposure. No difference was observed between H2SO4 and NaCl exposures.
8 A recent study (Linn et al., 1994) has suggested that exposure to ozone with H2SO4
9 may enhance the increase in airway responsiveness seen with ozone exposure alone. Fifteen
10 healthy and 30 asthmatic subjects were exposed to air, 0.12 ppm ozone, 100 /ig/m3 H2SO4,
11 and ozone + H2SO4 for 6.5 h on 2 successive days, with intermittent exercise. Airway
12 responsiveness was measured after each exposure day using a conventional methacholine
13 incremental challenge, and compared with baseline measured on a separate day. An
14 ANOVA using data from all subjects found an increase in airway responsiveness in
15 association with ozone exposure (p=0.003), but showed no significant change following
16 exposure to air or H2SO4 alone. Multiple comparisons did not reveal significant differences
17 in airway responsiveness between ozone and ozone + H2SO4 in healthy or asthmatic
18 subjects. However, asthmatic subjects showed the greatest increase in airway responsiveness
19 following the first day of ozone + H2SO4, and ANOVA revealed a significant interaction of
20 clinical status, ozone, acid, and day (p=0.03). Decreases in FEVj following methacholine
21 challenge for healthy subjects were 8% after air, 6% after H2SO4, 9% after ozone, and 13%
22 after ozone + H2SO4. Changes were smaller following the second exposure day, suggesting
23 attenuation of responsiveness with repeated exposure, as seen in previous studies of ozone
24 alone (U.S. Environmental Protection Agency, 1995). These studies suggest that exposure to
25 low concentrations of H2SO4 may enhance ozone-induced increases in airway responsiveness
26 in both healthy and asthmatic subjects.
27 Koenig et al. (1994) sought to determine whether exposure to H2SO4 or HNO3
28 enhanced changes in lung function or airway responsiveness seen with exposure to ozone +
29 nitrogen dioxide (NO2). Adolescent asthmatic subjects were exposed to air, 0.12 ppm ozone
30 +0.3 ppm NO2, ozone + NO2 + 73 /ig/m3 H2SO4, and ozone + NO2 +0.05 ppm HNO3.
31 Exposures were by mouthpiece for 90 min, with intermittent exercise, on two consecutive
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1 days. Airway responsiveness was measured by methacholine challenge at screening and on
2 the day following the second pollutant exposure. No effects on airway responsiveness were
3 found for any atmosphere. However, challenge following pollutant exposure utilized only
4 doses of methacholine well below the level causing significant reductions in FEVj for these
5 subjects at baseline, making it unlikely that small or transient changes in responsiveness
6 would be detected. Six subjects did not complete the protocol because of illness, symptoms,
7 and other factors which may or may not have been related to pollutant exposure; these data
8 were not included in the analysis.
9 In summary, the data suggest that there is no significant effect of ambient level
10 exposure to the particles tested on airway responsiveness in healthy or asthmatic subjects.
11 Observations of possible delayed increases in responsiveness in healthy subjects exposed to
12 450 /-tg/m3 H2SO4 (Utell et al., 1983a), and H2SO4 enhancement of ozone effects on airway
13 responsiveness in healthy and asthmatic subjects (Linn et al., 1994) require confirmation in
14 additional studies, utilizing standard challenge protocols.
15
16 11.2.1.5 Effects Of Acid Aerosols On Lung Clearance Mechanisms
17 Brief (1- to 2-h) exposures to H2SO4 aerosols have shown consistent effects on
18 mucociliary clearance in three species: donkeys, rabbits, and humans. The direction and
19 magnitude of the effect are dependent on the concentration and duration of the acid aerosol
20 exposure, the particle size of the acid aerosol, and the size of the tracer aerosol. Clearance
21 studies in animals are discussed in Section 11.2.2.5.
22 Initial studies in healthy nonsmokers by Leikauf et al. (1981) found that exposure to
23 110 jug/m3 H2SO4 (MMAD =0.5/mi) for 1 h at rest accelerated bronchial mucociliary
24 clearance, while a similar exposure to 980 /ig/m3 H2SO4 slowed clearance. A second study
25 (Leikauf et al., 1984) utilizing a smaller tracer aerosol (4.2 /*m) to assess more peripheral
26 airways, found slowing of clearance with both 108 and 983 jiig/m3 H2SO4, in comparison
27 with distilled water aerosol. Spektor et al. (1989) extended these studies, exposing ten
28 healthy subjects to H2SO4 or distilled water aerosols for up to 2 h. Two different tracer
29 aerosols were used, one administered before and the other after exposure. Following a 2 h
30 exposure to 100 /xg/m3 H2SO4, clearance halftime tripled compared with control, with
31 reduced clearance rates still evident 3 h after exposure. These findings suggested that brief,
April 1995 11.34 DRAFT-DO NOT QUOTE OR CITE
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1 resting exposures to H2SO4 at «100 /-ig/m3 accelerate clearance in large bronchi but slow
2 clearance in more peripheral airways.
3 Data from studies in asthmatics is less clear. Spektor et al. (1985) exposed ten
4 asthmatic subjects to 0, 110, 319, and 911 /xg/m3 H2SO4 for 1 h. The effects were difficult
5 to interpret because of inhomogeneous distribution of the tracer aerosol in the more severe
6 asthmatics. However, clearance appeared decreased following acid exposure in the
7 six subjects with the mildest asthma (not dependent on regular medications).
8 Laube et al. (1993) recently examined the effects of acid fog on mucociliary clearance
9 in asthmatics. Seven nonsmoking subjects with mild asthma (baseline FEVj 90 to 118%
10 predicted) were exposed in a head dome to 500 /ig/m3 H2SO4 or NaCl (MMAD ~ 10 pirn)
11 for 1 h with 20 min of exercise. Mucociliary clearance was measured using inhalation of a
12 technetium-99M sulfur colloid aerosol after exposure to the test aerosol. Tracheal clearance
13 was measured in four subjects, and was increased in all four after H2SO4 exposure
14 (no statistical analysis was performed because of the small number of subjects). Outer zone
15 lung clearance was increased in six of seven subjects after H2SO4 exposure (p < 0.05). The
16 dose of H+ inhaled orally correlated significantly with the change in outer zone lung
17 clearance (r = 0.79, p = 0.05).
18
19 11.2.1.6 Effects Of Acid Aerosols Studied By Bronchoscopy And Airway Lavage
20 Fiberoptic bronchoscopy with BAL has proved a useful technique for sampling the
21 lower airways of humans in clinical studies of oxidant air pollutants. The type and number
22 of cells recovered in BAL fluid reflect changes in alveolar and distal airway cell populations,
23 providing a relatively sensitive measure of inflammation. Increases in serum proteins
24 recovered in BAL fluid can be a result of increased epithelial permeability, a consequence of
25 injury and/or inflammation. Alveolar macrophages obtained by BAL can be assessed in vitro
26 for functional changes important in inflammation and host defense. In addition, proximal
27 airway cells and secretions can be recovered using airway washes or proximal airway lavage
28 (Eschenbacher and Gravelyn, 1987).
29 Only one study has utilized bronchoscopy to evaluate the effects of exposure to acid
30 aerosols. Frampton et al. (1992) exposed 12 healthy nonsmokers to aerosols of NaCl
31 (control) or H2SO4 (MMAD = 0.9, GSD = 1.9) at 1000 /ig/m3 for 2 h. Four 10-min
April 1995 11-35 DRAFT-DO NOT QUOTE OR CITE
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1 exercise periods at =40 L/min were included. Subjects brushed their teeth and rinsed with
2 mouthwash prior to and once during each exposure to reduce oral ammonia levels.
3 Fiberoptic bronchoscopy with BAL was performed 18 h after exposure. No evidence for
4 airway inflammation was found. Markers for changes in host defense, including lymphocyte
5 subset distribution, antibody-dependent cellular cytotoxicity of alveolar macrophages, and
6 alveolar macrophage inactivation of influenza virus, were not significantly different between
7 H2SO4 and NaCl exposures.
8 In an effort to define possible effects of H2SO4 exposure on airway mucus, Gulp et al.
9 (1994) determined the composition of mucins recovered during bronchoscopy of subjects
10 studied by Frampton et al. (1992), as well as from some subjects not exposed. Secretions
11 were lipid extracted from airway wash samples and analyzed with regard to glycoprotein
12 content, protein staining profiles, and amino acid and carbohydrate composition. Mucin
13 composition was similar when non-exposed subjects were compared with NaCl-exposed
14 subjects, indicating that aerosol exposure per se did not alter mucus composition. No
15 differences were found between H2SO4 and NaCl exposure with regard to absolute yields of
16 high-density material, proportion of glycoproteins, presence of glycoprotein degradation
17 products, carbohydrate composition, or protein composition.
18 In these studies, bronchoscopy was performed 18 h after exposure in order to detect
19 delayed effects. Transient effects of exposure to acid aerosols on alveolar macrophage
20 function or mucous composition have therefore not been excluded.
21
22 11.2.1.7 Acid Aerosols And Other Pollutants
23 Previous studies have suggested that exposure to H2SO4 does not potentiate responses to
24 other pollutants. A number of more recent studies have also failed to find interactions in
25 effects of pollutant mixtures that include H2SO4. Anderson et al. (1992) found no effects on
26 lung function following exposure to 200 /ig/m3 carbon black alone, or carbon particles coated
27 with H2SO4. Aris et al. (1990) found no effects on airways resistance of exposure to
28 mixtures of hydroxymethanesulfonic acid and H2SO4. Balmes et al. (1988) found no
29 differences between the effects of H2SO4 and HNO3 exposure in asthmatics, and no
30 interaction with exposure to both aerosols by mouthpiece. Koenig et al. (1989) found that
April 1995 H_36 DRAFT-DO NOT QUOTE OR CITE
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1 exposure of adolescent asthmatic subjects to 68 /xg/m3 H2SO4 with 0.1 ppm SO2 did not
2 increase the responses seen with H2SO4 alone.
3 In one recent study (Koenig et al., 1994), 28 adolescent asthmatic subjects were
4 exposed to air, 0.12 ppm ozone + 0.3 ppm NO2, ozone + NO2 + 68 /ig/m3 H2SO4, and
5 ozone + NO2 + 0.05 ppm HNO3. Exposures were by mouthpiece for 90 min, with
6 intermittent exercise, on two consecutive days. No significant effects on lung function were
7 seen for any of the atmospheres. However, six subjects did not complete the study protocol
8 for a variety of reasons; these subjects were characterized by the authors as having moderate
9 to severe asthma, based on results of methacholine challenge. Although the reasons for
10 withdrawal of these subjects were not clearly related to exposures, all discontinued
11 participation following exposure to pollutants rather than to clean air. Thus, the subjects
12 who were unable to complete the study may have been more responsive; because their data
13 could not be included in the analysis, a significant pollutant effect on a minority of subjects
14 may have been missed.
15 Two recent studies suggest that exposure to 100 mg/m3 H2SO4 may enhance airway
16 effects of exposure to ozone. Linn et al. (1994) exposed 15 healthy and 30 asthmatic
17 subjects to air, 0.12 ppm ozone, 100 jig/m3 H2S04 (MMAD =0.5 /um), and ozone +
18 H2SO4 for 6.5 h on two consecutive days. Each subject received all 4 pairs of exposures,
19 each separated by one week. Subjects were exposed in small groups in an environmental
20 chamber, with six, 50-min exercise periods each day. Acidic gargles were used to reduce
21 oral ammonia. Lung function and methacholine responsiveness were measured at the end of
22 each exposure day. Reductions in FEVj and FVC, and increases in airway responsiveness,
23 were observed in association with ozone exposure in both healthy and asthmatic subjects.
24 Some subjects in both the asthmatic and nonasthmatic group demonstrated greater declines in
25 lung function after the first day of acid + ozone than after ozone alone (Figure 11-2),
26 although the group mean differences were only marginally significant by ANOVA. From
27 these data, a "hypothetical average subject", under the specific conditions of the study, would
28 be expected to lose 100 ml FEVj during ozone exposure relative to clean air exposure, and
29 would lose 189 ml FEVj during ozone + H2S04 exposure. When the responsive subjects
30 were re-studied months later, increased responsiveness to acid + ozone compared with ozone
April 1995 11-37 DRAFT-DO NOT QUOTE OR CITE
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100
-100 --
1 -200
-300
-400
o 6 6 £
•
1 1 1 1 1
r
rl T
r 1
i
-1 1 1 1 U
t
J
^
L"t
1
12 12 12 12
Clean Acid Ozone Ozone+Acid
| A • • • • -AAsthmatics O O Nonasthmatics + 4 All |
Figure 11-2. Decrements in ¥EV1 (± SE) following 6.5-h exposures on 2 successive
days.
Source: Linn et al. (1994).
1 was again demonstrated, although individual responses to O3 + H2SO4 in the original and
2 repeat studies were not significantly correlated.
3 Frampton et al. (1995) exposed 30 healthy and 30 asthmatic subjects to 100 /-ig/m3
4 H2SO4 or NaCl for 3 h followed the next day by 0.08, 0.12, or 0.18 ppm ozone for 3 h. All
5 exposures included intermittent exercise. Each subject received two of the three ozone
6 exposure levels. Exposure to H2SO4 or NaCl did not alter lung functions. As shown in
7 Table 11-3, changes in spirometry following exposure to ozone were small, consistent with
8 the relatively low concentrations, short exposure duration, and moderate exercise levels (VE
9 30.6 to 36.2 L/min for a total of 60 min). Figure 11-3 shows the percentage changes in
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I
TABLE 11-3. PULMONARY FUNCTION RESPONSES AFTER AEROSOL AND OZONE EXPOSURES IN
SUBJECTS WITH ASTHMA3
H
6
o
1
o
o
H
W
n
si
Time of Measurement
0.08 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
0.12 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
0.18 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
FVC
NaCl
3.80 ± 0.17
3.64 ± 0.17
3.51 ± 0.18
3.67 ± 0.17
3.67 ± 0.15
3.97 ± 0.22
3.72 ± 0.20
3.72 ± 0.21
3.91 ± 0.22
3.87 ± 0.22
3.89 + 0.23
3.76 ± 0.23
3.76 ± 0.23
3.81 ± 0.25
3.90 + 0.24
(L)
H2S04
3.73 ± 0.17
3.59 ± 0.18
3.64 ± 0.17
3.70 ± 0.16
3.74 ± 0.18
3.95 ± 0.22
3.76 ± 0.19
3.76 + 0.20
3.85 ± 0.21
3.87 ± 0.21
3.99 ± 0.22
3.71 ± 0.22
3.74 ± 0.24
3.87 + 0.23
3.84 ± 0.25
FEVt
NaCl
2.85 ± 0.11
2.84 ± 0.12
2.73 ± 0.12
2.91 + 0.12
2.92 ± 0.10
2.98 ± 0.17
2.94 ± 0.17
2.90 ± 0.19
3.10 ± 0.18
3.07 ± 0.18
2.92 ± 0.16
2.90 + 0.19
2.90 ± 0.19
3.03 ± 0.19
3.06 + 0.17
(L)
H2S04
2.79 ± 0.10
2.72 ± 0.12
2.79 ± 0.11
2.89 ±0.11
2.92 + 0.13
3.05 + 0.17
3.01 ± 0.16
2.97 ± 0.18
3.08 ± 0.17
3.04 + 0.18
3.04 ± 0.17
2.99 ± 0.16
2.96 ± 0.18
3.03 ± 0.17
2.99 ± 0.18
sGaw (cm H2O/L/sec)
NaCl H2SO4
0.204 + 0.021 0.209 ± 0.020
-
0.176 ± 0.024 0.177 + 0.022
-
-
0.220 ± 0.015 0.236 + 0.020
-
0.186 + 0.019 0.209 + 0.025
-
-
0.183 ± 0.016 0.207 + 0.016
-
0.170 + 0.016 0.179 ± 0.018
-
-
aValues are expressed as means + SEM.
-------
^z
O
0.2T
0.1 •-
0--
-0.1-•
-0.2-'
-0.3-
NaCI
H2S04
0.08
0.12
0.18
ppm Ozone
Figure 11-3. Asthmatic Subjects. The absolute change in FVC (liters) 4-h after
exposure to each of the three ozone concentrations for the NaCI and
H2SO4 aerosol preexposure conditions.
Source: Frampton et al., 1995.
1 FVC 4 h after ozone exposure; these changes were similar to those found immediately after
2 exposure. With H2SO4 pre-exposure, FVC decreased following ozone in a concentration-
3 response fashion. The ANOVA revealed significant main effects of ozone exposure as well
4 as a significant interaction between aerosol and ozone exposure for effects on FEVj and FVC
5 among the asthmatic subjects, but not the healthy subjects. Four-way ANOVA revealed an
6 interaction between ozone and aerosol for the entire group (p=0.0022) and a difference
7 between healthy subjects and subjects with asthma (p=0.0048). Surprisingly, decrements in
8 FVC were found with 0.08 ppm ozone preceded by NaCI that were of similar magnitude to
9 those seen with 0.18 ppm ozone preceded by H2SO4. The authors concluded that, for
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1 asthmatic subjects, H2SO4 alters the response to ozone in comparison with NaCl pre-
2 exposure. Interpretation of these findings would be facilitated by a similar study including
3 air as a further control pre-exposure atmosphere. However, considered together, these two
4 studies (Frampton et al., 1995 and Linn et al., 1994) suggest that H2SO4 aerosol exposure
5 may enhance airway responsiveness to ozone.
6
7 11.2.1.8 Particulate Matter Other Than Acid Aerosols
8 Few studies have examined the effects of particles other than acid aerosols, despite the
9 fact that ambient particulate matter consists of a mixture of soluble and insoluble material of
10 varying chemical composition. Human safety considerations limit experimental exposures to
11 particles considered to be essentially inert and non-carcinogenic. As reviewed in the 1982
12 Criteria Document (U.S. Environmental Protection Agency, 1982), Andersen et al. (1979)
13 examined effects on healthy subjects of exposure to Xerox toner at concentrations ranging
14 from 2 to 25 mg/m3. These concentrations are not relevant to outdoor environmental
15 exposures. Nevertheless, the studies were remarkable for the virtual absence of symptomatic
16 or lung functional responses. Utell et al. (1980) exposed healthy young subjects with acute
17 influenza to a NaNO3 aerosol or NaCl (control), and observed significant reductions in
18 specific airway conductance in response to the NaNO3 aerosol, but not to NaCl aerosol, for
19 up to 1 week following the acute illness. These studies suggested that individuals with acute
20 viral illness may experience bronchoconstriction from particulate nitrate pollutants that do not
21 have effects on healthy subjects. However, the concentration of particles in these
22 experiments was ~1 mg/m3, more than 100 times greater than peak ambient concentrations.
23 Three more recent studies have attempted to examine effects of exposure to carbon
24 black particles, either alone or in combination with other pollutants. First, Kulle et al.
25 (1986) exposed 20 healthy nonsmokers (10 males and 10 females) to air, 0.99 ppm SO2, 517
26 Mg/m3 activated carbon aerosol (MMAD = 1.5 /*m, GSD = 1.5), and SO2 + activated
27 carbon for four hours in an environmental chamber. Two 15-minute exercise periods (VE =
28 35 L/min) were included in the exposure. The exposure days were separated by one week
29 and were bracketed by control air exposures on the day prior to and the day following the
30 experimental exposure. Measurements included respiratory symptoms, spirometry, lung
31 volumes, and airway responsiveness to methacholine. The carbon aerosol exposure resulted
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1 in no significant effects on symptoms or lung function, and exposure to carbon + SO2 did
2 not enhance the very small effects on lung function seen with SO2 alone. Results of
3 methacholine challenge testing were not provided.
4 Second, a separate report from the same laboratory (Green et al., 1989) examined
5 potential interactions between formaldehyde (HCHO) and carbon exposure. Twenty-four
6 healthy nonsmokers without airway hyperresponsiveness were exposed for two hours to air,
7 3.01 ppm HCHO, 510 /zg/m3 activated carbon aerosol (MMAD = 1.4 ^ig, GSD = 1.8) and
8 HCHO + carbon. Exposures incorporated exercise (VE = 57 L/min) for 15 of each 30
9 minutes. The exposures were separated by one week. Measurements included symptoms,
10 spirometry, lung volumes, and serial measurements of peak flow. There were no significant
11 effects on symptoms or decrements in lung function with exposure to carbon alone. The
12 combination of carbon and HCHO increased cough at 20 and 80 minutes of exposure when
13 compared to either pollutant alone. There were also small (less than 5%) but statistically
14 significant decrements in FVC, FEV3, and peak flow with carbon + HCHO, compared with
15 either pollutant alone. The authors speculated that the enhancement of cough with carbon +
16 HCHO resulted from increased delivery of HCHO adsorbed to carbon.
17 Finally, the studies by Anderson et al. (1992), summarized previously, were designed
18 to test the hypothesis that inert particles in ambient air may become coated with acid, thereby
19 delivering increased concentrations of acid sulfates to "sensitive" areas of the respiratory
20 tract. Carbon black particles (MMAD = 1 /xm, GSD «= 2 /*m) were coated with H2SO4
21 using fuming H2SO4. Electron microscopy findings suggested successful coating of the
22 particles. Fifteen healthy and 15 asthmatic subjects were exposed for 1 h to acid-coated
23 carbon, with a total suspended paniculate concentration of 358 /ig/m3 for asthmatic subjects
24 and 505 /*g/m3 for healthy subjects. On separate occasions, subjects were also exposed to
25 carbon black alone ( = 200 pg/m3, estimated as the difference between total suspended
26 paniculate and non-carbon paniculate concentrations), H2SO4 alone (-100 /-tg/m3), and air.
27 No adverse effects of particle exposure on lung function or airway responsiveness were
28 observed for either study group.
29 Clinical studies of single paniculate pollutants or simple mixtures may not be
30 representative of effects that occur in response to complex ambient mixtures. In an attempt
31 to examine effects of an ambient air pollution atmosphere under controlled laboratory
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1 conditions, Yang and Yang (1994) exposed 25 asthmatic and 30 healthy subjects to polluted
2 air collected in a motor vehicle tunnel in Taiwan. This compressed air sample contained
3 202 fjig/m3 particles as well as 0.488 ppm NO2, 0.112 ppm SO2, and 3.4 ppm carbon
4 monoxide (CO). The chemical and size characteristics of the particles were not provided.
5 Mouthpiece exposure to polluted air was performed at rest for 30 min, and lung function and
6 methacholine responsiveness were assessed after exposure. Small but significant decrements
7 in FEVj and FVC were observed in asthmatic, but not healthy subjects when compared with
8 baseline measurements. However, no control exposure to air was performed, which
9 seriously limits interpretation of these results. The small decrements in lung function could
10 have resulted from exposure conditions other than the pollutants, such as humidity or
11 temperature of the inhaled air, which were not specified.
12 Thus, few studies have examined effects of particles other than acid aerosols on lung
13 function, although available data suggest inert particles in the respirable range have little or
14 no acute effects at levels well above ambient concentrations. No studies have examined
15 effects on mucociliary clearance, epithelial inflammation, or host defense functions of the
16 distal respiratory tract in humans
17
18 11.2.1.9 Summary and Conclusions
19 Controlled human studies offer the opportunity to study the responses of human subjects
20 under carefully controlled conditions, but are limited to short-term exposures to pollutant
21 atmospheres without severe health risks. Outcome measures are limited by safety issues, but
22 have been extended beyond measures of lung function and symptoms to include mucociliary
23 clearance, BAL, and airway biopsies.
24 Human clinical studies of particle exposure remain almost completely limited to the
25 study of acid aerosols, primarily of H2SO4, with the majority of these focussing on
26 symptoms and pulmonary function. Only two studies (Frampton et al., 1992; Gulp et al.,
27 1995) have utilized BAL to examine effects of particle exposure in humans. No studies have
28 examined effects of particle or acid aerosol exposure on airway inflammation in asthmatic
29 subjects. There are no studies examining the effects of particle exposure on antigen
30 challenge in allergic or asthmatic subjects.
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1 Ten studies since 1988 have confirmed previous findings that healthy subjects do not
2 experience decrements in lung function following single exposures to H2SO4 at levels up to
3 2,000 /ig/m3 for 1 h, even with exercise and use of acidic gargles to minimize neutralization
4 by oral ammonia. Mild lower respiratory symptoms occur at exposure concentrations in the
5 mg/m3 range, particularly with larger particle sizes. Acid aerosols alter mucociliary
6 clearance in healthy subjects, with effects dependent on exposure concentration and the
7 region of the lung being studied.
8 Asthmatic subjects appear to be more sensitive than healthy subjects to the effects of
9 acid aerosols on lung function, but the effective concentration differs widely among studies.
10 Adolescent asthmatics may be more sensitive than adults and may experience small
11 decrements in lung function in response to H2SO4 at exposure levels only slightly above peak
12 ambient levels. Although the reasons for the inconsistency among studies remain largely
13 unclear, subject selection and acid neutralization by NH3 may be important factors. Even in
14 studies reporting an overall absence of effects on lung function, occasional asthmatic subjects
15 appear to demonstrate clinically important effects. Two studies from different laboratories
16 have suggested that responsiveness to acid aerosols may correlate with degree of baseline
17 airway hyperresponsiveness. There is a need to identify determinants of responsiveness to
18 H2SO4 exposure in asthmatic subjects. In very limited studies, elderly and individuals with
19 chronic obstructive pulmonary disease do not appear to be particularly susceptible to the
20 effects of acid aerosols on lung function.
21 Two recent studies have examined the effects of exposure to both H2SO4 aerosols and
22 ozone on lung function in healthy and asthmatic subjects. Both studies found evidence that
23 100 jig/m3 H2SO4 may potentiate the response to ozone, in contrast with previous studies.
24 Human studies of particles other than acid aerosols provide insufficient data to draw
25 conclusions regarding health effects. However, available data suggest that inhalation of inert
26 particles in the respirable range, including three studies of carbon particles, have little or no
27 effect on symptoms or lung function in healthy subjects at levels above peak ambient
28 concentrations.
29
30
31
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1 11.2.2 Laboratory Animal Studies
2 11.2.2.1 Introduction
3 This section reviews the effects of acidic aerosols on laboratory animals. Almost all of
4 the available data have been derived from studies using acidic sulfates, namely ammonium
5 bisulfate (NH4HSO4) and sulfuric acid (H2SO4).
6
7 11.2.2.2 Mortality
8 A number of studies reported in the previous CD (U.S. Environmental Protection
9 Agency, 1982) examined the acute lethality of acid aerosols, mainly H2S04, and there are
10 little new data. As is evident with other toxicologic endpoints, large interspecies differences
11 occurred, with the guinea pig appearing to be the most sensitive, compared to the mouse, rat
12 and rabbit. But fairly high concentrations of H2SO4, generally above 4,000 /zg/m3, were
13 required for lethality, even in a species as sensitive as the guinea pig. Furthermore within a
14 particular species of experimental animal, the H2SO4 concentration required for lethality was
15 dependent upon particle size, with smaller particles being less effective than larger ones.
16 As reported in the previous CD (U.S. Environmental Protection Agency, 1982), the
17 cause of death due to acute, high-level H2SO4 exposure was laryngeal or bronchial spasm.
18 Since these are irritant responses, differences in the deposition pattern of smaller and larger
19 acid droplets may account for the aforementioned particle size dependence of lethal
20 concentration; larger particles would deposit to a greater extent in the upper bronchial tree,
21 where the bulk of irritant receptors are located. As the acid size is reduced, deeper
22 pulmonary damage occurs prior to death. Lesions commonly seen are focal atelectasis,
23 hemorrhage, congestion, pulmonary and perivascular edema, and desquamation of
24 bronchiolar epithelium; hyperinflation is also often evident.
25 There are few data to allow assessment of lethality for acid sulfate aerosols other than
26 H2SO4. Pattle et al. (1956) noted that if sufficient ammonium carbonate was added into the
27 chamber in which guinea pigs were exposed to H2SO4 so as to provide excess NH3,
28 protection was afforded to acid levels which, in the absence of NH3, would have produced
29 50% mortality. This implies that H2SO4 is more acutely toxic than its neutralization
30 products [i.e., NH4HSO4 and/or (NH4)2SO4]. Pepelko et al. (1980) exposed rats for 8 h/day
31 for 3 days to (NH4)2SO4 at 1,000,000 to 2,000,000 ^g/m3 (2 to 3 /*m, MMAD); no
April 1995 11.45 DRAFT-DO NOT QUOTE OR CITE
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1 mortality resulted. On the other hand, 40 and 17% mortality was observed in guinea pigs
2 exposed once for 8 h to 800,000 to 900,000, or 600,000 to 700,000 /ig/m3, respectively, of
3 similarly sized-particles; no mortality was observed at levels < 600,000 /ig/m3. Death was
4 ascribed to airway constriction, rather than to extensive lung damage. As with H2SO4,
5 guinea pigs were more sensitive than other species examined to the lethal effects of
6 (NH4)2SO4.
7 In summary, very high concentrations of acid sulfates are required to cause mortality in
8 otherwise healthy animals. The mechanisms for this mortality are not expected to relate to
9 human mortality observed in epidemiological studies.
10
11 11.2.2.3 Pulmonary Mechanical Function
12 Many studies examining the toxicology of inhaled acid aerosols at sublethal levels used
13 changes in pulmonary function as indices of response. A survey of the database since
14 publication of the previous CD (U.S. Environmental Protection Agency, 1982) is presented
15 in Table 11-4.
16 One of the major exposure parameters which affects response is particle size. Studies
17 by Amdur (1974) and Amdur et al. (1978a,b), summarized in the previous CD, showed that
18 the irritant potency of H2SO4, (NH4)2SO4, or NH4HSO4, as measured by pulmonary
19 resistance in guinea pigs, increased with decreasing particle size (i.e., the degree of response
20 per unit mass of sulfate [SO4=] at any specific exposure concentration increased as particle
21 size decreased, at least within the size range of 1 to 0.1 /mi). If this is compared to the
22 relationship between particle size and mortality, it is evident that the relative toxicity of
23 different particle sizes also depends upon the exposure concentration. At high concentrations
24 above the threshold for lethality, large particles were more effective in eliciting response,
25 while at lower (sublethal) levels, smaller particles were more effective.
26 Pulmonary functional responses to H2SO4 described previously suggested a major site
27 of action to be the conducting airways, as evidenced by exposure-induced alterations in
28 resistance. However, some earlier data also suggested that high exposure levels may affect
29 more distal lung regions, as evidenced by changes in pulmonary diffusing capacity (DL^)
30 noted in dogs exposed to 889 /*g/m3 (Lewis et al., 1973). Deep lung effects of H2SO4 are
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TABLE 11-4. EFFECTS OF ACIDIC SULFATE PARTICLES ON PULMONARY MECHANICAL FUNCTION
a
O
O
O
d
o
H
M
Species, Gender,
Strain, Age, or
Particle Body Weight
H2SO4 Rat
H2SO4 Rat
H2SO4 Rat
H2SO4 Guinea pig, M
Hartley
H2SO4 Rabbit, M
NZW
H2SO4 Guinea pig, M
Hartley,
260-325 g
H2SO4 Guinea pig, M
Hartley,
290-4 10 g
(NH4)2SO4 Guinea pig, M
Hartley, 10 wk
(NH4)2SO4 Rat, M
SD, 14 wk
Exposure Technique Mass Concentratioi
(RH) (jig/m3)
Whole body
Whole body
Whole body
Whole body
Nose-only (50%)
Nose-only (50%)
Nose-only (50%)
Whole body
(50-60%)
Whole body
(50-60%)
2,370
6,350
6,590
1,000;3,200
250
300
200
1,000
1,000
Particle Characteristics
Size (/an); ag
0.5 (MMD)
0.44 (MMD)
0.31 (MMD)
0.54 (MMD); 1.32
0.3 (MMAD); 1.6
0.08 (MMD); 1.3
0.06 (MMD); 1.4
0.4 (MMAD); 2.2
0.4 (MMAD); 2.3
Exposure Duration
14 weeks
6 weeks
13 weeks
24 h/d, 3-30 d
1 h/day, 5 days/week, up to
12 mo
1 h
1 h
6 h/day, 5 days/week, 1 or 4
weeks
6 h/day, 5 days/week, 1 or 4
weeks
Observed Effect
NC: VT, f, RL, Cd, pH,
PaCO2
iPaCO2
tpH
Hypo- to hyperresponsive
airways
NC: RL
Hyperresponsive by 4 mo
NC: VC, 1C, VA, TLC;
IDLco, (3 h postexp)
NC: RL
NC: RV; tFRC, VC, TLC,
DLco, Cd, AN2
tRV, tFRC, AN2
Reference
Lewkowski et al. (1979)
Lewkowski et al. (1979)
Lewkowski et al. (1979)
Kobayashi and Shinozaki
(1993)
Gearnart and Schlesinger
(1986)
Chen et al. (1991)
Chen et al. (1992b)
Loscutoffetal. (1985)
Loscutoffet al. (1985)
Key to abbreviations:
NC: No significant change
t: Significant increase
i: Significant decrease
Cd: Dynamic compliance
DLco: Diffusing capacity, CO
f: Respiratory frequency
FRC: Functional residual capacity
1C: Inspiratory capacity
AN2: Change in distribution of ventilation as measured by nitrogen washout technique
PaCO2: Partial pressure of CC^ in arterial blood
pH: Arterial pH
RL: Pulmonary resistance
RV: Residual volume
TLC: Total lung capacity
VT: Tidal volume
VA: Alveolar volume
VC: Vital capacity
O
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1 also evident from studies of morphologic and lung defense endpoints, discussed in subsequent
2 sections.
3 Studies reported in the previous CD (U.S. Environmental Protection Agency, 1982)
4 indicated that the particle size of the acid aerosol affected the temporal pattern of any
5 pulmonary function response. For example, the response to 100 /*g/m3 H2SO4 at 1 fim was
6 slight and rapidly reversible, while that with 0.3 /mi droplets was greater and more
7 persistent. At any particular size, however, the degree of change in resistance and
8 compliance in guinea pigs was observed to be concentration related.
9 Although the earlier studies by Amdur and colleagues appeared to provide a reasonable
10 picture of the relative effects of acid particle size and exposure concentration on the
11 bronchoconstrictive response of guinea pigs at sublethal exposure levels, there is some
12 conflict between these results and reports by others discussed in the previous CD (U.S.
13 Environmental Protection Agency, 1982). Whereas the former work supported a
14 concentration dependence for respiratory mechanics alterations (i.e., animals in each
15 exposure group responded uniformly and the degree of response was related to the exposure
16 concentration), others found that individual guinea pigs exposed to H2SO4 at similar sizes
17 showed an "all-or-none" constrictive response, i.e., in atmospheres above a threshold
18 concentration, some animals manifested major changes in pulmonary mechanics
19 ("responders"), while others were not affected at all ("nonresponders") (Silbaugh et al.,
20 1981b). As the exposure concentration was increased further, the percentage of the group
21 which was affected (i.e., the ratio of responders to nonresponders) increased, producing an
22 apparent concentration response relationship. However, the magnitude of the change in
23 pulmonary function was similar for all responders, regardless of exposure concentration.
24 Sensitivity to this all-or-none response may be related to an animal's baseline airway caliber
25 prior to H2SO4 exposure, because responders had higher pre-exposure values for resistance
26 and lower values for compliance, compared to nonresponders. In any case, the threshold
27 concentration for the all-or-none response was fairly high (> 10,000 /xg/m3 H2SO4). Reasons
28 for the discrepancy with the studies of Amdur and colleagues are not known; they may
29 involve differences in guinea pig strains, ages, or exposure conditions, or differences in
30 techniques used to measure functional parameters. In any case, the dyspneic response of the
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1 guinea pig responders is similar to asthma episodes in humans, in both its rapidity of onset
2 and in the associated characteristic obstructive pulmonary function changes.
3 A more recent approach used to evaluate the acute pulmonary functional response to
4 H2SO4 involves co-inhalation of CO2 (Wong and Alarie, 1982; Matijak-Schaper et al., 1983;
5 Schaper et al., 1984). This procedure assesses the response to irritants by measuring a
6 decrease in tidal volume (VT) (based upon changes in inspiratory volume and pressure) which
7 is routinely increased above normal by adding 10% CO2 to the exposure atmosphere.
8 Although the exact mechanism underlying a reduction in response to CO2 is not clear, the
9 assumption is that the change in ventilatory response after irritant exposure is due to direct
10 stimulation of irritant receptors. A concentration-dependent decrease in CO2-enhanced
11 ventilation has been found in guinea pigs following 1-h exposures to H2SO4 (=1 jtm, MMD)
12 at levels >40,100 /ig/m3 (Wong and Alarie, 1982). Subsequently, Schaper et al. (1984)
13 exposed guinea pigs for 0.5 h to H2SO4 at 1,800 to 54,900 jig/m3 (0.6 /xm, AED).
14 At concentrations > 10,000 /xg/m3, the level of response (i.e., the maximum decrease in
15 ventilatory response to CO2) increased as a function of exposure concentration.
16 At concentrations below 10,000 pig/m3 there was no clear relationship between exposure
17 concentration and response; any effects were transient, occurring only at the onset of acid
18 exposure.
19 The results of the studies with CO2 differ from those of both Silbaugh et al. (1981b)
20 and Amdur and colleagues, in that there was neither an "all or none" response as seen by the
21 former, nor was there a concentration-response relationship observed at H2SO4
22 concentrations < 10,000 ng/m3, as reported by the latter. In addition, Amdur and colleagues
23 observed sustained changes in lung function, rather than a fading response, at low
24 concentrations. The reasons for these differences are unknown, but may partly reflect
25 inherent sensitivity differences in the measurement techniques used as noted above.
26 The specific mechanisms underlying acid sulfate-induced pulmonary functional changes
27 are not known, but may be due to irritant receptor stimulation resulting from direct contact
28 by deposited acid particles or from humoral mediators released as a result of exposure.
29 In terms of the latter, a possible candidate in mediation of the bronchoconstrictive response,
30 at least in guinea pigs, is histamine (Charles and Menzel, 1975). On the other hand,
31 evidence for a direct response to H2SO4 in altering pulmonary function was found using the
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1 CO2 coinhalation procedure. Schaper and Alarie (1985) noted that the responses to histamine
2 and H2SO4 differed in both their magnitude and temporal relationship, suggesting direct
3 action of the inhaled acid or a role of other humoral factors.
4 Whatever the underlying mechanism, the results of pulmonary function studies indicate
5 that H2SO4 is a bronchoactive agent that can alter lung mechanics of exposed animals
6 primarily by constriction of smooth muscle; however, the threshold concentration for this
7 response is quite variable, depending upon the animal species and measurement procedure
8 used. In general, exposure to H2SO4 at levels < 1,000 /ig/m3 does not produce
9 physiologically significant changes in standard tests of pulmonary mechanics, except in the
10 guinea pig. Although in this species such effects may be markers of exposure, their health
11 significance in normal individuals is not always clear. On the other hand, all subgroups of
12 an exposed population may not be equally sensitive.
13
14 11.2.2.3.1 Airway Responsiveness
15 Some lung diseases (e.g., asthma) involve a change in airway "responsiveness", which
16 is an alteration in the degree of reactivity to exogenous (or endogenous) bronchoactive agents
17 resulting in increased airway resistance at levels of these agents which would not affect
18 airways of normal individuals. Such altered airways are called hyperresponsive. The use of
19 pharmacologic agents capable of inducing smooth muscle contraction, a technique known as
20 bronchoprovocation challenge testing, can assess the state of airway responsiveness after
21 exposure to a nonspecific stimulus such as an inhaled irritant. Human asthmatics and, to
22 some extent, chronic bronchitics, typically have hyperresponsive airways, but the exact role
23 of this in the pathogenesis of airway disease is uncertain. Hyperresponsiveness may be a
24 predisposing factor in clinical disease, or it may be a reflection of other changes in the
25 airways which precede it. In any case, current evidence supports the hypothesis that an
26 increase in airway responsiveness is a factor in the pathogenesis of obstructive airway disease
27 (O'Connor etal., 1989).
28 The ability of H2SO4 aerosols to alter airway responsiveness has been assessed in a
29 number of studies. Silbaugh et al. (1981a) exposed guinea pigs for 1 h to 4,000 to
30 40,000 /ig/m3 H2SO4 (1.01 ^m, MMAD) and examined the subsequent response to inhaled
31 histamine. Some of the animals showed an increase in pulmonary resistance and a decrease
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1 in compliance at H2S04 concentrations > 19,000 /*g/m3 without provocation challenge; only
2 the animals showing this constrictive response during acid exposure also had major increases
3 in histamine sensitivity. This suggested that airway constriction may have been a
4 prerequisite for the development of hyperresponsiveness. On the other hand, Chen et al.
5 (1992b) found bronchial hyperresponsiveness, but no change in baseline resistance, in guinea
6 pigs exposed for 1 h to 200 ptg/m3 H2SO4 (0.06 /*m, MMD). Perhaps the smaller size of
7 this aerosol was responsible for producing effects at a lower concentration.
8 Kobayashi and Shinozaki (1993) exposed guinea pigs to fairly high H2SO4 levels,
9 namely 1,000 and 3,200 jig/m3 (0.54 /mi), 24 h/day for 3, 7, 14 or 30 days, and examined
10 airway response to inhaled histamine. Unlike the study of Silbaugh et al. and similar to that
11 of Chen et al., acid exposure did not change the baseline resistance measured prior to
12 bronchoprovocation challenge. Exposure to 3,200 /wg/m3 of acid resulted in airway
13 hyporesponsivess at 3 days, hyperresponsiveness at 14 days and a return to normal levels of
14 responsivess by 30 days of exposure. Thus, acid exposure resulted in a transient alteration in
15 airway function. The authors speculated that the hyporesponsiveness, and eventual return to
16 normal, was due to changes in mucous secretion in the airways, which would affect the
17 ability of the inhaled histamine challenge aerosol to contact airway receptors.
18 Airway responsiveness following chronic exposure to H2SO4 was examined by Gearhart
19 and Schlesinger (1986), who exposed rabbits to 250 jttg/m3 H2SO4 (0.3 /mi, MMD) for
20 1 h/day, 5 days/week, and assessed responsiveness after 4, 8 and 12 mo of exposure, using
21 acetylcholine administered intravenously rather than inhaled. Hyperresponsiveness was
22 evident at 4 mo, and a further increase was found by 8 mo; the response at 12 mo was
23 similar to that at 8 mo, indicating a stabilization of effect. There was no change in baseline
24 resistance. Thus, repeated exposures to H2SO4 produced hyperresponsive airways in
25 previously normal animals.
26 The mechanism which underlies H2SO4-induced airway hyperresponsiveness is not
27 clear. However, some recent studies have suggested possibilities. One may involve an
28 increased sensitivity to mediators involved in airway smooth muscle control. For example,
29 guinea pigs exposed to H2SO4 showed a small degree of enhanced response to histamine, but
30 a much more pronounced sensitivity to substance P, a neuropeptide having effects on
31 bronchial muscle tone (Stengel et al., 1993). El-Fawal and Schlesinger (1994) exposed
April 1995 H_51 DRAFT-DO NOT QUOTE OR CITE
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1 rabbits for 3 h to 50 to 500 /xg/m3 H2SO4 (0.3 /mi), following which bronchial airways were
2 examined in vitro for responsiveness to acetylcholine and histamine. Exposures at
3 >75 jttg/m3 produced increased responsiveness to both constrictor agents. Detailed
4 examination of the response in tracheal segments suggested that the acid effect may result
5 from interference with airway contractile/dilatory homeostatic processes, in that there was a
6 potentiation of the response of airway constrictor receptors and a diminution of the response
7 of dilatory receptors.
8
9 11.2.2.4 Pulmonary Morphology and Biochemistry
10 Morphologic alterations associated with exposure to acid aerosols are outlined in
11 Table 11-5.
12 Single or multiple exposures to H2SO4 at fairly high levels (»1,000 Aig/m3) produce a
13 number of characteristic morphologic responses (e.g., alveolitis, bronchial and/or bronchiolar
14 epithelial desquamation, and edema). As with other endpoints, the sensitivity to H2SO4 is
15 dependent upon the animal species. Comparative sensitivities of the rat, mouse, rhesus
16 monkey and guinea pig were examined by Schwartz et al. (1977), using concentrations of
17 H2SO4 >30,000 fjLg/m3 at comparable particle sizes (0.3 to 0.6 /mi) and assessing airways
18 from the larynx to the deep lung. Both the rat and monkey were quite resistant, while the
19 guinea pig and mouse were the more sensitive species. The nature of the lesions in the latter
20 pair were similar, but differed in location; this was, perhaps, a reflection of differences in
21 the deposition pattern of the acid droplets. Mice would tend to have greater deposition in the
22 upper respiratory airways than would the guinea pig (Schlesinger, 1985), which could
23 account for the laryngeal and upper tracheal location of the lesions seen in the mice. The
24 relative sensitivity of the guinea pig and relative resistance of the rat to acid sulfates is
25 supported by results from other morphological studies (Busch et al., 1984; Cavender et al.,
26 1977b; Wolff etal., 1986).
27 Repeated or chronic exposures to H2SO4 at concentrations < 1,000 /ig/m3 produce a
28 response characterized by hypertrophy and hyperplasia of epithelial secretory cells.
29 In morphometric studies of rabbits exposed to 125 to 500 /ig/m3 H2SO4 (0.3 /mi) for 1 to
30 2 h/day, 5 d/week (Schlesinger et al., 1983; Gearhart and Schlesinger, 1988; Schlesinger
31 et al., 1992b), increases in the relative number density of secretory cells (as determined by
April 1995 11-52 DRAFT-DO NOT QUOTE OR CITE
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Particle
H2SO4
H2S04
H2S04
H2S04
H2SO4
H2SO4
H2S04
H2SO4
H2S04
Species, Gender,
Strain, Age, or
Body Weight
Guinea pig
Guinea pig, M/F
Hartley, 2-3 mo
Rabbit, M
mixed,
2.5-2.7 kg
Rabbit, M
mixed,
2.5-2.7 kg
Rabbit, M
NZ White, 3-3.5 kg
Rat
Rat
Rat
Rhesus monkey
Exposure Mass Concentration
Technique (RH) (/*g/m3)
Whole body
(70-90%)
Whole body (80%)
Oral tube or nose-
only (80%)
Nose-only (80%)
Nose-only (60%)
Whole body
(40-60%)
Whole body (50%)
Whole body
(£60%)
Whole body
(£60%)
32,600
1,200,9,000,
27,000
250-500
250
125
2,000
700-1,200
45,000
68,000
172,000
150,000
361,000
502,000
Particle Characteristics
Size (urn); ag
1 (MMAD); 1.49
0.8-1 (MMAD); 1.5-1.6
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMD); 1.6
0.3 (MMD); =2
0.03-0.04 (CMD); 1.8-2.1
0.52 (CMD)
0.4 (MMAD)
0.45 (CMD)
0.3-0.5 (CMD)
0.43 (MMAD); 1.6
0.48 (MMAD); 1.5
Duration
4h
6h
1 h/day,
5 days/week,
4 weeks
1 h/day,
5 days/week
up to 52 weeks
2 h/day,
5 days/week
up to 12 mo
8 h/day,
82 days
Continuous, up
to 180 days
11 days
6 days
7 days
3 days
7 days
7 days
Observed Effect
Focal atelectasis; epithelial desquamation in
terminal bronchioles
At 27,000 ftg/m3: interstitial edema only in
"responders"; no change in "nonresponders" or
at 1,000 and 10,000 /tg/m3. Concentration-
dependent increase in height of tracheal mucus
layer at all concentrations.
Increased epithelial thickness in small airways;
increase in secretory cells in mid
to small airways
Increase in secretory cell no. density throughout
bronchial tree increase in
number of small airways
No bronchial inflammation; increase in
secretory cell number density in small
airways at 12 mo
Some hypertrophy of epithelial cells, mainly at
alveolar duct level; no effect on turnover rate
of terminal bronchiolar epithelial or Type II
cells
No effect
No effect in nasal passages, trachea, bronchi,
alveolar region
No effect
Reference
Brownstein (1980)
Wolff et al. (1986)
Schlesinger et al.
(1983)
Gearhart and
Schlesinger (1988)
Schlesinger et al.
(1992b)
Juhos et al. (1978)
Moore and
Schwartz (1981)
Schwartz et al.
(1977)
Schwartz et al.
(1977)
-------
O
o
o
£
£
0
TRACT M
f RESPIRATORY
O
C/J
3
y
b
3
PI
1
(£4
^
{/J
u
a
^
..
o
Cfl
H
g
W
I
S^
IT)
i— 1
H
a
«a
PS
Observed Effect
H a
30
•S3
II
tO
'I
a »"
8 I
•c 5
U 0
Q) N
«
0,
B
•S
§1=
11
M
1
^
a i
||
"1
H
"2 ° «
O . S
U U IMt
rf*f
.2 o"
tj 'H ^>
u G "5
o- i: S
oo oo 00
|
£
1
"
•a
0
•g
•s
§ - •! * a a
« 1J 5 'g e 3 -13
||| || f°
1 S 2 -all »
At 71,000 ^g/m3: focal
of alveolar septa, inflami
infiltration; necrosis of b
epithelium; focal epitheli;
larger bronchi; ciliary de
38,000 /ig/m3: minimal
change in density and ler
(A V) 1/i
a- s-s-
•O -O T3
t- r- •*
'O ^O
§- ^
^ ^ U
£EK
_ « o
6 o
HI
cT ocT <-^
c^ c^i r^"
|-
|s
S vi
(X
?
ffi
I
•~*
~S
a
1
£
per trachea;
na, inflammatory
Lesions in larynx and up
epithelial ulceration, edei
infiltration
tn M
2i S
~*. *^
x ^
Q O
< <
ss
^s
o d
II
sg
f
o ^5
0 VI
S
J
fS
33
a
2
•a
„
e
I
33
e cilia loss;
100,000 /ig/m3:
At 100,000 jtg/m3: sora
ulceration of larynx. < 1
no effect
5
00
^
.,
§
i
^r
•7"
o
g
8
g
— •
f
'o
^
1
g
rt
U
No effect
VI Vi VI
>,>,>,
•a -d -a
>o »ri »n
Q O Q
<^ m M
oo oo r--
o o o
|||
2 8 §
-^
TJ
£
_u
"o
^
eo
s s 8
--IS
fie a
«
33
^
1
^-^
13
4)
U
•a
U
>
ed
O
No effect
} Mortality
}
tfl tfl «
S" £ S*
•^ -a •a
>n *o »o
Q Q Q
ON tn rs
oo oo r-
o o o
III
2" ^" §
6?
T)
c.
f
1
^
Guinea pig
8
CN
33
^
S
^
•a
U
1
CO
pertrophy and
11s and secretory
Interstitial thickening; hy
:, hyperplasia of Type II ce
cells in bronchioli
^m
U
" s
tt ^
N
fN
Q
1
5s
o
0
5
t
"o
^
s
w>
S.
a x
|| -
isal
»^
S-
oo
2
^-^
•a
U
•3
"i?
o
'5
2
t-i
rrt
No effect (proximal acini
•o
r-
q
1*
oo
^
S
s
^T
oo
6
Q
^
t
"o
^
s
1
5-
TS M
U
f
April 1995
11-54
DRAFT-DO NOT QUOTE OR CITE
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,j> TABLE 11-5 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT MORPHOLOGY
& Species, Gender, Particle Characteristics
i—> Strain, Age, or Exposure Mass Concentration Exposure
^ Particle Body Weight Technique (RH) (/*g/tn3) Size (pm); ag Duration Observed Effect Reference
^ (NH4)2S04 Rat, M, SD Whole body 1,030 0.42 (MMAD); 2.25 6 h/day, Interstitial thickening Buschet al. (1984)
adult 5 days/week,
___^__ 20 days
(NH4>2SO4 Rat Nose-only 70 0.2 (MMAD) 4 h/day, Increased alveolar septal thickness; Kleinman et al. (1995)
4 days/week, decreased average alveolar diameter
8 weeks
-------
1 histochemical staining) have been found to extend to the bronchiolar level, where these cells
2 are normally rare or absent. Depending upon the study, the changes began within 4 weeks
3 of exposure and persisted for up to 3 mo following the end of exposure. The mechanism
4 underlying increases in secretory cell numbers at low H2SO4 exposure levels is also
5 unknown; it may involve an increase in secretory activity of existing cells, or a transition
6 from another cell type.
7 A shift in the relative number of smaller airways (<0.25 jim) in rabbits was found by
8 4 mo of exposure to 250 /ig/m3 (0.3 /jm) for 1 h/day, 5 days/week (Gearhart and
9 Schlesinger, 1988). Changes in airway size distribution due to irritant exposure, specifically
10 cigarette smoke, has been reported in humans (Petty et al., 1983; Cosio et al., 1977), and
11 this seems to be an early change relevant to clinical small airways disease.
12 The specific pathogenesis of acid-induced lesions is not known. As with pulmonary
13 mechanics, both a direct effect of deposited acid droplets on the epithelium and/or indirect
14 effects, perhaps mediated by humoral factors, may be involved. For example, similar lesions
15 have been produced in guinea pig lungs by exposure to either histamine or H2SO4 (Cavender
16 et al., 1977a). In addition, some lesions may be secondary to reflex bronchoconstriction, to
17 which guinea pigs are very vulnerable, rather than primary effects separable from
18 constriction. Thus, damage at the small bronchi and bronchiolar level may be due not only
19 to direct acid droplet-induced injury, but to indirect, reflex-mediated injury as well
20 (Brownstein, 1980).
21 Morphologic and cellular damage to the respiratory tract following exposure to acid
22 aerosols may be determined by methods other than direct microscopic observation. Analysis
23 of bronchoalveolar lavage fluid can also provide valuable information, and this procedure has
24 seen increasing use since publication of the previous CD. Levels of cytoplasmic enzymes,
25 such as lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6PD), are
26 markers of cytotoxicity; increases in lavageable protein suggest increased permeability of the
27 alveolar epithelial barrier; levels of membrane enzymes, such as alkaline phosphatase, are
28 markers of disrupted membranes; the presence of fibrin degradation products (FDP) provides
29 evidence of general damage; and sialic acid, a component of mucoglycoprotein, indicates
30 mucus-secretory activity. (It should, however, be noted that lavage analysis may not be able
31 to provide identification of the site of injury nor indicate effects in the interstitial tissue.)
April 1995 11-56 DRAFT-DO NOT QUOTE OR CITE
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1 Henderson et al. (1980b) exposed rats for 6 h to H2SO4 (0.6 /mi, MMAD) at 1,500,
2 9,500, and 98,200 /xg/m3, and found FDP in blood serum after exposure at all
3 concentrations. No FDP was found in lavage fluid, but since the washing procedure did not
4 include the upper respiratory tract (i.e., anterior to and including the larynx), FDP in the
5 serum was concluded to be an indicator of upper airway injury. A concentration-dependent
6 increase in sialic acid content of the lavage fluid was also observed, indicating increased
7 secretory activity within the tracheobronchial tree.
8 Chen et al. (1992a) exposed guinea pigs to fine (0.3 /mi) and ultrafine (0.04 /mi)
9 aerosols of H2SO4 at 300 /xg/m3 for 3 hi day for 1 or 4 days. Animals were sacrificed 24 h
10 after each of these exposures. Following the single exposure to either size, lavage fluid
11 showed increases in LDH and total protein, and the change in LDH was evident at 24 h with
12 the fine, but not the ultrafine, particles. These responses did not occur following the 4 day
13 exposure.
14 Wolff et al. (1986) exposed both rats and guinea pigs for 6 h to H2SO4 (0.8 to 1 /mi,
15 MMAD), at concentrations of 1,100 to 96,000 /ig/m3 for rats and 1,200 to 27,000 jwg/m3 for
16 guinea pigs. No changes in lavageable LDH, protein, nor sialic acid were found in the rat.
17 However, some of the guinea pigs exhibited bronchoconstriction after exposure to
18 27,000 /ig/m3, and only these animals showed increased levels of lavageable protein, sialic
19 acid and LDH. In other studies, no changes in lavageable protein were found in the lungs of
20 rats exposed for 3 days to 1,000 /xg/m3 (0.4 to 0.5 /mi, MMAD) H2SO4 (Warren and Last,
21 1987), nor for 2 days to 5,000 /*g/m3 (0.5 /mi, MMAD) (NH4)2SO4 (Warren et al., 1986).
22 An important group of biological mediators of the inflammatory response, as well as of
23 smooth muscle tone, are the eicosanoids, (e.g., prostaglandins and leukotrienes). Modulation
24 of these mediators could be involved in damage to the respiratory tract due to inhaled
25 particles. Preziosi and Ciabattoni (1987) exposed isolated, perfused guinea pig lungs for 10
26 min to aerosols of H2SO4 (no concentration or particle sizes were given). An increase in
27 thromboxane B2 but no change in leukotriene B4 in the perfusate was found. Schlesinger
28 et al. (1990b) exposed rabbits to 250 to 1,000 /ig/m3 H2SO4 (0.3 /mi) for 1 h/day for 5 days.
29 Lungs were lavaged and the fluid assayed for eicosanoids. A concentration-dependent
30 decrease in levels of prostaglandins E^ and F2a and thromboxane B2 were noted, while there
31 was no change in leukotriene B4. The effects, which were determined to be due to the
April 1995 H_57 DRAFT-DO NOT QUOTE OR CITE
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1 hydrogen ion rather than the sulfate ion, indicate that acid sulfates can upset the normally
2 delicate balance of eicosanoid synthesis/metabolism which is necessary to maintain
3 pulmonary homeostasis. Since some of the prostaglandins are involved in regulation of
4 muscle tone, this imbalance may be involved in the development of airway hyperresponsivess
5 found with exposure to acid sulfates.
6 Other biochemical markers of pulmonary damage have been used to assess the toxicity
7 of acid sulfate particles. The proline content of the lungs may provide an index of collagen
8 metabolism. No change in soluble proline content was found in rat lungs after exposure for
9 7 days to 4,840 /xg/m3 (0.5 ^m, MM AD) (NH4)2SO4, nor due to a 7 day exposure to
10 1,000 fjLg/m3 (0.5 jum) H2SO4 (Last et al., 1986). A series of studies assessed collagen
11 synthesis in rat lung minces after in vivo exposure; this is a possible indicator of the potential
12 for pollutants to produce fibrosis. Exposure for 7 days to H2SO4 at 40, 100, 500, and
13 1,000 /ig/m3 (0.4 to 0.5 ^m, MMAD) resulted in an increase in collagen synthesis rate only
14 at 100 /ig/m3; higher levels had no effect (Warren and Last, 1987). No effect on collagen
15 synthesis by rat lung minces was found due to 7-day exposures to (NH4)2SO4 at 5,000 /ig/m3
16 (0.8 to 1 ion, MMAD) (Last et al., 1983).
17 Other parameters of pulmonary damage are changes in lung DNA, RNA, or total
18 protein content. No significant changes in any of these parameters were found in rats after
19 exposure to 1,000 /*g/m3 H2SO4 (< 1 jim) for 3 days (Last and Cross, 1978), nor in protein
20 content in rats exposed for up to 9 days to a similar concentration of H2SO4 (Warren and
21 Last, 1987).
22
23 11.2.2.5 Pulmonary Defenses
24 Responses to air pollutants often depend upon their interaction with an array of
25 non-specific and specific respiratory tract defenses. The former consists of nonselective
26 mechanisms protecting against a wide variety of inhaled materials; the latter requires
27 antigenic stimulation of the immune system for activation. Although these systems may
28 function independently, they are linked, and response to an immunologic insult may enhance
29 the subsequent response to nonspecific materials. The overall efficiency of lung defenses
30 determines the local residence times for inhaled deposited material, which has a major
April 1995 11-58 DRAFT-DO NOT QUOTE OR CITE
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1 influence upon the degree of pulmonary response; furthermore, either depression or
2 over-activity of these systems may be involved in the pathogenesis of lung diseases.
3 Studies of altered lung defenses resulting from inhaled acid aerosols have concentrated
4 on conducting and respiratory region clearance function and nonspecific activity of
5 macrophages; there are only a few studies of effects upon immunologic competence.
6
7 11.2.2.5.1 Clearance Function
8 Clearance, a major nonspecific defense mechanism, is the physical removal of material
9 that deposits on airway surfaces. As discussed in Chapter 10, the mechanisms involved are
10 regionally distinct. In the conducting airways, clearance occurs via the mucociliary system,
11 whereby a mucus "blanket" overlying the ciliated epithelium is moved by the coordinated
12 beating of the cilia towards the oropharynx. In the alveolar region of the lungs, clearance
13 occurs via a number of mechanisms and pathways, but the major one for both microbes and
14 nonviable particles is the alveolar macrophage (AM). These cells exist freely within the fluid
15 lining of the alveolar epithelium, where they move by ameboid motion. The phagocytic
16 ingestion of deposited particles helps prevent particle penetration through the alveolar
17 epithelium and subsequent translocation to other sites. These cells contain proteolytic
18 enzymes, which digest a wide variety of organic materials, and they also kill bacteria through
19 oxidative mechanisms. In addition, AMs are involved in the induction and expression of
20 immune reactions. Thus, the AM provides a link between the lung's non-specific and
21 specific defense systems. These cells also are in the effector chain for lung damage (e.g., by
22 release of proinflammatory cytokines).
23
24 Mucociliary Transport
25 The assessment of acid effects upon mucociliary clearance often involved examination
26 only of mucus transport rates in the trachea, since this is a readily accessible airway and
27 tracheal mucociliary clearance measurements are more straightforward to perform than are
28 those aimed at assessing clearance from the entire tracheobronchial tree. Table 11-6 outlines
29 studies of acid sulfate effects upon tracheal mucociliary clearance.
30 Although many of the studies involved fairly high concentrations of acid aerosols, most
31 demonstrated a lack of effect. The most likely explanation for this is that the sizes of the
April 1995 11.59 DRAFT-DO NOT QUOTE OR CITE
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I
1— >
VO
VO
t^i
i— i
K- *
8
g
3
6
o
z
3
O
c
o
s
o
5S
Q
H
M
Particle
H2S04
H2S04
H2SO4
H2S04
H2S04
H2SO4
NH4HSO4
(NH4)2S04
(NH4)2S04
H2S04
H2S04
H2S04
H2SO4
TABLE 11-6.
Species, Gender,
Strain, Age, or
Body Weight
Tracheal
Dog, M/F
Beagle,
3 years
Donkey, M/F
adult
Rat
Rat
Rat, M/F
F344/Crl
12-16 weeks
Guinea pig, M/F
Hartley
2-3 mo
Sheep
Donkey
Sheep
Bronchial
Rabbit, M
NZW/mixed,
2.5-3 kg
Rabbit, M
mixed
2.5-2.7 kg
Rabbit, M
NZW
2.5-3 kg
Rabbit, M
NZW
2.5-3 kg
EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
Exposure Technique Mass Concentration (/*g/m3)
(RH)
Nose-only (80%)
Nasophary ngeal catheter
(45%)
Whole body (82%)
Nose-only (80%)
Whole body (80%)
Whole body (80%)
Head-only (20-30%)
Nasophary ngeal catheter
(45%)
Head-only (20-30%)
Oral tube (75%)
Oral tube or nose-only
(80%)
Nose-only (80%)
Nose-only (60%)
1,000
5,000
1,000
500
200-1,400
1,000-100,000
10,000-100,000
1,100, 11,000,96,000
1,400,9,000,27,000
1,000
300-3,000
1,100
100-2,200
250-500
250
1,250
Particle Characteristics
Size (pm); a
0.3 (MMAD); 1.2
0.3 (MMAD); 1.2
0.9 (MMAD); 1.3
0.9 (MMAD); 1.3
0.4 (MMAD); 1.5
0.6-0.8 (MMAD); 1.5-2.6
0.4-0.6 (MMAD); 1.3-1.4
0.9-1 (MMAD); 1.6-1.8
0.8-0.9 (MMAD); 1.5-1.6
0.1(CMD);2.1
0.4 (MMAD); 1.5
0.1 (CMD);2.1
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMD); 1.6
Exposure Duration
Ih
1 h
1 h
Ih
1 h
6h
0.5 h
6h
6h
4h
1 h
4h
1 h
1 h/days,
5 days/week,
4 weeks
1 h/day,
5 days/week,
12 mo
2 h/day,
5 days/week up to
12 mo
Observed Effect
NC
NC
^
i
NC
t
t
t at 96,000 Mg/m3
I at 1 ,400 /»g/m3
NC
NC
NC
t , i (depending on
concentration and
duration)
t ; persistent
1 by 1 week;
progressive
slowing after 19
weeks; persistent
t followed by *
PE; persistent
Reference
Wolff etal. (1981)
Schlesinger et al. (1978)
Wolff et al. (1980)
Wolff et al. (1986)
Sackneretal. (1981)
Schlesinger et al. (1978)
Sackneretal. (1981)
Chen and Schlesinger (1983);
Schlesinger et al. (1984)
Schlesinger et al. (1983)
Gearhart and Schlesinger
(1988)
Schlesinger et al. (1992b)
-------
I
t— k
VO
VO
Ui
1— »
H-1
ON
»— '
o
5
^
H
6
o
z
3
O
C
O
3
O
90
O
i— i
H
W
TABLE 11-6 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
Species, Gender, Particle Characteristics
Particle Body Weight (RH) Size (/urn); ag
Bronchial
H2SO4 Rabbit, M oral tube 250; 250; 500 0.3 (MMAD); 1.6
mixed nose-only
6 mo
H2SO4 Donkey Nasopharyngeal catheter 200-1,400 0.4 (MMAD); 1.5
(45%)
H2SO4 Rat, M Nose-only (39%; 85%) 3,600 1.0 (MMAD); 1.9-2.3
SD
200 g
NH4HSO4 Rabbit, M Oral tube (78%) 600-1,700 0.4 (MMAD); 1.6
mixed
2.5-2.7 kg
(NH4)2SO4 Rabbit, M Oral tube (78%) 2,000 0.4 (MMAD); 1 .6
mixed
2.5-2.7 kg
(NH4)2SO4 Rat, M Nose-only (39%; 85%) 3,600 0.4 (MMAD); 1.9-2.3
SD
200 g
Alveolar
H2SO4 Rat, M Whole body (30-80%) 3,600 1.0
SD
200 g
H2SO4 Rabbit, M Oral tube 1,000 0.3 (MMAD); 1.5
NZW
2.5-3 kg
H2SO4 Rabbit, M Nose-only (80%) 250 0.3 (MMAD); 1.6
NZW
2.5-3 kg
Exposure
Duration
1 h/day,
5 days/week,
4 weeks
1 h
4h
1 h
1 h
4h
4h
1 h
1 h/day,
5 days/week,
1, 57, 240 day
Observed Effect
t only some days at
250/oral and
500/nasal; persistant
t up to 14 days PE
for all.
i in some animals at
all concentrations;
progressive slowing
in some animals with
continued exposures.
NC
i at l,700fig/m3
NC
NC
NC
t
t
Reference
Schlesinger et al. (1983)
Schlesinger et al. (1978)
Phalen et al. (1980)
Schlesinger (1984)
Schlesinger (1984)
Phalen et al. (1980)
Phalen et al. (1980)
Naumann and Schlesinger
(1986)
Schlesinger and Gerhart
(1986)
-------
OS
TABLE 11-6 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
.
Particle
Species, Gender,
Strain, Age, or
Body Weight
Exposure Technique Mass Concentration 0*g/m3) •
(RH)
Particle Characteristics
Size (pm); a.
Exposure
Duration
Observed Effect
Reference
Alveolar (cont'd)
H2S04
Rabbit, M
NZW
3-3.5 kg
Nose-only (80%)
500
0.3(MMAD); 1.6
2 h/day,
14 days
Schlesinger and Gearhart
(1987)
Key to abbreviations:
NC: No significant change
t: Significant increase
*: Significant decrease
PE: Post exposure
-------
1 aerosols were such that significant tracheal deposition did not occur. This is supported by
2 the results of Wolff et al. (1981), who found tracheal transport rates in dogs to be depressed
3 only when using 0.9 jum H2SO4; no effect was seen with a 0.3 fj,m aerosol at an equivalent
4 mass concentration. In addition, the use of tracheal clearance rate as a sole toxicologic
5 endpoint may be misleading, inasmuch as a number of studies have demonstrated alterations
6 in bronchial clearance patterns in the absence of changes in tracheal mucous transport.
7 Studies assessing the effects of acid aerosols upon bronchial mucociliary clearance are
8 also outlined in Table 11-6. Responses following acute exposure to H2SO4 indicate that the
9 nature of clearance change (i.e., a slowing or speeding) is concentration dependent;
10 stimulation of clearance generally occurs at low concentrations, and retardation generally
11 occurs at higher levels. However, the actual concentration needed to alter clearance rate
12 may depend upon the anatomic location within the bronchial tree from which clearance is
13 being measured, in relation to the region which is most affected by the deposited acid.
14 Studies in humans indicated that low H2SO4 concentrations (i.e., = 100 to 500 /xg/m3) may
15 accelerate clearance, compared to unexposed subjects, from the large proximal airways
16 where little acid deposits, while slowing clearance from the distal ciliated airways where
17 there is greater acid deposition. At higher concentrations, i.e., mucociliary clearance from
18 both the proximal and distal bronchial tree may be depressed (Leikauf et al., 1984).
19 Comparison of responses to H2SO4 show interspecies differences in the sensitivity of
20 mucociliary clearance to acid aerosols. As an example, the acceleration of tracheal transport
21 found by Wolff et al. (1986) in the rat with «100,000 /zg/m3 H2SO4 seems anomalous since,
22 in other species, levels > 1,000 Mg/m3 depress mucociliary function. The reasons for this
23 apparent discrepancy are not known. The rat is less susceptible to the lethal effects of
24 H2SO4, and it does not have strong bronchoconstrictive reflex responses following H2SO4
25 exposures. These characteristics suggest that the mucociliary system of the rat may also
26 differ in sensitivity from the other species studied, a view supported by the lack of effect of
27 H2SO4 on bronchial clearance found by Phalen et al. (1980) following exposure at 3,600
28 i*g/m3 for 4 h and by the similarity in bronchial clearance response in donkeys and rabbits
29 to single 1-h exposures of H2SO4 (Table 11-6). Although the lack of response of tracheal
30 transport in the guinea pig at H2S04 levels > 1,000 ;ug/m3 is also surprising, its response at
April 1995 11-63 DRAFT-DO NOT QUOTE OR CITE
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1 1,000 ju,g/m3 is also different from that of the rat and more in line with other species (Wolff,
2 1986).
3 The relative potency of acid sulfate aerosols, in terms of altering mucociliary clearance,
4 is related to their acidity (H+ content). Schlesinger (1984) exposed rabbits for 1 h to
5 submicrometer aerosols of NH4HSO4, (NH4)2SO4, and Na2SO4. Exposure to NH4HSO4 at
6 concentrations of =600 to 1,700 Mg/m3 significantly depressed clearance rate only at the
7 highest exposure level. No significant effects were observed with the other sulfur oxides at
8 levels up to =2,000 /*g/m3. When these results are compared to those from a study using
9 H2SO4 (Schlesinger et al., 1984), the ranking of irritant potency was H2SO4 > NH4HSO4
10 > (NH4)2SO4, Na2SO4; this strongly suggests a relation between the hydrogen ion
11 concentration and the extent of alteration in bronchial mucociliary clearance.
12 The mechanism by which deposited acid aerosol alters clearance is not certain. The
13 effective functioning of mucociliary transport depends upon optimal beating of cilia and the
14 presence of mucus having appropriate physicochemical properties, and both ciliary beating as
15 well as mucus viscosity may be affected by acid deposition. At alkaline pH, mucus is more
16 fluid than at acid pH, so a small increase in viscosity due to deposited acid could "stiffen"
17 the mucus blanket, perhaps promoting the clearance mechanism and, thus, increasing its
18 efficiency (Holma et al., 1977). Such a scenario may occur at low H2SO4 exposure
19 concentrations, where ciliary activity would not be directly affected by the acid, and is
20 consistent with clearance acceleration observed at these concentrations with acute exposure.
21 However, the exact relation between mucus viscosity and transport rate is not certain;
22 differential alterations in Theological properties of the sol or gel layers may have different
23 effects upon the system (Puchelle and Zahm, 1984).
24 High concentrations of H2SO4 may affect ciliary beating, as discussed in the previous
25 CD (U.S. Environmental Protection Agency, 1982; Schiff et al., 1979; Grose et al., 1980).
26 An additional mechanism by which deposited acid may affect mucociliary clearance is via
27 altering the rate and/or amount of mucus secreted. A small increase in mucus production
28 could facilitate clearance, while more excessive production could result in a thickened mucus
29 layer which would be ineffectively coupled to ciliary beat. Finally, the airways actively
30 transport ions, and the interaction between transepithelial ion transport and consequent fluid
31 movement is important in maintaining the mucus lining. A change in ion transport due to
April 1995 11-64 DRAFT-DO NOT QUOTE OR CITE
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1 deposited acid particles may alter the depth and/or composition of the sol layer (Nathanson
2 and Nadel, 1984), perhaps affecting clearance rate. In any case, the pathological significance
3 of transient alterations in bronchial clearance rates in healthy individuals is not certain, but
4 such changes are an indication of a lung defense response. On the other hand, persistent
5 impairment of clearance may lead to the inception or progression of acute or chronic
6 respiratory disease and, as such, may be a plausible link between inhaled acid aerosols and
7 respiratory disease.
8 Short-term exposures to acid aerosols may lead to persistent clearance changes, as
9 indicated previously (Schlesinger et al., 1978). The effects of long-term exposures were
10 investigated by Schlesinger et al. (1983), who exposed rabbits to 250 or 500 /*g/m3 H2SO4
11 (0.3 urn, MMAD) for 1 h/day, 5 days/week for 4 weeks, during which time bronchial
12 mucociliary clearance was monitored. Clearance was accelerated on individual days during
13 the course of the acid exposures, especially at 500 /-ig/m3. In addition, clearance was
14 significantly faster, compared to preexposure levels, during a 2 week follow- up period after
15 acid exposures had ceased.
16 Another long-term exposure at relatively low H2SO4 levels was conducted by Gearhart
17 and Schlesinger (1988). Rabbits were exposed to 250 jug/m3 H2SO4 for 1 h/day,
18 5 days/week for up to 52 weeks, and some animals were also provided a 3 mo follow-up
19 period in clean air. Clearance was slower during the first month of exposure and this
20 slowing was maintained throughout the rest of the exposure period. After cessation of
21 exposure, clearance became extremely slow and did not return to normal by the end of the
22 follow-up period. Differences in the nature of clearance change between this study and that
23 of Schlesinger et al. (1983) may be due to differences in exposure protocol daily (duration)
24 and/or concentration. In both studies, however, and as discussed earlier, histologic analyses
25 indicated the development of increased numbers of epithelial secretory cells, especially in
26 small airways, the likely consequence of which would be an increase in mucus production.
27 In addition, the slowing of clearance seen by Gearhart and Schlesinger (1988) was also
28 associated with a shift in the histochemistry of mucus towards a greater content of acidic
29 glycoproteins; this would tend to make mucus more viscous.
30 The longest duration study at the lowest concentration of H2SO4 yet reported is that of
31 Schlesinger et al. (1992b), in which rabbits were exposed to 125 /ig/m3 H2SO4 for 2 h/day,
April 1995 H_65 DRAFT-DO NOT QUOTE OR CITE
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1 5 days/week for up to 52 weeks. The variability of measured clearance time was increased
2 with acid exposure, and acceleration of clearance was noted at various times during the one-
3 year exposure period. However, following a 6-mo observation period, after exposures
4 ceased, a trend towards slowing of clearance was noted (compared to both control and rates
5 during acid exposure). In addition, and consistent with previous studies, an increase in the
6 number density of epithelial secretory cells was observed in small airways (<0.5 mm)
7 following 12 mo of acid exposure. This histological change had resolved by the end of the
8 6-mo post-exposure period.
9
10 Alveolar Region Clearance and Alveolar Macrophage Function
11 Only a few studies have examined the ability of acid aerosols to alter clearance of
12 particles from the alveolar region of the lungs (Table 11-6). Rats exposed to 3,600 /*g/m3
13 H2SO4 (l/*m) for 4 h showed no change in clearance (Phalen et al., 1980). On the other
14 hand, acceleration of clearance was seen in rabbits exposed for 1 h to 1,000 ^g/m3 H2SO4
15 (0.3 jum, MMAD) (Naumann and Schlesinger, 1986).
16 Two studies involving repeated exposures to acid aerosols have been reported. In one,
17 rabbits were exposed to 250 jtig/m3 (0.3 /zm, MMAD) H2S04 for 1 h/day, 5 days/week, and
18 inert tracer particles were administered on days 1, 57 and 240 following the start of the acid
19 exposures (Schlesinger and Gearhart, 1986). Clearance (measured for 14 days after each
20 tracer exposure) was accelerated during the first test, and this acceleration was maintained
21 throughout the acid exposure period. In the other study (Schlesinger and Gearhart, 1987),
22 rabbits were exposed 2 h/day for 14 days to 500 ^ig/m3 H2SO4 (0.3 fj.m, MMAD);
23 retardation of early alveolar region clearance of tracer particles administered on the first day
24 of exposure was noted. The results of these two studies suggest a graded response, whereby
25 a low exposure concentration accelerates early alveolar region clearance and a high level
26 retards it, such as was seen with mucociliary transport following acute H2SO4 exposure.
27 The mechanisms responsible for the altered alveolar region clearance patterns seen in
28 the above studies are not known. Observed clearance is the net consequence of a number of
29 differential underlying responses, which can include change in mucociliary transport rates
30 and altered functioning of AMs.
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1 A number of studies have examined the functional response of AMs following acidic
2 sulfate aerosol exposures. To adequately perform their role in clearance, AMs must be
3 competent in a number of functions, including phagocytosis, mobility and attachment to a
4 surface. Alterations in any one, or combination, of these individual functions may affect
5 clearance function. Naumann and Schlesinger (1986) noted a reduction in surface adherence
6 and an enhancement of phagocytosis in AMs obtained by lavage from rabbits following a 1-h
7 exposure to 1,000 /ig/m3 H2SO4 (0.3 jrni). The acid exposure produced no change in the
8 viability or numbers of recoverable AMs.
9 In a study with repeated H2S04 exposures, AMs were lavaged from rabbits exposed to
10 500 /ig/m3 H2SO4 (0.3 /*m) for 2 h/day for up to 13 consecutive days (Schlesinger, 1987a).
11 Macrophage counts increased after 2 of the daily exposures, but returned to control levels
12 thereafter. Neutrophil counts remained at control levels throughout the study, suggesting no
13 acute inflammatory response. Random mobility of AMs decreased after 6 and 13 of the
14 daily exposures. The number of phagocytically active AMs and the level of such activity
15 increased after 2 exposures, but phagocytosis became depressed by the end of the exposure
16 series. Although such studies demonstrate that H2SO4 can alter AM function, they have not
17 as yet been able to provide a complete understanding of the cellular mechanisms which may
18 underly the changes in pulmonary region clearance observed with exposure to acid aerosols.
19 The relative potency of acidic sulfate aerosols in terms of altering AM numbers or
20 function has been examined. Aranyi et al. (1983) found no change in total or differential
21 counts of free cells lavaged from mice exposed to 1,000 pig/m3 (NH4)2SO4 for 3 h/day for
22 20 days; this suggests a lack of inflammatory response to this sulfate aerosol. Additional
23 studies seem to suggest that the response to acid sulfates of AM is a function of the H+.
24 Schlesinger et al. (1990a) examined phagocytic activity of AMs recovered from rabbits
25 exposed for 1 h/day for 5 days to either 250 to 2,000 /ig/m3 H2SO4 (0.3/zm) or 500 to
26 4,000 /^g/m3 NH4HSO4 (0.3 jum); the levels were chosen such that the H+ concentration in
27 the exposure atmospheres were equivalent for both sulfate species. Phagocytic activity of
28 AMs was reduced following exposure to > 1,000 jug/m3 H2SO4 or to 4,000 jug/m3
29 NH4HSO4; exposure to 2,000 /-ig/m3 NH4HSO4 resulted in increased phagocytic activity.
30 While these exposure concentrations were quite high, the interesting observation was that for
31 a given level of sulfate, the response to H2SO4 was greater than that to NH4HSO4.
April 1995 11-67 DRAFT-DO NOT QUOTE OR CITE
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1 However, even when the data were assessed in terms of H+ concentration in the exposure
2 atmosphere, it was noted that exposure to the same concentrations of H+ did not result in
3 identical responses for the two different acid sulfate species; H+ appeared to be more
4 effective as the H2SO4 species. On the other hand, when AMs were incubated in acidic
5 environments in vitro, the phagocytic activity response was identical, regardless of the sulfate
6 species used, as long as the pH was the same. These results suggested an enhanced potency
7 of H2SO4 during inhalation exposures. Experimental evidence provided by Schlesinger and
8 Chen (1994) indicated that this difference noted in vivo was likely a reflection of different
9 degrees of neutralization by respiratory tract ammonia of the two species of inhaled acid
10 aerosols. It was shown that, for a given concentration of ammonia and within a given
11 residence time within the respiratory tract, more total H+ remained available from inhaled
12 sulfuric acid than from inhaled ammonium bisulfate when the exposure atmospheres had the
13 same total H+ concentration. Thus, the greater observed potency of inhaled sulfuric acid
14 compared to ammonium bisulfate for exposure atmospheres containing the same total H+
15 concentration is likely due to a greater degree of neutralization of the latter, and a resultant
16 greater loss of H+ prior to particle deposition onto airway surfaces. Thus, the respiratory
17 "fate" of inhaled acid sulfate particles should be considered in assessing the relationship
18 between exposure atmosphere and biological response, since a lower H+ concentration will
19 likely deposit onto lung tissue than is inhaled at the mouth or nose.
20 Interspecies differences in the effects of acid sulfates on AM function were examined
21 by Schlesinger et al. (1992a). Based upon in vitro exposures of AM to acidic media, a
22 ranking of response in order of decreasing sensitivity to acidic challenge and subsequent
23 effect on phagocytic activity was found to be: guinea pig > rat > rabbit > human.
24 As noted with other endpoints, the effect of H2SO4 upon AM function may be
25 dependent upon particle size. Chen et al. (1992a) observed that 300 jig/m3 H2SO4 enhanced
26 the phagocytic activity of AMs recovered from guinea pigs after 4 days (3 h/day) of exposure
27 to fine particles (0.3 /im), while an indentical exposure to ultrafine particles (0.04 /^m)
28 depressed phagocytic function.
29 The effects of acid sulfates upon the intracellular pH of AMs has been examined,
30 because this may be one of the determinants of the rate of many cellular functions (Nucitelli
31 and Deamer, 1982). Internal pH of AMs recovered from guinea pigs exposed to 300
April 1995 11-68 DRAFT-DO NOT QUOTE OR CITE
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1 H2S04 was depressed after a single 3-h exposure to both 0.3 and 0.04 /xm particles, but the
2 depression persisted for 24 h following exposure to the smaller size (Chen et al., 1992b).
3 A depression in pH was also noted 24 h following 4 days of exposure to the ultrafine, but
4 not the fine, aerosol. Thus, acid exposure produced a change in intracellular pH of the AMs
5 and the effect was particle size dependent.
6 It is possible that this and other differences in response between fine and ultrafine
7 particles reflect, to some extent, differences in the number of particles in aerosols of these
8 two size modes, in that at a given mass concentration of acid sulfate, there are a greater
9 number of ultrafine than fine particles. To examine this possibility, Chen et al. (1995) noted
10 that changes in intracellular pH of macrophages obtained following inhalation exposure to
11 H2SO4 aerosols were dependent both upon the number of particles impacting the cells, as
12 well as upon the total mass concentration of H+ in the exposure atmosphere, with a threshold
13 existing for both exposure parameters. The role of size in modulating toxicity due to PM is
14 discussed further in Section 11.5. It should, however, be noted that aside from number,
15 differences in deposition and neutralization may also affect differential responses to fine and
16 ultrafine particles.
17 A possible mechanism underlying the acid-induced alterations in intracellular pH was
18 examined by Qu et al. (1993), who exposed guinea pigs to 969 ^g/m3 H2SO4 (0.3 jiim
19 MMD, ag 1.73) for 3 h or to 974 /zg/m3 for 3 h/day for 5 days. Macrophages were
20 obtained following the end of each exposure protocol and examined for the ability of
21 internal pH to recover from an added intracellular acid load. Both H2SO4 exposures resulted
22 in a depression of internal pH recovery compared to air control. Subsequent analysis
23 indicated that this alteration in internal pH regulation was attributable to effects on the
24 Na+/H+ exchanger located in the cell membrane.
25 Macrophages are the source of numerous biologically active chemicals, and the effects
26 of acid sulfate upon some of these have been investigated. Zelikoff and Schlesinger (1992)
27 exposed rabbits to 50 - 500 ^g/m3 H2SO4 (0.3 /mi) for 2 h. AM recovered by lavage
28 following exposure were assessed for effects on tumor necrosis factor (TNF) release/activity
29 and production of superoxide radical, both of which are biological mediators involved in host
30 defense. Exposure to H2SO4 at > 75 /ig/m3 produced a reduction in TNF cytotoxic activity,
31 as well as a reduction in stimulated production of superoxide radical. Subsequently, Zelikoff
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1 et al. (1994) exposed rabbits for 2 h/day for 4 days to sulfuric acid at 500, 750 or
2 1,000 jug/m3. AM recovered from animals exposed at the highest acid level showed a
3 reduction in TNF and interleukin (IL)-la production/activity, both immediately and 24 h
4 following the last exposure. On the other hand, increased release of TNF from macrophages
5 obtained from guinea pigs was observed immediately following a single 3 h exposure, and 24
6 h following a 3 h/day 4 day exposure, to 300 ^g/m3 H2SO4 (0.3 pm. or 0.04 pirn) (Chen et
7 al., 1992a); in addition, production of hydrogen peroxide by these cells was enhanced
8 immediately after the 4 day exposure. These differences in TNF may reflect interspecies
9 differences in response to acid exposure and/or differences in experimental conditions.
10
11 11.2.2.5.2 Resistance to Infectious Disease
12 The development of an infectious disease requires both the presence of the appropriate
13 pathogen, as well as host vulnerability. There are numerous anti-microbial host defenses
14 with different specific functions for different microbes (e.g., there are some differences in
15 defenses against viruses and bacteria). The AM represents the main defense against gram
16 positive bacteria depositing in the alveolar region of the lungs. The ability of acid aerosols
17 to modify resistance to bacterial infection could result from a decreased ability to clear
18 microbes, and a resultant increase in their residence time, due to alterations in AM function.
19 To test this possibility, a rodent infectivity model has been frequently used. In this
20 technique, mice are challenged with a bacterial aerosol after exposure to the pollutant of
21 interest; mortality rate and survival time are then examined within a particular postexposure
22 time period. Any decrease in the latter or increase in the former indicates impaired defense
23 against respiratory infection. A number of studies which have used the infectivity model
24 (primarily with Streptococcus sp.) to assess effects of acid aerosols were discussed in the
25 previous CD (U.S. Environmental Protection Agency, 1982). It was evident that acute
26 exposures to H2SO4 aerosols at concentrations up to 5,000 jug/m3 were not very effective in
27 enhancing susceptibility to this bacterially-mediated respiratory disease in the murine model.
28 More recent studies with mice, shown in Table 11-7, continue to support this conclusion.
29 However, a study using another animal suggests that H2SO4 may indeed alter
30 antimicrobial defense. Zelikoff et al. (1994) exposed rabbits for 2 h/day for 4 days to 500,
31 750, or 1,000 /ig/m3 H2SO4. Intracellular killing of a bacterium, Staphylococcus aureus, by
April 1995 11-70 DRAFT-DO NOT QUOTE OR CITE
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£
TABLE 11-7. EFFECTS OF ACID SULFATES ON BACTERIAL INFECTiyiTY IN VIVO
Species, Gender, Particle Characteristics
Strain, Age, or Exposure Technique Mass Concentration
Particle Body Weight (RH) (fig/m3) Size Gun); a. Exposure Duration Observed Effect References
H2SO4 Mouse, F
CD-I
30 days
Head-only (31%) 543
0.08 (VMD); 2.3
2 h
NC
Grose et al. (1982)
H2SO4 Mouse, F Head-only (31%) 365
CD-I
30 days
0.06 (VMD); 2.3
2 h/day, 5 days NC
Grose et al. (1982)
(NH4)2SO4 Mouse, F
CD-I
30 days
Whole body 1,000
Submicrometer
3 h/day, 20 days NC
Aranyi et al. (1983)
NC: No change
H
6
o
O
c
o
n
HH
3
-------
1 AMs recovered by lavage 24 h following the last exposure at the two highest acid
2 concentrations was reduced; bacterial uptake was also reduced at the same time point, but
3 only at the highest acid level. Thus, repeated H2SO4 exposures may reduce host resistance
4 to bacteria in the rabbit, in contrast to no effect on mouse infectivity.
5
6 11.2.2.5.3 Specific Immune Response
1 Most of the database involving effects of acid aerosols on lung defense is concerned
8 with non-specific mechanisms. Little is known about the effects of these pollutants on
9 humoral (antibody) or cell-mediated immunity. Since numerous potential antigens are
10 present in inhaled air, the possibility exists that acid sulfates may enhance immunologic
11 reaction and, thus, produce a more severe response, and one with greater pulmonary
12 pathogenic potential. Pinto et al. (1979) found that mice which inhaled H2SO4 for 0.5 h
13 daily and were then exposed weekly to a particulate antigen (sheep red blood cells) exhibited
14 higher serum and bronchial lavage antibody tilers than did animals exposed to the antigen
15 alone; unfortunately, neither the exposure mass concentration nor particle size of the H2SO4
16 was described. The combination of acid with antigen also produced morphologic damage,
17 characterized by mononuclear cell infiltration around the bronchi and blood vessels, while
18 exposure to acid or antigen alone did not. Thus, the apparent adjuvant effect of H2SO4 may
19 be a factor promoting lung inflammation.
20 Osebold et al. (1980) exposed mice to 1,000 jug/m3 H2S04 (0.04 /un, CMD) to
21 determine whether this enhanced the sensitization to an inhaled antigen (ovalbumin). The
22 exposure regimen involved intermittent 4 day exposures, up to 16 total days of exposure; no
23 increase in sensitization compared to controls was found. Kitabatake et al. (1979) exposed
24 guinea pigs to 1,910 /ig/m3 (< 1 jim, MM AD) for 0.5 h twice per week for 4 weeks,
25 followed by up to 10 additional paired treatments with the H2SO4 for 0.5 h each; the animals
26 were then exposed to aerosolized albumin for another 0.5 h. The breathing pattern of the
27 animals was monitored for evidence of dypsnea. Enhanced sensitization was found after
28 =4 of the albumin exposures. A subsequent challenge with acetylcholine suggested
29 hyperresponsive airways.
30 Fujimaki et al. (1992) exposed guinea pigs to 300, 1,000, and 3,200 pig/m3 H2SO4 for
31 2 or 4 weeks, following which lung mast cell suspensions were examined for antigen-induced
April 1995 11-72 DRAFT-DO NOT QUOTE OR CITE
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1 histamine release. Exposure for 2 weeks at the two highest concentrations resulted in
2 enhanced histamine release, but this response dissipated by 4 weeks of exposure. Thus,
3 H2SO4, at high concentrations, may affect the functional properties of mast cells; these cells
4 are involved in allergic responses, including bronchoconstriction.
5
6
7 11.3 SIMPLE BINARY MIXTURES
8 Most of the toxicological data concerning effects of PM are derived from exposures
9 using single compounds. Although such information is essential, it is also important to study
10 responses which result from inhalation of typical combinations of materials, because
11 population exposures are generally to complex mixtures. Toxicological interaction provides a
12 basis whereby ambient pollutants may act with synergism (effect greater than the sum of the
13 parts) or antagonism (effect less than the sum of the parts). Thus, the lack of any toxic
14 effect following exposure to an individual pollutant should always be interpreted with
15 caution, because mixtures may act differently than expected from the same pollutants acting
16 separately. Most toxicologic studies of pollutant mixtures involved exposures to mixtures
17 containing only two materials. These experiments are summarized below; complex mixture
18 studies are discussed in Section 11.4.
19 The extent of any toxicological interaction involving acidic sulfate aerosols depends on
20 the endpoint being examined, as well as on the co-inhalant. Most studies of interactions
21 using acidic sulfates employed ozone as the co-pollutant. Depending upon the exposure
22 regimen, endpoint, and animal species, either additivity, synergism, or antagonism was
23 observed. These studies are summarized in the O3 criteria document (U.S. Environmental
24 Protection Agency, 1995). Interaction studies of H2SO4 and nitrogen dioxide (NO2) are
25 discussed in the criteria document on the latter pollutant (U.S. Environmental Protection
26 Agency, 1993). The nature of interactions was dependent on the protocol; no unifying
27 principles emerged.
28 The database for binary mixtures containing PM other than acid sulfates is quite sparse
29 (Table 11-8). But, as with acidic sulfates, interaction depends upon pollutant combinations,
30 exposure regimen and biological endpoints. Some interaction was noted following exposure
31 of mice to mixtures of 9,400 /zg/m3 volcanic ash and 2.5 ppm SO2 (Grose et al., 1985), in
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TABLE 11-8. TOXICOLOGIC INTERACTIONS TO BINARY MIXTURES CONTAINING PM
E±I Co-Pollutant
(^ Chemical ftg/m^ ppm
<-" SO2 145
Fly ash 70,000
(6 /*m,
MMAD)
"— ' HNO3 380
^ (vapor)
-F^
O
§>
Tl
i-j SO2 2,500 —
6
0
>2J
Q SO2 2,500 —
H
0
C^
m
Acid Particle
Chemical /ig/mj (pm)
H2SO4 1,890
(<1 urn,
MMAD)
H2SO4 1,000, 10,000,
100,000
(0.8 pm,
MMAD,
-------
> TABLE
3. Co-Pollutant
^ Chemical /jg/mj ppm
(j\ SO2 2,500 —
SO2 2,500 —
HCHO 1,000; 2.4-3
HCHO — 4.1-5
i— '
SO2 2,500 —
O
fT HCHO — 2.4-3
H
0
O
g HCHO — 1
H
O
O
!— 1 HCHO — 4.1-5
M
11-8 (cont'd). TOXICOLOGIC
Acid Particle
Chemical W5/m3 (/am) .
Exposure Regime
volcanic 9,400 2 h
ash (0.65 /an,
MMAD,
ag=1.8)
volcanic 9,400 2 h/day, 5 days
ash (0.65 /an,
MMAD,
C black 1,000; 4h
2,400-6,800
(2.45 /an,
MMAD,
crg=2.54)
C black 4,800-13,200 4 h
Volcanic 9,400 2 h
ash (0.65 /an,
MMAD,
-------
TABLE 11-8 (cont'd). TOXICOLOGIC INTERACTIONS TO BINARY MIXTURES CONTAINING PM
vo
H
6
0
Co-Pollutant Acid Particle
Chemical Pg/m3 ppm Chemical ^g/m3 („«,) _ „ . *Xp°SUre Sp?KS' G'nder „ A .
r Exposure Regime Conditions Strain, Age Endpoints
HCHO — 1.8- C black 4,700-6,100; 4 h/day, 4 days Nose-only Mouse, F, infectivity of 5.
2.8; 10,000 Swiss, 20-23 g aureus
5 administered 1 day
after last pollutant
exposure;
differential counts
in lavage
HCHO — 5 C black 10,000 4 h/day, 4 days Nose-only Mouse, F, Fc-receptor
Swiss, mediated
20-23 g M0 phagocytosis
up to
40 days PE
acrolein — 2.5 C black 10,000 4 h/day, 4 days Nose-only Mouse, F, infectivity to
(2.4 pan, Swiss, 20-23 g S. aureus.
MMAD, P. mirabilis.
a=2.15) L. monocytogenes;
influenza A virus
administered 1 day
PE
Response to
Mixture
None
t Phagocytic
activity
from day 3-day 25
PE, return to
normal by day 40
PE
* Elimination of
virus; 1 killing of
L. monocytogenes;
i killing of S.
aureus; t killing of
P. mirabilis
t PMN count 4 h
after P. mirabilis
challenge;
no change total cell
no. by lavage after
S. aureus
Interaction
None
Possible
synergism: no
effect of C black
or HCHO alone
Possible
synergism: no
effect of either
alone
possible: no effect
of C black
possibly: greater
than either alone
none
Reference
Jakab (1992)
Jakab (1992)
Jakab (1993)
O
c!
O
H
W
O
0
-------
> TABLE 11-8 (cont'd). TOXICOLOGIC
Ci: Co-Pollutant Acid Particle
vg Chemical Mg/m3 ppm Chemical Mg/m' 0«n) Exposure Regime
^ SO2 2,700 — Volcanic 9,400 2 h/day, 5 days
ash (0.65,
MMAD,
INTERACTIONS TO BINARY MIXTURES CONTAINING
Exposure Species, Gender
Conditions Strain, Age Endpoints
Whole body Rat, pulmonary
Sprague-Dawley mechanics
(40 days)
Response to
Mixture Interaction
Reduced tidal None: effect due
volume and peak to SO2
expiratory flow; no
effect on breathing
frequency
PM
Reference
Raub et al. (1985)
O
O
z
s
O
d
I
O
90
n
H
m
Key abbreviations:
PE: post exposure
AM: alveolar macrophage
t: increase
I: decrease
-------
1 that synergism was suggested in terms of immune cell activity and numbers but no
2 interaction was found with overall bacterial infectivity. On the other hand, exposure of
3 mice to various concentrations of carbon black and formaldehyde (HCHO) produced no
4 evidence of interaction in terms of bacterial infectivity but possible synergism in terms of
5 macrophage phagocytic activity (Jakab, 1992).
6 The infectivity study of Jakab (1993), in which mice were exposed to acrolein and
7 carbon black (Table 11-8), is of interest because, as mentioned earlier, the microbial agents
8 were selected on the basis of the defense mechanisms they elicited. The results indicated that
9 while particle or acrolein exposure alone did not alter infectivity from any of the microbes,
10 exposure to the mixture did, and also suggested differential effects on different aspects of
11 antimicrobial defense. For example, the increase in intracellular killing of P. mirabilis was
12 ascribed to the increase in PMN levels after bacterial challenge. The reduced effectiveness
13 forL. monocy to genes and influenza virus were somewhat more persistent, which led the
14 authors to suggest that the particle/gas mixture had a greater impact upon acquired immune
15 defenses than on innate defense mediated by AMs and PMNs, this being the major defense
16 against 5. aureus and P. mirabilis.
17
18 11.3.1 Mixtures Containing Acidic Sulfate Particles
19 A few studies have examined the effects of exposure to multicomponent atmospheres
20 containing acidic sulfate particles. Studies of mixtures containing O3 or NO2 are summarized
21 elsewhere (U.S. Environmental Protection Agency, 1993, 1995).
22 Mannix et al. (1982) examined the effects of a 4 h exposure of rats to a SC^-sulfate
23 mix, consisting of SO2 (13,000 ^g/m3) plus 1,500 /xg/m3 (0.5 /mi, MMAD) of an aerosol
24 containing (NH4)2SO4 and Fe2(SO4)3. No change in particle clearance from the
25 tracheobronchial tree or pulmonary region was found.
26 A series of studies discussed in the previous CD (U.S. Environmental Protection
27 Agency, 1982) involved exposure of dogs to sunulated auto exhaust atmospheres (e.g., Hyde
28 et al., 1978) for 16 h/day for 68 mo followed by a 32- to 36-mo period in clean air. The
29 mixture consisted of 90 /xg/m3 H2SO4+ 1,100 /xg/m3 SO2, with and without irradiated auto
30 exhaust (which results in production of oxidants) and nonirradiated auto exhaust. The results
31 were dependent on the tune of examination, exposure, and the endpoint. The primary
April 1995 11-78 DRAFT-DO NOT QUOTE OR CITE
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1 finding was that groups exposed to SO2 and H2S04 showed emphysema like changes,
2 observed 32- to 36-mo postexposure. The authors considered the specific changes to be
3 analogous to an incipient stage of human centrilobular emphysema. Also, from the
4 pulmonary function results, it did not appear that auto exhaust exacaberated the effects of the
5 SO2-H2SO4 mixture.
6 Prasad et al. (1988) exposed rats for 5 h/day for 5 days to an atmosphere consisting of
7 460 /ig/m3 diesel exhaust particles (0.15 jum), 380 /*g/m3 HNO3 vapor, and 180 /ig/m2
8 H2SO4 (present as a surface coat on the diesel particles). Reduced activity of macrophage
9 surface (Fc) receptors and phagocytosis were noted, but interaction could not be determined
10 since the individual components were not tested separately.
11 In a later study, Prasad et al. (1990) examined particle clearance, lung histology and
12 macrophage phagocytic activity following nose-only exposures of rats (Sprague-Dawley, M,
13 6 weeks) for 5 h/day for 5 days to atmospheres consisting of 390 pig/m3 HNO3 vapor,
14 550 ^g/m3 diesel exhaust particles, and 190 /ig/m3 H2SO4 coated on the diesel particles
15 (0.15 jmi). There was no change in tracheobronchial or pulmonary clearance of tracer
16 particles with this mixture, compared to air controls. While no deep lung lesions nor any
17 change in turnover rate of epithelial cells from the nose, trachea or alveolar region were
18 noted, there was a decrease in the percentage of total macrophages assessed which had
19 internalized diesel particles following exposure to the mixture, compared to cells recovered
20 from animals exposed to the diesel particles alone. Furthermore, phagocytosis was depressed
21 up to 3 days following exposure to the mixture. The enhanced effect of the particles with the
22 surface acid coat is consistent with studies, described below, with other acid-coated particles.
23 Wong et al. (1994) exposed rats (M; F-344, nose-only) for 4 h/day, 4 days/week for
24 8 weeks to a complex mixture consisting of 350 jwg/m3 California road dust (5 /j.m MMAD)
25 + 65 /ig/m3 (NH4)2SO4 (0.3 jun) + 365 /*g/m3 NH4NO3 (0.6/un) + O3 (0.2 ppm), as well
26 as to O3 alone. Animals were sacrificed at 4 or 17 days after the last exposure to assess
27 stress inducible heat shock protein as an indicator of early pulmonary injury. An increase in
28 heat shock protein was observed with the mixture at both time points, but the effect of
29 O3 was greater than that due to the mixture.
30 Amdur and Chen (1989) exposed guinea pigs to simulated primary emissions from coal
31 combustion processes, produced by mixing ZnO, SO2, and water in a high temperature
April 1995 11.79 DRAFT-DO NOT QUOTE OR CITE
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1 combustion furnace. The animals were exposed 3 h/day for 5 days to ultrafine (0.05
2 CMD, ag=2) aerosols of zinc oxide (ZnO) at up to 5,000 /ig/m3 having a surface coating of ~
3 H2SO4 resulting from this process (ZnO had no effect in this study). Levels of SO2 in the
4 effluent ranged from 0.2 to 1 ppm. Acid sulfate concentrations as low as 20 to 30 /zg/m3 as
5 equivalent H2SO4 delivered in this manner resulted in significant reductions in total lung
6 volume, vital capacity, and DLco. The effects appeared to be cumulative, in that the
7 severity was increased with increasing exposure duration. These exposures also resulted in
8 an increase in the protein content of pulmonary lavage fluid and an increase in PMNs. The
9 investigators noted that much higher exposure levels of pure H2SO4 aerosol were needed to
10 produce comparable results, suggesting that the physical state of the associated acid in the
11 pollutant mixture was an important determinant of response. But one confounder in these
12 studies was that the number concentration was greater for the coated particles than for the
13 pure acid particles and, as mentioned earlier, both number and mass concentration likely play
14 roles in biological responses to acidic sulfate aerosols.
15 Other studies have examined responses to acid-coated particles. Chen et al. (1989)
16 exposed (nose-only) guinea pigs (male, Hartley, 250 to 300g) for 3 h to ultrafine ZnO
17 (0.05 /mi, ag = 1.86) onto which was coated 25 or 84 /*g/m3 H2SO4. Selected eicosanoids
18 were examined in lavage fluid obtained at 0, 72, and 96 h post-exposure. Immediately
19 following exposure, animals exposed to the higher acid concentration showed increased levels
20 of prostaglandin F2a compared to those found in animals exposed to ZnO alone. Levels of
21 prostaglandins El and 6-keto-PGFla, thromboxane B2 and leukotriene B4 were similar to
22 those found in animals exposed to the metal alone. During the post-exposure period, changes
23 in prostaglandin El, leukotriene B4 and thromboxane B2 were noted. But the authors
24 suggested that there was no causal relationship between these changes and alterations in
25 pulmonary function noted earlier (Amdur et al., 1986).
26 Chen et al. (1992b) exposed guinea pigs to acid-coated ZnO for 1 h, and examined
27 airway responsiveness to acetylcholine administered 1.5 h after exposure. In this study, the
28 equivalent concentrations of H2SO4 were 20 and 30 /ig/m3 coated on the 0.05 /mi ZnO
29 particles. Animals were also exposed to pure H2SO4 droplets at 202 /ig/m3 and having a
30 similar size as the coated particles (0.06 /mi, ag = 1.36). Hyperresponsiveness was found in
31 animals exposed to the acid-coated particles, but not in those exposed to furnace gases
April 1995 11-80 DRAFT-DO NOT QUOTE OR CITE
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1 (particle-free control) or to the ZnO alone. A similar quantitative change was noted in those
2 animals exposed to the pure droplet at about 10 times the concentration of the coated
3 particles (Amdur and Chen, 1989).
4 Amdur et al. (1989) exposed guinea pigs for 3 h or for 3 h/day for 5 days to a similar
5 atmosphere as above and examined pulmonary function. Levels of 30 ^g/m3 H2SO4
6 produced a significant depression in diffusing capacity (DLco). Repeated exposures at the
7 equivalent of 21 ^g/m3 H2SO4 resulted in reduced DLco after the 4th exposure day; at the
8 higher (30 /ig/m3) level of coated acid, DLco decreased gradually from the first exposure
9 day.
10 The interaction of acid coated particles with ozone was examined by Chen et al. (1991).
11 Guinea pigs (male, Hartley, 260 to 325 g) were exposed (nose-only) to sulfuric acid layer
12 ZnO particles (0.050 /*m CMD, ag=2) at 24 or 84 /ig/m3 H2SO4 or pure acid (0.08 ^m) at
13 300 /ig/m3 for 2 h, followed by 2 h rest period and 1 h additional exposure (whole body) to
14 air or 0.15 ppm O3. Other animals were exposed to acid coated ZnO having an equivalent
15 acid concentration (24 jig/m3) for 3 h/day for 5 days. This was followed by exposure for 1
16 h to 0.15 ppm O3 on day 9, or to two additional 3 h exposures to 24 /*g/m3 H2SO4
17 layered-ZnO on days 8 and 9. In the single exposure series, animals exposed only to the
18 higher coated acid concentration followed by ozone showed greater than additive changes in
19 vital capacity and DLco, while those exposed first to the pure acid droplet did not show any
20 change greater than that due to ozone alone. Animals exposed repeatedly and then to the two
21 added acid exposures showed greater reductions in lung volumes and DLco than did those
22 that did not receive the additional acid exposures. Finally, animals exposed to ozone after
23 acid showed reduced lung volumes and DLco not observed in animals exposed to either
24 ozone alone or acid alone. In terms of acid alone, neither single exposure to the coated acid
25 affected the endpoints, while exposure to the pure acid decreased DLco. The investigators
26 concluded that single or multiple exposures to the acid-layered ZnO resulted in an enhanced
27 response to subsequent exposures to acid or ozone and that the manner in which the acid was
28 delivered (i.e., as a pure droplet or as a surface coating) affected whether or not any
29 interaction occurred. However, it is likely that the number concentration of particles was
30 greater in the zinc oxide aerosol than in the pure acid aerosol, and the interaction may reflect
31 this greater particle number. It should also be noted that ZnO itself may have produced
April 1995 H_8i DRAFT-DO NOT QUOTE OR CITE
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1 some biological response, or contributed to any interaction with the acid, in some of the
2 studies reported for some endpoints.
3
4 11.3.2 Nitrates
5 11.3.2.1 Human Studies
6 Five studies have been conducted on human exposure to nitrate aerosols since 1979
7 (see Table 11-9). These studies have been discussed in the Acid Aerosol Issues Paper (U.S.
8 Environmental Protection Agency, 1989). The only obvious effect was a decrease in Gaw
9 and in PEFV curves in normal subjects with influenza exposed to 7,000 /*g/m3 of sodium
10 nitrate (NaNO3) aerosol. This is probably three orders of magnitude (i.e., approximately
11 1,000 times) above the nitrate concentration that may exist in the ambient air. These studies
12 indicate that, at least as far as lung function is concerned, there is no present concern for
13 pulmonary function effects from current ambient levels of nitrate aerosols.
14 Sackner et al. (1979) studied a diverse group of normal and asthmatic subjects exposed
15 to concentrations reaching 1,000 ^g/m3 NaNO3 for 10 min at rest. There were no significant
16 effects on an extensive battery of pulmonary function tests.
17 Utell et al. (1979) studied both normal and asthmatic volunteers exposed to
18 7,000 /xg/rn3 NaNO3 (0.46 /mi) aerosol for 16 min via mouthpiece. The major health effect
19 end points measured in their study included R^, both full and PEFV curves, airway
20 reactivity to carbachol, and aerosol deposition. Aerosol deposition as a percentage of inhaled
21 aerosol averaged about 50% for normals and about 56% for asthmatics; the group differences
22 were not significant. The exposure to NaNO3 aerosol was indistinguishable from the control
23 NaCl exposure in normals. Similarly, there were no effects of NaNO3 exposure on
24 asthmatics.
25 Utell et al. (1980) subsequently studied 11 subjects with influenza exposed to the same
26 NaNO3 regimen as above. The subjects were initially exposed at the tune of illness and then
27 were reexposed 1,3, and 6 weeks later. Aerosol deposition ranged from 45 to 50% over the
28 four exposure sessions. All subjects had cough and fever, and 10 of 11 subjects had viral or
29 immunologic evidence of acute influenza. Baseline measurements of FVC and FEVj were
30 within normal limits and did not change throughout the 6-week period. There were small but
31 significant decreases in Gaw following NaNO3 inhalation, but not after NaCl exposure. This
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T3
2.
TABLE 11-9. EXPOSURE CONDITIONS AND RESPONSES IN SUBJECTS EXPOSED TO NITRATES
a
oo
u>
Reference
Kleinman et al.
(1980)
Sackner et al.
(1979)
Stacy et al. (1983)
Utell et al. (1979)
Utell et al. (1980)
o
Abbreviations:
Nitrate Species
and Cone.
(^g/m3)
NH4NO3
200
NaNO3
10,100,100
1,000
1,000
80 (NH4NO3)
80 (NH4NO3)
+0.5 ppm
NO2
NaNO3
7,000
NaN03
7,000
Exposure Exercise Exercise
Duration Duration Ventilation
(min) (min) (L/min)
120 60 =20
10
240 30 55
16 (x2)
(32 Total)
16 (X2)
(32 Total)
MMAD = Mass median aerodynamic diameter. NaNOj =
NH4N03 =
Ammonium nitrate.
Relative
Temp. Humidity Number of
(°C) (Percent) Subjects
31 40 20
19
5
5
6
6
6
6
30 60 12
12
25 10
11
25 11
Subject Aerosol
Char. MMAD
Normal 1 . 1
Asthma
Normal 0.2
Asthma
Normal
Asthma
Normal
Asthma
Normal 0.55
Normal
Normal 0.46
Mild
Asthmatics
Influenza 0.49
Patients
Effects
No significant changes in
normals or asthmatics
except possible decrease in
Rp No symptom effects.
No changes.
No effects.
No effects.
No symptoms. SGaw
decreased 17% and max
40% TLC decreased 12%
after nitrate, within 2 days
of onset of illness.
Similar effects 1 week
later, but not 3 weeks
later.
Sodium nitrate. max40% TLC = Maximum expiratory flow at 40% of TLC on
SGaw = Specific airway conductance.a PEFV curve.
Rj = Total respiratory resistance.
-------
difference was present during acute illness and 1 week later, but was not seen at 3 and
6 weeks after illness. The decrease in SGaw seen on the initial exposure was accompanied by
a decrease in partial expiratory flow at 40%TLC; this was also observed at the 1-week
follow-up exposure. This study suggests that the presence of an acute viral respiratory tract
infection may render humans more susceptible to the acute effects of nitrate aerosols.
Nevertheless, the concentration of nitrates used in this exposure study exceed maximum
ambient levels by more than 100-fold.
In addition to NaNO3 aerosols, ammonium nitrate (NH4NO3) exposure has been studied
by Kleinman and associates (1980). Twenty normal and 19 asthmatic subjects were exposed
to a nominal 200 /*g/m3 of 1.1 /xm NH4NO3 aerosol. The 2-h exposures included mild,
intermittent exercise and were conducted under warm conditions (31 °C, 40% RH). There
were no significant physiologically meaningful effects of the NH4NO3 exposure in either
subject group.
Stacy et al. (1983) also studied the effects of 80 jug/m3 of NH4NO3 in a group of
healthy male adults. As in the Kleinman et al. (1980) study, there were no changes in lung
function or symptoms.
Nitrates (e.g., sodium nitrate) have not been found to cause any deleterious effects
(Utell et al., 1979, 1980; Kleinman et al., 1980; Stacy et al., 1983) at levels that might be
expected in the atmosphere.
11.3.2.2 Animal Studies
The toxicologic database supporting any health effects from inhaled nitrates is limited.
Sackner et al. (1979) exposed anesthetized dogs (via endotracheal tube) to sodium nitrate
aerosols (0.1 to 0.2 /im) at 0.9 or 11 mg/m3 for 7.5 min or at 5 mg/m3 for 4 h. No effect
on indices of pulmonary mechanical function, namely total respiratory resistance, functional
residual capacity, compliance, or specific respiratory conductance, were noted up to 2 to 3 h
postexposure. Sheep exposed (head only) to 0.9 mg/m3 for 20 min or to 5 mg/m3 for 4 h
showed no change in tracheal mucous velocity compared to controls.
Ehrlich (1979) examined the effect of 3-h exposures to various nitrate salts on
resistance to respiratory bacterial infection in mice. Animals were exposed to maximal
concentrations as follows: lead nitrate (2 mg/m3); calcium nitrate (2.8 mg/m3); sodium
April 1995 H_84 DRAFT-DO NOT QUOTE OR CITE
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1 nitrate (3.1 mg/m3); potassium nitrate (4.3 mg/m3); ammonium nitrate (4.5 mg/m3); and zinc
2 nitrate (1.25 mg/m3). Only zinc nitrate [Zn(NO3)2] resulted in any significant mortality
3 increase, the extent of which seemed to be concentration related; the highest concentration
4 increased mortality by about 20%. However, since the response was similar to that seen
5 with zinc sulfate, the effect was likely due to the zinc ion (Zn+2) rather than to the nitrate
6 ion (NOjO.
7 Busch et al. (1986) exposed rats and guinea pigs (whole body) with either normal lungs
8 or lungs with elastase-induced emphysema to 1 mg/m3 of ammonium nitrate (0.6 fim
9 MM AD, ag = 2.2) for 6 h/day, 5 days/week for 4 weeks. Using both light and electron
10 microscopy, the investigators concluded that there were no biologically significant effects of
11 nitrate exposure on lung structure. Loscutoff et al. (1985) exposed both normal and elastase-
12 treated rats and guinea pigs (whole body) to ammonium nitrate (1 mg/m3, 0.6 /mi MM AD,
13 ag = 2) for 6 h/day, 5 days/week for either 5 or 20 days and measured various pulmonary
14 function indices, namely diffusing capacity (DLCO), quasi-static compliance, residual volume,
15 functional reserve capacity and single breath N2-washout. No biologically significant
16 changes were noted in rats due to ammonium nitrate exposure, nor was there any interaction
17 between elastase treatment and aerosol exposure. Likewise, elastase treated guinea pigs were
18 no more sensitive to aerosol exposure than were normals and the only effect of exposure was
19 a slight change in the slope of the N2-washout curve, although it was actually in the direction
20 of improved function.
21 Charles and Menzel (1975) examined the effects of nitrate upon the release of histamine
22 by guinea pig lung fragments, response to some pollutants may be a function of their ability
23 to elicit biologic mediators. Lung fragments were incubated for 0.5 h with 20 to 200 mM
24 ammonium nitrate. Histamine was released in proportion to the concentration of salt present.
25 However, the response was not totally due to NO3_; ammonium (NH4+) ion was also a
26 possible contribution. The relation of this actual in vivo exposures is, however, not clear.
27 Other in vitro exposures suggest that NO3. may affect red blood cells by altering the
28 transport of calcium across the cell membrane (Kunimoto et al., 1984).
29
30
31
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1 11.4 COMPLEX MIXTURES
2 11.4.1 Introduction
3 The health effects of complex mixtures with particles are studied rarely because of their
4 inherent difficulties. A major exception is diesel emissions which are described in the
5 following, along with a few other reports on different mixtures. Older studies of complex
6 mixtures are summarized in the previous CD (U.S. Environmental Protection Agency, 1982).
7 They will not be reported here because they are not especially informative on first principles
8 of mixtures or specific-classes of mixtures.
9
10 11.4.2 Mixtures Containing Other PM
11 There is little available data on complex mixtures of other PM. Pick et al. (1984)
12 exposed rabbits (NZW, 1.5 to 2 kg) for 0.2 to 2 h to the pyrolysis products derived from
13 Douglas fir wood (exposure concentrations and particle size were not stated). They noted an
14 increase in the total number of cells recovered by lavage immediately postexposure, and the
15 magnitude of this increase was related to the exposure duration. The ratio of AMs, PMNs
16 and lymphocytes was constant at all exposure durations except for the longest, in which case
17 lymphocyte numbers increased. A depression in the uptake and intracellular killing of
18 Pseudomonas aeruginosa was found in AMs obtained from the smoke-exposed animals
19 compared to cells from air controls. Furthermore, cells from the smoke-exposed animals
20 were smaller, and had reduced surface adherence.
21 Clark et al. (1990) exposed dogs (mongrel, 15 to 20 kg) for 5 min to wood smoke
22 (from fir plywood sawdust and kerosene; no specified particle size or exposure concentration)
23 via an endotracheal tube. The lungs were examined for increased extra vascular water around
24 the pulmonary arteries, which was found to occur with smoke exposure but not in air sham
25 controls. This response was suggested to be due to increased microvascular permeability
26 without any increase in capillary pressure. A decrease in lung compliance was also noted
27 with smoke exposure.
28 Another complex mixture examined was a combination of gaseous sulfur (IV),
29 paniculate sulfur (IV) and paniculate sulfur (VI). A series of studies involved exposures
30 (whole body) of Beagle dogs (M, 34 mo old) for 22.5 h/day, 7 days/week for up to 290 days
31 to such an atmosphere, in which respirable sulfur IV (0.6 /zm MM AD, ag=2) was
April 1995 H_86 DRAFT-DO NOT QUOTE OR CITE
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1 maintained at a concentration of 300 /xg/m3 (Heyder et al., 1992; Maier et al., 1992;
2 Kreyling et al., 1992; Schulz et al., 1992; Takenaka et al., 1992). Various biological
3 endpoints were examined, and responses included reductions in nonspecific defense
4 capabilities of AMs such as phagocytosis and production of reactive oxygen species;
5 increases in protein and /3-N-acetylglucosaminidase in lavage fluid; increased rate of
6 clearance of test particles from lungs to blood (suggesting a change in the permeability of the
7 epithelium); minor changes in pulmonary function; and some histopathological effects, such
8 as hyperplasia of respiratory epithelium of the posterior nasal passages and a slight (but not
9 statistically significant) decrease in the volume density of alveolar septa. The exact role
10 played by specific components of this mixture could not be determined because responses to
11 individual components were not examined.
12
13 11.4.3. Atmospheric Particulate Matter
14 11.4.3.1. Introduction
15 The 1982 Air Quality Criteria Document for Particulate Matter and Sulfur Dioxides
16 (U.S. Environmental Protection Agency, 1982) reviewed studies showing that extractable
17 organic matter from ambient air paniculate matter collected from several urban localities was
18 genotoxic in in vitro tests such as the Ames Salmonella mutagenicity test and mammalian cell
19 transformation assays and was tumorigenic in subcutaneous injection and skin painting assays
20 in rodents. Also discussed were rodent subcutaneous injection and skin painting studies
21 showing tumorigenic activity of organic-solvent extracts of particulate matter emitted from
22 combustion sources known to contribute to ambient air particulate matter, such as diesel
23 engines, gasoline engines, and furnaces burning coal or oil. Polycyclic aromatic
24 hydrocarbons (PAHs) were discussed as the best-studied class of potential carcinogenic
25 compounds found in particulate extracts. The 1982 document also discussed evidence for the
26 genotoxicity of SO2 and bisulfite in in vitro tests, the equivocal evidence for an synergistic
27 tumorigenic interaction between SO2 and benzo[a]pyrene and the tumorigenic potential of
28 some metals found in ambient air particulate matter. The conclusion was reached that "all the
29 major types of airborne particulate matter may contain adsorbed compounds that are
30 mutagenic and/or carcinogenic to animals and may contribute in some degree to the incidence
31 of human cancer associated with exposure to urban air pollution".
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1 Pertinent research completed since the publication of the previous Agency document,
2 has included: mutagenicity or tumorigenicity testing of organic-solvent extracts of ambient
3 air paniculate matter collected from various localities, mutagenicity and tumorigenicity
4 testing of particular emission sources that contribute to ambient air particulate matter, and
5 fractionation studies of condensates or organic-solvent extracts of paniculate emissions from
6 specific sources. The research has focused mostly on particulate matter produced by the
7 pyrolysis or combustion of carbon-containing material; relatively little attention has been
8 given to the mutagenicity or carcinogenicity of acidic aerosols (i.e, particulate sulfates or
9 particulate nitrates). This section presents an overview of the results of this research. This
10 section also discusses epidemiological studies of the potential link between general air
11 pollution and cancer in humans and recent research on the use of biomarkers of genetic
12 damage to assess one class of carcinogens (polycyclic aromatic hydrocarbons, PAHs) found
13 in ambient air particulate matter.
14
15 11.4.3.2. Particulate Matter and Cancer in Animals
16 Concern for the possible carcinogenicity of particulate matter has historical origins
17 dating to 1775 when Percival Pott wrote about the frequent occurrence of scrotal cancer
18 among chimney sweeps. However, experimental evidence of the carcinogenicity of
19 particulate matter in animals was not produced until the middle part of this century in
20 investigations that collected particulate matter from several urban locations, extracted the
21 particulate matter with organic solvents and applied the extracts to the skin or to
22 subcutaneous regions of mice.
23 In general, the results of animal carcinogenicity studies demonstrate that ambient air
24 particulate matter contains extractable material that can produce tumors in animal systems
25 when applied to the skin or injected subcutaneously. Table 11-10 summarizes experimental
26 protocols used and tumor incidences obtained in animal carcinogenicity studies of samples of
27 organic-solvent extracts of ambient air particulate matter. No reports were located regarding
28 cancer bioassays with animals exposed by inhalation to aerosols of particulate matter
29 collected from ambient air. Tumor incidences were not greatly elevated in most studies that
30 exposed adult mice by skin painting or subcutaneous injection. Among the three such studies
31 listed in Table 11-10, there are 17 treated groups of mice (Leiter et al., 1942; Kotin et al.,
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TABLE 11-10. Carcinogenicity Tests of Samples of Ambient Air Particulate Matter in Animals.
3.
Reference
Sample Collection
Species/Strain/Sex
Exposure Protocol
Particulate Matter Source
and incidence of Animals
with Tumors
Comments
oo
Leiter et al., 1942
Particulate matter was
collected by filtering air
through cotton cloth at
sites in downtown
Pittsburgh and Chelsea,
Massachusetts, by
mechanical precipitation
in a "labyrinth" for the
intake and exhaust sites
for the Holland Tunnel
in New York City or by
electrical precipitation
on unoiled plates at
sites in Pittsburgh and
Chelsea. Period of
collection was not
specified. Particulate
matter was extracted
with benzene/ethylether.
Mice/C3H/M (n=20)
Mice/strain A/M.F
(n=10)
"Tars" were suspended
in tricaprylin and single
subcutaneous injections
containing 21,000 to
71,000 jig tar were
given in the right axilla
of each mouse.
Chelsea:
(Cloth sample): 2/38
(Precipitron sample): 0/39
Pittsburgh:
(Precipitron sample): 4/32
(Cloth sample): 5/33
Holland:
(New York intake): 0/30
(New York exhaust): 1/41
(New Jersey intake): 0/33
(New Jersey exhaust): 2/34
Numerator of
incidence is for
mice showing
sarcomas at the
injection site by the
end of a 12-month
observation period.
Denominator is the
time of mice
surviving at the
time of first tumor
appearance, cited as
5 months. No
injection site tumors
were found during
the observation
period in 20 control
C3H males that
were given single
subcutaneous
injections of the
vehicle, tricaprylin.
-------
f
TABLE 11-10. Carcinogenicity Testing of Samples of Ambient Air Particulate Matter in Animals.
Reference
Sample Collection
Species/Strain/Sex
Exposure Protocol
Particulate Matter
Source and
incidence of
Animals with
Tumors
Comments
D
O
Z
O
H
O
O
I— I
H
W
Kotinetal., 1954
Collection, via large
volume sample collector
onto Whatman filter
paper, occurred for 42 or
59 8-hour days at two Los
Angeles sites, 1 with
heavy industrial activity
and 1 with heavy traffic
congestion between
August and October 15.
Particulate matter from
the 2 sites was pooled and
extracted with benzene.
mice/C57 Black/M,F
(n=38)
A benzene solution of the
extracts (concentration was
not specified) was painted
on the skin in the
interscapular area, 3-times
weekly for life.
Los Angeles: 13/31
Numerator of incidence
is for mice with
papillomas at exposure
site; an unspecified
number of the
papillomas progressed to
carcinomas.
Denominator of
incidence is for number
of mice surviving until
the time of first tumor
appearance, 15 months
and 3 days. The authors
did not clearly specify
the duration of their
observation period, but
noted that nine mice still
were alive at the time
the report was written.
Benzene controls were
housed and painted in
the same manner as
treated mice. No skin
tumors were found
during the observation
period in the 37 controls
that were alive at the
time of first tumor
appearance.
-------
P.
Reference
TABLE 11-10 (Cont'd). Carcinogenicity Testing of Samples of Ambient Air Particulate Matter in Animals.
Particulate Matter
Source and
incidence of
Animals with
Tumors
Sample Collection
Species/Strain/Sex
Exposure Protocol
Comments
Hueperetal.,
1962
1 -month collection on
fiberglass filter
membranes located in
downtown and
industrialized areas
mice/Black mice/M,F
(n=36)
Monthly subcutaneous
injections of 400 j*g
benzene extract, suspended
in 0.1 mL tricaprylin,
were given for 11 months,
followed by 800 /*g
monthly until the 24th
month.
Atlanta: 6/72 New
Orleans: 1/72
Birmingham: 4/72
Los Angeles: 0/72
San Francisco: 3/72
Cincinnati: 3/72
Philadelphia: 3/72
Detroit: 5/72
Incidence was for
observable tumors at
injection sites. Maximal
observation period was 2
years. No injection site
tumors were found in 71
vehicle control mice.
O
O
2
o
H
O
g
a
§
o
-------
TABLE 11-10 (Cont'd). Carcinogenicity Testing of Samples of Ambient Air Particulate Matter in Animals.
2.
Reference
Sample Collection
Species/Strain/Sex
Exposure Protocol
Particulate Matter Source
and incidence of Animals
with Tumors
Comments
vb
to
H
6
o
z
3
O
d
o
H
M
O
*>
O
Epstein et al.,
1966
Particulate matter
samples were collected
with high-volume
samplers at Continuous
Air Monitoring Program
sites in 6 U.S. cities
during 1963. Samples
were combined by site
and extracted with
benzene.
Mice/Swiss
(ICR/Ha)/M,F
(n= 105 = 137)
Newborn mice were
subcutaneously injected
(in the neck) with 5,000,
10,000, and 15,000 /tg of
extracts suspended in
tricaprylin on days 1, 7
and 14 of life. Mice
were allowed to survive
until the end of a 50-52
week period.
LIVER TUMORS:
Controls: 4/67 M;
0/68 F
Chicago: 3/11 M;
0/33 F
Cincinnati: 5/6 M;
1/22 F
Los Angeles: 1/13 M;
0/15 F
New Orleans: 10/29 M;
0/30 F
Philadelphia: 4/13 M;
0/27 F
Washington: 4/13 M;
0/16 F
PULMONARY TUMORS:
Controls: 9/67 M;
4/68 F
Chicago: 6/11 M;
7/33 F
Cincinnati: 4/6 M;
3/22 F
Los Angeles: 4/13 M;
1/15 F
New Orleans: 7/29 M;
6/30 F
Philadelphia: 1/13 M;
6/27 F
Washington: 5/13 M;
7/16 F
Increased early mortality
before weaning occurred
in each treatment group
compared with vehicle
controls (16%) indicating
that a maximum tolerated
dose was exceeded.
Percentage mortality
before weaning was: 39%
Chicago; 53% Cincinnati;
61% Los Angeles; 29%
New Orleans; 35%
Philadelphia; 53%
Washington. Tumor
incidences are for the
number of mice with
tumors at a given site
divided by the number of
mice alive at weaning
minus those that were
autolyzed or cannabilized.
Malignant lymphomas
were also found in a few
treated groups at elevated
incidences compared with
controls, but neither the
magnitude or the
consistency of this finding
was as great as the
magnitude and consistency
of the increases in liver
and lung tumor incidence.
-------
TABLE 11-10 (Cont'd). Carcinogenicity Testing of Samples of Ambient Air Particulate Matter in Animals.
SO
VO
Ul
Reference
Sample Collection
Species/Strain/Sex
Exposure Protocol
Particulate Matter Source
and incidence of Animals
with Tumors
Comments
O
O
55
O
H
O
a
s
w
8
n
i—i
H
W
Asahina et al.,
1972
Particulate matter was
collected on air
conditioner filters for a
6-month period from
8/65 to 2/66 at an office
building in New York
City. Samples were
extracted with benzene,
which was removed by
evaporation.
Mice/Swiss
(ICR/Ha)/M,F
(n=53-86)
Newborn mice were
subcutaneously injected
(in the neck) with 0.1,
0.1 and 0.2 mL of
extracts suspended in
tricaprylin on days 1,
7 and 14 of life; each
mouse received total
doses of 0, 10,000, or
20,000 jig extract.
Mice were allowed to
survive until the end of
a 50-52 week period.
LIVER TUMORS:
Control: 3/31 M; 0/35 F
10 mg: 3/19 M; 0/28 F
20 mg: 4/13 M; 0/17 F
PULMONARY
ADENOMAS:
Control: 2/31 M; 1/35 F
10 mg: 0/19 M; 3/28 F
20 mg: 3/13 M; 1/17 F
LYMPHOMAS:
Control: 0/31 M; 2/35 F
10 mg: 1/19 M; 1/28 F
20 mg: 0/13 M; 1/17 F
Increased early mortality
before weaning occurred in
treated mice (33% and 43%
for 10,000 and 20,000 jtg)
compared with vehicle
control mice (23%).
Another group dosed with
40,000 /ig showed 86%
early mortality, thus
precluding its use in
meaningful cancer
evaluation. Tumor
incidences are for the
number of mice with
tumors at a given site
divided by the number of
mice alive at weaning
minus those that were
autolyzed or cannabilized.
Injection site tumors were
reported to be rare. The
extract was fractionated
into various fractions that
were tested for
tumorigenicity via the same
protocol. Active fractions
included a basic fraction,
an aromatic fraction and an
aliphatic fraction.
-------
TABLE 11-10 (Cont'd). Carcinogenicity Testing of Samples of Ambient Air Participate Matter in Animals.
3.
Lft
Paniculate Matter Source and
incidence of Animals with Tumors
Reference
Sample Collection
Species/Strain/Sex
Exposure Protocol
Comments
T1
7*
O
O
Epstein et al., 1979
Paniculate matter was collected
with high-volume samplers in
several U.S. cities in 1962.
The samples were composited
and extracted with benzene.
Extracts were stored at -4°C.
Mice/Swiss albino
(ICR/HA)/M,F (n=90-
233)
Newborn mice were
subcutaneously injected (in
the neck) with varying doses
of extracts suspended in
tricaprylin on days 1, 7 and
14 of life as indicated in the
next column. Mice were
allowed to survive until the
end of a 50-52 week period.
LIVER TUMORS:
CONTROLS:
(0, 0, Omgondays 1, 7 & 14)
1/44 M; 0/38 F
5, 10, 10: 5/51 M; 0/46 F
5, 10, 15: 5/23 M; 0/27 F
5, 15, 15: 2/32 M; 0/28 F
5, 15, 20: 1/28 M; 0/24 F
PULMONARY ADENOMAS,
SOLITARY:
0, 0, 0: 5/44 M; 3/38 F
5, 10, 10: 13/51M; 5/46 F
5, 10, 15: 7/23 M; 2/27 F
5, 15, 15: 5/32 M; 1/28 F
5, 15,20: 5/28 M; 5/24 F
TOTAL NUMBER OF TUMOR
BEARING MICE:
0, 0, 0: 7/44 M; 4/38 F
5, 10, 10: 29/51 M; 20/46 F
5, 10, 15: 11/23M; 9/27 F
5, 15, 15: 11/32M; 11/28F
5, 15, 20: 14/28 M; 19/24 F
Increased early mortality before
weaning occurred in treated
groups (32%-55%) compared with
vehicle control mice (12%).
Several other treatment groups
were included (but not shown in
this table) that injected 5,000 to
15,000 jig on only 1 or 2 of the
three injection days; tumorigenic
response was not as marked as in
those shown in previous column.
Lymphomas were also observed in
treated and control mice. Tumor
incidences are for the number of
mice with tumors at a given site
divided by the number of mice
alive at weaning minus those that
were autolyzed or cannabilized. A
significant dose-related increase in
total tumor incidence with
increasing dose was evident when
cumulative doses for all groups
were expressed on a gram body
weight basis and included in a
regression analysis.
O
H
O
i
O
I— I
H
m
-------
TABLE 11-10 (Cont'd). Carcinogenicity Testing of Samples of Ambient Air Particulate Matter in Animals.
s
Reference
Sample Collection
Species/Strain/Sex Exposure Protocol
Particulate Matter Source
and incidence of Animals
with Tumors
Comments
Lewtas et al.,
1991; Cupitt
et al., 1994
Particulate matter was
collected from two sites
in Boise, Idaho for 4
months during the
winter. Particulate
matter was extracted
with dichloromethane.
Two composite samples
were constructed: one
dominated by wood
smoke (WS) combustion
products (78% WS, 11%
MS, 11% residual) &
one with a greater
contribution from mobile
sources (MS) (51% WS;
33% Ms, 16% residual).
Mice/Sencar/NS
(n=40 per
treatment group)
Mice were given
single initiating dermal
doses (in acetone) at
dose levels of 0,
1,000, 2,000, 5,000
10,000, or 20,000
/ig/mouse, followed
by promoting doses of
2 fig TPA, 2x weekly
for 26 weeks.
Papillomas at
application site were
counted and tumor
multiplicity was
determined for each
dose group.
Incidences of tumors were
not reported, but estimated
tumor initiation potencies
were reported (i.e., slopes
of the tumor
multiplicity/dose curve
estimated by regression
analysis)
Wood-smoke dominated
sample: 0.095
papillomas/mouse/1,000 ^g
Wood smoke/Mobile
sources sample: 0.215
papillomas/mouse/1,000 /xg
Estimated tumor initiating
potencies for ambient air
paniculate samples were
intermediate between
estimates for cigarette smoke
condensate (0.0029
papillomas/mouse/1,000 ng)
and coke oven particulates
(2.10
papillomas/mouse/1,000 /ug).
NS = not specified
-------
1 1954; Hueper et al., 1962). Excluding the single outlying value of 42% (13/31) from the
2 Kotin et al. (1954) study, the group percentages of mice with contact site tumors range from
3 0 to 15% with a mean of 4.8%. In contrast, assays with newborn mice generally show
4 greater tumorigenic responses than the experiments with adult mice. For example, groups of
5 newborn mice, subcutaneously injected on days 1, 7, and 14 of life with total doses of
6 25,000 to 40,000 /ig of material extracted from a composite sample of ambient air particulate
7 matter collected from several U.S. cities in 1962, showed total tumor percentages (hepatic,
8 pulmonary and lymphatic tumors) after 1 year ranging from 33% (9/27) to 79% (19/24)
9 (mean = 47%; median = 45%) compared with vehicle control percentages of 16% (7/44)
10 and 10% (4/38) (Epstein et al., 1979; see Table 11-10). Although the newborn mouse assay
11 is a sensitive experimental technique to detect potential carcinogens, direct extrapolation of
12 these results to predict human response to ambient air particulate matter is questionable due
13 to uncertainties involving potential sensitivity differences among species or age (e.g.,
14 newborns versus adults) and likely dispositional differences (pharmacokinetic and
15 pharmacodynamic) associated with route of exposure (dermal or subcutaneous versus
16 inhalation) and physicochemical properties of the material (extracted organic matter versus
17 intact particulate matter with adsorbed organic matter). A further complication is that studies
18 with organic-solvent extracts of particulate matter utilize a concentrating process to obtain the
19 test material. For example, the 20,000 ^g dose of material injected into the newborn mice in
20 the Asahina et al. (1972) study was obtained from approximately 1,850 m3 of air, which is
21 approximately equivalent to the amount of air inhaled by human adults in 92 days (assuming
22 an inhalation rate of 20 m3/day).
23 In the only other available animal bioassay study, particulate matter extracts of ambient
24 air, collected at two sites in Boise, Idaho from November, 1986 to February, 1987, were
25 tested for tumor initiating activity in mouse skin tumor initiation assays (Lewtas et al., 1991;
26 Cupitt et al., 1994). Using tracer species and receptor modeling methods, the contribution
27 of residential wood smoke (WS) combustion and mobile engine (MS) combustion sources to
28 the collected samples was determined and used to construct two composite samples; one
29 dominated by wood smoke combustion products (78% WS; 11% MS; 11% residual) and
30 another with a greater contribution from mobile sources (51% WS; 33% MS; 16% residual).
31 Particulate matter samples were extracted with dichloromethane and solvent exchanged into
April 1995 11-96 DRAFT-DO NOT QUOTE OR CITE
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1 dimethylsulfoxide that was evaporated under dry nitrogen. Initiating doses of extracts
2 dissolved in acetone at dose levels of 0, 1,000, 2,000, 5,000, 10,000, or 20,000 ^g/mouse
3 were applied to the dorsal skin of groups of 40 Sencar adult mice. Following a one-week
4 period, 2 jug 12-o-tetradecanoylphorbol-13-acetate, a potent tumor promoter, was applied
5 twice weekly for 26 weeks. At 26 weeks, papillomas at the application site were counted
6 and tumor multiplicity (papillomas per mouse) was determined for each dose group. Slopes
7 of the tumor multiplicity/dose curve were estimated by regression analysis and used as a
8 measure of the tumor initiation potency of the samples. Estimated tumor initiation potencies
9 for the two samples were 0.095 and 0.215 papillomas/mouse/1,000 /xg for the
10 wood-smoke-dominated and wood-smoke/mobile-sources samples, respectively. Comparison
11 of the potency values for these ambient air extracts with those for extracts of paniculate
12 matter from specific sources of combustion showed them to be intermediate in the observed
13 range between the extremes of 0.0029 papillomas/mouse/1,000 /xg for cigarette smoke
14 condensate and 2.10 papillomas/mouse/1,000 ^mg for coke oven paniculate emissions (see
15 Figure 11-4). The comparative potency of organic extracts of different sources of paniculate
16 matter in the Sencar mouse skin tumor initiation assay has been proposed to be predictive of
17 human lung cancer risk based on a correlation between human lung cancer risks (estimated
18 from epidemiological data) for cigarette smoke, roofing tar emissions and coke oven
19 emissions and their respective potencies in the mouse skin tumor initiation assay (Lewtas,
20 1993).
21 In summary, extracts of ambient air paniculate matter collected from several sites
22 produced small increases in contact site tumors in adult mice after epicutaneous or
23 subcutaneous administration, significant increases in total lung, liver or lymphatic tumors in
24 mice after subcutaneous administration shortly after birth and significant increases in skin
25 tumors in adult mice after administration of initiating dermal doses followed by repeated
26 promoting doses of a phorbol ester.
27
28 11.4.3.3. Genotoxicity of Particulate Matter
29 As discussed in the 1982 document (U.S. Environmental Protection Agency, 1982),
30 supporting data for the carcinogenicity of paniculate matter comes from numerous studies
31 that have examined the in vitro genotoxicity of organic-solvent extracts of paniculate matter
April 1995 H_97 DRAFT-DO NOT QUOTE OR CITE
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100
papillomas/mouse/mg
Benzo[a]pyrene
SmokvCoal
Coke Oven
Aluminum Smelter
Rpofina Coal Tar
Diesel Car A —
Ambient Air 1
Gasoline (Non-Catalyst) —
Diesel Car B
Ambient Air 2
Gasoline Catalyst
Diesel Car C —
Woodstove
(softwood)
Residential Oil Heater
Woodstove
(hardwood)
Cigarette Smoke
Condensate
(80.0)
10
1.0
0.1
0.01
(2.10)
(1.30)
(0.61)
(0.21)
0.18
0.16'
(0.095)
(0.071)
(0.046)
(0.028)
(0.0087)
(0.0029)
0.001
Figure 11-4. Comparative potency of a series of complex mixtures and benzo[a]pyrene
in the Sencar mouse skin tumor initiation assay. The complex mixtures are
organic-solvent extracts of particulate emissions. "Ambient Air 1" is 0.21;
"Ambient Air 2" is 0.095. Numbers in parentheses are slopes from dose-
response curves (Source: Lewtas, 1993)
April 1995
11-98
DRAFT-DO NOT QUOTE OR CITE
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in ambient air collected at various locations throughout the world. The limitations and
potential inaccuracy of extrapolating positive results in genotoxicity tests to predict human
cancer consequences is well known and has been discussed elsewhere (see for example the
U.S. Environmental Protection Agency Cancer Guidelines, 1986 or Williams and
Weisburger, 1991) Nevertheless, the positive evidence found for organic-solvent extracts of
paniculate matter in several types of genotoxicity assays is generally accepted as being
supportive of the potential carcinogenicity of intact particulate matter.
The Ames Salmonella mutagenicity assay continues to be used widely to test the
mutagenicity of organic-solvent extracts of particulate matter. Positive results have been
published recently for particulate matter collected at sites in: Santiago, Chile (Adonis and
Gil, 1993); Rome, Italy (Crebelli et al., 1991); Mexico City, Mexico (Espinosa-Aguirre
et al., 1993); Ann Arbor, Michigan (Hoyer et al., 1992); Tokyo, Japan (Houk et al., 1992);
Silesia, Poland (Motykiewicz et al., 1989); Padova, Italy (Nardini and Clonfero, 1992); Los
Angeles, California (Pitts et al., 1985); Bormida Valley, Italy (Scarpato et al., 1993);
Allegheny County, Pennsylvania (Siderpoulos and Specht, 1994); Sagamihara, Japan (Takagi
et al., 1992); Fukuoka, Japan (Tokiwa et al., 1983); Pisa, Italy ( Barale et al., 1989; Velosi
et al., 1994); Morgantown, West Virginia (Whong et al., 1981); and Taipei, China (Wei et
al., 1991). In general, recent results from Ames assays demonstrate the presence of both
indirect mutagens requiring metabolic activation and direct mutagens not requiring activation.
When compared, mutagenic activities have been higher during winter when domestic heating
systems are operating than during warm months (Adonis and Gil, 1993; Motykiewicz et al.,
1989; Nardino and Clonfero, 1992; Scarpato et al., 1993; Takagi et al., 1992; Tokiwa et al.,
1983; Velosi et al., 1994; Whong et al., 1981; Wei et al., 1981). Polycyclic aromatic
hydrocarbons (e.g., benzo[a]pyrene, dibenz[a,h]anthracene) are historically the earliest
recognized carcinogenic components in extracts of particulate matter from combustion
sources. They are known to require metabolic activation, and are thought to be significant,
but not the sole, contributors to the mutagenicity. Other proposed contributors include
oxygenated aliphatic hydrocarbons, oxygenated PAHs (e.g., PAH ketones, quinones and
phenols) and heterocyclic (O, N or S) aromatic hydrocarbons (Lewtas, 1993; Motykiewicz
et al., 1989). Comparison of mutagenic activities of particulate extracts in Salmonella strain
TA98 with activity in strain TA98NR, a strain known to be resistant to 1-nitropyrene and
April 1995 H_99 DRAFT-DO NOT QUOTE OR CITE
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deficient in nitroreductases, has demonstrated the importance of direct-acting nitroarenes in
many localities (Adonis and Gil, 1993; Crebelli et al., 1991; Espinosa-Aguirre et al., 1993;
Nardino and Clonfero, 1992; Pitts et al., 1985; Takagi et al., 1992).
Less extensive genotoxicity testing of extracts of participate matter has been conducted
in mammalian systems, but the available results, from tests of ambient air samples from
several sites in Europe and the U.S., have been predominately positive. Organic solvent
extracts of paniculate matter samples induced increases in sister chromatid exchange in
cultured human lymphocytes and rodent cells (Lockard et al., 1981; Alink et al., 1983;
de Raat, 1983; Hadnagy et al., 1986), and increased frequency of chromosomal aberrations
in Chinese hamster V79 cells (Motykiewicz et al., 1988) and human lymphocytes (Krishna
et al., 1984; Hadnagy et al., 1986).
Genotoxicity testing of intact ambient air paniculate matter is limited. Crespi et al.
(1985) reported that an intact paniculate sample of an experimental, combustion-generated
soot in the culture medium of metabolically competent human lymphoblast cells (designated
AHH-1) produced dose-related mutations at the Hypoxanthine-Guanine-Phosphoribosyl-
Transferase (HPRT) locus; a methylene chloride extract of the particles was approximately
1,000 times more active than the particle when equal weights of the intact particles and
extracts of the particles were compared in the assay. Kelsey et al. (1994) found that particles
collected from Kuwait ambient air during the 1991 oil fires and ambient air particles
collected from Washington, D.C. (Standard Reference Material 1649 from the U.S. National
Bureau of Standards) both produced increased frequency of sister chromatid exchanges in
cultured human peripheral blood lymphocytes and slight increases in mutation frequency at
the HPRT locus in AHH-1 human lymphoblast cells. The activities of the two particles were
comparable on an equal particle mass basis.
11.4.3.4. Testing of Emission Sources Contributing to Particulate Matter
As discussed in chapter 5 of this document, important sources of paniculate matter
include stationary fuel combustion (e.g., domestic furnaces, electrical power generating
plants), industrial processes (e.g., coke oven emissions, aluminum production emissions) and
transportation-related fuel combustion (i.e., diesel or gasoline engine exhaust). Within the
past 15 years, extensive research has been conducted on the short-term genotoxicity and
April 1995 11-100 DRAFT-DO NOT QUOTE OR CITE
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animal carcinogenicity of specific sources of carbon-containing paniculate matter in ambient
air. This section presents an overview of the findings of research on gasoline engine exhaust
and emissions from burning of heating and cooking fuels, because of their potential
importance in contributing to paniculate matter in many localities (Lewis et al., 1988;
Stevens et al., 1990). Diesel engine exhaust is discussed in Section 11.8.4).
11.4.3.4.1. Carcinogenicity and Genotoxicity of Gasoline Engine Emissions
Evidence of the carcinogenicity of gasoline engine exhaust particles is available from
several assays with animals exposed by several routes. Extracts of gasoline engine exhaust
particles also produced predominately positive results in extensive genotoxicity testing.
Earlier studies (pre-1980) likely involved exhaust from engines using leaded gasoline, but
later studies used exhaust from engines using unleaded gasoline. Although the presence of
lead may have added to the carcinogenic potency of exhaust from engines using leaded
gasoline, organic-solvent extracts of exhaust condensate from engines using non-leaded
gasoline have also produced carcinogenic responses in animals and genotoxic effects in
short-term tests (e.g., Nesnow et al., 1982a, b; 1983; Grimmer et al., 1983; Grimmer et al.,
1984a; Rannug, 1983).
Organic-solvent extracts of paniculate matter in gasoline engine exhaust induced skin
tumors in mice given repeated dermal applications (Kotin et al., 1954; Wynder and Hoffman,
1962) and in mice given initiating dermal doses followed by tumor-promoting dermal doses
of a phorbol ester (Nesnow et al., 1982a, b; 1983). Gasoline exhaust condensate produced
injection site tumors in mice given subcutaneous injections (Pott et al., 1977), skin tumors in
mice given biweekly dermal applications for 104 weeks (Grimmer et al., 1983), lung tumors
in rats given lung implantations (Grimmer et al., 1984a), and lung tumors in Syrian golden
hamsters given intratracheal instillations once every 2 weeks (2,500 or 5,000 jig/hamster per
instillation) for life (Reznick-Schuller and Mohr, 1977). Bioassays conducted with
fractionated extracts of gasoline exhaust condensate administered dermally or by lung
implantation showed that most of the tumorigenic activity was associated with fractions
containing PAHs with more than 3 to 4 rings (Grimmer et al., 1983; Grimmer et al., 1984a).
Carcinogenic responses in rats, hamsters, or mice exposed by inhalation to dilutions of
gasoline engine exhaust were not found in several animal experiments. Brightwell et al.
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(1986; 1989) found no significantly increased incidence of primary lung tumors in groups of
Syrian golden hamsters or Fischer 344 rats exposed (16 hour/day, 5 days/week for up to
2 years) to two dilutions of exhaust from a 1.6-L gasoline engine or a gasoline engine
equipped with a catalytic converter (particle concentrations were below the limit of detection
of 210 /ig/m3) . Campbell (1936) found no increased incidence of tumors, compared with
controls, in groups of mice exposed by inhalation to diluted exhaust from gasoline engines
(particle concentrations were not determined) for 7 hours/day, 5 days/week for about 2
years. Yoshimura (1983), likewise, did not find carcinogenic responses in groups of
ICR-JCL mice, Sprague-Dawley-JCL rats or Syrian golden hamsters exposed to diluted
gasoline engine exhaust (particle concentrations were not reported) for 2 hours/day, 3
days/week for 12 months. Yoshimura (1983), however, reported that concurrent exposure to
inhaled gasoline engine exhaust and ingested carcinogens from drinking water
(diisopropanolnitrosamine for rats, ethyl carbamate for mice or diethylnitrosamine for
hamsters) enhanced the carcinogenic response compared with the response to the respective
carcinogen-contaminated drinking water alone. The frequency of pulmonary tumors
increased with combined exposure to gasoline exhaust and ingested carcinogens in mice from
72.7 to 91.7 %, in rats from 8.7 to 30.3 %, and in hamsters from 3.8 to 10 %. The
enhanced effect was seen at 12 months exposure in rats and hamsters and after 7 months in
mice.
Organic-solvent extracts of gasoline engine exhaust particles, from engines with or
without catalytic converters, was mutagenic, with or without exogenous metabolic activation,
in the Ames assay with Salmonella typhimurium strains (Wang et al., 1978; Oshinishi et al.,
1980; Claxton, 1981; Brooks et al., 1984; Norpoth et al., 1985; Lewtas, 1985; Westerholm
et al., 1988). Rannug (1983) found that extracts of exhaust particles from engines operated
with either leaded or lead-free gasoline displayed nearly equivalent mutagenic activities in the
Ames assay with or without metabolic activation. Norpoth et al. (1985) fractionated extracts
of exhaust particles and found that a fraction containing PAHs with 4 to 7 rings displayed the
greatest mutagenic activity with metabolic activation in the Ames test. Handa et al. (1983)
likewise reported that PAH-containing fractions of extracts of gasoline engine exhaust
particles or condensates were mutagenic with exogenous metabolic activation in S.
typhimurium.
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Extracts of gasoline engine exhaust particles induced mutations in mouse BALB/c3T3
cells (Curren et al., 1981), mouse lympohoma L5178YTK+/- cells (Lewtas, 1982), and
Chinese hamster ovary cells (Casto et al., 1981; Brooks et al., 1984). Organic-solvent
extracts also induced sister chromatid exchanges in Chinese hamster ovary cells (Brooks
et al., 1984; Lewtas and Williams, 1986), chromosomal aberrations in Chinese hamster
ovary cells (Brooks et al., 1984), morphological transformations in BALB/3T3 mouse cells
(Curren et al., 1981), and enhancement of viral-mediated transformation of Syrian hamster
embryo cells (Casto et al., 1981). Inhalation exposure of mice to diluted gasoline engine
exhaust 8 hours/day, for 10 days produced an increased frequency of micronucleated
bone-marrow cells compared with controls; the particulate matter concentration in the test
atmosphere was not reported (Massad et al., 1986).
11.4.3.4.2. Carcinogenicity and Genotoxicity of Emissions from Burning of Cooking and
Heating Fuels
Smoke from the burning of fuels used in cooking and heating (e.g., oil, coal and wood)
contains particulate matter with adsorbed organic compounds that are potential carcinogens.
Although this type of emission source of particulate matter has received less experimental
research attention than emissions from vehicular engines, several samples, including samples
of soots from chimneys, have been examined for genotoxicity in short-term tests and
carcinogenicity in animals.
Sufficient evidence is available for the carcinogenicity of particulate matter produced by
the burning of cooking and heating fuels. Several samples of organic-solvent extracts of
emissions from burning wood or coal showed tumor-initiating or complete carcinogenicity
activity in mouse skin (Grimmer et al., 1984, 1985; Mumford et al., 1990; Lewtas, 1993).
Long-term dermal application of organic-solvent extracts of air particles from unventilated
homes in which smoky coal was burned produced skin tumors in mice (Mumford et al.,
1990). Organic-solvent extracts of soot from the burning of solid oil shale fuel produced
skin tumors in mice after repeated dermal application and lung tumors in rats after repeated
intratracheal instillations (Vosamae, 1979). Supportive evidence comes from predominately
positive results in genotoxicity testing of extracts of several particulate matter samples
produced by the burning of wood or coal. Further supportive evidence comes from studies
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in which inhalation exposure to aerosols of coal tars from coke oven emissions produced
carcinogenic responses in mice and rats (Tye and Stemmer, 1967; MacEwen, 1976).
It should be noted that burning conditions for particular fuel sources are known to
influence the amount of particulate matter produced, the chemical composition of the
paniculate matter, and the ability of organic solvent extracts of particulate matter to produce
genotoxic (and presumably carcinogenic) effects.
Vosamae (1979) reported that twice weekly application for 5 months of a benzene
extract of soot from the burning of solid oil shale fuel induced skin tumors in 58/78 mice
that survived to the time of appearance of the first skin papillomas. Most of the skin tumors
(36/58) progressively developed into malignant skin neoplasms. In an experiment with a
similar protocol, a benzene extract of soot from the burning of liquid oil shale fuel produced
skin tumors in only 9/141 mice that survived the 5-month treatment period.
Grimmer et al. (1984b, 1985) reported that a condensate from the flue of a hard-coal
briquet-fired residential furnace produced significantly increased incidence of skin tumors in
mice. Female CFLP mice were given twice weekly dermal doses of the material (0, 205,
616 or 1,884.9 ^g) for 104 weeks. The condensate was fractionated and the fractions were
tested by the same protocol. Fractions containing PAHs with more than 3 rings were the
most active fractions and could account for approximately all of the carcinogenic activity of
the whole condensate.
Organic-solvent extracts of particulate matter collected in unventilated Chinese homes
burning smoky coal, smokeless coal, or wood were tested for skin tumor initiating activities
in mice (Mumford et al., 1990). Female Sencar mice were given initiating dermal doses of
0, 1,000, 2,000, 5,000, 10,000, or 20,000 /xg of the respective extracts followed by
twice-weekly promoting dermal doses of tetradecanoylphorbol-13-acetate for 26 weeks. At
the end of 26 weeks, dose-related increased incidences of skin papillomas were found in
groups treated with the individual extracts. For each extract, slopes of the tumor
multiplicity/dose curve were estimated by regression analysis and used as a measure of the
tumor initiation potency of the samples. Estimated tumor initiation potencies were 0.49, 1.3,
and 2.7 papillomas/mouse/1,000 pig of extract for the wood, smokeless coal, and smoky coal
extracts, respectively. The smoky coal and wood extract samples were also assayed for
complete carcinogenicity at dermal doses of 1,000 /ig/mouse, given twice a week for 52
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weeks, to female Sencar mice. The mice were held for observation for another 25 weeks.
No skin tumors were found in a vehicle control group of 40 mice by the end of the
experiment. The smoky-coal-treated group showed carcinomas in 38% of the mice at 52
weeks and 88% of mice at the end of the experiment. By the end of the experiment, only
5% (2/40) of the wood-treated mice developed skin tumors.
Lewtas (1993) reported that organic-solvent extracts of particulate emissions from a
wood stove burning either softwoods or hardwoods were active in the mouse skin tumor
initiating assay using the protocol described by Nesnow et al. (1982a,b) and Mumford et al.
(1990). Estimated tumor initiation potencies for these samples were 0.046
papillomas/mouse/1,000 /ig of extract for the softwood emission particles and 0.0087
papillomas/mouse/1,000 pig for the hardwood sample.
Vosamae (1979) gave groups of albino rats ten intratracheal instillations, at one week
intervals, of 100,000 /xg of an extract of soot obtained from burning oil shale solid fuel.
One group received tar dissolved in Tween 40 and another group received tar dissolved in
peach oil. Epidermoid lung neoplasms developed in 31/70 rats treated with the Tween 40
solution and still alive at the time of appearance of the first lung tumor. In the other treated
group, only 3/57 rats developed benign lung epithelial lung tumors. Vehicle control groups
showed no lung tumors.
Inhalation exposure to aerosols of coal tars from coke ovens produced carcinogenic
responses in two rodent bioassays. Tye and Stemmer (1967) exposed male C3H/HeJ mice to
aerosols of coal tars at concentrations of 0.2 mg/1 (200,000 jwg/m3) (first 8 weeks) or
0.12 mg/L (120,000 /xg/m3) (remainder of experiment), for 2 hours, 3 times weekly for up
to 55 weeks. Among the 32 treated mice (of an original 100) that survived to at least 46
weeks, the time at which the first tumor was noted, 4 showed lung adenocarcinomas, 19
showed intrabronchial adenomas, and 10 showed lung squamous metaplasia. In contrast,
32/50 air-control mice survived to 46 weeks and none of these survivors showed lung tumors
by 55 weeks. MacEwen (1976) reported that 90-day continuous exposure to 10,000 /xg/m3
coal tar aerosols produced skin tumors in 44/55 ICR CF-1 mice and 18/43 CAFj/JAX mice
compared with 3/225 and 0/225 control mice of the respective strains. Continuous exposure
of Sprague-Dawley rats to the same aerosol by the same protocol produced lung squamous
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cell carcinomas in 38/38 male rats and 31/38 female rats; no lung tumors were found in 36
male or 37 female air-control rats (MacEwen, 1976).
Results from genotoxicity testing of particulate matter from the burning of cooking and
heating fuels have been predominately positive.
Organic extracts of particle emissions from wood combustion in wood stoves or open
fireplaces were mutagenic both with and without exogenous metabolic activation in the Ames
Salmonella assay (Lewtas, 1985, 1988; Ramdahl et al., 1982; Alfheim et al., 1984a, b;
Alfheim and Ramdahl, 1984; van Houdt et al., 1986; Lofroth et al., 1986; Mumford et al.,
1987; Heussen, 1991). Extracts of soots from chimneys of domestic woodburning or
coalburning stoves and fireplaces also were mutagenic in Salmonella (Medalia et al., 1983).
Extracts of woodstove combustion emissions (particulate and vapor phases) induced sister
chromatid exchange in Chinese hamster ovary cells (Hytonen et al., 1983; Alfheim et al.,
1984b) and transformations of Syrian hamster embryo cells (Alfheim et al., 1984b). Testing
of fractions of organic extracts of wood stove particulate emissions in the Ames assay
showed that acidic or basic fractions had little activity; most of the activity was in a neutral
fraction (Lewtas, 1988). Within the neutral fraction, the activity was distributed among
aliphatic (27.9%), aromatic (23.3%), moderately polar (11.6%), and highly polar (32.6%)
fractions, suggesting that several classes of neutral organic compounds play a role in the
expression of the mutagenicity of particles produced by the burning of wood.
11.4.3.5. Discussion of Evidence for Genotoxicity and Carcinogenicity in Animals
Positive findings have been reported for a few cancer bioassays involving dermal or
subcutaneous exposure of mice to extracts of several types of samples of particulate matter
(Kotin et al., 1954; Leiter et al., 1942; Hueper et al., 1962; Epstein et al., 1966; 1979;
Asahina et al., 1972; Lewtas et al., 1991). In addition, organic-solvent extracts of
particulate matter samples collected from numerous worldwide localities were genotoxic in
extensive testing with the Ames Salmonella reverse-mutation assay and, in less extensive
testing, in short-term clastogenicity assays with cultured human or animals cells. Several
studies have shown that significant portions of the genotoxic or carcinogenic activity of
whole extracts of emitted particulate matter are accounted for by fractions containing
complex mixtures of neutral organic molecules including PAHs, and that benzo[a]pyrene, one
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of the most potent carcinogenic PAHs known, accounts for only a small portion of the total
activity, usually less than 10% (see Lewtas, 1988, Grimmer et al., 1983, 1984a,b, 1985,
1987a,b). An area of significant uncertainty concerns the lack of data, including
dose-response data, from long-term inhalation animal bioassays with samples of ambient air
paniculate matter.
11.4.3.6. Particulate Matter and Cancer in Humans
The 1982 Air Quality Criteria Document for Particulate Matter and Sulfur Dioxides
(U.S. Environmental Protection Agency, 1982) and its 1986 Addendum (U.S. Environmental
Protection Agency, 1986a) noted that epidemiological studies have found no clear evidence to
substantiate hypothesized associations between increased cancer rates and elevations in
atmospheric concentrations of paniculate matter (as a class) or of sulfur oxides. The
previous Agency documents acknowledged, however, the existence of epidemiological studies
that provide evidence of increased cancer risk associated with occupational exposure to
airborne paniculate matter emitted from processes involving combustion or pyrolysis of
carbon-containing material. Specific types of paniculate matter pollution for which
epidemiological evidence of an occupational lung cancer effect exists include coal gasification
emissions (Doll et al., 1972), coke oven emissions (Lloyd et al., 1971; Redmond et al.,
1976), and roofing tar emissions (Hammond et al., 1976). The documents concluded,
however, that there was no well-accepted basis for the quantification of the "relative
contributions or levels of such paniculate matter components to possible carcinogenic effects
of paniculate matter pollution as a whole" (U.S. Environmental Protection Agency, 1982).
Results from several analytical epidemiological studies examining the potential link
between general ambient air pollution and cancer have been published since the preparation
of the previous Air Quality Criteria Documents. In contrast to many of the earlier
epidemiological studies, these case-control and prospective cohort studies incorporated
smoking history data and ambient air pollution data in their analyses. Because the
hypothesized association between lung cancer mortality and air pollution continues to receive
attention, the results and limitations of earlier descriptive epidemiological studies examining
general air pollution and lung cancer mortality are first discussed in this section. More
complete descriptions of these studies can be found in reviews by Friberg and Cederlof
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(1977), Doll (1978), Speizer (1983), and Pershagen and Simonato (1993). Review of recent
analytical epidemiology studies (case-control and prospective cohort studies) follows the
general discussion of the descriptive epidemiology studies.
Descriptive epidemiological studies showed that mortality from lung cancer in several
countries during the 1950s and 1960s was more common in urban areas than rural areas
(i.e., there was a lung cancer gradient; for reviews see Carnow and Meier, 1973; Higgins,
1976; Doll, 1978; Speizer, 1983; Pershagen and Simonato, 1993). Closer examination of the
urban/rural lung cancer gradient in the descriptive studies showed that the gradient was less
consistent in nonsmokers and in females compared with males (Doll, 1978; Pershagen and
Simonato, 1993). These results, coupled with knowledge that the urban atmosphere can
contain elevated concentrations of a variety of materials that caused cancer in laboratory
animals and caused lung cancer in humans exposed to high levels under occupational
conditions (e.g., metals such as nickel or chromium and PAHs adsorbed to particulates
produced by the combustion of carbon-containing materials), led to the hypothesis that
chronic exposure to urban air pollutants may cause lung cancer. Paniculate products of the
pyrolysis and combustion of fossil fuels and other carbon-containing material are especially
of interest because of their relative importance in contributing to fine-particulate air
pollution.
There are at least two major limitations to the descriptive studies of the urban/rural
lung cancer gradient. The first is that major confounding factors (e.g., tobacco smoking and
occupational exposures to lung carcinogens) are likely to contribute significantly to the
apparent association between urban air pollution and lung cancer. Several investigators have
postulated that a non-additive interaction between tobacco smoking and some component of
the urban environment may be involved in the apparent increased lung cancer mortality risk
in urban smokers (Doll, 1978; Vena, 1982; Jedrychowski et al., 1990; Pershagen and
Simonato, 1993). The second major limitation is that these studies used only qualitative,
surrogate measures of exposure (such as years of residency in areas with "high, medium or
low" levels of air pollution). Quantitative monitoring of air pollution relevant to chronic
exposure of individuals was not carried out, and exposure-response relationships, therefore,
can not be explored.
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The apparent urban/rural lung cancer gradient also has been examined in several
prospective cohort studies and retrospective case/control studies that collected personal
tobacco smoking histories and used place of residence as a surrogate index of exposure to air
pollution (see Friberg and Cederlof, 1978; Pershagen and Simonato, 1993 for review). Some
of the studies also collected occupational history data. A major limitation to these studies,
however, is that, like the-descriptive epidemiological studies, attempts to quantify exposure
levels to ambient air pollution were not part of the experimental designs (e.g., collection of
air pollutant monitoring data specific to reported place of residence). Prospective cohort
studies that compared urban and rural lung cancer mortality and found elevated
smoking-adjusted relative risks for lung cancer mortality in urban groups generally did not
find relative risks that exceeded 1.5 (see for example Buell et al., 1967). Some studies did
not find elevated smoking-adjusted and/or occupation-adjusted relative risks in urban areas
compared with rural areas (see for example Hammond, 1972; Hammond and Garfinkel,
1980). Similarily, mixed results were found among case-control studies that examined
potential associations between smoking, place of residence, and lung cancer. For example,
Haenzel and colleagues (Haenzel et al., 1962; Haenzel and Taeuber, 1964) studied residence
and smoking histories for a sample of 10% of all U.S. lung cancer deaths in 1958-1959
(about 2100 white males and 683 white females; > 35 years old) compared with a sample of
the general U.S. population of about 25,000 males and 35,000 females identified through the
U.S. census bureau. In both sexes, urban residence was associated with greater lung cancer
mortality in cigarette smokers than in smokers with a rural residence; the urban/rural
gradient was less evident in nonsmokers. Standardized mortality rate ratios (SMRs) for lung
cancer, adjusted for age and smoking history, were consistently higher, by factors ranging
from 1.41 to 2.00, for males or females who resided in urban areas for 10-39 years,
40 years or longer, or who were lifetime residents compared with males or females who
resided in rural areas for similar periods (Haenzel et al., 1962; Haenzel and Taeuber, 1964).
In contrast, Samet (1987) collected smoking, residence, and occupational histories for
422 lung cancer cases (283 males and 139 females) and 727 population controls (475 males
and 252 females) in New Mexico, but found no consistent associations between residence
history variables (e.g., number of years living in counties with more than 500,000 people)
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and lung cancer risk using a multiple logistic regression analysis and adjustment for smoking
history, age, and sex.
Several case-control studies that included attempts to semi-quantitatively characterize
exposure to indices of ambient air pollution are available. In a case-control study,
Jedrychowski et al. (1990) classified areas of Cracow, Poland into areas of low (total
suspended particles [TSP] < 150 ^g/m3 and SO2 < 104 /*g/m3), medium (TSP > 150
/jg/m3 or SO2 > 104 /*g/m3, but not both) or high (TSP > 150 /*g/m3 and S02 > 104
/ig/m3) air pollution based on daily measurements made between 1973 and 1980 at
20 sampling sites. Information on occupation, smoking habits, and last place of residency
were collected from next of kin for 901 male and 198 female subjects who died in Cracow
between 1980 and 1985 with lung cancer and 875 male and 198 female controls who died in
Cracow during the same period from causes other than respiratory disease. While a
statistically significant increased relative risk for lung cancer (adjusted for age, smoking, and
occupational exposure) was found for men who resided in the high-pollution areas (1.48;
95% CL: 1.08, 2.01), an increased relative risk was not not found not for men in the
medium- or low-pollution areas, nor for women who resided in any of the areas.
Katsouyanni et al. (1991) studied 101 female lung cancer patients and 89 female control
patients with orthopedic conditions who all were permanent residents of Athens admitted to
hospitals between 1987-1989. Exposure to increasing levels of air pollution appeared to be
associated with increased risk for lung cancer, but the relative risk was small and not
statistically significant. Using a logistic regression model that included risk variables for
age, years of schooling, smoking, and estimated exposure to air pollution, an interaction
between air pollution and smoking was apparent; comparison of the lowest and highest air-
pollution exposure quartiles gave relative risks of 0.81 for non-smokers, 1.35 for 15-year
smokers, and 2.23 for 30-year smokers. In a prospective cohort study, cancer incidence and
mortality were monitored in approximately 6,000 nonsmoking, California Seventh-Day
Adventists during a 6-year follow-up period between 1977 and 1982 (Abbey et al., 1991;
Mills et al., 1991). Using Cox proportional hazards regression models that included
covariates of age, sex, total years of past smoking, and educational attainment, statistically
significant increased incremental risks during the follow-up period for all malignant neoplasm
incidence were found for females (n = number of cancer cases = 175), but not males
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(n = 108), when exposure was expressed as an incremental number of hours per year when
TSP concentrations exceeded 100, 150, or 200 /zg/m3, but not concentrations of 60 or
75 /ig/m3. The largest increases in site-specific cancer risk estimates associated with TSP
exposure occurred for respiratory cancers of the larnyx, lung and pleura, but small numbers
of cancer cases limited the statistical power of the study to examine cancer incidence for each
site separately (e.g., only 17 cancers of the larnyx, lung, or pleura occurred in the cohort).
In a recent prospective mortality study referred to as the "Six Cities Study", (discussed
in detail in Chapter 12), Dockery et al. (1993) reported that air pollution was positively
associated with death from cardiopulmonary disease, but the association between lung cancer
mortality and fine paniculate pollution was less certain, presumably because the incidence for
lung cancer deaths in the cohort (8.4%) was much less than that for cardiopulmonary deaths
(53.1%).
Recent analytical epidemiological studies that have examined the association between
lung cancer and indices of exposure to air pollution including particulate matter, while also
adjusting for tobacco smoking and other major potential risk factors, provide some evidence
to support the hypothesis of an association between ambient air pollution found in certain
localities and lung cancer. However, most investigators believe that the epidemiological
evidence obtained thus far does not substantiate causality, although the hypothesis remains
credible.
11.4.3.7. Biomarkers of Genetic Damage
One of the major methodological problems with the epidemiological studies examining
the association between lung cancer and ambient air particulate matter pollution to date is
that exposure of individuals is not directly monitored. This is a difficult problem to solve,
because of the complex makeup of ambient air particulate matter, the uncertainty concerning
which components may be responsible for any putative carcinogenic effect, and the potential
for confounding occupational factors or "lifestyle" factors, such as smoking and diet, that
might add to an individual's exposure to potentially carcinogenic agents. Nevertheless,
several groups of investigators have been exploring the use of adducts between DNA and
PAHs (PAH-DNA adducts) as biomarkers to aid in the assessment of individual exposure to
one class of potential carcinogens in ambient air particulate matter.
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Polycyclic aromatic hydrocarbons adsorbed to particulate matter are present in several
complex mixtures, including tobacco smoke and coke oven emissions, that are well
established as being carcinogenic to humans. Because carcinogenic PAHs are thought to
initiate the multistage process of cancer via covalent modification of DNA, the measurement
of PAH-DNA adducts in white blood cells (using benzo[a]pyrene-DNA adducts for a
reference) has been examined as a means of quantifying the biologically effective dose of
PAHs in humans exposed to coke oven emissions (Van Schooten et al., 1990), cigarette
smoke (Phillips et al., 1990), or iron and steel foundry emissions (Perera et al., 1988).
Recently, PAH-DNA adduct levels in white blood cells have been measured in three
populations with suspected differences in exposure to ambient air particulate matter: Polish
coke oven workers, other residents of Polish towns around coke oven plants, and residents of
a rural region of Poland (Hemminki et al., 1990; Perera et al., 1992; Grzybowska et al.,
1993). Using blood samples collected in the winter, the general pattern of adducts and the
average levels of adducts were similar in coke oven workers and residents of towns with
coke oven plants, while the levels in the rural residents were 2 to 3 tunes lower (Hemminki
et al., 1990). Subsequently, analysis of blood samples drawn in the summer showed that
coke-plant town residents had average adduct levels that were lower than the average for
coke oven workers and similar to rural residents (Grzybowska et al., 1993). The authors
commented that the seasonal change in the relative levels of adducts in the town residents
may be reflective of the use of coal combustion for domestic heating in the winter; the same
seasonal variation was found in the mutagenic activity in Ames tests of extracts of samples of
ambient air particulate matter from the same region (Motykiewicz et al., 1989). Large
degrees of variation in levels of PAH-DNA adducts were noted among individuals within
each "exposure" group.
Several investigators have noted some potential limitations in the use of PAH-DNA
adducts as biomarkers of exposure to ambient air particulate matter. Kriek et al. (1993)
and Lewtas et al. (1993) both noted that substantial interindividual variation in PAH-DNA
adducts has been observed in several populations, and that this variation may be due, in part,
to individual variation in metabolic activities (e.g., PAH metabolism or DNA repair), in
addition to individual differences in exposure levels. In a study that monitored personal
exposure to benzo[a]pyrene in air and placental PAH-DNA adducts in pregnant Chinese
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women who used smoky coal for domestic purposes in vented or unvented homes, Mumford
et al. (1993) did not find a significant exposure-response relationship between monitored
benzo[a]pyrene concentrations in air and levels of PAH-DNA adducts or the percentage of
samples with detectable PAH-DNA adducts. Mumford et al. (1993) suggested that dietary
intake of PAH may have been responsible for the lack of an exposure-response relationship,
and that PAH-DNA adducts may be used as a qualitative, but not quantitative, measure of
exposure to combustion emissions. Heussen et al. (1994) measured white-blood-cell
PAH-DNA adducts (using the 32P-postlabeling technique) in five individuals before and after
a 1-week exposure to residential air in homes with open fireplaces, but found no
"combustion-related" increase in DNA adducts, even though extracts of air samples showed
an increased mutagenic activity in Ames tests, with and without metabolic activation, after
one week of open-fireplace use. Heussen et al. (1994) proposed that the exposure conditions
may have presented too low a concentration of paniculate PAHs or too short a duration for
the production of increased PAH-DNA adducts in the exposed subjects, or that unknown,
nonaromatic compounds, rather than PAHs, may account for the observed mutagenic activity
of the air samples.
Although PAH-DNA adducts are being examined as biomarkers for exposure to
ambient air particulate matter from combustion sources, their use as a biomarker for general
ambient air particulate matter is limited due to the complexity of the chemical makeup of
ambient air particulate matter and the potential variability across localities.
1 11.4.4 Diesel Exhaust Emissions
2 Diesel engines emit both gas phase pollutants (hydrocarbons [HCs], oxides of nitrogen
3 [NOX], and carbon monoxide [CO]) and carbonaceous PM. A description of the diesel
4 engine, its combustion system, pollutant formation mechanisms and emission factors as well
5 as the cancer and noncancer health effects of diesel exhaust emissions has been reviewed in
6 another document (U.S. Environmental Protection Agency, 1994). The information
7 summarized here is drawn from that document.
8 In addition to the potential carcinogenicity of diesel exhaust, there has been concern
9 that diesel PM may contribute to other health problems, especially those associated with the
10 respiratory tract. Other components of diesel exhaust, such as sulfur dioxide (SO^, nitrogen
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1 dioxide (N02), formaldehyde, acrolein, and sulfuric acid may contribute to some of these
2 potential health effects. The discussion begins with noncancer effects, proceeds to
3 mutagenicity and carcinogenicity, and ends with a summary of potential mechanisms.
4 Within the text, exposures are expressed in terms of the concentration of diesel
5 particles. Other major measured components in the studies are presented in the tables which
6 have additional details about the studies, including references. The diesel assessment
7 document (U.S. Environmental Protection Agency, 1994) should be consulted for a complete
8 evaluation of diesel emissions.
9
10 11.4.4.1 Noncancer Health Effects
11 Effects of Diesel Exhaust on Humans
12 The effects of short term exposure to diesel exhaust have been investigated primarily in
13 occupationally-exposed workers (Table 11-11). Symptoms of acute exposure to high levels
14 of diesel exhaust include mucous membrane, eye, and respiratory tract irritation (including
15 chest tightness and wheezing) and neuropsychological effects of headache, lightheadedness,
16 nausea, heartburn, vomiting, weakness, and numbness and tingling in the extremities. Diesel
17 exhaust odor can cause nausea, headache, and loss of appetite.
18 In studies of humans exposed to diesel exhaust, minimal and not statistically significant
19 changes were reported over the course of a workshift in respiratory symptoms and pulmonary
20 function in underground miners, bus garage workers, dock workers, and locomotive
21 repairmen. In diesel bus garage workers, there was an increased reporting of burning and
22 watering of the eyes, cough, labored breathing, chest tightness, and wheezing, but no
23 reductions in pulmonary function associated with exposure to diesel exhaust. In stevedores
24 pulmonary function was adversely affected over a workshift exposure to diesel exhaust but
25 normalized after a few days without exposure.
26 The chronic effects of exposure to diesel exhaust have been evaluated in humans in
27 epidemiologic studies of occupationally exposed workers. Most of the epidemiologic data
28 indicate the absence of an excess of chronic respiratory disease associated with exposure to
29 diesel exhaust. In a few of these studies, a higher prevalence of respiratory symptoms,
30 primarily cough, phlegm, or chronic bronchitis, were observed among the exposed.
31 Reductions in several pulmonary function parameters including FVC and FEVj, and to a
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TABLE 11-11. HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Kahn et al. (1988)
El Batawi and
Noweir (1966)
Battigelli (1965)
Katz et al. (1960)
Hare and Springer
(1971)
Hare et al. (1974)
Linnell and Scott
(1962)
Battigelli (1965)
Reger et al. (1978)
Ames et al. (1982)
Jorgensen and
Svensson (1970)
13 Cases of acute exposure,
Utah and Colorado coal
miners.
161 Workers, two diesel bus
garages.
Six subjects, eye exposure
chamber, three dilutions.
14 Persons monitoring diesel
exhaust in a train tunnel.
Volunteer panelists who
evaluated general public's
response to odor of diesel
exhaust.
Odor panel under highly
controlled conditions
determined odor threshold for
diesel exhaust.
13 Volunteers exposed to three
dilutions of diesel exhaust for
15 min to 1 h.
Five or more VC maneuvers
by each of 60 coal miners
exposed to diesel exhaust at
the beginning and end of a
work shift.
Pulmonary function of
60 diesel-exposed compared
with 90 non-diesel-exposed
coal miners over work shift.
240 Iron ore miners matched
for diesel exposure,
smoking and age were given
bronchitis questionnaires
and spirometry pre- and
postwork shift.
Acute reversible sensory irritation, headache;
nervous system effects, broncho-constriction were
reported at unknown exposures.
Eye irritation (42%), headache (37%), dizziness
(30%), throat irritation (19%), and cough and
phlegm (11%) were reported in this order of
incidence by workers exposed in the service and
repair of diesel powered buses.
Time to onset was inversely related and severity
of eye irritation was associated with the level of
exposure to diesel exhaust.
Three occasions of minor eye and throat
irritation; no correlation established with
concentrations of diesel exhaust components.
Slight odor intensity, 90% perceived, 60%
objected; slight to moderate odor intensity, 95%
perceived, 75% objected; almost 75% objected;
almost 95% objected.
In six panelists, the volume of air required to
dilute raw diesel exhaust to an odor threshold
ranged from a factor of 140 to 475.
No significant effects on pulmonary resistance
were observed as measured by plethysmography.
FEV,, FVC, and PEFR were similar between
diesel and non-diesel-exposed miners. Smokers
had an increased increased number of
decrements over shift than nonsmokers.
Significant work shift decrements occurred in
miners in both groups who smoked; no significant
differences in ventilatory function changes
between miners exposed to diesel exhaust and
those not exposed.
Among underground (surrogate for diesel
exposure) miners, smokers and older age groups,
frequently of bronchitis was higher. Pulmonary
function was similar between groups and
subgroups except for differences accountable to
age.
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Gamble et al. 200 Salt miners performed
(1978) before and after workshift
spirometry. Personal
environmental NO2 and
inhalable particle samples were
collected.
Gamble et al. 232 Workers in four diesel bus
(1987a) garages were administered
acute respiratory
questionnaires and before and
after workshift spirometry.
Compared to lead, acid battery
workers previously found to
be unaffected by their
exposures.
Ulfvarson et al. Workshift changes in
(1987) pulmonary function were
evaluated in crews of roll-on/
roll-off ships and car ferries
and bus garage staff.
Pulmonary function was
evaluated in six volunteers
exposed to diluted diesel
exhaust, 2.1 ppm NO2, and
0.6 mg/m3 paniculate matter.
Battigelli et al. 210 Locomotive repairmen
(1964) exposed to diesel exhaust for
an average of 9.6 years in
railroad engine houses were
compared with 154 railroad
yard workers of comparable
job status but no exposure to
diesel exhaust.
Gamble et al. 283 Male diesel bus garage
(1987b) workers from four garages in
two cities were examined for
impaired pulmonary function
(FVC, FEVj, and flow rates).
Study population with a mean
tenure of 9 ± 10 years S.D.
was compared to a nonexposed
"blue collar" population.
Smokers had greater but not significant
reductions in spirometry than ex- or nonsmokers.
NO2, but not paniculate, levels
significantly decreased FEV1, FEF25,
FEF50, and FEF75 over the workshift.
Prevalence of burning eyes, headache,
difficult or labored breathing, nausea,
and wheeze were higher in diesel bus workers
than in comparison population.
Pulmonary function was affected
during a workshift exposure to
diesel exhaust, but it normalized after a
few days with no exposure. Decrements
were greater with increasing intervals
between exposures. No effect on pulmonary
function was observed in the experimental
exposure study.
No significant differences in VC, FEV1(
peak flow, nitrogen washout, or diffusion
capacity nor in the prevalence of dyspnea,
cough, or sputum were found between the
diesel exhaust-exposed and nonexposed
groups.
Analyses within the study populations population
showed no association of respiratory symptoms
with tenure. Reduced FEVj and FEF50 (but not
FEF75) were associated with increasing tenure.
The study population had a higher incidence of
cough, phlegm, and wheezing unrelated to tenure.
Pulmonary function was not affected in the total
cohort of diesel-exposed of diesel-exposed but
was reduced with 10 or more years of tenure.
April 1995
11-116 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Ames et al. (1984)
Purdham et al. Respiratory symptoms and
(1987) pulmonary function were
evaluated in 17 stevedores
exposed to both diesel and
gasoline exhausts in car ferry
operations; control group was
11 on-site office workers.
Reger et al. (1982) Differences in respiratory
symptoms and pulmonary
function were assessed in
823 coal miners from six
diesel equipped mines
compared to 823 matched coal
miners not exposed to diesel
exhaust.
Changes in respiratory
symptoms and function were
measured during a 5-year
period in 280 diesel-exposed
and 838 nonexposed U.S.
underground coal miners.
Respiratory symptoms and
function were assessed in
2,659 miners from
21 underground metal mines
(1,709 miners) and nonmetal
mines (950 miners). Years of
diesel usage in the mines were
surrogate for exposure to
diesel exhaust.
Attfield et al. Respiratory symptoms and
(1982) function were assessed in
630 potash miners from six
potash mines using a
questionnaire, chest
radiographs and spirometry.
A thorough assessment of the
environment of each mine was
made concurrently.
Attfield (1978)
No differences between the two groups for
respiratory symptoms. Stevedores had lower
baseline lung function consistent with an
obstructive ventilatory defect compared with
controls and those of Sydney, Nova Scotia,
residents. Caution in interpretation is warranted
due to small sample size. No significant size.
No significant changes in lung function over
workshift nor difference between two groups.
Underground miners in diesel-use mines reported
more symptoms of cough and phlegm and had
lower pulmonary function. Similar trends were
noted for surface workers at diesel-use mines.
Pattern was consistent with small airway disease
but factors other than exposure to diesel exhaust
thought to be responsible.
No decrements in pulmonary function or
increased prevalence of respiratory symptoms
were found attributable to diesel exhaust. In fact,
5-year incidences of cough, phlegm, and dyspnea
were greater in miners without exposure to diesel
exhaust than in miners exposed to diesel diesel
exhaust.
Questionnaire found an association between an
increased prevalence of cough and aldehyde
exposure; this finding was not substantiated by
spirometry data. No adverse symptoms or
pulmonary function decrements were related to
exposure to NO2, CO, CO2, dust, or quartz.
No obvious association indicative of diesel
exposure was found between health indices, dust
exposure, and pollutants. A higher prevalence of
cough and phlegm, but no differences in FVC
and FEVl5 were found in these diesel-exposed
potash workers when compared to predicted
values from a logistic model based on blue- collar
staff working in nondusty jobs.
April 1995
11-117 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Gamble et al.
(1983)
Gamble and Jones
(1983)
Edling and Axelson
(1984)
Edling et al. (1987)
Respiratory morbidity was
assessed in 259 miners in
5 salt mines by respiratory
symptoms, radiographic
findings and spirometry. Two
mines used diesels extensively,
2 had limited use, one used no
diesels in 1956, 1957, 1963,
or 1963 through 1967.
Several working populations
were compared to the salt
mine cohort.
Same as above. Salt miners
were grouped into low,
intermediate and high exposure
categories based on tenure in
jobs with diesel exposure.
Pilot study of 129 bus
company employees classified
into three dieselexhaust
exposure categories clerks (0),
bus drivers (1), and bus
garage workers.
Cohort of 694 male bus
garage employees followed
from 1951 through 1983
were evaluated for mortality
from cardiovascular disease.
Subcohorts categorized by
levels of exposure were clerks
(0), bus drivers (1), and bus
garage employees (2).
After adjustment for age and smoking, salt
miners showed no symptoms, increased
prevalence of cough, phlegm, dyspnea or air
obstruction (FEV,/FVC) compared to
aboveground coal miners, potash workers or blue
collar workers. FEVj, FVC, FEF50, and FEF75
were uniformly lower for salt miners in
comparison to all the comparison populations.
No changes in pulmonary function were
associated with years of exposure or cumulative
exposure to inhalable particles or NO2.
A statistically significant dose-related association
of phlegm and diesel exposure was noted.
Changes in pulmonary function showed no
association with diesel tenure. Age- and
smoking-adjusted rates of cough, phlegm, and
dyspnea were 145, 169, and 93% of an external
comparison population. Predicted pulmonary
function indices showed small but significant
reductions; there was no dose-response
relationship.
The most heavily exposed group (bus garage
workers) had a fourfold increase in risk of dying
from cardiovascular disease, even after correction
for smoking and allowing for 10 years of
exposure and 15 years or more of
inductionlatency time.
No increased mortality from cardiovascular
disease was found among the members of these
five bus companies when compared with the
general population or grouped as sub-cohorts with
different levels of exposure.
Source: quoted from U.S. Environmental Protection Agency, 1994.
1 lesser extent forced expiratory flow at 50 and 75% of vital capacity (FEF50 and FEF75), have
2 also been reported. Two studies, each with methodological problems, detected statistically
3 significant decrements in pulmonary function when compared with matched controls. These
4 two studies coupled with other reported nonsignificant trends in respiratory flow-volume
April 1995
11-118 DRAFT-DO NOT QUOTE OR CITE
-------
1 measurements suggest that diesel exhaust exposure may impair pulmonary function among
2 occupational populations. A preliminary study of the association of cardiovascular mortality
3 and exposure to diesel exhaust found a fourfold higher risk ratio. A more comprehensive
4 study by the same investigators, however, found no significant difference between the
5 observed and expected number of deaths caused by cardiovascular disease.
6 The results of the epidemiologic studies addressing noncarcinogenic health effects
7 resulting from exposure to diesel exhaust must be interpreted cautiously because of a myriad
8 of methodological problems, including incomplete information on the extent of exposure to
9 diesel exhaust, the presence of confounding variables (smoking, occupational exposures to
10 other toxic substances, and the short duration and low intensity of exposure). These
11 limitations restrict definitive conclusions about diesel exhaust being the cause of any
12 noncarcinogenic health effects, observed or reported.
13
14 Effects Of Diesel Exhaust On Animals
15 In short-term and chronic exposure studies, toxic effects have been related to high
16 concentrations of diesel paniculate matter. Data from short-term exposures indicate minimal
17 effects on pulmonary function, even though histological and cytological changes were
18 observed in the lungs (Table 11-12). Exposures for several months or longer to levels
19 markedly above environmental ambient concentrations resulted in accumulation of particles in
20 the lungs, increases in lung weight, increases in AMs and leukocytes, macrophage
21 aggregation, hyperplasia of alveolar epithelium, and thickening of the alveolar septa. Similar
22 histological changes, as well as reductions in growth rates and alterations in indices of
23 pulmonary function, have been observed in chronic exposure studies. Chronic studies have
24 been carried out using rats, mice, guinea pigs, hamsters, cats, and monkeys. Reduced
25 resistance to respiratory tract infections has been reported in mice exposed to diesel exhaust.
26 Reduced growth rates have been observed most often in studies with exposures of at
27 least 2,000 /ig/m3 diesel paniculate matter which lasted for 16 h or more per day
28 (Table 11-13). No effects on growth or survival were noted at levels of 6,000 to
29 8,000 pig/m3 of PM when the daily exposures were only 6 to 8 h/day.
30 Changes in pulmonary function have been noted in a number of different species
31 chronically exposed to diesel exhaust (Table 11-14). The lowest exposure levels that resulted
April 1995 11-119 DRAFT-DO NOT QUOTE OR CITE
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> TABLE 11-12
EH Exposure
i— » Species/Sex Period
VO Rat, F-344, M; 20 h/day
*•" Mouse, A/J; 7 days/week
Hamster, Syrian 10-13 weeks
Rat, F-344, M, 7 h/day
F; Mouse, 5 days/week
CD-l.M, F 19 weeks
Cat, Inbred, M 20 h/day
7 days/week
4 weeks
Rat, Sprague- 20 h/day
Dawley, M 7 days/week
4 weeks
Guinea Pig, 20 h/day
Hartley, M, F 7 days/week
4 weeks
Rat, F-344, M 20 h/day
5.5 days/ week
I—* 4 weeks
^ Guinea Pig, 20 h/day
Ni Hartley 7 days/week
° M, F 8 weeks
O "Irradiated exhaust.
?0 PMN = Polymorphonuclear leukocyte.
£ AM = Alveolar macrophage.
H
. SHORT-TERM EFFECTS OF DIESEL EXHAUST ON LABORATORY ANIMALS
Particles
teg/m3)
1,500
0.19/tm
210
1,000
4,400
6,400
6,400
6,800"
6,800"
6,000
6.8 /tin,
6,300
C x T CO N02 S02
Gig-h/m3) (ppm) (ppm) (ppm)
2,100,000 to 6.9 0.49 —
, MMD 2,730,000
140,000 — — —
665,000 — — —
2,926,000 - - -
3,584,000 14.6 2.1 2.1
3,584,000 16.9 2.49 2.10
3,808,000 16.1" 2.76" 1.86"
3,808,000 16.7 2.9 1.9
(<0.01 ppmO3)"
2,640,000 — — —
MMD
7,056,000 17.4 2.3 2.1
(< 0.01 ppm 03)a
Effects
Increase in lung wt; increase in thickness
of alveolar walls; no species difference
No effects on lung function; increase in
PMNs and proteases and AM aggregation
in both species
Few effects on lung function; focal
pneumonitis or alveolitis
Decreased body wt; arterial blood pH
reduced; vital total lung capacities
increased
Exposure started when animals were
4 days old; increase in pulmonary flow;
bradycardia
Macrophage aggregation; increase in
PMNs; Type 2 cell proliferation;
thickened alveolar walls
Increase in relative lung wt; AM
aggregation; hypertrophy of goblet cells;
focal hyperplasia of alveolar epidielium
References
Kaplan et al. (1982)
Mauderly et al. (1981)
Pepelko et al. (1980a)
Pepelko (1982a)
Wiester et al. (1980)
White and Garg (1981)
Weister et al. (1980)
J_j Source: quoted from U.S. Environmental Protection Agency, 1994.
0
o
H
0
c!
O
H
M
O
0
-------
3.
TABLE 11-13. EFFECTS OF CHRONIC EXPOSURES TO DIESEL EXHAUST
ON SURVIVAL AND GROWTH OF LABORATORY ANIMALS
VO
L/i
t— *
I—*
i
to
o
>
1
o
^^
o
H
O
r^^
O
H
W
O
Exposure
Species/Sex Period
Rat, F-344, M, F; 7 h/day
Monkey, 5 days/week
cynomolgus, M 104 weeks
Rat, F344, M; 20 h/day
Guinea Pig, 5 days/week
Hartley, M 106 weeks
Hamster, Chinese, 8 h/day
M 7 days/week
26 weeks
Rat, Wistar, M 6 h/day
5 days/week
87 weeks
Rat, F-344, M, F; 7 h/day
Mouse CD-I 5 days/week
130 weeks
Rat, Wistar, F; 19 h/day
Mouse, MMRI, F 5 days/week
104 weeks
Rat, F-344 16h/day
M, F 5 days/week
104 weeks
Rar= 16 h/day
F-344/Jcl. 6 days/week
130 weeks
Particles
(/ig/m3)
2,000
0.23-0.36 /»m, MMD
250
750
1,500
0.19 /*ni, MMD
6,000
12,000
8,300
0.71 urn, MMD
350
3,500
7,000
0.25 iaa, MMD
4,240
0.35 /im, MMD
700
2,200
6,600
no1
410"
l,080d
2,310d
3,720e
0.2-0. 3 pan, MMD
C x T
(/xg-h/m3)
7,280,000
2,650,000
7,950,000
15,900,000
8,736,000
17,472,000
21,663,000
1,592,000
15,925,000
31,850,000
41,891,0000
5,824,000
18,304,000
54,912,000
1,373,000
5,117,000
13,478,000
28,829,000
46,426,000
CO
(ppm)
11.5
2.7"
4.4"
7.1a
—
—
50.0
2.9
16.5
29.7
12.5
—
—
32.0
1.23
2.12
3.96
7.10
12.9
N02
(ppm)
1.5
0.1"
0.27b
0.5b
—
—
4.0-6.0
0.05
0.34
0.68
1.5
—
—
—
0.08
0.26
0.70
1.41
3.00
SO2
(ppm) Effects References
0.8 No effects on growth or survival Lewis et al. (1989)
— Reduced body weight in rats at 1,500 /ig/m3 Schreck et al. (1981)
—
—
— No effect on growtii Vinegar et al.
- (1981a,b)
— No effect on growth or mortality rates Karagianes
et al. (1981)
— No effect on growth or mortality rates Mauderly et al.
— (1984, 1987b)
—
1.1 Reduced body wts; increased mortality in mice Heinrich et al.
(1986a)
— Growth reduced at 2,200 and 6,600 /ig/m3 Brightwell et al.
- (1986)
—
0.38 Concentration-dependent decrease in body Research Committee
1 .06 weight; earlier deaths in females exposed to for HERP Studies
2.42 3,720 /tg/m3, stabilized by 15 mo (1988)
4.70
4.57
"Estimated from graphically depicted mass concentration data.
bEstimated from graphically presented
cData for tests with light-duty engine;
dLight-duty engine.
'Heavy-duty engine.
mass concentration data
for NO2 (assuming 90% NO and
10% NO2).
similar results with heavy-duty engine.
™ Source: Quoted from U.S. Environmental Protection Agency
Q
H
W
(1994).
-------
3.
TABLE 11-14. EFFECTS OF DIESEL EXHAUST ON
PULMONARY FUNCTION OF LABORATORY ANIMALS
VO
<5!
H-
t
H- k
Ni
0
§
>
HH
H
6
o
2
o
H
O
c^
s
w
n
H
M
Species/Sex
Rat, F-344
M, F
Monkey, M
Cynomolgus
Rat, F-344, M
Rat, Wistar, F
Hamster, Chinese,
M
Rat, F-344,
M, F
Hamster, Syrian
M, F
Rat, F-344;
Hamster Syrian
Rat, Wistar, F
Cat, inbred, M
Exposure
Period
7 h/day
5 days/week
104 weeks
7 h/day
5 days/week
104 weeks
20 h/day
5.5 days/week
87 weeks
7-8 h/day
5 days/week
104 weeks
8 h/day
7 days/week
26 weeks
7 h/day
5 days/week
130 weeks
19 h/day
5 days/week
120 weeks
16 h/day
5 days/week
104 weeks
19 h/day
5 days/week
140 weeks
8 h/day
7 days/week
124 weeks
Particles
(/ig/m3)
2,000
0.23-0.36 fim MMD
2,000
0.23-0.36 /«n, MMD
1,500
0.19/tm, MMD
3,900
0.1 fim, MMD
6,000
12,000
350
3,500
7,000
0.23-0.26 /tm, MMD
4,240
0.35 /mi, MMD
700
2,200
6,600
4,240
0.35 urn, MMD
6,000"
12,000b
C x T CO
(/tg-h/m3) (ppm)
7,280,000 11.5
7,280,000 11.5
14,355,000 7.0
14,196,000- 18.5
16,224,000
8,736,000 -
17,472,000 -
1,593,000 2.9
15,925,000 16.5
31,850,000 29.7
48,336,000 12.5
5,824,000 -
18,304,000 -
54,912,000 -
56,392,000 12.5
41,664,000 20.2
83,328,000 33.3
N02 S02
(ppm) (ppm) Effects
1.5 0.8 No effect on pulmonary function
1.5 0.8 Decreased expiratory flow; no effect on vital
or diffusing capabilities
0.5 — Increased functional residual capacity,
expiratory volume and flow
1.2 3.1 No effect on minute volume, compliance or
resistance
— — Decrease in vital capacity, residual volume,
— — and diffusing capacity; increase in static
deflation lung volume
0.05 — Diffusing capacity, lung compliance reduced
0.34 - at 3,500 and 7,000 /*g/m3
0.68 -
1.5 1.1 Significant increase in airway resistance
— — Large number of pulmonary function changes
— — consistent with obstructive and restrictive
— — airway diseases at 6,600 /tg/m3 (no specific
data provided)
1.5 1.1 Decrease in dynamic lung compliance;
increase in airway resistance
2.7 2.1 Decrease in vital capacity, total lung capacity,
4.4 5.0 and diffusing capacity after 2 years; no effect
on expiratory flow
References
Lewis et al. (1989)
Lewis et al. (1989)
Gross (1981b)
Heinrich et al. (1982)
Vinegar et al. (1980,
1981a,b)
Mauderly et al.
(1988)
McClellan et al.
(1986)
Heinrich et al.
(1986a)
Brightwell et al.
(1986)
Heinrich et al.
(1986a)
Pepelko et al.
(1980b, 1981)
Moorman et al.
(1985)
al to 61 weeks exposure.
b62 to 124 weeks of exposure.
Source: Quoted from U.S. Environmental Protection Agency
(1994).
-------
1 in impaired pulmonary function varied among the species tested but were in excess of
2 1,000/ig/m3.
3 Histological changes occurring in the respiratory tract tissue of animal exposed
4 chronically to high concentrations of diesel exhaust include alveolar histiocytosis,
5 macrophage aggregation, tissue inflammation, increases in polymorphonuclear leukocytes,
6 hyperplasia of bronchiolar and alveolar Type 2 cells, thickened alveolar septa, edema,
7 fibrosis, and emphysema (Table 11-15). Biochemical changes in the lung associated with
8 these histopathological findings included increases in lung DNA, total protein, and activities
9 of alkaline and acid phosphatase, and glucose-6-phosphate dehydrogenase; increased synthesis
10 of collagen; and release of inflammatory mediators such as leukotriene LTB and
11 prostaglandin PGF2a. Some studies have also suggested that there may be a threshold of
12 exposure to diesel exhaust below which pathologic changes do not occur. These no-effect
13 levels were reported to be 2,000 ^g/m3 for cynomolgus monkeys, 110 to 350 />ig/m3 for rats,
14 and 250 /ig/m3 PM for guinea pigs exposed for 7 to 20 h/day, 5 to 5.5 days/week for 104 to
15 130 weeks.
16 The pathological effects of diesel exhaust particulate matter appear to be strongly
17 dependent on the relative rates of pulmonary deposition and clearance (Table 11-16).
18 At particle concentrations of about 1,000 ^g/m3 or above, pulmonary clearance becomes
19 reduced, with concomitant focal aggregations of particle-laden AMs. The principal
20 mechanism of reduced particle clearance appears to be the result of impaired AM function.
21 This impairment seems to be nonspecific and applies to insoluble particles deposited in the
22 alveolar region. Other data suggest that the inability of particle-laden AMs to translocate to
23 the mucociliary escalator is correlated to the average composite particle volume per AM in
24 the lung. Data from rats indicate that when this particle volume exceeds a critical level,
25 impairment appears to be initiated. Such data for other laboratory species and humans,
26 unfortunately, are very limited.
27 There is a considerable body of evidence that the major noncancerous health hazards
28 posed by exposure to diesel exhaust are to the lung. These data also denote that the
29 exposures that cause pulmonary injury are lower than those inducing detectable increases in
30 lung tumors. These same data further indicate that the inflammatory and proliferative
31 changes in the lung play a key role in the etiology of pulmonary tumors in exposed rats.
April 1995 11-123 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 11-15. HISTOPATHOLOGICAL EFFECTS OF DIESEL EXHAUST
IN THE LUNGS OF LABORATORY ANIMALS
§
Ui
1— »
V
§
O
?0
ffl
1
O
2
O
H
O
^
0
H
W
O
•*
Q
H
W
Species/Sex
Rat, F-344, M
Mouse A/J, M;
Hamster,
Syrian, M
Monkey,
Cynomolgus, M
Rat, F-344, M,
F
Rat, Sprague-
Dawley, M;
Mouse, A/HFJ,
M
Hamster,
Chinese, M
Hamster,
Syrian, M, F
Rat, Wistar, M
Rat, F-344, F
Rat, F-344, M,
F; Mouse CD-I,
M, F
Exposure
Period
20 h/day
7 days/week
12-13 weeks
7 h/day
5 days/week
104 weeks
7 h/day
5 days/week
104 weeks
8 h/day
7 days/week
39 weeks
8 h/day
5 days/week
26 weeks
7-8 h/day
5 days/week
120 weeks
6 h/day
5 days/week
87 weeks
8 h/day
7 days/week
104 weeks
7 h/day
5 days/week
130 weeks
Particles
(A«g/m3)
1,500
0.19 urn, MMD
2,000
0.23-0.36 nm,
MMD
2,000
0.23-0.36 ^m,
MMD
6,000
6,000
12,000
3,900
0.1 urn, MMD
8,300
0.71 fan, MMD
4,900
350
3,500
7,000
0.23 /*m, MMD
C XT CO
(/ig-h/m3) (ppm)
2,520,000- —
2,730,000
7,280,000 11.5
3,640,000 11.5
13,104,000 -
6,240,000 —
12,480,000 —
16,380,000- 18.5
18,720,000
21,663,000 50.0
28,538,000 7.0
1,592,000 2.9
15,925,000 16.5
31,850,000 29.7
NO2 SQj
(ppm) (ppm) Effects
— — Inflammatory changes; increase in lung
weight; increase in thickness of alveolar
walls
1.5 0.8 AM aggregation; no fibrosis, inflammation
or emphysema
1.5 0.8 Multifocal histiocytosis; inflammatory
changes; Type II cell proliferation; fibrosis
— — Increase in lung protein content and collagen
synthesis but a decrease in overall lung
protein synthesis in both species; prolyl-
hydroxylase activity increased in rats
inutero
— — Inflammatory changes; AM accumulation;
— — thickened alveolar lining; Type II cell
hyperplasia; edema; increase in collagen
1.2 3.1 Inflammatory changes, 60% adenomatous
cell proliferation
4.0-6.0 — Inflammatory changes; AM aggregation;
aleovar cell hypertrophy; interstitial fibrosis,
emphysema (diagnostic methodology not
described)
1.8 13.1 Type II cell proliferation; Inflammatory
changes; bronchial hyperplasia; fibrosis
0.05 — Alveolar and bronchiolar epithelial
0.34 — metaplasia in rats at 3,500 and 7,000 pg/m3;
0.68 — fibrosis at 7,000 pg/m3 in rats and mice;
inflammatory changes
References
Kaplan et al.
(1982)
Lewis et al. (1989)
Bhatnagar et al.
(1980)
Pepelko (1982a)
Bhatnagar et al.
(1980)
Pepelko (1982a)
Pepelko (1982b)
Heinrich et al.
(1982)
Karagianes et al.
(1981)
Iwai et al. (1986)
Mauderly et al.
(1987a,b)
Henderson et al.
(1988)
-------
TABLE 11-15 (cont'd). HISTOPATHOLOGICAL EFFECTS OF DIESEL EXHAUST
IN THE LUNGS OF LABORATORY ANIMALS
K>
Ui
Species/Sex
Rat, M, F,
F-344/Jcl.
Hamster,
Syrian, M, F
Mouse, NMRI,
F
Rat, Wistar, F
Guinea Pig,
Hartley, M
Cat, inbred, M
Exposure
Period
16 h/day
6 days/week
130 weeks
19 h/day
5 days/week
120 weeks
19 h/day
5 days/week
120 weeks
19 h/day
5 days/week
140 weeks
20 h/day
5.5
days/week
104 weeks
8 h/day
7 days/week
124 weeks
Particles
(^g/m3)
110s
410*
1,080"
2,310"
3,720b
4,240
4,240
4,240
250
750
1,500
6,000
6,000°
12,000f
C XT
0»g-h/m3)
1,373,000
5,117,000
13,478,000
28,829,000
46,336,000
48,336,000
48,336,000
56,392,000
2,860,000
8,580,000
17,160,000
68,640,000
41,664,000
83,328,000
CO
(ppm)
1.23
2.12
3.96
7.10
12.9
12.5
12.5
12.5
—
20.2
33.2
NO2
(ppm)
0.08
0.26
0.70
1.41
3.00
1.5
1.5
1.5
—
2.7
4.4
SO,
(ppm)
0.38
1.06
2.42
4.70
4.57
1.1
1.1
1.1
—
2.1
5.0
Effects
Inflammatory changes; Type n cell
hyperplasia and lung tumors seen at
>400 fig/m3; shortening and loss of cilia in
trachea and bronchi
Inflammatory changes; thickened alveolar
septa; bronchiole-alveolar hyperplasia;
emphysema (diagnostic methodology not
described)
Inflammatory changes; bronchioloalevolar
hyperplasia; alveolar lipoproteinosis; fibrosis
Thickened alveolar septa; AM aggregation;
inflammatory changes; hyperplasia; lung
tumors
Minimal response at 250 and ultrastructural
changes at 750 /*g/m3; thickened alveolar
membranes; cell proliferation; fibrosis at
6,000 fig/m3; increase in PMN at 750 ng/m3
and l,500/*g/m3
Inflammatory changes; AM aggregation;
bronchiolar epithelial metaplasia; Type II
cell hyperplasia; peribronchiolar fibrosis
References
Research
Committee for
HERP Studies
(1988)
Heinrich et al.
(1986a)
Heinrich et al.
(1986a)
Heinrich et al.
(1986a)
Barnhart et al.
(1981, 1982)
Vostaletal. (1981)
Plopper et al.
(1983)
Hyde et al. (1985)
"Light-duty engine.
'Heavy-duty engine.
°1 to 61 weeks exposure.
d62 to 124 weeks of exposure.
AM = Alveolar macrophage.
PMN = Polomerphonuclear leukocyte.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
to
O
H
6
O
3
O
d
s
M
i
o
H
W
Species
Exposure
Period
Particles
(/»g/m3)
C x T
(Mg-h/m3)
CO NO2 SOj
(ppm) (ppm) (ppm)
Effects
Reference
ALVEOLAR MACROFHAGE STATUS
Guinea Pig,
Hartley
Rat, F-344, M
Rat, F-344, M
Rat F-344/Crl,
M, F
Mouse, CD,
M,F
Rat
20 h/day
5.5 days/week
8 weeks
7 h/day
5 days/week
104 weeks
20 h/day
5.5 days/week
26, 48, or
52 weeks
7 h/day
5 days/week
104 weeks (rat),
78 weeks
(mouse)
7 h/day
5 day/week
12 weeks
250
1,500
0.19^m, MMD
2,000
0.23-0.36 fan MMD
250"
750*
l,500b
0.19 /tin, MMD
350
3,500
7,000
0.25 /tm, MMD
200
1,000
4,500
0.25fim, MMD
220,000
1,320,000
7,280,000
715,000-
8,580,000
1,274,000C
12,740,000°
25,480,000°
84,000
420,000
1,890,000
2.9 - -
7.5 - -
11.5 1.5 0.81
2.9 - -
4.8 - -
7.5 — —
2.9 0.05 -
16.5 0.34 —
29.7 0.68 —
CLEARANCE
_ _ _
_ _ _
No significant changes in absolute numbers of alveolar
macrophages (AMs)
Little effect on viability, cell number, oxygen
consumption, membrane integrity, lyzomal enzyme
activity, or protein content of AMs; decreased cell
volume and ruffling of cell membrane and depressed
luminescence of AM
AM cell counts proportional to concentration of DP at
750 and 1,500 /*g/m3; AM increased in lungs in
response to rate of DP mass entering lung rather than
toral DP burden in lung; increased PMNs were
proportional to inhaled concentrations and/or duration
of exposure; PMNs affiliated with clusters of
aggregated AM rather than DP
Significant increases of AM in rats and mice exposed
to 7,000 ^g/m3 DP for 24 and 18 mo, respectively,
but not at concentrations of 3,500 or 350 /ig/m3 DP
for the same exposure durations; PMNs increased in a
dose-dependent fashion in both rats and mice exposed
to 3,500 or 7,000 pg/m3 DP and were greater in mice
than rats
Evidence of apparent speeding of tracheal clearance at
the 4,500 jig/m3 level after 1 week of "To
macroaggregated-albuminand reduced clearance of
tracer aerosol in each of the three exposure levels at
12 weeks; indication of a lower percentage of ciliated
cells at the 1,000 and 4,500 /tg/m3 levels
Chen et. al.
(1980)
Castranova et
(1985)
Strom (1984)
Vestal et al.
(1982)
al.
Henderson et al.
(1988)
Wolff and Gray
(1980)
-------
> TABLE 11-16 (cont'd). EFFECTS OF EXPOSURE TO DIESEL EXHAUST ON THE PULMONARY
U DEFENSE MECHANISMS OF LABORATORY ANIMALS
^5 Exposure
<-t* Species Period
Rat, F-344 7 h/day
M, F 5 days/week
18 weeks
<0.5 /tin, MMD
Rat, F-344, M 7 h/day
5 days/ week
26-104 weeks
Rat, Sprague- 4-6 n/day
Dawley 7 days/week
0.1 to 14.3 weeks
Rat, F-344, 7 h/day
>— M, F 5 days/week
T" 130 weeks
»— '
NJ
P-H
Particles
150
940
4,100
2,000
0.23-0.36 /im
MMD
900
8,000
17,000
350
3,500
7,000
0.25 ^m, MMD
C XT
(Mg-h/m3)
94,500
592,000
2,583,000
1,820,000-
7,280,000
2,500-
10,210,000
1,593,000
15,925,000
31,850,000
CO NO2
(ppm) (ppm)
— —
11.5 1.5
- 5.0
— 2.7
- 8.0
2.9 0.1
16.5 0.3
29.7 0.7
S02
(ppm) Effects
— Lung burdens of DP were concentration-related;
— clearance half-time of DP almost double in
— 4, 100 /ig/m3 group compared to 150 /ig/m3 group.
0.8 No difference in clearance of 59Fe3O4 particles
1 day after tracer aerosol administration; 120 days
after exposure tracer aerosol clearance was
enhanced; Lung burden of DP increased
significantly between 12 to 24 months of exposure
0.2 Impairment of tracheal mucociliary clearance in a
0.6 concentration-response manner
1.0
— No changes in tracheal mucociliary clearance after
— 6, 12, 18, 24, or 30 mo of exposure; increases in
— lung clearance half-times as early as 6 mo at
7,000 pg/m3 level and 18 mo at 3,500 /ig/m3 level;
no changes seen at 350 pg/m3 level; after 24 mo of
diesel exposure, long-term clearance half-times
were increased in the 3,500 and 7,000 pg/m3
groups
Reference
Griffis et al. (1983)
Lewis et al. (1989)
Battigelli et al.
(1966)
Wolff et al. (1987)
\DCROBIAL-INDUCED MORTALITY
Mice, CD-I, F
No change in mortality in mice exposed
intratracheally to 100 /tg of DP prior to exposure to
aerosolized Streptococcus sp.O
Hatch et al. (1985)
-------
3.
oo
TABLE 11-16 (cont'd). EFFECTS OF EXPOSURE TO DIESEL EXHAUST ON THE PULMONARY
DEFENSE MECHANISMS OF LABORATORY ANIMALS
Exposure Particles
Species Period (/jg/m3)
Mice CD-I, F 7 h/day 2,000
5 days/week 0.23-0.36 /tm MMD
4, 12, or
26 weeks
Mice, CR/CD-1 , F 8 h/day 5,300 to 7,900
7 days/week
2 hup to
46 weeks
C x T
(/ig-h/m3)
280,000-
1,820,000
11,000-
20,350,000
CO
(ppm)
11.5
19
to
22
NO2
(ppm)
1.5
1.8
to
3.6
S02
(ppm)
0.8
0.9
to
2.8
Effects
Mortality similar at each exposure duration when
challenged with Ao/PR/8/34 influenza virus; in mice
exposed for 3 and 6 mo, but not 1 mo, there were
increases in the percentages of mice having lung
consolidation, higher virus growth, depressed
interferon levels and a four-fold reduction in
hemagglutin antibody levels
Enhanced susceptibility to lethal effects of
S. pyogenes infections at all exposure durations
(2 and 6 h; 8, 15, 16, 307, and 321 days);
inconclusive results with S. typhimurium because of
high mortality rates in controls; no enhanced
mortality when challenged with A/PR8-3 influenza
virus
Reference
Hahon et al.
(1985)
Campbell et al.
(1980, 1981)
"Chronic exposure lasted 52 weeks.
bChronic exposure lasted 48 weeks.
°Calculated for 104-week exposure.
DP = Diesel exhaust particles.
AM = Alveolar macrophage.
PMN = Poly mo rphonuclear leukocyte.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
1 11.4.4.2 Mutagenicity
2 Since 1978, over 100 publications have appeared in which genotoxicity assays have
3 been employed with diesel emissions, the volatile and particulate fractions (including
4 extracts), or individual chemicals found in diesel emissions. These studies are reviewed in
5 the Health Assessment Document for Diesel Emissions (U.S. Environmental Protection
6 Agency, 1994). The subject has been reviewed in the recent International Agency for
7 Research on Cancer (IARC) monograph (International Agency for Research on Cancer,
8 1989) which contains an exhaustive description of the available studies and other review
9 articles (Claxton, 1983; Pepelko and Peraino, 1983) and the proceedings of several symposia
10 on the health effects of diesel emissions (U.S. Environmental Protection Agency, 1980;
11 Lewtas, 1982; Ishinishi et al., 1986; International Agency for Research on Cancer, 1989).
12 Extensive studies with Salmonella have unequivocally demonstrated direct-acting
13 mutagenic activity in both particulate and gaseous fractions of diesel exhaust. The induction
14 of gene mutations has been reported in several in vitro mammalian cell lines after exposure
15 to extracts of diesel particles. Dilutions of whole diesel exhaust did not induce sex-linked
16 recessive lethals in Drosophila or specific-locus mutations in male mouse germ cells.
17 Structural chromosome aberrations and sister chromatid exchanges (SCE) in mammalian
18 cells have been induced by particles. Whole exhaust induced micronuclei, but not SCE or
19 structural aberrations, in bone marrow of male Chinese hamsters exposed to whole diesel
20 emissions for 6 mo. In 7-week exposures, neither micronuclei nor structural aberrations
21 were increased in bone marrow of female Swiss mice. Likewise, whole diesel exhaust did
22 not induce dominant lethals or heritable translocations in male mice exposed for 7.5 and
23 4.5 weeks, respectively.
24
25 11.4.4.3 Diesel Carcinogenicity Studies
26 Epidemiologic Studies of Diesel Exhaust Carcinogenicity
27 It is difficult to study the health effects of diesel exhaust in the general population
28 because diesel emissions are diluted in the ambient air; hence, exposure is very low. Thus,
29 populations occupationally exposed to diesel exhaust are studied to determine the potential
30 health effects in humans. The occupations involving potential exposure to diesel exhaust are
April 1995 11-129 DRAFT-DO NOT QUOTE OR CITE
-------
1 miners, truck drivers, transportation workers, railroad workers, and heavy-equipment
2 operators.
3 All the occupational studies considered in this section have a similar problem—an
4 inability to measure accurately the actual exposure to diesel exhaust. Most studies compared
5 persons in job categories that would presumably have some exposure to diesel exhaust with
6 either standard populations (that have presumably no exposure to diesel exhaust) or with men
7 working in other job categories in industries with little or no potential for diesel exhaust
8 exposure. The study of the U.S. railroad workers was the only one in which the job
9 categories were verified based on an industrial hygiene survey. A few studies included
10 measurements of diesel fumes, but there was no standard method for the measurement.
11 Neither was any attempt made to correlate these exposures with the cancers observed in any
12 of these studies, nor was it clear exactly which extract should be measured to assess the
13 occupational exposure to diesel exhaust.
14 An excess risk of lung cancer was observed in four out of seven cohort studies and
15 seven out of eight case-control studies. Of these studies, three cohort (Howe et al., 1983;
16 Wong et al., 1985; Boffetta and Stellman, 1988) and three case-control studies (Garshick
17 et al., 1988; Hayes et al., 1989; Steenland et al., 1990) observed an exposure-response
18 relationship by using duration of employment as a surrogate for exposure. However,
19 because of the lack of actual data on exposure to diesel exhaust in these studies and other
20 methodologic limitations, such as lack of latency analysis, etc., the evidence of
21 carcinogenicity in humans falls short of being sufficient, and hence, is considered to be
22 limited. An additional five cohort studies (Gustavsson et al., 1990; Guberan et al., 1992;
23 Emmelin et al., 1993; Swanson et al., 1993; Hansen, 1993) and three case-control studies
24 (Boffetta et al., 1990; Cordier et al., 1993; Notani et al., 1993) have been published after the
25 initial EPA analysis and are reviewed in the Addendum to Chapter 8 of the Health
26 Assessment Document for Diesel Exhaust (U.S. Environmental Protection Agency, 1994).
27 The reviews of these studies indicate that the designation of "limited" evidence of
28 carcinogenicity in humans will not change.
29
30
April 1995 11-130 DRAFT-DO NOT QUOTE OR CITE
-------
1 Animal Carcinogenicity Studies
2 Based on positive inhalation exposure data in rats and mice, intratracheal instillation in
3 rats, and injection or skin painting in mice and supported by positive mutagenicity studies,
4 the animal evidence for carcinogenicity of diesel exhaust is considered to be adequate (U.S.
5 Environmental Protection Agency, 1994). The contribution of the various fractions of diesel
6 exhaust to the carcinogenic response is less certain. The effects of the gaseous phase are
7 equivocal. The presence of known carcinogens adsorbed to diesel particles and the
8 demonstrated tumorigenicity of particle extracts in a variety of injection, instillation- and
9 skin-painting studies provides evidence for the involvement of the organic fraction. Studies
10 showing that pure carbon particles can also induce tumors, on the other hand, indicate that
11 the carbon core of the diesel particle is also involved in the carcinogenic process.
12 The potential for diesel exhaust to induce tumors in laboratory animals has been
13 extensively investigated. Inhalation studies are presented in Table 11-17. Studies employing
14 rats exposed for two years or more to high PM concentrations (up to 8,000 /ig/m3), resulting
15 in large particle loads in the lungs, were generally positive in demonstrating diesel exhaust-
16 induced increases in lung tumors. Inhalation of diesel exhaust was negative in mice, except
17 for studies involving exposure of two strains from birth. Attempts to induce significant
18 increases in lung tumor incidence in Syrian golden hamsters, cats, or monkeys were
19 unsuccessful. The negative results in cats and monkeys may be explained by an inadequate
20 exposure duration (2 years) in these longer-lived species, whereas hamsters are generally less
21 sensitive to lung tumor induction by inhalation than are rats or mice.
22 Although inhalation of sufficient doses of diesel exhaust will induce lung cancer in rats
23 and in at least some strains of mice, the relationship between exposure levels and response is
24 less clearcut. Significant increases in lung tumors were not reported at concentrations less
25 than about 2,000 /ig/m3 PM; the response at higher concentrations varies considerably.
26 A significant percentage of this variation can probably be attributed to the exposure regime.
27 A better method than concentration alone for assessing exposure-response relationships could
28 be achieved by comparing cumulative exposure (concentration X daily exposure duration X
29 days of exposure). Only those studies conducted for a sufficient length of time (>24 mo)
30 for expression of carcinogenic responses have been included in this analysis. Examination of
April 1995 H_131 DRAFT-DO NOT QUOTE OR CITE
-------
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11-132 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-17 (cont'd). SUMMARY OF ANIMAL CARCINOGENICITY STUDIES
VO
o
O
2
O
H
§
O
t— I
3
Study
Takaki et al.
(1988)
Light-duty
engine
Ishinishi et al.
(1988b)
Heavy-duty
engine
Iwai et al.
(1986)
Takemoto et
al. (1986)
Species/ Sex/
Strain Total Number
Rat/F344 M +
M +
M +
M +
M +
Rat/F344 M +
M +
M +
M +
M +
Rat/F344 F, 24
F, 24
F, 24
Rat/F344 F, 12
F, 21
F, 15
F, 18
F, 123
F, 123
F, 125
F, 123
F, 124
F, 123
F, 123
F, 125
F, 123
F, 124
Particle
Exposure Concentration
Atmosphere (^g/m3)
Clean air
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Clean air
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Clean air
Filtered exhaust
Whole exhaust
Clean air
Clean air
Whole exhaust
Whole exhaust
0
100
400
1,100
2,300
0
500
1,000
1,800
3,700
0
0
4,900
0
0
4,900
0
0
2,000-4,000
2,000-4,000
Other
Treatment
None
None
None
None
None
None
None
None
None
None
None
None
None
None
DIPNh
None
DIPNh
Exposure
Protocol
16 h/day,
6 days/week,
for up to
30 mo
16 h/day,
6 days/week,
for up to
30 mo
8 h/day,
7 days/week,
for 24 mo
4 h/day,
4 days/week,
18-24 mo
Postexposure
Observation
Adenomas
NA 1/23 (0.8)
1/23 (0.8)
1/25 (0.8)
0/23 (0)
1/24(8.1)
Adenomas
NA 0/123 (0)
0/123 (0)
0/125 (0)
0/123 (0)
0/124 (0)
Adenomas
NA 1/22 (4.5)
0/16 (0)
3/19 (0)
NA
Tumor Type and
Adenosquamous
Carcinomas
2/123(1.6)
1/23 (0.8)
0/125 (0)
5/123(4.1)
2/124(1.6)
Adenosquamous
Carcinomas
1/123 (0.8)
0/123 (0)
0/125 (0)
4/123 (3.3)
6/124 (4.8)
Adenocarcinoma
and
Adeno-Squamous
Carcinoma
0/22 (0)
0/16 (0)
3/19 (15.8)
Adenoma
0/12 (0)
10/21 (47.6)
0/15 (0)
12/18 (66.7)
Incidence (%)"
Squamous Cell
Carcinomas
1/23 (0.8)
1/23 (0.8)
0/125 (0)
0/123 (0)
0/124 (0)
Squamous Cell
Carcinomas
0/123 (0)
1/123 (0.8)
0/125 (0)
0/123 (0)
2/124(1.6)
Large Cell and
Squamous Cell
Carcinomas
0/22 (0)
0/16 (0)
2/19 (10.5)
Carcinoma
0/12 (0)
4/21 (19)
0/15 (0)
7/18 (38.9)
Comments
All
Tumors
4/123 (3.3)
3/123 (2.4)
1/125 (0.8)
5/123(4.1)
3/124 (2.4)
All
Tumors
1/123 (0.8)
1/123 (0.8)
0/125 (0)
4/123 (3.3)
8/124
(6.5)c
All
Tumors
1/22 (4.5)f
0/16 (0)
8/19
-------
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TABLE 11-17 (cont'd). SUMMARY OF ANIMAL CARCINOGENICITY STUDIES
Study
Ishmishi et al.
(1988b)
Light duty
Heavy duty
Lewis et al.
(1986)
Species/ Sex/
Strain Total Number
Rat/F344 NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Rat/F344 M
,5
,8
, 11
,5
,9
, 11
,5
,9
11
,5
,6
, 13
+ F, 288"
Exposure
Atmosphere
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Whole exhaust
Clean air
Whole exhaust
Particle
Concentration Other Exposure Postexposure
(pg/m3) Treatment Protocol Observation
100
100
100
1,100
1,100
1,100
500
500
500
1,800
1,800
1,800
0
2,000
None
None
None
None
None
None
None
None
None
None
None
None
None
None
16 h/day,
6 days/week,
for 12 mo
16 h/day,
6 days/week,
for 12 mo
7 h/day,
5 days/week,
24mo°
6
12
18
6
12
18
6
12
18
6
12
18
mo
mo
mo
mo
mo
mo
mo
mo
mo
mo
mo
mo
NA
Tumor Type and Incidence (%)" Comments
Adenomas
0/5 (0)
0/8 (0)
0/11(0)
0/5 (0)
0/9 (0)
0/11(0)
0/5 (0)
0/9 (0)
0/11(0)
0/5 (0)
0/6 (0)
0/13 (0)
No tumors
Carcinomas
0/5 (0)
0/8 (0)
0/11 (0)
0/5 (0)
0/9 (0)
0/11 (0)
0/5 (0)
0/9 (0)
0/11(0)
0/5 (0)
0/6 (0)
1/13 (7)
All Tumors
0/5 (0)
0/8 (0)
0/11 (0)
0/5 (0)
0/9 (0)
0/11(0)
0/5 (0)
0/9 (0)
0/11 (0)
0/11 (0)
0/6 (0)
1/13 (7)
0/192 (0)
0/192 (0)
"Table values indicate number exposed/number with tumors (% animals with tumors).
bNumber of animals examined for tumors.
Significantly different from clean air controls.
dDiphenyInitrosamine; 6.25 mg/kg/week sc during first 25 weeks of exposure.
'Diphenylnitrasamine; 12.5 mg/kg/week sc during first 25 weeks of exposure.
f Splenic lymphomas also detected in controls (8.3%), filtered exhaust group (37.5%) and whole exhaust group (25%).
g5.3% incidence of large cell carcinomas.
hl g/kg, ip I/week for 3 weeks starting 1 mo into exposure.
'Includes adenomas, squamous cell carcinomas, adenocarcinomas, adeno squamous cell carcinoma, and mesotheliomas.
J4.5 mg/DEN/kg, sc, 3 days prior to start of inhalation exposure.
kS ingle ip dose 1 mg/kg at start of exposure.
'Butylated hydroxytoluene 300 mg/kg, ip for Week 1, 83 mg/kg for Week 2, and 150 mg/kg for Weeks 3 to 52.
m!2 mg/m3from 12 weeks of age to termination of exposure. Prior exposure (in utero) and of parents was 6 mg/rf.
"120-121 males and 71-72 females examined histologically.
"Not all animals were exposed for full term, at least 10 males were killed at 3-, 6-, and 12-mo exposure.
NS = Not specified.
NA = Not applicable.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
1
2
3
4
the rat data, shown and plotted in Figure 11-5 reveals that most studies indicate a trend of
increasing tumor incidence at exposures exceeding 1 x 107 /*g-h/m3.
O Mauderty etal. (1987)
• Heinrich et al. (1986b)
Ishinishi etal. (1988b
d Brightwell et al. (1989)
A Iwai etal. (1986)
1234
Cumulative Exposure (107jig • h/m1 )
Figure 11-5. Cumulative exposure data for rats exposed to whole diesel exhaust.
1 Particle Effect in Diesel Exhaust-Induced Carcinogenicity
2 The relative contribution of the carbon core of the diesel particles versus organics
3 adsorbed to the surface of the particles to cancer induction is still somewhat uncertain. The
4 primary evidence for the importance of the adsorbed organics is the presence of known
5 carcinogens among these chemicals. These include polycyclic aromatics as well as
6 nitroaromatics. Organic extracts of particles have also been shown to induce tumors in a
7 variety of injection, intratracheal instillation and skin painting studies, and Grimmer et al.
8 (1987) has, in fact, shown that the great majority of the carcinogenic potential following
9 intratracheal instillation resided in the fraction containing four- to seven-ring PAHs.
10 Evidence for the importance of the carbon core is provided by studies of Kawabata
11 et al. (1986), that showed induction of lung tumors following intratracheal instillation of
12 CB that contained no more than traces of organics and studies of Heinrich (1990) that
April 1995
11-138 DRAFT-DO NOT QUOTE OR CITE
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1 indicated that exposure via inhalation to CB (Printex 90) particles induced lung tumors at
2 concentrations similar to those effective in diesel studies. Other particles of low solubility
3 such as titanium dioxide (Lee et al., 1986) have also been shown to induce lung tumors,
4 although at much higher concentrations than necessary for carbon particles or diesel exhaust.
5 Pyrolyzed pitch, on the other hand, essentially lacking a carbon core but having PAH
6 concentrations at least three orders of magnitude greater than diesel exhaust, was no more
7 effective in tumor induction than was diesel exhaust (Heinrich et al., 1986b). These studies
8 suggest that the insoluble carbon core of the particle is at least as important as the organic
9 components and possibly more so for lung tumor induction at high particle concentrations
10 (> 2,000 jtg/m3).
11 Diesel PM is composed of an insoluble carbon core with a surface coating of relatively
12 soluble organic constituents. Studies of diesel particle composition have shown that the
13 insoluble carbon core makes up about 80% of the particle mass and that the organic phase
14 can be resolved into a more slowly dissolving component and a more quickly dissolving
15 component. Since macrophage accumulation, epithelial histopathology, and reduced
16 clearance have been observed in rodents exposed to high concentrations of chemically inert
17 particles (Morrow, 1992), it appears possible that the toxicity of diesel particles results from
18 the carbon core rather than the associated organics. However, the organic component of
19 diesel particles consists of a large number of polycyclic aromatic hydrocarbons and
20 heterocyclic compounds and their derivatives. A large number of specific compounds have
21 been identified. These components of diesel particles may also be responsible for the
22 pulmonary toxicity of diesel particles. It is not possible to separate the carbon core from the
23 adsorbed organics in order to compare the toxicity. As an approach to this question, a study
24 has been performed in which rats were exposed to either diesel exhaust or to carbon black,
25 an inert analog of the carbon core of diesel particles. Rats were exposed for 16 h/day,
26 5 days/week, for up to 24 mo to either 2,500 or 6,500 /ig/m3 of the particle (duration
27 adjusted concentrations = 1,200 and 3,100 jug/m3) (Nikula et al., 1991). Although the study
28 is primarily concerned with the role of particle associated organics in the carcinogenicity of
29 diesel exhaust, non-neoplastic effects are also mentioned. According to the preliminary
30 report, both diesel exhaust and carbon black exposure resulted in macrophage hyperplasia,
31 epithelial hyperplasia, bronchiolar-alveolar metaplasia, and focal fibrosis. Although the
April 1995 11-139 DRAFT-DO NOT QUOTE OR CITE
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1 analyses have not yet been completed, the preliminary report states that the number and
2 intensity of the lesions seems to correspond to the exposure time and concentration and that
3 the morphological characteristics of the lesions were similar in the animals exposed to diesel
4 and to carbon black. The preliminary results suggest that the chronic noncancer effects of
5 diesel exhaust exposure are caused by the persistence of the insoluble carbon core of the
6 particles, rather than by the extractable organic layer. On this basis, the variety for non-
7 cancer effects is based on the calculation of the human equivalent dose with the retained mass
8 of the carbon core per unit of pulmonary surface area as the expression of dose which is
9 considered equivalent across species.
10
11 Metabolism and Mechanism of Action of Carcinogenic Compounds of Diesel Exhaust
12 The role of the carbonaceous core (soot particle) and a particle overload effect in the
13 pulmonary carcinogenesis of diesel exhaust is also of concern. Several studies (Vostal, 1986;
14 Kawabata, 1986; Heinrich, 1990; Wolff et al., 1990; Oberdorster and Yu, 1990) have
15 provided data indicating that the carbonaceous core may have a promotional effect related to
16 the ability of the particle to induce chronic inflammation and promote epithelial cell
17 proliferation. More recent work (Mauderly et al., 1994; Nikula et al., 1994) has shown that
18 carbon black was also carcinogenic in rats exposed to particle concentrations of 2,500 or
19 6,500 jug/m3 for 24 mo. The carbon black particles were similar to the soot particles of
20 diesel exhaust but contain markedly lower amounts of adsorbed organic compounds.
21 A study by Wolff et al. (1990) addressed this topic by comparing the inflammatory
22 responses in rats exposed to diesel exhaust (10,000 /zg/m3) or CB particles (10,000 /xg/m3).
23 Although the level of lung DNA adducts was slightly higher for diesel exhaust exposure,
24 both exposures resulted in inflammatory responses, as determined by increased numbers of
25 neutrophils and macrophages and increased acid proteinase in the BAL fluid.
26 Oberdorster and Yu (1990) evaluated the significance of a particle effect in the
27 tumorigenic response of the lung to diesel exhaust exposure. Using data from studies
28 examining the effects of long-term inhalation exposure to diesel exhaust, TiO2 particles, CB,
29 or toner particles, it was reported that only the surface area of retained particles in the lung
30 showed a reasonable concentration-response relationship relative to tumor incidence and that
31 particle overload (retained mass or volume of particles) alone may not be the determining
April 1995 11-140 DRAFT-DO NOT QUOTE OR CITE
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1 factor in lung tumor formation. In this respect, it was shown that particles lacking adsorbed
2 organics (pure CB or TiO2 particles) and diesel exhaust particles exhibited a similar
3 relationship between particle surface area and tumor incidence. The investigators
4 hypothesized a tumorigenic effect would probably require that a "critical" surface area of
5 retained particles be attained for the manifestation of any mechanisms of tumorigenicity.
6 The possibility of a particle effect in the tumorigenic response has also been
7 demonstrated by Heinrich (1990) in which female Wistar rats (72 per group) were exposed to
8 Printex 90 CB particles for 10 mo followed by a 20-mo exposure-free observation period or
9 for 20 mo followed by a 10-mo exposure-free observation period. A particle concentration
10 of 6,090 jig/m3 was used in both protocols. The Printex 90 particles had an extremely low
11 organic content («1,000-fold less than that of diesel exhaust particles). The tumor rates for
12 the 10- and 20-mo exposure durations were 17% (14% malignant) and 8% (all malignant),
13 respectively. Although the lower tumor incidence for the longer exposure period was not
14 consistent, the results demonstrate that the tumor incidences for CB particles with an organic
15 content 1,000-fold less than diesel exhaust particles are equivalent to those reported for diesel
16 exhaust exposures. The fact that these particles were able to exert a significant tumorigenic
17 response implicates the carbon core of diesel exhaust particles as possible tumor initiators in
18 diesel exhaust-induced carcinogenicity at high particle concentrations.
19 The potential importance of the particle in the pulmonary carcinogenicity of inhaled
20 diesel exhaust in rats was reported by Mauderly et al. (1994). In this long-term exposure
21 study, rats were exposed 16 h/day, 5 days/week for 24 mo to whole diesel exhaust or CB
22 (free of adsorbed organics) at particle concentrations of 2,500 or 6,500 Mg/m3. Controls
23 were exposed to clean air. Lung weights were increased in rats exposed to the highest
24 concentrations of both diesel exhaust or CB but were slightly higher for the diesel exhaust
25 group. The lung burdens of paniculate matter were significantly greater for the diesel
26 exhaust-exposed rats at 18 and 23 mo. A substantial transfer of particles from the lungs to
27 lung-associated lymph nodes was observed, but no difference was noted between the diesel
28 exhaust and CB exposure groups. Inflammation and cytotoxicity detected in lavage fluid was
29 greater for diesel exhaust-exposed rats, but the difference was proportional to the higher lung
30 burden of retained particles noted for these animals. Preliminary data based on
31 approximately 100 male and 100 female rats indicated that the numbers of lung tumors
April 1995 \l-\4\ DRAFT-DO NOT QUOTE OR CITE
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1 observed grossly at necropsy were nearly identical for the diesel exhaust and CB exposure
2 groups. Tumor type observed included squamous cysts, squamous cell carcinomas, papillary
3 adenocarcinomas, tubular adenocarcinomas, and solid carcinomas. The growth of tumors
4 transplanted into athymic mice has also been similar for diesel exhaust and CB exposures, 74
5 and 73%, respectively. In summary, these preliminary observations suggest that no
6 difference exists in the type or incidence of lung tumors in rats following long-term exposure
7 to diesel exhaust or CB, and that the particle-associated organics may not significantly
8 involved in the pulmonary carcinogenicity of diesel exhaust in rats.
9 The carcinogenic potential of many PAHs is well-documented, and, therefore, the
10 potential involvement of PAHs in diesel exhaust-induced carcinogenesis must be considered.
11 However, the recent reports by Heinrich (1990), Mauderly et al. (1994), and Nikula et al.
12 (1994) provide data that call into question the importance of PAHs in diesel exhaust-induced
13 carcinogenesis in these types of experiments that use exceptionally high particle
14 concentrations. Bond et al. (1990a) reported that DNA adduct levels were similar in Type 2
15 cells of rats exposed either to diesel exhaust or carbon black particles. Although speculative
16 at this time, the information in these studies suggest that PAHs may not be instrumental in
17 diesel exhaust-induced carcingenicity. Bond et al. did report DNA adducts in both carbon-
18 and diesel-exposed rats, but adducts were induced at lower concentrations by diesel exhaust.
19 The greater lung burden and toxicity of diesel particles at comparable concentrations indicate
20 that organics do play a role in toxicity and possibly carcinogenicity, although probably not a
21 major role.
22
23 Cancer Assessment
24 The U.S. Environmental Protection Agency (1994) has developed a draft qualitative and
25 quantitative cancer assessment for diesel emissions. The summary to follow was drawn from
26 that document. That draft is currently undergoing external review by the public and the
27 Clean Air Scientific Advisory Committee. On the basis of limited evidence for
28 carcinogenicity of diesel engine emissions in humans, supported by adequate evidence in
29 animals and positive mutagenicity data, diesel engine emissions are considered to best fit the
30 weight-of-evidence Category Bl. Agents classified into this category are considered to be
April 1995 11-142 DRAFT-DO NOT QUOTE OR CITE
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1 probable human carcinogens. This is in agreement with the 2A classification by the
2 International Agency for Research on Cancer.
3 Risk estimates can be derived from either human or animal experiments. Each type of
4 study has its own strengths and limitations. Estimates based on human studies reflect direct
5 observation of an association between exposure and human cancer. These human estimates,
6 however, are limited by the difficulty of reconstructing reliable estimates of exposures many
7 years in the past and distinguishing the influence of confounding exposures to other
8 carcinogens. Conversely, estimates based on animal studies benefit from precisely measured
9 exposures and the absence of many potentially confounding factors; but use of animal
10 estimates involves uncertainty in the extrapolation of dose and response rates to humans, as
11 well as extrapolation from experimental to ambient concentrations over about three orders of
12 magnitude.
13 From human studies, published unit risk estimates range from 6 x 10"4 to
14 3 x 10"3/pig/m3. An upper bound risk estimate of 3 x 10~3//ig/m3 was reported for London
15 transport workers. (In view of the nonpositive findings of this study, a lower bound estimate
16 would encompass 0.) Upper bound risk estimates of 6 x 10"4 and 2 x 10~3/jig/m3 were
17 calculated for railroad workers, assuming mean occupational exposure concentrations of
18 500 or 125 ng/m3, respectively.
19 From animal experiments, upper bound unit risk estimates can be calculated using the
20 linearized multistage procedure, a default method used when the mechanism of action is
21 unknown, the information required by a mechanistic model is unavailable, or the suspected
22 mechanism or background conditions are consistent with linearity at low incremental
23 exposures. The linearized multistage procedure was applied to three rat experiments that
24 collectively span a 50-fold range of doses and yielded unit risk estimates ranging from 1.6 to
25 7.1 x 10"5//ng/m3 (the upper 95% bound of the cancer risk from a lifetime exposure). These
26 estimates are based on two assumptions: (1) that carbon particles are primarily responsible
27 for both toxic and carcinogenic effects, and (2) that equivalent sensitivity occurs across
28 species when dose is expressed as mass per unit surface of the alveolar region. Dosimetric
29 adjustments were made from rats to humans and from experimental regimes to continuous
30 lifetime exposure. In addition, an alternative low-dose extrapolation model was developed to
April 1995 11-143 DRAFT-DO NOT QUOTE OR CITE
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1 account for possible tumor-initiating effects of the particles. Much of the data needed to
2 estimate the model's parameters, however, are lacking.
3 In view of the uncertainty inherent in these types of calculations, the human and animal
4 estimates should be viewed as complementary. For a bounding estimate intended to
5 determine whether an exposure level has a potential to pose a hazard to human health, the
6 published human estimates may be practical for exposure levels in the range of observations
7 in these studies. On the other hand, projection of the public health impact of an exposure
8 level may benefit from using estimates derived from animal experiments, because of the
9 closely controlled conditions and their precisely measured exposure levels, absence of many
10 confounding factors, and narrow confidence limits around the tumor incidence rates. A unit
11 risk estimate of 3.4 x 10~5//ig/m3 for continuous lifetime exposure, which is the geometric
12 mean of the upper bound estimates calculated from the three rat experiments, is therefore
13 recommended (U.S. Environmental Protection Agency, 1994).
14
15
16 11.5 ULTRAFINE PARTICLES
17 Particles used in toxicological studies are mainly in the fine and coarse mode size
18 range. This section addresses the hypothesis that ultrafine particles can cause acute lung
19 injury and focuses on experimental studies in which ultrafine particles generated as fumes
20 were used. The ultrafine (nucleation mode) particle phase has a median diameter of =»20 nm
21 (see Figure 3-13). Ultrafine particles with a diameter of 20 nm have an approximately
22 6 order of magnitude higher number concentration than a 2.5 /xm diameter particle, when
23 inhaled at the same mass concentration and particle surface area is also highly increased
24 (Table 11-18). Although many classes of ultrafine particles can be found in the atmosphere
25 (e.g., smog, metallurgical dusts and fumes, carbon black, combustion nuclei, oil smokes),
26 few have been studied as particles in this size fraction.
27 Inhalation studies in rats with aggregated ultrafine particles have shown that these
28 particles still required high concentrations (in the mg/m3) range and repeated exposures to
29 produce effects in laboratory animals, although they were more active than larger-sized
30 particles of the same composition. These particles included ultrafine TiO2 aggregates (Ferin
31 et al., 1992; Oberdorster et al., 1992; Heinrich, 1994) as well as aggregated carbon black
April 1995 11-144 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-18. NUMBERS AND SURFACE AREAS OF MONODISPERSE
PARTICLES OF UNIT DENSITY OF DIFFERENT SIZES AT A MASS
CONCENTRATION OF 10 jig/m3
Particle Diameter
j*m
0.02
0.1
0.5
1.0
2.5
Particle Number
per cm3 air
2,400,000
19,100
153
19
1.2
Particle Surface Area
fj.m2 per cm3 air
3,016
600
120
60
24
1 particles (Heinrich, 1994; Mauderly et al., 1994; Nikula et al., 1994). Effects observed
2 after subchronic or chronic exposure of rats included chronic inflammation, pulmonary
3 fibrosis, and induction of lung tumors. No acute effects were observed, even at the highest
4 exposure concentrations. Although the studies of TiO2 and carbon black involved particles of
5 submicron size (0.2 to 0.3 jim), they are still considerably larger than 20 nm ultrafine
6 particles. Thus, these results may not fully reflect the toxicity of 20 nm particles.
1 From these studies, it appeared that particle surface area is an important parameter for
8 expressing exposure-response and dose-response relationships of inhaled highly insoluble
9 particles. This means that aggregated ultrafine particles, because of their highly increased
10 surface area, could be fitted into the overall dose-response curve with other larger-sized
11 particles (Oberdorster et al., 1992, 1994). The finding that ultrafine particles can penetrate
12 into the interstitium more easily than larger-sized particles (Takenaka et al., 1986; Ferin et
13 al., 1992) is also very important. This transport across the epithelium appears to be
14 facilitated if ultrafine particles deaggregate upon deposition and are present as singlet
15 particles.
16 In contrast, specific types of inhaled singlet ultrafine particles can induce severe acute
11 lung injury at low inhaled mass concentrations relative to aggregated ultrafine particles.
18 These model ultrafine particles were generated by heating of polytetrafluoroethylene
19 (Teflon*; PTFE); the resulting condensation aerosol consisted of singlet ultrafine particles.
20 More than 25 years ago it was recognized that the toxicity of pyrolysis products of PTFE is
21 associated with particulate phase rather than with gas phase constituents (Waritz and Kwon,
April 1995 H_145 DRAFT-DO NOT QUOTE OR CITE
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1 1968). However, it was demonstrated more recently that these particles are of ultrafine size
2 (Lee and Seidel, 1991; Seidel et al., 1991). These particles form upon heating of Teflon* to
3 a critical temperature of «420 to 450 °C and have a median diameter of —26 nm, with a
4 geometric standard deviation of 1.4 (Oberdorster et al., 1995a). The toxicity of PTFE fumes
5 has been recognized for a long time, dating back to the 1950's when exposures of rabbits,
6 guinea pigs, rats, mice, cats, and dogs resulted in acute mortality (Treon et al., 1955).
7 Further studies in experimental animals by several investigators (Scheel et al., 1968;
8 Coleman et al., 1968; Griffith et al., 1973; Lee et al., 1976; Alarie and Anderson, 1981)
9 confirmed that these fumes are highly toxic to birds and mammals. Extensive pulmonary
10 epithelial and interstitial damage and alveolar flooding occurred after only short-durations of
11 exposure. Accidental exposures of humans to fumes generated from polymers also
12 demonstrated the high toxicity of these fumes for humans (Nuttall et al., 1964; Goldstein et
13 al., 1987; Dahlqvist et al., 1992). Associated effects include pulmonary edema, nausea and
14 headaches, together characterized by the term "polymer fume fever" in analogy to the
15 well-known symptoms of metal fume fever (Rose et al., 1992).
16 The toxicity of polymer fumes was initially associated with toxic gas phase products,
17 such as hydrogen fluoride (HF), carbonyl fluoride, and perfluoroisobutylene (PFIB).
18 However, detailed studies by Waritz and Kwon (1968) as well as more recent studies have
19 shown that the high toxicity is associated with the particulate phase. For example, HF
20 studies showed that concentrations as high as 1300 ppm are needed to cause effects in the
21 respiratory tract of exposed rats; these effects occur only in the upper respiratory tract, not in
22 the lung periphery where the fume particles have been shown to be most effective (Stavert et
23 al., 1991). Concentrations of HF in fumes generated at the critical temperature are only
24 = 10 ppm, and therefore, cannot be responsible for the observed toxicity of the fumes
25 (Oberdorster et al., 1995a). The more toxic gas phase compounds, carbonyl fluoride and
26 PFIB are generated only at temperatures approaching 500 °C when heating PTFE (Coleman
27 et al., 1968; Waritz and Kwon, 1968). Furthermore, rat inhalation studies with PFIB alone
28 showed that lung pathology was detected only when a high concentration of 90,000 /xg/m3
29 was exceeded (Lehnert et al., 1993). Further proof that the particles of polymer fumes
30 represent the toxic entity is provided by studies in which the particulate phase was removed
April 1995 11-146 DRAFT-DO NOT QUOTE OR CITE
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1 by filters and subsequently the gas phase compounds did not show toxicity in exposed rats
2 (Waritz and Kwon, 1968; Warheit et al., 1990; Lee and Seidel, 1991).
3 It has also been suggested that highly toxic radicals on the surface of the polymer fume
4 particles may cause the acute effects. However, studies by Seidel et al. (1991) with fumes
5 from different polymers showed similar toxicities to the lung regardless as to whether
6 significant amounts of radicals could be detected on those particles or not. Although this still
7 does not exclude that some reactive toxic compounds may be attached to the particle surface,
8 all of these studies provide convincing evidence that the ultrafine particles are the cause of
9 the PTFE fume-associated, acute lung injury. It has also been shown that aging of the fumes
10 leading to particle aggregation diminishes their toxicity, indicating that the presence of
11 ultrafine particles as singlets is highly important for the toxicity of these particles (Lee and
12 Seidel, 1991; Warheit et al., 1990).
13 To exclude the possibility that oxygen-derived radicals from the generation process may
14 be responsible for the observed pulmonary toxicity, PTFE particles were generated in a
15 nitrogen atmosphere (Waritz and Kwon, 1968) or in an argon gas atmosphere (Oberdorster
16 et al., 1995b). Results showed that the inhaled PTFE fumes generated in this way showed
17 the same high pulmonary toxicity in rats that was observed with PTFE fumes generated in
18 air. The toxicity consisted of severe hemorrhagic, pulmonary edema and influx of PMNs
19 into the alveolar space within 4 h after a 15-min exposure of healthy rats to an ultrafine
20 particle mass concentration of about 40 to 50 fig/m3; this was accompanied by high mortality
21 (Oberdorster et al., 1995b). It was also determined by these investigators that a number
22 concentration of 1 x 105 PTFE particles/cm3 is equivalent to a mass concentration of
23 =8 /ig/m3. Pulmonary lavage data showed that up to 80% of lavageable cells consisted of
24 PMNs. Acute mortality was also observed in up to 50% of rats exposed to these
25 concentrations of 5 x 105 particles/cm3. Epithelial as well as endothelial cell damage
26 occurred, resulting in both interstitial and alveolar edema. Analysis of the particle
27 disposition in lung tissue using electron energy loss spectroscopy revealed that, shortly after
28 the exposure, ultrafine particles could be found in epithelial cells as well as interstitial and
29 endothelial sites. The authors concluded that freshly-generated ultrafine PTFE particles
30 inhaled as singlets at low mass concentrations can cause severe acute lung injury and that
31 ultrafine particles, in general, penetrate readily through epithelial-endothelial barriers.
April 1995 11-147 DRAFT-DO NOT QUOTE OR CITE
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1 Nose-only exposures to as low as «10 /ig/m3 (1 X 105 particles/cm3) of ultrafine PTFE
2 particles for 30 min were found to result in significant inflammatory responses in exposed
3 rats (Oberdorster et al., 1995c).
4 Additional studies with ultrafine PTFE particles directed at evaluating mechanistic
5 events in the lung by using in situ hybridization techniques on lung tissue showed that the
6 highly inflammatory reaction was characterized by significant increases in message for the
7 pro-inflammatory cytokine TNFa and the low molecular weight protein metallothionein
8 (Johnston et al., 1995). Furthermore, increases in abundance for messages encoding IL-la,
9 IL-1/3, IL-6, TNFa and the antioxidants MnSOD and metallothionein were found in RNA
10 extracted from lung tissues. In addition to the increase in message of these pro-inflammatory
11 cytokines and antioxidants, abundance for message of inducible NOS was also increased,
12 whereas message for VEGF (vascular endothelial growth factor) was decreased in the acute
13 phase (Johnston et al., 1995). The authors suggested that the acute lung damage affecting
14 epithelial and endothelial barrier functions may be due to the activities of reactive oxygen
15 and reactive nitrogen species originating from highly activated inflammatory cells and
16 produced via inducible NOS.
17 In summary, certain freshly-generated ultrafine particles, when inhaled as singlets at
18 very low mass concentrations (10 to 50 fJLg/m3), can be highly toxic to the lung. Mechanisms
19 responsible for this high toxicity could include: (1) high pulmonary deposition efficiencies of
20 these particles; (2) the large numbers per unit mass of these particles; (3) their increased
21 surface area available for reaction; and (4) the presence of radicals on the particle surface
22 depending on the process of generation of the particles. Results of studies with ultrafine
23 model particles indicate that particle number may be the more important dose parameter.
24
25
26 11.6 METALS
27 11.6.1 Introduction
28 The metals discussed in this section are those commonly found to be present in the
29 ambient atmosphere of U.S. urban areas in concentrations greater than 1 ng/m3 (see
30 Chapter 6). These sections are intended as general summaries on each metal since the
31 majority, with the exception of lead, do not have current documentation or health risk
April 1995 11-148 DRAFT-DO NOT QUOTE OR CITE
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1 standards. Each section briefly discusses physical and chemical properties of the metal
2 and/or important compounds; their pharmokinetics, including deposition, uptake, distribution,
3 metabolism and elimination; associated data on acute and chronic health effects in humans
4 and animals; and comparative toxicity in humans and laboratory animals.
5
6 11.6.2 Aluminum
7 11.6.2.1 Chemical and Physical Properties
8 Aluminum metal is a tin-white, malleable, ductile, solid that does not occur naturally in
9 its elemental form. It is the third most abundant element in the earth's crust and is found in
10 a large variety of minerals and ores (Sleppy, 1992). Aluminum belongs to Group III A of the
11 periodic system of elements and exhibits a valence of +3 in all compounds, except for a few
12 high-temperature gaseous species for which the valence may be +1 or +2 (Staley and
13 Haupin, 1992). Aluminum is a good reducing agent and reacts with oxygen and moisture hi
14 air to form an aluminum oxide film on the exposed surfaces (Budavari, 1989; Brady and
15 Humiston, 1986; Staley and Haupin, 1992). It can form organometallic compounds by direct
16 aluminum-to-carbon bonds or by bonds represented as Al-X-R, where X may be oxygen,
17 nitrogen, or sulfur, and R is a suitable organic radical (Staley and Haupin, 1992).
18 In aqueous solutions, aluminum is amphoteric (Brady and Humiston, 1986; Sleppy, 1992).
19 Elemental aluminum and aluminum oxide (A12O3) are insoluble in water, whereas some other
20 aluminum compounds are moderately water soluble. For example, aluminum chlorohydrate
21 (A12C1H5O5 or A12(OH)5C1 • 2H2O) dissolves in water to form slightly turbid colloidal
22 solutions; and aluminum trichloride (A1C13 • 6H2O) and aluminum fluoride (A1F3) are
23 moderately soluble in hot water (Budvari, 1989).
24
25 11.6.2.2 Pharmacokinetics
26 Absorption and Distribution
27 Most aluminum compounds enter the lung as particles of poorly soluble compounds
28 (Ganrot, 1986). Some of these particles are taken up by alveolar macrophages through
29 phagocytosis, then transported through the respiratory system and ultimately swallowed. The
30 remaining aluminum is taken up by macrophages in lung tissue, where it is retained
31 indefinitely.
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1 Following oral exposure in laboratory animals, aluminum is distributed in the blood.
2 Al+3 ions are present almost exclusively in the plasma where they competitively bind to the
3 iron-binding sites of transferrin (Ganrot, 1986; Moshtaghie and Skillen, 1986). Considerable
4 binding of Al+3 also occurs in the metabolically active areas of bone (Ganrot, 1986). The
5 density of transferrin receptors in different organs influences aluminum distribution. The
6 cells accumulating the most aluminum are large, long-lived postmitotic cells such as neurons
7 (Ganrot, 1986). Within these cells, Al+3 accumulates in the lysosomes, cell nucleus, and
8 chromatin. In organs composed of postmitotic cells, this accumulation is expected to
9 increase the concentration of Al+3. However, in other organs, the accumulation of Al+3 and
10 the elimination of dead cells that are replaced by cells with a lower Al+3 concentration leads
11 to a steady state aluminum concentration.
12 Several laboratory animal studies indicate that aluminum is absorbed by the lungs
13 following inhalation exposure (Steinhagen et al., 1978; Stone et al., 1979; Thomson et al.,
14 1986). Although these studies indicate that absorption by the lungs has occurred, aluminum
15 levels in other tissues, urine, and plasma were not assessed. Following short or long term
16 inhalation exposure to aluminum chlorohydrate, elevated aluminum levels were found in the
17 lung (rats, Guinea pigs), adrenal glands (rats), and peribronchial lymph nodes (Guinea pigs)
18 (Stone et al., 1979; Steinhagen et al., 1978). Rats and hamsters had elevated aluminum
19 levels in lymph nodes and lymphatic drainage areas following repeated exposure to
20 aluminum dusts (Christie et al., 1963). No appreciable accumulation was found in the brain,
21 heart, spleen, kidneys, or liver of either species.
22 Aluminum is normally found in human tissue, with a total body burden of aluminum in
23 healthy humans of about 30-50 mg (Alfrey, 1981; Alfrey et al., 1980; Cournot-Witmer
24 et al., 1981; Ganrot, 1986). About 50% of the body burden is in the skeleton and 25% in
25 the lungs (Ganrot, 1986). Most aluminum detected in lungs is probably due to accumulated
26 inhaled insoluble aluminum compounds (Ganrot, 1986).
27
28 Metabolism
29 In the body, aluminum exists in four different forms: as free ions, as low-molecular-
30 weight complexes, as physically bound macromolecular complexes, and as covalently bound
31 macromolecular complexes (Ganrot, 1986). The free ion, Al+3, easily binds to many
April 1995 11-150 DRAFT-DO NOT QUOTE OR CITE
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1 substances and structures, so that its fate is determined by its affinity to each of the ligands
2 and their relative amounts and metabolism.
3 Aluminum also forms low-molecular-weight complexes that are often very stable
4 chelates with organic acids, amino acids, nucleotides, phosphates, and carbohydrates. The
5 complexes, especially the nonpolar ones, are metabolically active. Because aluminum has a
6 very high affinity for proteins, polynucleotides, and glycosaminoglycans, much of it likely
7 exists in the body as physically bound macromolecular complexes with such substances.
8 These macromolecular complexes are expected to be much less metabolically active than the
9 small, low-molecular-weight complexes. Aluminum also forms complexes with structures
10 that are so stable that they are essentially irreversible macromolecular complexes. For
11 example, evidence suggests that the nucleus and chromatin are often aluminum binding sites
12 in cells (Crapper McLachlan, 1989; Dryssen et al., 1987; Ganrot, 1986; Karlik and Eichorn,
13 1980.)
14
15 Excretion
16 In humans, most inhaled aluminum is excreted through the kidney. Urinary levels in
17 six volunteers rapidly increased to 14 to 414 ^ig/L from pre-exposure levels (3 /xg/L) after a
18 one-day exposure (8-h workshift) to a time-weighted average (TWA) concentration of
19 2,400 ng Al/m3 (Sjogren et al., 1985). Urinary Al levels of seven welders occupationally
20 exposed to Al fumes or dust for 6 mo increased three-fold after an 8-h workshift compared to
21 preshift concentrations (Mussi et al., 1984). During longer exposure periods (25 workers
22 exposed for 0.3-21 years to approximately 1,500 jug/m3 Al), urinary Al levels averaged
23 82 /ig/L, compared to 29 /ig/L following a 16 to 37 day exposure-free interval (Sjogren
24 etal., 1988).
25 There is a relationship between the duration of AL exposure and urinary concentrations
26 in humans (Sjogren et al., 1985, 1988). Welders exposed to 250 /ig/m3 (8-h workshift) for
27 more than 10 years had a urinary Al half-life of at least 6 mo, compared to nine days for
28 individuals exposed for less than a year (Sjogren et al., 1988). The excretion half-life was
29 eight hours following a single AL exposure (Sjogren et al., 1985). However, when
30 measured after an exposure-free period, urinary concentrations were related to the total
31 number of years exposed. Apparently, the longer the exposure in humans, the greater the
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1 retention of AL. No studies were located regarding excretion in laboratory animals
2 following inhalation of AL or its compounds.
3
4 11.6.2.3 Health Effects
5 Human Data
6 No data were located on effects in humans of acute inhalation exposure to AL.
7 Longer-term studies were limited and consisted of occupational case studies and
8 epidemiology studies in AL smelter and potroom workers. The studies did not specify the
9 concentration or form of AL exposure, except as "aluminum dust," and reported confounding
10 exposure to known carcinogens and respiratory irritants. Based on these data, the respiratory
11 tract is the primary target of AL inhalation. Respiratory effects are usually largely limited to
12 irritation, and are generally transient and not severe. No data were located that indicate
13 exposure to AL causes death or cancer in humans. Human toxicity data are summarized in
14 Table 11-19.
15 Many AL industry workers are exposed to AL dusts found in potrooms where hot
16 aluminum metal is recovered from AL ore. However, these workers are also simultaneously
17 exposed to other toxicants such as polycyclic aromatic hydrocarbons (PAHs), carbon
18 monoxide, sulfur dioxide, hydrogen fluoride, other respirable dusts, and many also smoke.
19 Common reported symptoms include asthma, cough, and decreased pulmonary function
20 (Abramson et al., 1989; Chan-Yeung et al., 1983; Simonsson et al., 1985). No effect on
21 bronchitis incidence or pulmonary function was reported in a longitudinal study of aluminum
22 die-casting workers, where confounding exposures may be lower (Discalz; et al., 1992), but
23 AL exposure levels were not reported.
24 Case reports show that some aluminum workers develop lung fibrosis when exposed to
25 AL dusts (De Vuyst et al., 1986; Gaffuri et al., 1985; Musk et al., 1980). However, AL
26 exposures in these studies were not quantified, and the workers also experienced confounding
27 exposure to other dusts and fumes. Workers inhaling AL oxide dust (96% < 1.2 pm
28 diameter) at unspecified levels as a prophylactic treatment for silicosis have not developed
29 respiratory problems (Dix, 1971). Based on this, the Mclntyre Research Foundation
30 recommended an AL powder concentration of 30,000 particles of respirable size per cm3 for
31 10 minutes daily (duration not stated). Stokinger (1981) converted this to a mass
April 1995 1M52 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-19. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ALUMINUM COMPOUNDS
•^
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6
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W
Exposure
Concentration
Exposure Chemical Particle size and
ppm /ig Al/m3 protocol form distribution
N/A NS Occup Al dusts NS
Duration
NS
N/A NS Occup Al dusts NS
1-30 yr
N/A NS Occup Al dusts NS
1-21 yr
N/A NS Occup Al dusts NS
26 yr
N/A NS Occup Alumina NS
10-24 yr dust
(A1203)
Species,
Strain,
(Number) Sex
Human
(54) M
Human
(2103) M
Human
(5891) M
Human
(6455) M
Human
(4)M
Assays performed: Effect(s)
Clinical, radiographic, pathological,
environmental features: One worker with lung
flbrosis, pneumonia, encephalopathy, seizures.
Al found in lungs but not brain. No x-ray
abnormalities in 43 other workers.
Historical cohort study, CS: Concomitant
exposure to PAHs in coal tar pitch and tobacco
smoke. Excessive deaths from pancreatic, lung,
lymphatic, and brain cancers.
Historical cohort study, CS: Concomitant
exposure to PAHs in coal tar pitch and tobacco
smoke. Inc lung cancer.
Mortality survey, CS: Concomitant exposure to
PAHs in coal tar pitch and tobacco smoke.
Slight inc in mortality due to lung cancer.
Radiographic examination of lung; histology of
transbronchial biopsies; pulmonary levels of Al:
Normal lung function and radiographs. Al
concentrations (ppm wt.w.) of 400, 530, 590,
1080 in lungs. No flbrosis at 400. Slight
flbrosis in lung of one worker at 1080.
Note: Concomitant exposure to PAHs in coal tar
pitch and tobacco smoke.
Reference
McLaughlin et al.
(1962)
Milham (1979)
Gibbs and Horowitz
(1974)
Mur et al. (1987)
Gaffuri et al. (1985)
n
i—i
H
M
-------
TABLE 11-19 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ALUMINUM COMPOUNDS
2.
o
o
z
3
tO
c
s
M
Exposure
Concentration
ppm ing Al/m3
N/A NS
N/A NS
N/A NS
N/A 0-53,000
as A1F3
N/A UK
Exposure
protocol
Occup
Duration
NS
Occup
Duration
NS
Occup
Duration
NS
Occup
2yr
Occup
Duration
NS
Chemical Particle size and
form distribution
Al dusts NS
Al dusts NS
Al dusts NS
A1F3 or Al 25-35% A1F3 dust
sulphate <5 /*m
Al silicate UK
dusts used
for cat
litter
Species,
Strain,
(Number) Sex
Human
(DM
Human
NS
Human
(797) M
Human
(19) M
Human
(13) M,
(4)F
Assays performed: Effect(s) Reference
Occup history, Al identified by electron probe Chen et al. (1978)
analysis of lung biopsy: Case report showing
granulomatous response (extensive interstitial
granulomas composed of macrophages, foreign
body giant cells, and birefringent crystalline
structures) in lung, similar to that observed hi
rabbits following Al dust inhalation.
Review of epidemiological studies: Suggests Abramson et al.
exposure produces asthma-like syndrome due to (1989)
irritant rather than allergic mechanism.
Evidence of reduced lung function consistent
with chronic airflow limitation.
Epidemiology study, spirometry, chest Chan-Yeung et al.
radiography, environmental monitoring: Cough, (1983)
wheezing, altered pulmonary function (dec mean
FEV and maximal mid-expiratory flow rate).
Methacholine provocation tests, CS: Nocturnal Simonsson et al.
wheezing, breathlessness, reversible airways (1985)
obstruction, dyspnea, hyperreactivity (dec
CS: Fibrosis in three workers, potentially due to Musk et al. (1980)
silica.
O
I— I
a
-------
TABLE 11-19 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ALUMINUM COMPOUNDS
S
H-t
H-*
1
O
£
g
6
o
o
H
O
O
H
W
s
Q
H
W
Exposure
Concentration
Exposure
ppm fj,g Al/m3 protocol
N/A NS Occup
Duration
NS
N/A NS Occup
Avg.
11.6,
14.8 yr
N/A NS Occup
Duration
NS
Chemical Particle size and
form distribution
Al dusts NS
(metallic
Al, Al
oxide)
Al dusts NS
Alumina, NS
silica
Species,
Strain,
(Number) Sex
Human
(DM
Human
(76) M
Human
(344) M
Assays performed: Effect(s) Reference
Mineralogical analysis of BAL, lung tissue, De Vuyst et al.
mediastinal lymph node: Severe lung fibrosis (1986)
and bronchial carcinoma. Metallic Al particles
(0.5/im-5 /im) found in BAL, lung tissue, and
lymph nodes.
Spirometry, bronchitis prevalence: No effect on Discalzi et al. (1992)
FVC, FEVj. Low incidence of bronchitis,
occurring mostly in smokers.
Note: Longitudinal study of aluminum die-
casting workers.
CS, chest x-ray, gross and microscopic Shaver and Riddel
pathology: In 35 cases, interstitial lung fibrosis (1947)
(non-nodular), profound emphysema, cough,
dyspnea.
Abbreviations:
Al = aluminum; A1F3 = aluminum trifluoride; ALK = alkaline phosphatase; BAL = bronchoalveolar lavage; BC = blood chemistry; CS = clinical signs;
d = day; dec = decreased; FVC = forced vital capacity; FEVj = forced expiratory volume in 1 second; inc = increased; M = male; N/A = not applicable;
NS = not specified in the literature reviewed; occup = occupational; PAH = polycyclic aromatic hydrocarbons; PF = pulmonary function; resp = respiratory;
wt.w = wet weight; yr = years.
-------
1 concentration of 350,000 ^g/m, assuming a particle diameter of 2 /im and a specific gravity
2 of AL of 2.7.
3 Epidemiological studies of AL workers have not shown an increase in deaths due to
4 cardiovascular diseases (Gibbs and Horowitz, 1979; Milham, 1979; Mur et al., 1987;
5 Rockette and Arena, 1983; Theriault et al., 1984; Waldron-Edward et al., 1971). Nor has
6 there been excess mortality from Alzheimer's or other neurological diseases in workers
7 inhaling large quantities of AL dust (Gibbs, 1985). No studies were located regarding other
8 systemic, developmental, or reproductive effects in humans following inhalation exposure to
9 AL or AL compounds.
10 Several studies were found regarding cancer in workers from AL reduction factories
11 following inhalation exposure (Gibbs and Horowitz, 1979; Milham, 1979; Mur et al., 1987;
12 Rockette and Arena, 1983; Theriault et al., 1984). These studies show excessive deaths
13 from cancer of the lung, pancreas, lymphatic system, brain, or bladder; however, the authors
14 concluded that is unclear whether these cancers were caused by exposure to AL dusts or by
15 concomitant exposure to carcinogens (tobacco smoke or PAHs from coal tars) in the
16 factories. Exposure concentrations for AL were not provided in the studies.
17
18 Laboratory Animal Data
19 Limited information is available regarding respiratory effects in laboratory animals
20 following inhalation exposure to aluminum dusts, as summarized in Table 11-20. Two
21 studies involved exposure of rats, Guinea pigs, and hamsters to aluminum chlorohydrate, a
22 common component of antiperspirants (Drew et al., 1974; Steinhagen et al., 1978). Other
23 studies used aluminum oxide (Christie et al., 1963) or pure aluminum flakes (Thomson
24 et al., 1986). These studies report a proliferation of macrophages detected in lavage fluid or
25 in alveolar walls. Granulomatous reactions characterized by giant vacuoled macrophages,
26 sometimes accompanied by pneumonia, were also reported.
27 Rats exposed to either aluminum trichloride (A1C13, 360 /*g Al/m3) or aluminum
28 trifluoride (A1F3, 420 pig Al/m3) dusts for 5 mo had increased lysozyme levels resulting from
29 damaged pulmonary alveolar macrophages. In addition, exposure to aluminum trichloride
30 produced increased protein levels in lavage fluid and increased alkaline phosphatase activity,
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TABLE 11-20. LABORATORY ANIMALS EXPOSURE CONDITIONS AND EFFECTS
FOR ALUMINUM COMPOUNDS
Exposure
Concentration
ppm fig Al/m3
Acute Studies
N/A 10,000
50,000
100,000
200,000
1,000,000
N/A 0
33,000
N/A 0
10,000
Chronic Studies
N/A 0
50
500
5,000
Exposure Chemical Particle size and
protocol form distribution
4h Al flakes 2.62-3.28 /im
(99% pure) (geo. mean 2.82
/im)
>90% <5 /train
diameter
MMAD 1.58/mi,
Tg = 1.91
4 h/d A1C1H NS
3 d aerosol
6 h/d A1C1H NS
20 d aerosol
6 h/d A1C1H dust 84% BAD (/im):
5 d/wk 6.20, 5.78, 5.34
6 mo 50,000 /ig/m3 with multi-focal
microgramulomas in lungs and hilar lymph
nodes.
MFO activity, BW, CS, HP: Inc lung weight, Drew et al. (1974)
incr in neutrophils and macrophages in bronchial
walls.
MFO activity, HP: Granulomatous nodules in Drew et al. (1974)
lungs and bronchoalveolar junction at
10,000 /ig/m3. Thickened alveolar walls,
probably adaptive macrophage response from
particulate accumulation.
BW, HP, BC: Lung nodules at 500 /*g/m3. Steinhagen et al.
Enlarged lymph nodes. Exposure-related (1978)
granulomatous reactions characterized by giant
vacuoled macrophages containing basophilic
material and eosinophilic cellular debris at
>500 /ig/m3.
n
H-i
H
W
-------
TABLE 11-20 (cont'd). LABORATORY ANIMALS EXPOSURE CONDITIONS AND EFFECTS
FOR ALUMINUM COMPOUNDS
I—*
Ol
Exposure
Concentration
Species,
Exposure
H-
^ .
01
00
o
<5
H
1
O
o
H
O
c;
o
H
M
ppm /tig Al/m3
N/A 0
50
500
5,000
N/A 420
N/A 360
Abbreviations:
6
5
6
6
5
5
6
5
5
Al = aluminum; A1C13
BAL = bronchoalveolar
F = female; EAD
protocol
h/d
d/wk
mo
h/d
d/wk
mo
h/d
d/wk
mo
Chemical
form
Particle size and
distribution
A1C1H dust 84% EAD
A1F3 dust
A1C13 dust
6.20,
ffg: 3
3.49
UK
UK
5.78
.88,
= aluminum trichloride; A1C1H =
(/xm):
, 5.34
4.82,
Strain,
(Number) Sex
Guinea pig,
Hartley
(10)
(10)
Rat,
(50)
Rat,
(50)
M,
F
S-D
M
S-D
M
aluminum chlorohydrate;
lavage; BPL = bronchopulmonary lavage;
= equivalent
aerodynamic
= lactate dehydrogenase; M = male; MFO =
NS = not specified
resp = respiratory;
in the literature reviewed;
wk
= week;
wt.w = wet
Assays performed: Effect(s)
BW, HP, BC: Lung nodules at 500, inc lung
weight at 5,000 /xg/m3. Exposure-related
granulomatous reactions characterized by giant
vacuoled macrophages containing basophilic
material and eosinophilic cellular debris at
>500 /xg/m3.
BW, BC: Incr lysozyme levels from damaged
PAMs at 420 /xg/m3. No apparent effect on G6P
or ALK, suggesting no adverse effect on Type I
or II cells.
BW, BC: Incr lysozyme levels from PAMs at
360 /xg/m3. No apparent effect on G6P,
suggesting no adverse effect on Type I alveolar
cells. Incr ALK at 360 /xg/m3, suggesting effect
on Type II cells. Transient inc in lavage protein
levels.
Reference
Steinhagen et al.
(1978)
Finelli and Que Hee
(1981)
Finelli and Que Hee
(1981)
A1F3 = aluminum trifluoride; ALK = alkaline phosphatase;
BC = blood chemistry; BW = body weight; CS = clinical signs; d =
diameter; G6P = glucose-6-phosphate
= mixed
PAH =
weight;
function oxidase;
dehydrogenase; h = hour; HP = histopathology;
MMAD = mass median aerodynamic diameter; mo = month;
polycyclic aromatic hydrocarbons; PAMs = pulmonary alveolar macrophages; PF
yr =
= years.
day; dec = decreased;
inc = increased; LDH
N/A = not applicable;
= pulmonary function;
O
HH
3
-------
1 suggesting that aluminum trichloride affects Type II alveolar cells (Finelli and Que Hee,
2 1981). These types of changes are often considered to be an adaptive response to many
3 types of dusts. Pulmonary function in rats was not affected following exposure to alumina
4 (A12O3) fibers for 86 weeks (Pigott et al., 1981).
5 No changes in heart, kidney or liver weights or histology were seen in animals exposed
6 to aluminum chlorohydrate in antiperspirants (Drew et al., 1974; Steinhagen et al., 1978).
7 In rats, liver weights increased (by 9.4%) after 3 mo exposure to aluminum trichloride
8 (360 ^g Al/m3), and kidney weights increased by 9% or 12% after exposure to aluminum
9 trichloride (360 /ig Al/m3) or aluminum trifluoride (420 ^ig Al/m3), respectively. Body
10 weight was not affected in male rats after exposure for 5 mo (Finelli and Que Hee, 1981).
11 No studies were located regarding other systemic, developmental, or reproductive effects in
12 animals following inhalation exposure to aluminum or aluminum compounds.
13 Only one study was found that addressed cancer in animals following inhalation
14 exposure to aluminum (Kobayashi et al., 1968). However, the results are not reliable
15 because the study is seriously flawed (insufficient number of animals, lack of sufficient
16 controls and exposure duration).
17
18 11.6.2.4 Factors Affecting Susceptibility
19 No data were located that addressed populations especially susceptible to the inhalation
20 effects of aluminum. However, since the respiratory system is the major target of inhaled
21 aluminum, individuals with unpaired respiratory function may be at increased risk. The
22 developing respiratory tract of children may also pose an increased susceptibility.
23 Other information on potential susceptible populations comes from other exposure
24 routes. Although inhaled aluminum compounds are absorbed, it is unclear if the extent of
25 absorption is high enough for systemic toxicity to be an issue. However, Alzheimer's
26 disease patients may have increased vulnerability to the aluminum effects. The metal has
27 been hypothesized to play a role in the development of Alzheimer's, and Alzheimer's patients
28 may have an altered blood-brain barrier, which may allow increased Al accumulation in the
29 brain (Shore and Wyatt, 1983). However, there are numerous uncertainties regarding any
30 involvement of aluminum in the etiology of Alzheimer's disease.
April 1995 H_159 DRAFT-DO NOT QUOTE OR CITE
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1 Dialysis patients and others with renal dysfunction may have increased sensitivity to
2 aluminum. Tissue levels of aluminum are increased in dialysis patients (Alfrey, 1980; Alfrey
3 et al., 1980), partly due to increased exposure, such as from aluminum hydroxide dosing.
4 However, dialysis patients also have elevated parathyroid hormone levels, which may
5 enhance aluminum absorption, as well as decreased renal function, which decreases
6 excretion.
7
8 11.6.3 Antimony
9 11.6.3.1 Chemical and Physical Properties
10 Antimony is a member of Group 5A of the periodic table. Because it exhibits both
11 metallic and nonmetallic properties, it is classified as a metalloid. Antimony has four
12 possible oxidation states: -3, 0, +3, and +5. The +3 state is the most common and
13 stable (Agency for Toxic Substances and Disease Registry, 1992), although elemental
14 antimony (oxidation state 0) is stable as well, and not readily attacked by air or moisture (Li
15 et al., 1992). In solutions, antimony does not exist as a simple cation (i.e., Sb+3 or Sb+5).
16 Rather, hydrolyzed forms are found, Sb(OH)3 for trivalent antimony, and Sb(OH)6' for
17 pentavalent antimony. Under oxidizing conditions, Sb(OH)6~ is the dominant species in
18 solutions with a pH greater than 3 and under reducing conditions, Sb(OH)3 is the dominant
19 species. A wide variety of organoantimony compounds are known which can be broadly
20 subdivided into Sb(III) and Sb(V) compounds (Freedman et al., 1992).
21 Antimony compounds for which inhalation toxicity data exist vary in their relative
22 solubility in water. Antimony trioxide (SbbO3) is insoluble in cold water and decomposes in
23 hot water, whereas the pentsulfide (Sb2O5) is very slightly soluble in water. Antimony
24 trisulfide (Sb2S3) is moderately soluble in water at 18 °C, but the pentoxide (Sb5S5) is
25 insoluble. Antimony trichloride (SbCl3), on the other hand, is moderately soluble at low
26 temperatures (ca. 0 °C) but soluble in all proportions at 80 °C, whereas antimony potassium
27 tartrate K(SbO) C4H4O6 • l/2 H2O is only moderately soluble in either cold or hot water.
28
29
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1 11.6.3.2 Pharmocokinetics
2 Absorption and Distribution
3 No quantitative data were located on absorption of antimony from the respiratory tract
4 of humans. Indirect evidence of absorbed antimony is provided by occupational studies that
5 reported elevated antimony levels in blood and urine of antimony-trioxide exposed workers
6 (Brieger et al., 1954; Cooper et al., 1968).
7 The retention and clearance of antimony from the lungs depends primarily on solubility
8 (Leffler et al., 1984) and particle size (Felicetti et al., 1974a; Leffler et al., 1984). After
9 exposure to radiolabeled antimony tartrate aerosol (in trivalent and pentavalent forms),
10 whole-body counting in mice found antimony to be initially cleared rapidly from the lungs,
11 followed by a slower, steady decrease in antimony levels. This biphasic clearance is due to
12 the more rapid absorption of soluble material (i.e., trivalent form) from the lungs into the
13 systemic circulation and longer lung retention of less soluble (i.e., pentavalent) and smaller
14 particles. It was also observed that 1.6 /mi antimony particles deposited in the upper
15 respiratory tract to a greater degree than 0.7 or 0.3 /xm particles (Felicetti et al., 1974a;
16 Thomas etal., 1973).
17 Data from both live and deceased smelter workers indicate that antimony is retained in
18 the lungs for long periods of time (Gerhardsson et al. 1982; McCallum 1963, 1967;
19 McCallum et al. 1971; Vanoeteren et al. 1986a, 1986b, 1986c). Gerhardsson et al. (1982)
20 measured antimony content in lungs from 40 deceased smelter workers and found antimony
21 levels in the exposed men (316 mg/kg) to be 12-times greater (p< 0.001) than levels in
22 nonexposed referents. Also, lung antimony concentration did not decrease with increasing
23 postexposure period, indicating a long biological half-life for lung antimony. Studies by
24 Vanoeteren et al. (1986a, 1986b, 1986c) also confirm that antimony accumulates in lung and
25 is retained for long periods of tune.
26 In a chronic inhalation study of rats by Bio/dynamics Incorporated (1990), the rate at
27 which antimony trioxide was cleared by the lungs depended on the concentration, with
28 clearance half-tunes of 2.3, 3.6, and 9.5 mo for the low-, mid, and high-concentration
29 groups. Substantial amounts of antimony were still found in lungs of the rats after one year
30 of exposure (10.6, 120, and 1,460 /ig/g lung tissue, respectively).
April 1995 1M61 DRAFT-DO NOT QUOTE OR CITE
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1 Antimony is transported throughout the body via blood, with relative partitioning
2 between erythrocytes and plasma a function of valency; in hamsters levels were greater in the
3 erythrocytes following exposure to the trivalent form compared to the pentavalent (Felicetti
4 et al., 1974b). Species differences exist in blood clearance of antimony, with levels
5 persisting longer in rats than in mice and dogs (Felicetti et al., 1974a; Thomas et al., 1973).
6 Antimony accumulates in the liver, thyroid, skeleton, and fur of animals; the largest burden
7 is in the fur (Felicetti et al., 1974a,b). In hamsters that inhaled antimony tartrate, liver
8 uptake of trivalent antimony was more rapid than that of the pentavalent form (Felicetti
9 et al., 1974b), but the opposite was true for the skeleton.
10
11 Metabolism
12 Antimony can covalently bind with sulfhydryl groups and phosphate, as well as interact
13 reversibly with endogenous ligands (e.g., proteins). Pentavalent antimony can be reduced to
14 trivalent antimony. In both humans and animals, inorganic antimony (as opposed to organic
15 antimony) is not methylated in vivo (Bailly et al., 1991), but is excreted primarily in the bile
16 (conjugated to glutathione) and urine.
17
18 Excretion
19 Occupational studies found elevated urinary antimony levels in workers exposed to
20 antimony trioxide (Cooper et al., 1968; Ludersdorf et al., 1987). In animals, trivalent and
21 pentavalent antimony are eliminated in the urine and feces. The urine/feces ratio of
22 antimony is dependent on valence state; with urinary excretion dominating after pentavalent
23 antimony injection and mainly fecal excretion after trivalent form administration (Edel et al.,
24 1983; Felicetti et al., 1974b). Some antimony in the feces after inhalation exposure is
25 probably due to unabsorbed antimony cleared from lungs via mucociliary action into the
26 gastrointestinal tract. There is a biphasic clearance of trivalent antimony tartrate from the
27 body; 90% was excreted within 24 h after exposure, followed by a slower phase with a half-
28 life of 16 days (Felicetti et al., 1974b).
29
30
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1 11.6.3.3 Health Effects
2 Human Data
3 Acute inhalation exposure information on antimony is largely lacking for humans.
4 Quantitative data on antimony exposure are mainly taken from occupational studies in which
5 workers were exposed for extended periods to antimony trichloride, antimony oxide, or
6 antimony ore, or a mixture of these compounds. The studies are very limited due to
7 inadequate information on particle size of the antimony dust and concurrent exposure to other
8 chemicals. Toxicity data for humans are summarized in Table 11-21.
9 Occupational exposure to antimony trioxide and/or pentoxide dust at extremely high
10 concentrations (2 to 138 mg) over long periods (months to years) result in antimony
11 pneumoconiosis, an inflammation of the lungs due to the irritation caused by the inhalation of
12 dust (Cooper et al., 1968; Potkonjak and Pavlovich, 1983; Renes, 1953). Pneumoconiosis
13 is characterized by chronic coughing, wheezing, and upper airway inflammation. No
14 particular clinical findings or lung function changes distinguish this pneumoconiosis (called
15 antimoniosis) from other types of simple pneumoconioses. Chext x-rays are characterized by
16 numerous small opacities densely distributed in the middle and lower lung fields (Potkonjak
17 and Pavlovich, 1983). Opacities are usually of the p, pinhead type. Sporadically pq type are
18 seen, but not r type nor massive fibrosis (pmf). Other respiratory effects include chronic
19 bronchitis, chronic emphysema, pleural adhesions, and irritation in exposed workers
20 (Potkonjak and Pavlovich, 1983). Alterations in pulmonary function (airway obstruction,
21 bronchospasm, and hyperinflation) have also been reported in workers exposed to airborne
22 antimony (Cooper et al., 1968; Potkonjak and Pavlovich, 1983).
23 As for non-respiratory system impacts, ocular conjunctivitis and dermatosis in workers
24 have resulted from exposure to airborne antimony (Potkonjak and Pavlovich, 1983; Renes,
25 1953), possibly due to direct ocular contact with antimony. Among reported systemic
26 effects, cardiovascular effects (increased blood pressure, altered electrocardiogram [ECG]
27 recordings) were observed in workers exposed to mg levels of antimony trisulfide for 8
28 months to 2 years (Brieger et al., 1954; Renes, 1953). Also, gastrointestinal symptoms
29 (abdominal pain, diarrhea, vomiting, ulcers) have been reported in workers chronically
30 exposed to mg levels of the trichloride, trisulfide, or oxide Sb compounds (Brieger et al.,
31 1954; Renes, 1953; Taylor, 1966). Nerve tenderness and a tingling sensation were also
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I
H^
s
l^»
TABLE
Exposure
Concentration
ppm jtg Sb/m3
Acute Studies
NA 73,000
11-21. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY AND COMPOUNDS
Exposure
NR
(accidental
exposure)
Chemical
form
Antimony
trichloride
fumes
Particle size and Species, Strain,
distribution (Number) Sex
NR Human
(7)M
Assays performed: Effect(s)
Clinical observations: Gastrointestinal symptoms
(abdominal pain, nausea, vomiting) and headache
occurred. Transient upper respiratory tract irritation was
reported, but possibly due to concomitant exposure to
hydrogen chloride vapor.
Reference
Taylor
(1966)
Note: Ingestion is also possible route.
1— *
^
s
o
s
,>
1
o
o
z
H
O
d
s
w
o
Chronic Studies
NA 10,070- 2 wk-
11,810 5 mo
(occup)
NA 8,870- 17.91 yr
45,950 (avg)
(9-31 yr)
(occup)
Mixture of NR Human
fumes (78) M
(35-68% Sb;
2-5% As;
0.01-0.04% Se;
0.04-0.3% Pb;
0.1-0.4% Cu)
Antimony 80% < 5 fim Human
trioxide (38.73- (51) M
88.86%) and
antimony
pentoxide (2.11-
7.82%) dusts
Clinical symptoms, chest X-ray (6 men only), physical
examination: Symptoms include abdominal cramps,
diarrhea, vomiting, and dermatitis. Laryngitis (11%),
pharyngitis (8%), pneumonitis (5.5%), rhinitis (20%),
septal perforations (3.5%), and tracheitis (19%) were
reported. Nerve tenderness and tingling also reported.
Physical examination, lung function, chest x-ray (2-5 times
over 25-year period): X-rays revealed diffuse, densely
distributed punctate opacities in mid-lung, enlarged, dense
shadows and emphysematous changes in upper and lower
regions (pneumonoconiosis). Chronic coughing.
Conjunctivitis and upper airway inflammation due to dust
irritation. Dermatosis hi 32 of 51 workers. Other effects
included chronic bronchitis, emphysema, inactive
tuberculosis, and pleural adhesions. No tumors were
evident.
Note: Dusts also contained free silica (0.82-4.72%), ferric
trioxide (0.9-3.81), and arsenic oxide (0.21-6.48%).
Renes
(1953)
Potkonjak
and
Pavlovich
(1983)
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TABLE 11-21 (cont'd) HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY AND COMPOUNDS
Exposure
Concentration
ppm ng Sb/m3
NA 2,150
NA 80-138,000
Exposure
protocol
8h/d
5d/wk
8 mo-2 yr
(occup)
1-15 yr
(occup)
Chemical
form
Antimony
trisulfide
dust
Antimony
ore and
antimony
trioxide
dust
Particle size and Species, Strain,
distribution (Number), Sex
NR Human
(113) M
NR Human
(28) NS
Assays performed: Effect(s)
Physical examination: Ulcers (7/1 1 1), altered
ECG (T-waves) (37/75), and altered BP
(38/113). No skin or respiratory irritation
reported.
Pulmonary function tests (14 subjects), chest x-
ray (13 subjects): X-ray revealed
pneumoconiosis in 3/13 workers, and suspected
pneumoconiosis in an additional 5.
Reference
Brieger et al.
(1954)
Cooper et al.
(1968)
Abbreviations:
BP = blood pressure; ECG = electrocardiogram; d = days; dec = decreased; h = hour; inc = increased; F = female; M = male; MMAD = mass median
aerodynamic diameter; NA = not applicable; NS = not specified; NR = not reported; occup = occupational; a = geometric standard deviation of distribution;
WBC = white blood cells; wk = weeks; wt = weight; yr = years.
-------
1 reported in workers exposed to high concentrations of antimony oxide (Renes, 1953).
2 However, no clear causal relationship have been established between the antimony exposures
3 and the above effects due to possible impact of concurrent exposure to other chemicals (e.g.,
4 hydrogen chloride, sodium hydroxide) in the workplace.
5 Only one report evaluated effects of antimony exposure on reproductive or
6 developmental endpoints. Belyaeva (1967) reported increased incidence of spontaneous
7 abortions and disturbances in menstrual cycle in exposed female workers at an antimony
8 metallurgical plant (antimony trioxide, antimony pentasulfide, and metallic antimony). Body
9 weights of children from exposed mothers lagged behind those from controls after 1 year.
10 No quantitative exposure data were available and no description of the control group was
11 provided; but antimony was detected in the blood of exposed workers at 10 times higher
12 levels than for controls and was also found in other body fluids.
13 The study by Potkonjak and Pavlovich (1983) reported that cancer incidence was not
14 affected in workers exposed to 8,900 to 46,000 /*g Sb/m3 for 9-31 years.
15
16 Laboratory Animal Data
17 Toxicity data for laboratory animals are summarized in Table 11-22. Like humans,
18 laboratory animals develop respiratory signs associated with pneumonoconiosis, progressing
19 to proliferation of alveolar macrophages to fibrosis. For example, Brieger et al. (1954)
20 found lung inflammation in rabbits exposed to 19,900 /xg/m3 antimony trisulfide for 5 days.
21 Also, a concentration-related increase in numbers of alveolar macrophages occurred in rats
22 exposed to antimony trioxide (7 to 210 ^ig Sb/m3) for 13 weeks or 1 year (Bio/dynamics
23 Incorporated, 1985, 1990). Microscopic lung examination revealed interstitial inflammation
24 at the 6, 12, 18 and 24 mo sacrifices. Granulomatous inflammation/granulomas were seen in
25 all exposure groups at 18 and 24 mo. Increased numbers of alveolar and intraalveolar
26 particle-laden macrophages were seen at every exposure duration in all but the control
27 groups, but there were no indications that the increases in particle-laden macrophages in
28 lungs of the low and mid concentration group rats were anything but a normal compensatory
29 response. However, clearance half-times in the high concentration groups were 3 times
30 greater than in the low and mid concentration groups, indicating that clearance mechanisms
31 may be compromised at the higher exposure levels. With respect to interstitial inflammation
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TABLE 11-22. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY
AND COMPOUNDS
-
s
O
O
1
o
s
n
3
Exposure
Concentration
ppm fig Sb/m3
Exposure
protocol
Chemical
form
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s) Reference
Acute Studies
NA 19,940
7 h/d
5 d/wk
5d
Antimony
trisulfide
aerosol
< 2 nm Rabbit, NS ECG recording, autopsy: Effects included Brieger et al.
(5) NS altered ECG (not specified), parenchymatous (1954)
changes in myocardium, liver, and renal
tubular epithelium, and inflammation of lungs.
Subchronic and Chronic Studies
NA 0
17,480
NA 2,200
7 h/d
5 d/wk
52 wk
7 h/d
5 d/wk
6wk
Antimony
ore
(antimony
trisulfide,
stibnite)
dust
Antimony
trisulfide
aerosol
MMAD = 4.78 Rat, Wistar Body wt, gross and light microscopy: Clinical Groth et al.
(90) M, (90) F observation of hemorrhage around ears during (1986); Wong et
first 2 mo. Foci on pleura! surfaces of lung al. (1979)
lobes. Alveolar wall thickening (interstitial
fibrosis, alveolar wall cell hypertrophy and
hyperplasia) and cuboidal cell metaplasia at 6
mo and inc interstitial fibrosis at 12 mo. Inc
tumor incidence (squamous cell carcinomas,
bronchioloalveolar adenomas and carcinomas)
in females.
< 2 /j,m Rat, Wistar ECG recording, autopsy: Lung exhibited Brieger et al.
(10) M congestion and focal areas of hemorrhage (1954)
(mild), considered to be secondary to heart
failure. Heart had hyperemia, "flabbiness" of
myocardium, and swelling of myocardial
fibers. Respiratory inflammation, renal and
hepatic parenchymatous degeneration, and
myocardial damage and altered ECG (elevation
of the RS-T segments and flattening of T-
waves) at 2,200 ftg/m3.
-------
Os
OO
Exposure
Concentration
ppm
NA
NA
NA
NA
NA
/*g Sb/m3
4,020
3,810
(7 wk)
3,980
(10 wk)
0
210
920
4,110
19,610
0
209,000
0
1,600
4,200
Exposure
protocol
7h/d
5d/wk
6wk
7h/d
5d/wk
7 or 10 wk
6h/d
5d/wk
13 wk
(up to 13 wk
postexposure)
4h/d
63-78 d
6h/d
5d/wk
12 mo
Chemical
form
Antimony
trisulfide
aerosol
Antimony
trisulfide
aerosol
Antimony
trioxide
dust
Antimony
trioxide
NS
Antimony
trioxide
dust
Particle size and
distribution
< 2 /im
< 2 pm
MMAD = 2.9,
3.9, 2.9, and 3.4
fun for respective
levels; ag = 1.6,
1.5, 1.6, and 1.5,
respectively
NR
MMAD 0.4-0.44
ffg = 1.5-1.6
Species, Strain,
(Number) Sex
Rabbit, NS
(6)M
Dog, NS
(2) F per
regimen
Rat, Fischer
(50) M, (50) F
Rat, NS
(10-24) F
Rat, Fischer
(49) F
Assays performed: Effect(s)
ECG recording, hematology, clinical chemistry, liver
function tests, histopathology: Myocardial damage
(dilation of heart, flabby myocardium, swelling of
myocardial fibers), altered ECG (altered T-waves).
ECG recording, hematology, clinical chemistry,
histopathology: No effects at 7 wk, but swelling of
myocardial fibers, altered ECG (not specified) at 10 wk.
Body wt, organ wts, hematology, clinical chemistry,
gross and histopathology examinations of major organs:
Reduced body wt at two high levels. Lung lesions
included degenerating macrophages and cellular debris
in lumen of alveoli in all exposed groups. Multifocal
pneumonocyte hyperplasia, nonsuppurative alveolitis,
and focal alveolar wall thickening at two highest
concentrations. Cornea! irregularities and alopecia in
high-concentration group.
Maternal, reproductive, and developmental evaluation:
Dec number of pregnancies in 33 % of animals and in
number of offspring. Histopathology of uterine and
ovarian tissues revealed lack of ova in follicles,
misshapen ova, cysts, and uterine metaplasia.
Histopathology of spleen, adrenals, ovaries, uterus,
skeletal muscle, bone, brain, thyroid, thymus, pancreas,
digestive glands, lymph nodes, heart, liver, kidney,
esophagus, stomach, small intestine): Respiratory focal
fibrosis at both concentrations
Reference
Brieger et al.
(1954)
Brieger et al.
(1954)
Bio/dynamics
Incorporated
(1985)
Belyaeva
(1967)
Watt (1980)
-------
TABLE 11-22 (cont'd) LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY
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AT* is v^vsivJjrvs«jr^.Lri3
Exposure
Concentration Exposure Chemical Particle size and Species, Strain,
ppm ng Sb/m3 protocol form distribution (Number) Sex Assays performed: Effect(s)
NA 0 6 h/d Antimony MMAD = 3.7 Rat, Fischer Clinical signs, body wt, hematology, organ
7 5 d/wk trioxide (avg) (65) M, (65) F wts, gross and microscopic examination: Inc
480 1 yr dust a. = 1.7 number of alveolar macrophages, interstitial
4,010 (< 12 mo inflammation, hyperplasia of reticuloendothelial
postexposure) cells occurred at 7 ftg/m3 and above (6 and 12
mo postexposure).
NA 83,600- 25 h/wk Antimony MMAD = 0.6 Rat, Srague- Gross and microscopic histopathology of lungs
104,500 14.5 mo trioxide /j.m Dawley (>2mo): Pleura! foci at 9 mo; increased
dust (50) M mottling with increasing duration.
Proliferation, swelling, and desquamation of
alveolar lining cells early. Lipid pneumonia,
fatty degeneration in alveolar macrophages,
progressing to necrosis, accumulation of
intracellular lipids. Absence of fibrosis in
lymph nodes.
NA 83,600- 100 h/wk Antimony MMAD = 0.6 Rat, NS Gross and microscopic histopathology of lungs
104,500 14.5 mo trioxide ^m (50) M (^2 mo): Mottling at 9 mo. Proliferation,
dust swelling, and desquamation of alveolar
macrophages. Lipid pneumonia, fatty
degeneration in alveolar macrophages,
progressing to necrosis, accumulation of
intracellular lipids. Death in 18%, due to
pneumonia.
Reference
Bio/dynamics
Incorporated
(1990)
Gross et al.
(1952)
Gross et al.
(1955)
-------
TABLE 11-22 (cont'd) LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY
AND COMPOUNDS
Exposure
Concentration
ppm
Sb/m3
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number), Sex
Assays performed: Effect(s)
Reference
NA 0 7 h/d Antimony MMAD = 2.8 Rat, Wistar Body wt, gross and light microscopy Groth et al.
36,000 5 d/wk trioxide (90) M, (90) F examination: Clinical observation was (1986); Wong et
52 wk aerosol hemorrhage around ears during first 2 mo. Foci al. (1979)
on pleural surfaces of lung lobes. Alveolar
wall thickening (interstitial fibrosis, alveolar
wall cell hypertrophy and hyperplasia) and
cuboidal cell metaplasia at 6 mo and inc
interstitial fibrosis at 12 mo. Inc incidence of
tumors (squamous cell carcinomas,
bronchioloalveolar adenomas and carcinomas)
in female rats.
NA
NA
0
1,600
4,200
0
1,600
4,200
6 h/d
5 d/wk
lyr
6 h/d
5 d/wk
Antimony
trioxide
dusts
Antimony
trioxide
dusts
Low: 0.44 /mi,
ffg_ = 2.23
High: 0.4 /mi, ag
= 2.13 (Ferret's
diameter)
Low: 0.44 /mi,
erg = 2.23
High: 0.4 /mi, ag
= 2.13 (Ferret's
diameter)
Pig, Sinclair Hematology, clinical chemistry, ECG, organ Watt (1983)
miniature wt, histopathology: Inc lung weight and
(2-3) F nonneoplastic pulmonary effects (focal fibrosis,
hyperplasia, pigmented macrophages,
multinucleated giant cells) at 1,600 and 4,200
/*g/m3. Severity inc with concentration.
Rat, Fischer Hematology, clinical chemistry, ECG, organ Watt (1983)
(49) F wt, histopathology: Inc incidence of lung
tumors (scirrhous carcinoma, squamous cell
carcinoma, bronchoalveolar adenomas) at 4,200
/tg/m3. Inc lung weight and nonneoplastic
pulmonary effects (focal fibrosis, hyperplasia,
pigmented macrophages, multinucleated giant
cells) at 1,600 and 4,200 /*g/m3. Severity inc
with concentration.
-------
TABLE 11-22 (cont'd) LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ANTIMONY
AND COMPOUNDS
Exposure
Concentration Exposure Chemical Particle si;
ppm fig Sb/m3 protocol form distribui
'js and Species, Strain,
tion (Number) Sex Assays performed: Effect(s) Reference
Subchronic and Chronic Animal (cont'd)
NA 38,100 2h/d Antimony <1 ^m
7 d/wk trioxide
2 wk initially,
then 3 h/d for
8-265 d
Guinea pigs Electrocardiogram, hematology, organ wt, Dernehl et al.
(24) NS histopathology: Interstitial pneumonitis, inc (1945)
lung wt, subpleural petechial hemorrhages.
Liver effects included inc wt, cloudy swelling,
and fatty degeneration. Dec WBC and splenic
hyperplasia and hypertrophy were reported.
Abbreviations:
BP = blood pressure; ECG = electrocardiogram; d = days; dec = decreased; h = hours; inc = increased; F = female; M = male; MMAD = mass median
aerodynamic diameter; mo = months; NA = not applicable; NS = not specified; NR = not reported; ag = geometric standard deviation of distribution; WBC
= white blood cells; yr = years.
O
O
O
H
W
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1 and granulomatous inflammation, statistical significance of incidence data was not reported in
2 the study, but the data were subsequently evaluated using trend and pairwise (Fisher Exact)
3 tests to the statistical significance of increases in severity grades and incidence (Allen and
4 Chapman, 1993). An evaluation of male and female graded responses for interstitial and
5 granulomatous inflammation using logistic regression techniques found no effect in females at
6 any concentration level and marginally significant effects (for increased severity of interstitial
7 inflammation) at the high concentration level for males during the exposure period (first
8 12 months). However, in the second, follow-up year, 4,500 /xg Sb2O3/m3 caused increases
9 in both the incidence and severity of these responses for both male and female rats sacrificed
10 at 18 and 24 months (p < 0.05). At higher concentrations (1,600 to 83,600 /*g Sb/m3),
11 more severe respiratory effects (interstitial fibrosis, hyperplasia, and lipoid pneumonia)
12 occurred in rats (Bio/dynamics, 1990; Dernehl et al., 1945; Gross et al., 1952, 1955; Groth
13 et al., 1986; Watt, 1980, 1983; Wong et al., 1979).
14 Inhaled antimony trisulfide dust exposures (in mg ranges) for acute to subacute
15 durations produced degenerative changes in the myocardium and related ECG abnormalities
16 in several laboratory animal species (Brieger et al., 1954). With a five-day exposure, ECG
17 alterations (unspecified) occurred in rabbits exposed to 19,940 /^g/m3. With longer
18 exposures (6-10 weeks), rats, rabbits, and dogs exhibited altered ECGs and swelling of
19 myocardial fibers at concentrations at least four times lower (2,000 to 4,000 /*g/m3) than
20 required to produce similar changes following acute exposure in rabbits. However, no
21 changes in ECG readings were seen in pigs exposed to similar concentrations for a year
22 (Watt, 1983).
23 Renal effects (tubular epithelial changes) have been reported in rabbits acutely exposed
24 to high concentrations (19,940 ^g/m3) antimony trisulfide (Brieger et al., 1954). No changes
25 in the kidney were observed in rats after subchronic exposure to lower concentrations of
26 antimony trioxide (Bio/dynamics Incorporated, 1985) or acute exposure to antimony trisulfide
27 (Bio/dynamics Incorporated, 1990; Groth et al., 1986; Wong et al., 1979).
28 Alopecia (hair loss) and eye irritation occurred in rats exposed to antimony trioxide for
29 13 weeks at 4,100 or 19,600 ptg/m3 (Bio/Dynamics Incorporated, 1985). Cataracts were
30 observed in rats exposed to antimony trioxide for a year (Bio/Dynamics Incorporated, 1990).
31 An ophthalmoscopic examination was performed on all rats at pretest, 6, 12, 18 and 24 mo.
April 1995 11-172 DRAFT-DO NOT QUOTE OR CITE
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1 Mild, compound-related ocular irritation was noted at 6 mo, but no signs of compound
2 related ocular disease were noted at 12 or 18 mo. Examination of all surviving rats at 24 mo
3 revealed increased incidence of conjunctivitis, and cataracts (females only; principally
4 posterior subcapsular cataracts). Statistical analysis of the cataract response at 24 mo was
5 performed for both male and female rats (Allen and Chapman, 1993). Trend test and
6 pairwise comparisons (Fishers Exact) revealed no concentration-response relationship for the
7 male rats; at the high concentration, however, a statistically significant increase in female
8 cataracts was clearly indicated by both trend and pairwise tests (p < 0.01).
9 Exposure to high concentrations of antimony trioxide (209,000 /xg antimony/m3) prior
10 to conception and throughout gestation resulted in decreased number of offspring born to rats
11 (Belyaeva, 1967). In dams that failed to conceive, metaplasia of the uterus and disturbances
12 in the ovum-maturing process were observed.
13 Animal data suggest that antimony is carcinogenic in rats. Lung tumors developed in
14 rats exposed to antimony trioxide or antimony trisulfide (>4,200 /ig Sb/m3) for a year
15 (Groth et al., 1986; Watt, 1980, 1983; Wong et al., 1979). However, no effect was seen in
16 rats exposed to 4,010 /xg/m3 as antimony trioxide (Bio/dynamics Incorporated, 1990) or in
17 guinea pigs exposed to 4,200 pig/m3 as antimony trioxide (Watt, 1983).
18
19 11.6.3.4 Factors Affecting Susceptibility
20 Individuals with preexisting chronic respiratory or cardiovascular problems may have
21 greater susceptibility to toxic effects of antimony (Brieger et al. 1954; Cooper et al. 1968;
22 Potkonjak and Pavlovich 1983; Renes 1953). The developing respiratory tract in children
23 may also pose increased susceptibility. Animal data also suggest renal effects following
24 extended antimony exposure (Brieger et al. 1954; Price et al. 1979). Although there is no
25 evidence to indicate whether similar effects would be occur in humans, it is possible that
26 individuals with kidney dysfunction may be unusually susceptible.
27
28 11.6.4 Arsenic
29 11.6.4.1 Physical/Chemical Properties
30 Arsenic is a metalloid belonging to Group 5A of the periodic table. Arsenic has
31 valence states of -3, 0, +3 and +5 (Weast, 1989), although the +3 and +5 forms of
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1 arsenic are the most common states (World Health Organization, 1987). Elemental arsenic is
2 oxidized to arsenic trioxide (+3 oxidation state) upon exposure to air (American Conference
3 of Governmental Industrial Hygienists, 1991). Arsenic occurs in the environment in both
4 organic and inorganic compounds (Ishinishi, 1986). Arsenic trioxide, in particulate form, is
5 the most common compound of arsenic found in ambient air (Ishinishi, 1986), but it may be
6 oxidized to arsenic pentoxide (+5 oxidation state). In aerated water, As"1"3 is oxidized to
7 As"1"5, especially at alkaline pH (Agency for Toxic Substances and Disease Registry, 1992).
8 Elemental arsenic is insoluble in water, but arsenic trioxide and arsenic pentoxide are both
9 moderately soluble.
10 Workers in smelters, glass factories, arsenical pesticide manufacture, pesticide
11 applicators, and wood preserving plants are potentially exposed to relatively high levels of
12 arsenic as dusts and vapors. Another source of potential occupational arsenic exposure is the
13 use of gallium arsenide in semiconductor technology. Smelter workers are exposed primarily
14 to trivalent arsenic (arsenic trioxide) and wood preservers to pentavalent arsenic. The
15 general population near these types of manufacturing plants are exposed by inhalation to low
16 but detectible levels of arsenic.
17
18 11.6.4.2 Pharmacokinetics
19 Absorption and Distribution
20 In smelter workers exposed to arsenic trioxide, urinary excretion accounted for about
21 40 to 60% of the inhaled dose (Pinto et al., 1977). Smith et al. (1977) showed that amounts
22 of different arsenic species (As (III), As (V), methylarsonic acid and dimethylarsinic acid) in
23 urine samples of copper smelter workers exposed to inhaled inorganic arsenic (primarily
24 As2O3) correlated well with each other and with exposure. Particles > 5 /xm diameter were
25 more closely correlated with excretion of arsenic compounds, although the correlation for
26 exposure to particles < 5 /im was also highly significant (p < 0.001). The authors
27 attributed this to greater deposition efficiency of particles > 5 pm and to that size fraction
28 accounting for more than half of the total airborne arsenic.
29 No laboratory animals studies on absorption of arsenic via inhalation were found. In
30 hamsters, intratracheal instillation of relatively soluble oxy compounds of arsenic (sodium
31 arsenate, sodium arsenite, arsenic trioxide) resulted in 60 to 90% clearance from the lungs in
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1 one day, whereas arsenic trisulfide and lead arsenite (only slightly soluble) largely remained
2 in the lungs and were only slowly absorbed (Marafante and Vahter, 1987); calcium arsenate
3 was solubilized and cleared from the lungs more slowly (Pershagen et al., 1982). Leffler et
4 al. (1984) instilled dust from a smelter (19% arsenic and 1.6% antimony) into hamster lungs
5 and found a lung clearance half-life of 20 h for arsenic and 40 h for antimony, compared to a
6 half-life of 13 h for arsenic trioxide (5 ± 2 /mi MM AD).
7 Soluble arsenic salts are rapidly and completely absorbed from the gastrointestinal tract
8 of humans. Less than 5% of an oral dose of 1-8 mg arsenic was eliminated in the feces
9 (Bettley and O'Shea, 1975). Similar absorption was seen in the monkey (Charbonneau et al.,
10 1978) and in mice (Vahter and Noren, 1980). Marafante and Vahter (1987) found a good
11 correlation between the solubility of arsenic compounds in dilute HC1 and their absorption
12 from the gastrointestinal tract of hamsters. After a single oral dose of 2 mg 74arsenic/kg for
13 each compound, the absorption based on 3-day fecal elimination was 51% for sodium
14 arsenite, 88% for sodium arsenate, 31% for lead arsenate, and 17% for arsenic trisulfide.
15 Inorganic arsenic is freely distributed to all tissues after it is absorbed into the
16 bloodstream. Tissue levels of arsenic in humans have been studied using autopsy data.
17 Kadowaki (1960) found the highest levels in nails (0.89 /xg/g) followed by hair, bone, teeth,
18 and skin and lower levels in soft tissues. Hair arsenic levels are increased in occupationally
19 exposed workers, as high as 44 /^g/g Bencko et al. (1986).
20 No inhalation data were found for the distribution of arsenic in laboratory animal
21 species, but in mice given a single oral dose of 74arsenic as arsenate or arsenite, the highest
22 tissue concentrations were seen within 2 h in the kidneys, liver, and bile, and tissue levels
23 decreased by 72 h (Vahter and Norin, 1980). Arsenate was cleared more rapidly than
24 arsenite from soft tissues (except kidney). In contrast, rats retained up to 50% of a single
25 injected dose of radioactive arsenate in red blood cells 2 days after dosing, and 26%
26 remained after 64 days. The persistence in blood is due to strong binding of arsenic to free
27 sulfhydryl groups in rat hemoglobin; once bound to the hemoglobin availability and, thus, the
28 toxicity of arsenic is greatly reduced in rats (Mast et al., 1990; Vahter et al., 1982). For
29 this reason, the rat is not an appropriate toxicokinetic model for extrapolation of metabolic
30 data to humans. Dimethylarsenic, a metabolite of inorganic arsenic, has low affinity for
31 tissues, is rapidly excreted, and is not distributed in tissues.
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1 Metabolism
1 Inorganic arsenic metabolism is similar in humans and laboratory animals (mice,
3 rabbits, and hamsters). Arsenate (As+5) is reduced to arsenite (As+3),which is methylated to
4 form monomethyl arsenic acid (MM A). MM A is then reduced (As+5 to As+3) and
5 methylated to form dimethyl arsinic acid (DMA). The methylated forms of arsenic as well
6 as inorganic arsenic species, are excreted in the urine; methylation facilitates the urinary
7 excretion. Glutathione (GSH) appears to be the electron receptor in the reduction reactions,
8 and the reduction is predominantly enzymatically mediated, although GSH can non-
9 enzymatically reduce As+5. Methylation is mediated by two methyltransferases, and
10 S-adenosylmethionine is the methyl donor and electron acceptor (Levine et al., 1988).
11
12 Excretion
13 In humans, the predominant methylated form in urine is DMA, with lesser amounts of
14 MMA. Six adult males given a single oral tracer dose of 74arsenic/kg as arsenate (capsule).
15 Of the dose excreted in the urine after 5 days (58% of administered), 51% was DMA, 21%
16 MMA, and the remainder inorganic species. Interindividual variability in methylation was
17 indicated by a DMA range of 40-56% and an MMA range of 15-25%.
18 Although there were no data on excretion of arsenic in laboratory animals after
19 inhalation, oral and intravenous studies suggest that methylation of arsenic is required for
20 efficient excretion. In mice given a single oral or intravenous dose of 74arsenic as arsenate
21 (As+5), reduced arsenite (As+3) and DMA were detected in the bladder urine in one h; in
22 mice given As+3, very little As+5 was found in plasma or urine, but DMA was found in
23 urine. In rabbits given an intravenous injection of As+5, As+3 was found in the bladder
24 urine at 0.5 h, but DMA did not appear until 2 h. These findings indicated that reduction
25 was prerequisite to methylation (Vahter and Endvall, 1983). In a similar study, Marafante
26 et al. (1985) found after intravenous dosing of rabbits with 74As as arsenate that reduction of
27 As+5 was more rapid than methylation. That is, within 15 min, 10% of total arsenic in
28 plasma was As"1"3; As"1"5 concentrations in plasma decreased with a half time of one h; As+3
29 was cleared with half times of 10 min and 2 h; and DMA levels in plasma peaked at 4 h.
30 After 24 h, urinary DMA, As+3, and unchanged As"1"5 accounted for 35%, 5%, and 25% of
31 the administered dose.
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1 11.6.4.3 Health Effects
2 Human Data
3 Data on toxicity of inhalation exposures are mainly limited to qualitative occupational
4 studies for workers breathing arsenic dusts (arsenic trioxide). Respiratory effects, including
5 lung cancer, and peripheral neurological effects are toxic endpoints with inhalation exposure.
6 Chronic encephalopathy has also been associated with exposure to arsenic fumes in case
7 reports.
8 In humans, acute symptoms are seen after airborne exposure to high levels of arsenic
9 trioxide in an occupational setting. Symptoms include severe irritation of the nasal mucosa,
10 larynx, and bronchi (Holmqvist, 1951; Pinto and McGill, 1953). It is not clear if these
11 effects were chemically related to arsenic or a result of irritation due to the dusts inhaled.
12 Irritation of mucous membranes of the nose and throat leading to hoarseness, laryngitis,
13 bronchitis, or rhinitis and sometimes perforation of the nasal septa have been reported in
14 workers exposed to arsenic dusts (Pinto and McGill, 1953), but effect levels cannot be set
15 due to insufficient exposure data.
16 Hyperpigmentation and hyperkeratosis are skin changes characteristic of chronic
17 exposure to arsenic and are seen in individuals exposed to arsenic through inhalation or
18 ingestion. The only available chronic inhalation studies are those for occupational exposures.
19 Occupational exposure to sodium arsenite dusts in a factory manufacturing sheep dip was
20 reported by Perry et al. (1948). Among 31 chemical workers with high exposure to arsenic
21 (mean value about 400 jig/m3, average time of employment 24 years), there was a 90%
22 incidence of hyperpigmentation and a 29% incidence of hyperkeratoses. In 56 controls (from
23 the same plant and possibly subject to some level of exposure), there was a 16% incidence of
24 hyperpigmentation and a 4% incidence of hyperkeratoses. Perry et al. (1948) noted that
25 although most of the exposed workers wore dust masks, it was likely that they were not used
26 properly. Considerable exposure to arsenic did occur as indicated by the high urinary
27 arsenic levels, which averaged 243 mg arsenic/L in the high exposure chemical workers.
28 Considering the high incidence of hyperpigmentation in the "controls", and the possibility
29 that direct skin contact and accidental ingestion of the dust were likely, total uptake of
30 arsenic may have been much higher than that indicated by the air concentrations.
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1 Feldman et al. (1979) studied 70 copper smelter workers and a control group of 41
2 non-smelter workers, on whom clinical neurologic examinations were conducted; of the
3 smelter group, 37 were classified as high exposure and 33 as low based on arsenic levels in
4 nails, hair, and urine. Weak associations were found between arsenic exposure and clinical
5 neurologic findings, decreased action potential amplitude, and slower motor and sensory
6 nerve conduction velocity. Associations were weak since there were only three cases of
7 motor neuropathy and five cases of mixed sensorimotor neuropathy in the arsenic-exposed
8 workers.
9 Morton and Caron (1989) reported two cases of chronic encephalopathy associated with
10 high exposure to arsenic fumes in a wood treatment plant. Beckett et al. (1986) also
11 reported a case of acute encephalopathy due to occupational exposure to arsenic in a smelting
12 plant for a subject who had worked intermittently for 20 years with the smelting process and
13 had previous exposures, one of which (5 years earlier) caused cough, diarrhea, rash, and
14 neuro-behavioral symptoms. The urinary levels were 21 jig/L arsenic, which is only slightly
15 higher than normal.
16 Lagerkvist et al. (1986) reported that increased peripheral vasospastic disorders and
17 Reynaud's phenomenon were found in Swedish arsenic workers exposed to airborne arsenic
18 dusts. The effect on the blood vessels was quantified by measurement of systolic blood
19 pressure in fingers and toes after local cooling.
20 No reproductive or developmental studies were located for humans following inhalation
21 exposure to arsenic.
22 Studies in smelter worker populations have shown an association between lung cancer
23 mortality and arsenic exposure (Axelson et al., 1978; Enterline and Marsh, 1982).
24 An excess of lung cancer deaths in pesticide workers chronically exposed to arsenic has been
25 shown in mortality studies and cohort studies (Ott et al., 1974; Mabuchi et al., 1979;
26 Matanoskietal., 1981).
27
28 Laboratory Animal Data
29 Laboratory animal toxicity data from inhalation exposures to arsenic compounds are
30 summarized in Table 11-23. Limited acute data were available on the inhalation toxicity of
31 arsenic in animals. Aranyi et al. (1985) exposed mice to an aerosol of arsenic trioxide for 3
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3.
TABLE 11-23. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
ARSENIC AND COMPOUNDS
1— '
s
1— '
1
Cj
VO
O
>
H
b
0
5;
o
d
0
H
W
Exposure
Concentration
ppm /tg As/m3
Acute Studies
0
270
500
940
Chronic Studies
0
60
200
5,200
19,100
39,000
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number) Sex Assays performed: Effect(s) Reference
3 h/d As2O3 MMAD = 0.4 Mice, GDI Simultaneously challenged with an aerosol of viable Aranyi et al.
1,5, aerosol /on; ag = 2.6 (42-292) F Streptococcus zooepidemicus or radiolabeled 35S- (1985)
or 20 d Klebsiella pneumonia to determine mortality:
Mortality in Streptococcal assay, decreased
bacteriocidal activity.
continuously As2O3 MMAD <0.3 Rats, Wistar Body wt, hematology, clinical chemistry, and Glaser et al.
for 18 mo aerosol /tm (20-40) M macroscopic and microscopic examination: No (1985)
effects.
6 h/d GaAs MMADs = Pregnant Mice, Maternal, reproductive, and developmental Mast et al.
7 d/wk aerosol 1.1, 1.2, and Swiss CD (22-24) endpoints: Reduced maternal weight (p< 0.05) on (1990)
Gd4-17 1.3 /mi, F gd 9-15 for the two high-concentration dams.
respectively; Dyspnea occurred in 50% of animals for the 5,200
a = 2 and 19,000-/ig/m3 groups and in all animals in the
39,000-/tg/m3 group in some portion of the exposure
period; incidence, duration, and severity were
concentration-related. The 19,000 and 39,000-/ig/m3
groups had grey and/or mottled lungs.
Developmental toxicity (concentration-related dec
number of live fetuses/litter and corpora lutea/dam
and inc number of early resorptions/litter was
observed in exposed groups; significant only in the
39,000-/ig/m3 group; dec mean fetal body wt was
concentration-related; significant in the two high-
concentration groups; concentration-related increase
in reduced ossification of sternebrae per litter;
significant in the two high-concentration groups).
n
H-i
H
W
-------
t
!5!
TABLE 11-23 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
ARSENIC AND COMPOUNDS
ppm
Exposure
Concentration
/*g As/mJ
5,200
19,100
39,000
Exposure
protocol
6h/d
7d/wk
Gd 4-19
Chemical
form
GaAs
aerosol
Particle size and
distribution
MMADs = 1.1,
1.2, and 1.3 pm,
respectively;
Species, Strain,
(Number) Sex
Pregnant Sprague
Dawley Rats
(30-31) F
Assays performed:
Effect(s)
Maternal, reproductive, and developmental
endpoints: Maternal toxicity at 19,000 ^g/m3
and above (pulmonary effect (dyspnea).
Reference
Mast et
(1990)
al.
Developmental toxicity at 19,000 /*g/m3 and
above (reduced fetal body weight at two high
concentration groups; concentration-related;
increased incidence of skeletal variations,
specifically ossification of sternebrae
(significant) and incompletely ossified vertebral
centra, was concentration-related and significant
in the two high-concentration groups).
£^ Abbreviations:
oo
o
6
o
s
As2O3 = arsenic trioxide; d = days; dec = decreased; F = females; h = hours; GaAs = gallium arsenide; Gd = gestational day; inc = increased; M = males;
MMAD = mass median aerodynamic diameter; mo = months; Na3As = sodium arsenite dust; NS = not specified; ag = geometric standard deviation of
distribution; wk = weeks; wt = weight.
8
O
I— I
H
W
-------
1 h at levels of 0, 270, 500, or 940 /xg arsenic/m3. Additional groups were exposed for 3
2 h/day for 5 or 20 days. At the end of exposure, mice were given an aerosol exposure of
3 viable streptococci, and death of exposed and controls was recorded over 14 days. Separate
4 groups were challenged with aerosols of 35S-labeled Klebsiella pneumoniae to evaluate
5 macrophage functionality (bacterial killing) in a 3-h period. In the streptococcal assay, a
6 concentration-related increase in mortality occurred. Bacteriocidal activity was markedly
7 decreased after a single exposure to 940 /xg arsenic/m3, but no consistent or significant
8 effects were seen at lower exposure levels after one or several exposures.
9 In a chronic inhalation study, male Wistar rats (20-40/group) were continuously
10 exposed to 0, 60, or 200 jig arsenic/m3 as arsenic trioxide for 18 mo (Glaser et al., 1986).
11 No effects on body weight, hematology, clinical chemistry, or macroscopic and microscopic
12 examination outcomes were observed.
13 Carcinogenicity bioassays for arsenic have been conducted mainly in rats and mice.
14 Ishinishi et al. (1977) reported that 15 weekly intratracheal instillations of arsenic trioxide
15 (260 /zg), copper ore (3.95% arsenic), or refinery flue condensate (10.5% arsenic) to Wistar
16 rats did not increase the incidence of tumors over those of controls during the lifespan of the
17 animals. In a study by Pershagen et al. (1984), 15 weekly intratracheal instillations of
18 arsenic trioxide (250 /ig As/m3) in hamsters increased the incidence of respiratory tract
19 adenomas and papillomas, but the hamsters had also received a carrier dust (charcoal carbon)
20 that increased the lung retention of arsenic. However, in one inhalation study Berteau et al.
21 (1978) found that female mice exposed to 1% aqueous aerosol of sodium arsenite, 20 to
22 40 mm/day, 5 days/week, for 55 weeks did not show an increase in tumor incidence.
23 Mast et al. (1990) conducted an inhalation developmental study in rats and mice
24 exposed 6 h/day to gallium arsenite (5,000, 19,000, or 39,000 fig arsenic/m3) on days 4-17
25 (mice) or 4 to 19 (rats) of gestation. Maternal toxicity was observed at the two highest
26 concentrations in both mice (reduced body weight, dyspnea, mottled lungs) and rats
27 (dyspnea). Slight growth retardation (statistically significant decrease in fetal body weight)
28 was seen in pups at the two highest levels. A significant decrease in incomplete ossification
29 of sternebrae was also observed with exposure to 19,000 /ig/m3 and above. No significant
30 increases in malformations were seen.
31
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1 11.6.4.4 Factors Affecting Susceptibility
2 The respiratory system is most sensitive to arsenic toxicity in humans following
3 inhalation exposure (Holmqvist 1951; Pinto and McGill 1953). Therefore, individuals with
4 pre-existing respiratory conditions (such as asthma, bronchitis) may have greater
5 susceptibility than healthy individuals to respiratory effects from arsenic exposure. The
6 developing respiratory tract in children may also pose an increased susceptibility.
7 Developmental toxicity has also been observed and thus fetuses may also represent a
8 susceptible population.
9
10 11.6.5 Barium
11 11.6.5.1 Chemical and Physical Properties
12 Barium is a silvery-white, relatively soft, ductile metal belonging to the alkaline-earth
13 group of elements in Group 2 (IIA) of the periodic system of elements (Boffito, 1992;
14 DiBello et al., 1992). Elemental barium is not found free in nature (DiBello et al., 1992),
15 the element being fairly volatile and extremely reactive. Barium reacts readily and
16 exothermically with oxygen and halogens at room temperature. It also reacts vigorously with
17 water, releasing hydrogen and forming barium hydroxide, Ba(OH)2 (Boffito, 1992). Barium
18 forms compounds in the +2 valence state; in aqueous solution, barium is present as a cation
19 with a +2 charge (DiBello et al., 1992), with some compounds, e.g., barium carbonate
20 (BaCO3) and barium chloride (BaCl2) being slightly soluble in warm water (ca 20 to 25 °C)
21 (Lide, 1992). Barium forms organometallic compounds such as barium acetate and barium 2-
22 ethylhexanoate (DiBello et al., 1992).
23
24 11.6.5.2 Pharmacokinetics
25 Human
26 Limited information exists on pharmacokinetic properties of barium with inhalation
27 exposure in humans. Increased urinary levels of barium (250 mEq/mL) reported by Shankle
28 and Keane (1988) in humans following inhalation indicate that barium is absorbed by this
29 route. Analysis of barium in humans, as discussed by Schroeder et al. (1972) indicates that
30 barium is distributed predominantly to the skeleton and teeth. Barium exposure in this study
31 presumably occurred via the oral route. Case studies have shown that excretion of oral doses
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1 of barium in humans is about 3 % in urine, with most of the remainder in feces (Tipton
2 etal., 1966). Barium is not metabolized in the body but may be metabolically transported
3 or incorporated into complexes or tissues.
4
5 Laboratory Animals
6 Laboratory animal data indicate that clearance of inhaled barium compounds from the
7 lungs is related to the compound's solubility, with an initial rapid elimination phase for both
8 soluble barium chloride and for insoluble barium sulfate. Because of its chemical similarity
9 to calcium, barium accumulates in bone; about 25% of absorbed barium is transported to the
10 skeleton, and the remainder is excreted in the urine and feces within 2 weeks (Cuddihy
11 et al., 1974). The biological half-life of radioactive barium sulfate in the pulmonary region
12 has been calculated to be 8 days in dogs exposed via inhalation (Morrow et al., 1964), and
13 10 days in rats injected intratracheally (Cember et al., 1961).
14 Cuddihy and Griffith (1972) studied the distribution of barium after co-inhalation of
15 radiolabeled barium chloride and lanthanum chloride by dogs. By 5 days postexposure, a
16 much higher percentage of the initial body burden remained in the skeleton (about 30%) than
17 was in the lungs (about 0.2%). Similar studies were conducted with radiolabeled barium
18 chloride and radiolabeled barium sulfate (Cuddihy et al., 1974). Data for skeletal burden
19 were not available for barium sulfate, but lung burden accounted for less than half of the
20 total body burden by day 5, indicating that clearance had occurred (Cuddihy et al., 1974).
21 Distribution to blood was more rapid and extensive following exposure to barium chloride,
22 with peak levels of about 10% of the initial body burden shortly after exposure, compared
23 with a peak of about 2% of the initial body burden for barium sulfate (Cuddihy and Griffith,
24 1972; Cuddihy et al., 1974). For both compounds, initial elimination in urine and feces
25 accounted for about 13% of the initial body burden each. For barium sulfate, some of the
26 barium in the blood, urine, and feces probably represents barium cleared from the lungs by
27 mucociliary action and either absorbed (blood and urine) or not absorbed (feces) from the
28 gastrointestinal tract.
29 Data from intratracheally instilled barium may provide some information on the fate of
30 barium compounds deposited in the lungs following inhalation exposure. Radioactive barium
31 sulfate injected directly into the trachea of rats was taken up into the epithelial membranes
April 1995 11-163 DRAFT-DO NOT QUOTE OR CITE
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1 and remained there for at least several weeks (Gore and Patrick, 1982; Takahashi and
2 Patrick, 1987). These studies also show that barium in the trachea can be cleared to the
3 lymphatic system (Takahashi and Patrick, 1987). Data from rats exposed to barium sulfate
4 via intratracheal injection found that about 7% of the initial lung burden was finally cleared
5 to blood (Spritzer and Watson, 1964).
6
7 11.5.5.3 Health Effects
8 Studies evaluating barium effects following inhalation exposure are limited to case
9 reports of occupational exposure in humans and two experimental animal studies. These
10 studies are not adequate for firmly establishing the health effects of barium by inhalation
11 because of serious study limitations. The case reports are inadequate because data were
12 available for only a few exposed subjects and because exposure conditions (duration,
13 frequency, dose) were not well characterized. Laboratory animal studies were also poorly
14 characterized (lack of controls, number of animals not reported, duration and frequency of
15 exposure not indicated, inadequate methods and results). Due to these major limitations of
16 available data, results should be regarded as providing only preliminary or suggestive
17 evidence for health effects due to inhalation exposure to barium.
18
19 Human Data
20 Human toxicity data for inhalation exposure are provided in Table 11-24. Workers
21 exposed chronically to dust from barium sulfate had minimal radiologically observable
22 evidence of pneumoconiosis, accompanied by infrequent reporting of minor respiratory
23 symptoms (Doig, 1976). Essing et al. (1976) also reported few respiratory symptoms, slight
24 decrease in lung function (4/12), and a thickening of lung structure (5/12) after inhalation of
25 steatite (talcum) dust containing barium carbonate.
26 Shankle and Keane (1988) reported gastrointestinal effects (subjective symptoms),
27 neurological effects (absence of deep tendon reflexes and progressive weakness in
28 extremities), hypokalemia, and renal failure after a male worker accidentally inhaled large
29 amounts of barium carbonate powder. The kidney and nervous system are known targets of
30 oral exposure to barium; it is unclear whether the observed effects resulted from the
31 absorption of inhaled barium, from barium that was inhaled and ingested after mucociliary
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TABLE 11-24. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR BARIUM AND COMPOUNDS
VO
U)
Exposure
Concentration
ppm i
iig Ba/m3
Exposure
protocol
Chemical Particle size and Species, Strain,
form distribution (Number) Sex
Assays
performed:
Effect(s)
Reference
Acute Studies
NA NR Occup BaCO3
Single incident powder
- powder
blown in face
NR
Human
(DM
Subjective symptoms, physical examination, urinalysis:
Abdominal cramps, nausea, vomiting, diaphoresis,
excess salivation, progressive weakness. Absent deep
tendon reflexes. Hematuria, elevated serum creatinine,
hypokalemia, barium level of 250 mEq/mL.
Shankle and
Keane (1988)
Chronic Studies
oo
O
o
*
o
H
O
cj
§
G
H
W
NA NR Occup BaSO4
1947: 3.5-15 dust
yr
1961: 1 mo-18
yr
1963: 21 mo-
18 yr
1961 dust count Human
range: 2734- 1947: (5) M
11365 particles 1961:(11)M
per cu. ml 1963: (14) M
NA 600-2,300 7-27 yr
occup
Steatite NR
dust - 6%
BaC03
Human (12) M
Subjective symptoms, clinical examinations, chest Doig (1976)
radiography, spirometry (1966, 1969, 1973 follow-ups
only): Slight coughs, slight sputum. Basal crepitations
in 1/5 (1947) 1/11 (1961). Opacities varying in
intensity and profusion in 1/5 (1947), 7/11 (1961) and
9/14 (1963). Follow-up radiography indicated
progressive regression after exposure cessation.
Pulmonary function tests were average or better.
Subjective symptoms, physical examination, Essing et al.
spirometry, plethysmographic lung function test, blood (1976)
gas analysis, ECG, x-rays: Coughing with or without
discharge. Adiposity (8/12), inc BP (3/12). Slight dec
in lung function (4/12). Incomplete right bundle
branch block (2/12). Thickening of lung structure
(5/12), pronounced calcifications in walls of pelvic
vessels and femoral artery (1/12).
Abbreviations:
avg = average; B = both male and female; Ba = barium; BaCl2 = barium chloride; BaCO3 = barium carbonate; BaSO4 = barium sulfate; BP = blood pressure;
BW = body weight; d = day; dec = decreased; ECG = electrocardiography; HP = histopathology; h = hour; inc = increased; M = male; mEq =
milliequivalent; min = minute; mo = month; NA = not applicable; NR = not reported; occup = occupational exposure; ppm = parts per million; wk = week;
yr = years.
-------
1 clearance, or from barium that was directly ingested. Essing et al. (1976) also reported
2 nonrespiratory effects after chronic inhalation exposure to barium carbonate, including
3 cardiovascular effects (increased blood pressure in 3/12, incomplete right bundle branch
4 block in 2/12, and pronounced calcifications in walls of pelvic vessels and femoral artery in
5 1/12). Because the subjects were also smokers and overweight, it is unclear if these effects
6 were related to barium exposure.
7
8 Laboratory Animal Data
9 Toxicity data for laboratory animals are summarized in Table 11-25. Limited available
10 data indicate that the respiratory tract and possibly other organ systems are targets of inhaled
11 barium. Hicks et al. (1986) reported bronchoconstriction and increased blood pressure in
12 guinea pigs intratracheally administered 60 /ig Ba/m3/min as an aerosolized barium chloride
13 solution. Taresenko et al. (1977) exposed rats by inhalation to barium carbonate for 1 or
14 4 mo. Rats exposed to 23,380 pig Ba/m3 for 1 mo exhibited desquamative bronchitis and
15 focal thickening of interalveolar septa. Exposure of rats for 4 mo at 3,640 /ig Ba/m3 resulted
16 in pulmonary lesions; other organs (heart, liver, kidneys) also demonstrated histopathology in
17 the form of granular dystrophy and reduced biliary excretion was seen. The reproductive
18 organs in both male and female rats (at doses of 3,640 and 9,380 jig Ba/m3, respectively)
19 were also affected (decreased sperm production in males, shortened estrous cycle in females)
20 by inhalation exposure to barium carbonate and impaired reproductive capabilities occurred
21 in exposed males mated with unexposed females.
22 Other effects observed by Tarasenko et al. (1977) in rats exposed for 1 mo to
23 23,380 pig Ba/m3 included hematological changes, enzyme inhibition, metabolic changes and
24 vascular tonus (all of which were unspecified). Decreased body weight, hematological
25 changes, increased urinary calcium, inhibition of serum activities of cholinesterase and
26 alkaline phosphatase were observed after the 4 mo exposure protocol (3,640 /ig Ba/m3).
27
28 11.6.5.4 Factors Affecting Susceptibility
29 Populations that may have increased susceptibility to barium via inhalation exposure
30 include patients with cardiovascular problems (particularly hypertension), smokers, others
31 with a history of lung disease, and those taking certain prescription drugs. The developing
April 1995 11-186 DRAFT-DO NOT QUOTE OR CITE
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I
I—*
VO
VO
U)
TABLE 11-25. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR BARIUM
AND COMPOUNDS
Exposure
Concentration
ppm /ig Ba/m3
NA 23,380
Exposure
protocol
h/dNR
d/wk NR
1 mo
Chemical
form
BaC03
aerosol
Particle size and
distribution
80% of particles
were < 2 /xm
Species, Strain,
(Number) Sex
Rat, Albino
NR
Assays performed: Effect(s)
Reference
HP of respiratory tract and lungs, heart, liver and kidneys; Tarasenko
urine and blood analyses, bromsulfophthalein test: (1977)
Desquamative bronchitis, focal thickening of interalveolar
septa; granular dystrophy in other organs studied. Blood
changes, unspecified enzyme inhibition, metabolic changes,
vascular tonus, dec biliary excretion.
et al.
NA
0
Males:
805
3,640
Females:
2,170
9,380
4h/d
6 d/wk
4 mo
BaCO3
dust
NR
Rat, Albino BW, urine and blood analyses, ECG, bromsulfophthalein
(NR) B test for liver function, HP of lungs, liver, heart, kidneys,
testicles and ovaries; reproductive parameters: Dec BW.
Dec blood Hb, dec thrombocyte count dec blood glucose,
dec blood protein, inc leukocyte count, inc blood
phosphorous, inc urinary calcium, inhibition of
cholinesterase and alkaline phosphatase activities. Inc
arterial BP. Dec biliary function. Pulmonary lesions
(perivascular and peribronchial sclerosis with focal
thickening of the interalveolar septa); granular dystrophy in
liver, heart and kidneys; dec number and motility of
spermatozoids, desquamated epithelium of ducts. Impaired
fertilization, dec viability of offspring, inc embryonal
mortality (females mated with exposed males). All above
effects observed in males exposed to 3640 jug Ba/m3.
Shortened estrous cycle, ovarian structural abnormalities,
underdeveloped offspring (females exposed to 9380 pig
Ba/m3).
Tarasenko et al.
(1977)
Abbreviations:
avg = average; B = both male and female; Ba = barium; BaCl2 = barium chloride; BaCO3 = barium carbonate; BaSO4 = barium sulfate; BP = blood pressure; BW = body weight; d = day; dec
= decreased; ECG = electrocardiography; HP = histopathology; h = hour; inc = increased; M = male; mEq = milliequivalent; min = minute; mo = month; NA = not applicable; NR = not reported;
occup = occupational exposure; ppm = parts per million; wk = week; yr = years.
-------
1 respiratory tract of children may also be susceptible. Long-term (7 to 27 years) occupational
2 exposure to high (600 to 2,300 jwg/m3) levels of barium was found to increase blood pressure
3 and other cardiovascular effects (Essing et al., 1976); suggesting possible increased risk for
4 individuals with high blood pressure or other cardiovascular problems with barium
5 inhalation. Although inhalation of barium has been associated with only minimal lung effects
6 (Doig, 1976; Essing et al., 1976), individuals with impaired lung function due to lung
7 disease or smokers might experience increased respiratory symptoms upon exposure to high
8 (mg) concentrations of inhaled barium.
9 Other information on factors increasing susceptibility to barium are limited to data from
10 oral or parenteral administration. However, some or all may be relevant to the inhalation
11 exposure route, since barium may be absorbed from the lungs. Oral and parenteral
12 administration of barium has been shown to decrease serum potassium in humans and
13 laboratory animals (Foster et al., 1977; Gould et al., 1973; Phelan et al., 1984; Roza and
14 Berman, 1971); thus, individuals taking diuretics may have a severe hypokalemic reaction to
15 barium absorption.
16
17 11.6.6 Cadmium
18 11.6.6.1 Chemical and Physical Properties
19 Cadmium is a metallic element found in Group 2B of the periodic table, which has
20 possible valences of 0, +1, and +2; it forms almost all of its compounds in the
21 +2 oxidation state. Rarely, the +1 oxidation state may be produced in the form of dimeric
22 Cd22+ species. This species is unstable in water or other donor solvents, and dissociates to
23 Cd2+ and Cd (Herron, 1992). Cadmium metal is slowly oxidized in moist air and when
24 heated in air, it rapidly forms cadmium oxide (Carr, 1992). Cadmium exists in the
25 environment as both inorganic salts and organocadmium compounds. Elemental cadmium
26 and its most commonly encountered compound in ambient air, cadmium oxide (CdO) are
27 both insoluble in water; whereas cadmium chloride (CdCl2) and cadmium sulfide (CdS) are
28 moderately water soluble.
29
30
April 1995 11-188 DRAFT-DO NOT QUOTE OR CITE
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1 11.6.6.2 Pharmacokinetics
2 Absorption and Distribution
3 Cadmium metal and cadmium salts have low volatility and exist in air primarily as fine
4 particles; when inhaled, some fraction of this paniculate matter is deposited in the airways or
5 the lung, and the rest is exhaled. While some soluble cadmium compounds (cadmium
6 chloride, cadmium oxide, and cadmium sulfate) may undergo limited absorption from
7 particles deposited in the tracheobronchial region, the main site of absorption is the alveoli.
8 No direct data are available on cadmium deposition, retention, or absorption in the human
9 lung. However, the detection of cadmium in the kidney (Ellis et al., 1985; Roels et al.,
10 1983) and in the urine (Blinder et al., 1985a, b; Jarup et al., 1988; Kawada et al., 1990;
11 Smith et al., 1980; Thun et al., 1989) of occupationally exposed workers indicates that
12 inhaled cadmium is absorbed.
13 Retention in the lung following cadmium inhalation has been reported as >40% in rats
14 (Moore et al., 1973). Based on the estimated amount of cadmium inhaled in mice exposed to
15 cadmium chloride, lung retention at an unspecified time of after exposure was 0.2 to 4% and
16 whole body retention was 10.5 to 23% (Potts et al., 1950). Princi and Geever (1950) found
17 that blood cadmium levels of dogs exposed to cadmium oxide were higher than those of dogs
18 exposed to comparable levels and particle sizes of cadmium sulfide, consistent with the
19 higher solubility and absorption of cadmium oxide in body fluids compared to cadmium
20 sulfide (Princi and Geever, 1950). Glaser et al. (1986) exposed rats via inhalation to
21 cadmium oxide (100 /xg/m3), cadmium chloride (100 /ig/m3), or cadmium sulfide
22 (100 jig/m3), and found the ratio of lung to kidney levels was higher for the sulfide than for
23 the other two, suggesting increased pulmonary retention. Also, the oxide and chloride were
24 distributed to the cytosolic compartment of lung tissue, while only «30% of cadmium
25 sulfide was in the cytosolic compartment (Glaser et al., 1986).
26 Oberdorster and Cox (1989) exposed rats to cadmium chloride aerosol via nose-only
27 inhalation and administered cadmium oxide or cadmium sulfide to rats via intratracheal
28 instillation. The pulmonary retention half-time for all three compounds was shorter in rats
29 (months) than for monkeys (years). The pulmonary retention half-time of cadmium chloride
30 in rats was =85 days. Pulmonary retention of cadmium oxide dust in the rats was biphasic,
31 with retention half-times of 9 days and =7 mo. Cadmium sulfide had a faster biphasic half
April 1995 H_189 DRAFT-DO NOT QUOTE OR CITE
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1 time of 11 and 76 days. It appears that the cadmium sulfide particles were retained in the
2 lungs and cleared by the alveolar macrophages and mucociliary action. The results of
3 Klimisch (1993) also suggest that inhaled cadmium compounds are more bioavailable to the
4 kidney than are ingested ones. Biphasic clearances were also observed in the monkey. The
5 order of long-term retention half-times in the monkey was cadmium oxide < cadmium
6 chloride < cadmium sulfide. The authors suggested that cadmium sulfide dust, like other
7 insoluble particles, is at least partly transported to the lymph nodes. Cadmium oxide
8 clearance from rat lungs may occur via rapid bronchial clearance followed by a much slower
9 alveolar clearance, due to impairment by cadmium-induced inflammation. Deposition of
10 cadmium in the rat and human lung has also been modeled by Oberdorster (1989, 1991).
11 Absorbed cadmium is widely distributed in the body, with the major portion of the
12 body burden located in the liver and kidney. Animals and humans appear to have a similar
13 pattern of distribution that is relatively independent of route of exposure, but somewhat
14 dependent on duration of exposure. Cadmium was found in autopsy samples from nearly all
15 organs of a worker extensively exposed to cadmium dust, with greatest concentrations in
16 liver, kidney, pancreas, and vertebrae (Friberg, 1950). In workers dying from inhalation of
17 cadmium, lung cadmium levels were somewhat lower than liver or kidney cadmium
18 concentrations (Beton et al., 1966). The concentration of cadmium in liver of
19 occupationally-exposed workers generally increases in proportion to intensity and duration of
20 exposure (Davison et al., 1988; Ellis et al., 1985). The concentration of cadmium in kidney
21 may rise more slowly after exposure (Gompertz et al., 1983) and begins to decline after the
22 onset of renal damage at a critical concentration of 160 to 285 /ig/g (Reels et al., 1981).
23 The amount of cadmium in the liver and kidney was much higher in rats following
24 cadmium oxide exposure than following cadmium chloride exposure (Glaser et al., 1986).
25 However, Oberdorster and Cox (1989) found significant kidney cadmium accumulation in
26 rats following nose-only exposure to cadmium chloride. They also found liver and kidney
27 Cd accumulation following intratracheal exposure to cadmium oxide dust but not cadmium
28 sulfide dust exposure. The reason for the difference between the two studies is unclear.
29 Oberdorster (1990) described the distribution of Cd from the blood into the liver. Cd is
30 then probably transported as Cd-metallothionein from the liver to the kidney, where it has a
31 very long biological half tune. Little is transported to the urine, except following significant
April 1995 11-190 DRAFT-DO NOT QUOTE OR CITE
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1 renal tubular damage. The liver is a major storage organ of the metal (Mason, 1990), and
2 the kidney a well-defined target organ for Cd toxicity and storage.
3 The placenta may act as a partial barrier to fetal exposure to cadmium. Cadmium
4 concentration has been found to be approximately half as high in cord blood as in maternal
5 blood (Lauwerys et al., 1978). Accumulation of cadmium in the placenta at levels about six
6 to seven times higher than maternal or fetal cord blood cadmium concentration has also been
7 reported (Kuhnert et al., 1982).
8
9 Metabolism
10 Cadmium is not known to undergo any direct metabolic conversion such as oxidation,
11 reduction, or alkylation. The cadmium(+2) ion does bind to anionic groups (especially
12 sulfhydryl groups) in proteins (especially albumin and metallothionein) and other molecules.
13 Of particular importance to the toxicokinetics and toxicity of cadmium is its interaction
14 with the protein, metallothionein. Metallothionein is a low-molecular-weight protein, very
15 rich in cysteine, which is capable of binding as many as seven cadmium atoms per molecule.
16 Metallothionein is inducible in most tissues by exposure to cadmium, zinc, and other metals,
17 as well as organic compounds. Metallothionein binding decreases the toxicity of cadmium,
18 and the ability of the liver to synthesize metallothionein appears to be adequate to bind all
19 cadmium accumulated (Goyer et al., 1989). When metallothionein-bound cadmium is
20 transported to the kidney, it is readily diffusible and filterable at the glomerulus and may be
21 effectively reabsorbed from the glomerular filtrate by the proximal tubule cells (Foulkes,
22 1978). Cadmium-induced renal toxicity is probably associated with cadmium not bound to
23 metallothionein (Goyer et al., 1989). Renal damage is believed to occur if the localization of
24 cadmium or an excessive concentration of cadmium prevent it from becoming bound to
25 metallothionein. The route of cadmium exposure does not appear to affect metallothionein
26 metabolism in liver and kidney, although inhalation exposure induces metallothionein in the
27 lung (Glaser et al., 1986; Hart, 1986).
28
29 Excretion
30 Braithwaite et al. (1991) studied 14 male workers (mean age 51 years) with mean
31 occupational Cd exposure of 15 years. All subjects had been exposed to levels >50 /ig/m3;
April 1995 11-191 DRAFT-DO NOT QUOTE OR CITE
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1 urinary and blood analyses were performed and in-vivo liver and kidney cadmium measured
2 using a neutron activation technique. Subjects were divided into two groups, those with
3 >500 fig/g of B-2-microglobin in the urine, and those with less. Subjects with elevated
4 excretion of 6-2-microglobin had statistically significantly higher mean concentrations of
5 cadmium in blood, urine, and liver, and a higher range of kidney cadmium burden. Strong
6 correlations were evident between urinary cadmium concentration and kidney cadmium and
7 estimated body burden of cadmium, supporting the theory that urinary excretion of cadmium
8 derives mainly from the kidney following tubular damage. Although urinary cadmium is
9 most frequently measured, most inhaled or ingested cadmium is excreted in the feces. This
10 excreted cadmium represents mostly material that was swallowed, but not absorbed from the
11 gastrointestinal tract.
12 Cadmium excretion in urine of occupationally exposed workers increases proportionally
13 with body burden of cadmium, but the amount of cadmium excreted represents only a small
14 fraction of the total body burden unless renal damage is present; then, urinary cadmium
15 excretion increases markedly (Roels et al., 1981). Bio/Dynamics Incorporated (1980) found
16 that cadmium retention in rats was higher for soluble cadmium compounds (cadmium
17 carbonate and cadmium oxide) than for insoluble cadmium pigments, and that excretion was
18 much higher in the feces than in the urine.
19 Cadmium has a very-long biological half-life, that in humans is estimated to be 10 to
20 30 years in kidney and 4.7 to 9.7 years in liver (Ellis et al., 1985). Absorbed cadmium is
21 rapidly cleared from plasma, and taken up by the erythrocytes. Transport in plasma occurs
22 via proteins including albumin, globulins, transferrin and metallothionein. Urinary cadmium
23 excretion plateaus at human exposures above 500 /ig/m3 X year, possibly because of renal
24 saturation at this level and the inability of the kidney to further increase excretion (Smith
25 etal.,1980)
26
27 11.6.6.3 Health Effects
28 Humans Data
29 As shown in Table 11-26, there is very strong evidence that the kidney and respiratory
30 tract are the main target organs of cadmium toxicity.
April 1995 11-192 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-26. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
3.
Ui
Exposure
Concentration
ppm /tg Cd/m3
Exposure
protocol
Chemical
form
Species,
Particle size and Strain,
distribution (Number) Sex
Assays performed: Effect(s)
Reference
Acute Studies
N/A NS
N/A NS
5hr
accident
1 hr
accident
CdO
fumes,
dust
NS
solder
fumes
NS Human
(5)M
NS Human
(1)M
Case reports; symptoms, HP of lungs in one
fatal case: Mild symptoms during exposure;
cough, chest pain, dyspnea, fever at 4-10 hrs
post-exposure and severe chest pain, wheezing,
persistent cough at 8 hr-7 d. Cause of one
death was pulmonary edema. Cd level for fatal
case est at 7,500 /*g/m3. based on level in
lungs.
Case report; symptoms, x-ray: Up to 4 yrs
post-exposure, dyspnea, cough, myalgia, fever.
Initial chest x-ray showed infiltrates.
Beton et al. (1966)
Barnhart and
Rosenstock (1984)
Chronic Studies
N/A 0
50
0-12 yr
occup
CdO
dust
"95% of CdO dust Human
had a particle size (87-240) B
(MMAD) <5 fan"
Urinary 6-2m: Tubular proteinuria (defined as
> 95th percentile of normal population) was
correlated with exposure duration. Workers
employed 6-12 yr had 3.2 times the rate as
those employed 0-3 yr. Prevalence of
proteinuria was, 19% for workers with 6-12 yr
exposure to =50 /*g/m3, compared with 3% in
controls.
Kjellstrom et al.
(1977)
,
o
H
lO
I
w
i
n
3
Note: Concomitant exposure to nickel
hydroxide.
-------
I.
L/l
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm
N/A
jig Cd/m3
see com-
ments
~ Exposure
protocol
>3 mo
occup
Chemical Particle size and
form distribution
CdO NS
dust
Species,
Strain,
(Number) Sex
Human
(326) M,
Assays performed: Effect(s)
Proteinuria (beta-2-microglobulin): 1 %
proteinuria (i.e., nonresponse) at <359 /ig/m3
Reference
Jarup et al. (1988)
X yr, 9% proteinuria at 359-1,710 yr x /ig/m3
(avg 691 yr x jug/m3). Modeling predicted 4%
proteinuria at cumulative exposure of 500 yr x
/jg/m3. Proteinuria defined as >97.5th
percentile of normals. Majority of workers with
tubular proteinuria had higher cum blood Cd
than workers with same cum exposure, but no
proteinuria, suggesting cum blood Cd is more
sensitive than cum air Cd. This is the same
cohort as Kjellstrom et al., 1977.
Note: Cum exposure based on individual
exposure and work area measurements
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
VO
Exposure
Concentration
Exposure
ppm ng Cd/m3 protocol
N/A 20-45,200 >6yr
dep on area median 25
yr
occup
Chemical Particle size and
form distribution
CdO NS
dust, fume
CdS04
mist
Species,
Strain,
(Number) Sex Assays performed: Effect(s)
Human Medical evaluation, urinary Cd, creatinine
(11-16) M clearance, uric acid, 6-2m; pulmonary function:
High exposure group (urinary Cd 45.7 |tg/L;
>6 yr at >200) had dec creatinine clearance,
inc uric acid and 6-2m excretion compared to
the low exposure group (urinary Cd 13.1 /ig/L;
not worked in areas with fume or dust
exposure). Also dec tubular reabsorption of
phosphorus, dec plasma bicarbonate in high exp
group. When divided by total exp subgroups,
no effect on fi-2m excretion at < 700 /*g/m3 x
yr; 15% incidence of B-2m-uria at 700-
3,500 /ig/m3 X yr. No sig decline of FVC with
total exposure.
Reference
Smith et al. (1980)
Note: Individual TWA exposure calculated
from personal and area sampling and adjusted
for use of respirators.
-------
2.
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm jtig Cd/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species,
Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
vo
o\
T1
H
6
o
25
O
H
I
§
G
H
W
N/A 3-1,500
1-46 yr
occup
CdO
dust,
fumes;
CdSO4
mist
NS
± N/A 3-1,166
19 yr
geom
mean
occup
Cd, CdO,
CdS
dust or
fume
NS
Human Urinary total protein, fi-2m, kidney and liver Cd Ellis et al. (1985)
(82) M content measured by in vivo NAA: Liver Cd
significantly correlated with exposure. Renal
abnormality observed in most workers with liver
Cd levels >40 ppm and exposure >400-
500 /*g/m3 X yr. Avg kidney concentration for
active workers was 230 ppm and 125 ppm in
those with abnormal and normal kidney
function, respectively. TWE (in pg/m3 x yr):
Normals: 0.105 (active), 0.379 (retired);
Proteinuria: 1.69 (active), 3.14 (retired). A
logistic model predicted 7% proteinuria at an
exposure of 100 /ig/m3 X yr.
Human Blood pressure, urinary Cd, B-2m, RBP,
(45) M calcium, phosphate: Inc kidney stones,
Thun et al. (1989);
followup to Ellis et
hypertension, prostatic disease. Inc excretion of al. (1985) and Smith
fi-2m and RBP in exposed group, dec tubular
reabsorption of calcium, phosphorus. No
enzymuria (indicator for tubular epithelium
necrosis). Small inc in mean serum creatinine,
indicating glomerular dysfunction. Using
logistic regression to model prevalence of renal
abnormalities, sharp increase at 300,000 //g/m3
x days (820 /tg/m3 x yr).
Note: Exposure generally dec with time.
Cumulative exposure est based on work history,
adjusted by 0.25 for times and areas where
respirators used.
et al. (1980)
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
3.
3
O
d
o
H
W
O
o
t-H
3
Exposure
Concentration
ppm
N/A
N/A
Mg Cd/m3
7-390
(TWA)
0,
340-600
Exposure
protocol
1-14 yr
occup
ave 3.7 yr
1-39 yr
occup
Chemical Particle size and
form distribution
NS NS
NiCd
battery
manu-
facture
CdO NS
dust
Species,
O* "
Strain,
(Number) Sex
Human
(65) F
Human
(75) M
Assays performed: Effect(s)
Urinary fi-2m and NAG, serum creatinine and
urea: Urinary B-2m and NAG correlated with
blood Cd. Age-adjusted urinary NAG sig inc at
urinary Cd > 3 /tg/g creatinine.
Kidney function (several measures) in copper-
cadmium workers: Several measures of kidney
function fit a threshold model versus exposure.
Total protein, retinol binding protein, albumin,
Reference
Chia et al. (1989)
Mason et al. (1988)
and B-2m had a threshold est at 1,100 /*g/nr x
yr. Tubular resorption of urate and phosphate
had higher thresholds. Measures (creatinine
clearance, serum creatinine, B-2m) of
glomerular filtration rate (GFR) indicated a
reduction in GFR with exposure, but there was
no a well-defined threshold. Tubular proteinuria
incidence inc at exposure > 1,000 jtg/m3 x yr.
N/A 0 4-24 yr NS NS "respirable Human Medical history, urinary Cd, B-2m, other
10-200 occup solder cadmium" (58) M, proteins, GFR: No difference from controls in
fumes (2) F subjective complaints or incidence of kidney
stones. However, within the exposed group,
kidney stones sig more common among those
with urinary Cd >6.3 nmol/mmol creatinine
than among those with lower levels. Excretion
of B-2m, orosomucoid, and albumin correlated
with Cd. For B-2m, apparent threshold at
9nmol Cd/mmol creatinine. Avg GFR sig less
than expected.
Blinder et al. (1985a)
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
3.
00
O
O
Z
O
H
O
H
W
Exposure
Concentration
ppm
N/A
N/A
N/A
/ig Cd/m3
0
95-19,580
(avg 520)
0
3-350
(range)
0.18 and
3.0 (avg)
NS
~ Exposure Chemical Particle size and
protocol form distribution
4-24 yr NS NS "respirable
occup solder cadmium"
fumes
Avg 10.4 NS NS "respirable
yr cadmium cadmium"
occup pigment
dust
NS NS NS
smelter
Species,
Strain,
(Number) Sex
Human
(58) M,
(2)F
Human
(9-53) NS
Human
(36-40) M
Assays performed: Effect(s)
Urinary Cd, ft-2m: Cumulative Cd exposure est
at 350-900 /xg/m3 x yr. A few cases with
slight tubular proteinuria at < 1 ,000 itg/m3 X
yr; at >3,000 /xg/m3 x yr, 74% prevalence of
slight 6-2m-uria, and 54% prevalence of
pronounced fl-2m-uria. Proteinuria did not
reverse after exposure ended and two subjects
developed proteinuria after cessation of
exposure.
Note: Exposure levels are from personal
samplers on workers using cadmium-containing
solders.
Urinary Cd, B-2m, NAG, metallothionein: Cd
in urine correlated better with urinary
metallothionein than the other two proteins. 15-
2m was unaffected at this level of exposure,
which resulted in urinary Cd geometric mean of
1.02 itg/g creatinine.
Note: Avg exposure levels reported separately
for two different job categories.
Urinary Cd, NAG, AAP, GOT: NAG and
AAP sig elevated in exposed group. Based on
probit modeling based on data grouped by Cd
level, 10% chance of elevated NAG value at 6.3
Hg Cd/g creatinine and 10% chance of elevated
AAP value at 5.0 iig Cd/g creatinine.
Reference
Blinder et al. (1985b)
Kawada et al. (1990)
Mueller et al. (1989)
n
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
l-»
so
5>
^
t
SO
O
?»
H
™
o
o
H
O
H
M
Exposure
Concentration
ppm jig Cd/m3
N/A 0
390
110
(avg of
different
areas)
N/A NS
N/A 0
50
150
500
Species,
Exposure Chemical Particle size and Strain,
protocol form distribution (Number) Sex Assays performed: Effect(s)
>21 yr NS NS Human Incidence of proteinuria: Overall incidence of
occup Brazing (33-41) M proteinuria was 21% in exposed group, and ave
fumes exposure of cohort was 780 /ig/m3 x year.
Mean cumulative exposure of workers with
normal and abnormal renal function was 459
and 1,137 /ng/m3 x year, respectively.
10.4 yr Cd NS Human Urinary Cd, transferrin, albumin, B-2m, retinol
avg form not (58) M binding protein, and other proteins: Elevated
occup stated ave urinary levels of transferrin, albumin an 8-
2m, compared to controls. Prevalence of inc
levels sig only for transferrin and albumin,
HMW proteins.
Cd: 6.23 /xg/g creatinine (range, 0.87-165).
5-24 yr NS NS "respirable Human Pulmonary function, kidney function:
avg 14 yr solder cadmium" (31-57) B Proteinuria found in 42% of the entire exposed
occup fumes (2) F cohort several years after exposure ceased, and
inc with duration of exposure. No effect on
pulmonary function (FVC, FEVj, etc.) in any
group of workers exposed to cadmium-
containing solders for 5-24 years. Control for
smoking and renal damage did not change lack
of effect. Main body of information in Elinder
et al. (1985a,b). Exposed group was divided
into high, medium, and low, and ave exposure
estimated for each group.
Reference
Falck et al. (1983)
Bernard et al. (1990)
Edling et al. (1986)
n
-------
2.
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm
Cd/m3
Exposure Chemical
protocol form
Particle size and
distribution
Species,
Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
N/A
0
36-600
N/A
0,
"low",
>200
N/A
30
40
90
>1 yr
occup
"Cd fume"
Cu-Cd
alloy
manufctr
NS
> 6 yr Cd fume,
median: Cd sulfate
26.4 yr aerosol
(low), 27.1
yr (high)
occup
1-11 yr CdO
ave 5, 8 yr dust
occup
NS
NS
Human Pulmonary function (FEVj, FVC, TLCO), x- Davison et al. (1988)
(101) M ray, liver cadmium (NAA analysis): Exposed
workers had sig lower FEV1; FVC, TLCO
compared to referents; the effect was related to
cum exposure and to liver cadmium. Reduction
in FEVj was seen at cum exposure as low as
<400 /ig/m3 x yr and at liver Cd < 12.5 ppm;
no statistical test of these groups alone was
conducted.
Note: Exposure levels est based on area and
breathing zone measures.
Human Pulmonary function, urinary Cd: Workers with Smith et al. (1976)
(12-17) M high exposure had dec FVC compared with low
exposure workers and controls. No effect on
FEVj. Chest x-rays showed interstitial fibrosis
in 29% of exposed workers. Dec FVC was
inversely correlated with urinary Cd, and with
months of work in Cd fume, but not Cd sulfate
areas. Avg urinary Cd was 13.1 /*g/L in "low"
group and 45.7 j*g/L in >0.2 group.
Human Recovery of lung function after reduction or Chan et al. (1988)
(8) M, cessation of exposure in cadmium battery
(36) F workers, medical history: Total lung capacity
inc after reduction of exposure. After cessation
of exposure, vital capacity, FEV, prevalence of
respiratory symptoms improved.
Two subcohorts: reduced exposure and no
longer exposed
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
3.
t— *
t— k
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i— '
O
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6
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O
Exposure
Concentration
Exposure Chemical Particle size and
ppm ng Cd/m3 protocol form distribution
N/A 1-356 (total 4.4 yr ave CdO NS
dust), max (F) dust and
resp dust= 7.5 yr ave fume
650 (I)
27.5 yr
(II)
N/A 50-350 >20yr CdO NS
ave 32 yr dust and
fume
N/A NS 14.5 yr Cd fume NS
ave
occup
Species,
Strain,
(Number) Sex
Human
(90) M
(grp I)
(25) M
(grp ID
(26) F
Human
(18) NS
Human
(31) M
Assays performed: Effect(s) Reference
Pulmonary function (FVC, MEFR, PEFR); Lauwerys et al.
chest x-ray, urinary Cd, B-2m: F workers (1979)
exposed only in one area, to 10 (total
[apparently Cd] dust), 4 (respirable dust). No
effect on lung or kidney function in this group.
Group I (M), exposed <20 yr, had slight
(-6%), stat. sig dec in FVC, FEV^ PEFR, but
no sig effect on urinary proteins. Group II (M),
exposed > 20 yr, had inc frequency of cough,
mod (9-12%) dec in FVC, FEV^ PEFR,
proteinuria (inc HMW protein and/or LMW
protein), dec hematocrit.
Chest x-ray, pulmonary function, urinary Lauwerys et al.
protein: Grade I dyspnea more frequent in (1979)
exposed group. Slight, but nonsig dec in
spirometric indices (FEV^ PEFR, VC, etc.).
Proteinuria in 7/18 workers, suggesting kidney
is more sensitive than lung.
Urinary Cd, IQ, attention, psychomotor speed, Hart et al. (1989b)
vigilance, memory, conceptual reasoning, mood:
High urinary Cd cohort performed less well
than low urinary Cd group on measures of
attention, psychomotor speed, memory
Note: Historical level of =300 /ag/m3 reported
in one measure.
O
h—(
3
-------
> TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND
^ Exposure
t^ Concentration
J£j Exposure Chemical Particle size and
ppm /ig Cd/m3 protocol form distribution
N/A mean 808 > 1 yr CdO NS
/ig/m3 x fume
yr
Species,
Strain,
(Number) Sex Assays performed: Effect(s)
Human Serum testosterone, LH, FSH; urinary Cd: No
(101) M effect on testicular endocrine effects. RBP,
creatinine in urine correlated with cumulative
exposure index. Reproductive function was not
assessed.
COMPOUNDS
Reference
Mason (1990)
N/A
N/A
7,000-
1,500,000
dep on area
20,000-
1,000,000
>6 mo
CdO dust NS
yr
CdO dust NS
Elinder et al. (1985c)
Human Mortality, cohort study: Sig inc cancer of the Thun et al. (1985)
(590) M respiratory system (lung, trachea, bronchus)
(SMR == 165) and nonmalignant gatrointestinal
disease (not correlated with exp) (SMR = 383).
Lung cancer mortality sig inc with cum exp.
Note: Some workers also exposed to arsenic.
Human Mortality, cohort study: Inc deaths due to
(522) M nephritis and nephrosis, related to exposure
duration (SMR=300). SMR for lung cancer =
133 (not sig), SMR for prostate cancer = 108.
SMR inc with latency period. Based on
combining data from 6 populations, SMR for
lung cancer = 1.21, p = 0.008, prostate cancer
SMR=162, p=0.02.
Note: Exposure levels were lower at later
measurement periods; coexposure to nickel.
-------
TABLE 11-26 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm
N/A
exposure
/xg Cd/m3 protocol
NS <2->15
yr occup
Chemical Particle size and
form distribution
CdO NS
(cadmium
hydroxide
dust)
Species,
Strain,
(Number) Sex
Human
(2559) M,
(466) F
Assays performed: Effect(s)
Mortality lung cancer deaths: Trend in lung
cancer deaths approached significance among
early workers, but only because of sig excess at
high exposure. Among later workers, no trend
was found.
Reference
Sorahan (1987)
Note: No control for smoking.
Tj
H
6
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2
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H
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cj
S
w
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Abbreviations:
avg = average; AAP = alanine aminopeptidase (brush border enzyme); ALKP = alkaline phosphatase; AM = alveolar macrophages; AP = acid phosphatase;
B = both male and female; B-2m = 6-2-microglobulin; 8-2m-uria = B-2-microglobulinuria; BAL = bronchoalveolar lavage; Cd = cadmium; CdCl2 = cadmium
chloride; CdO = cadmium oxide; CdS = cadmium sulfide; CdSO4 = cadmium sulfate; cum = cumulative; d = day; dec = decreased; dep = depending; EM
= electron microscopy; exp = exposure; est = estimated; FEVj = forced expiratory flow in 1 second; FSH = follicle stimulating hormone; FVC = forced vital
capacity; GFR = glomerular filtration rate; geom = geometric; GFR = glomerular filtration rate; GOT = gamma glutamyltranspeptidase; HMW = high
molecular weight; hr = hour; HP = histopathology; inc = increased; LDH = lactate dehydrogenase; LH = luteinizing hormone; LMW = low molecular weight;
MEFR = maximal expiratory flow rate; MMAD = mass median aerodynamic diameter; mo = month; N/A = not applicable; NAA = neutron activation analysis;
NAG = N-acetyl-D-glucosaminidase; NS = not specified; occup = occupational; PEFR = peak expiratory flow rate; PMN = polymorphonuclear cells; ; ppm
= parts per million; ; RBC = red blood cell; RBP = retinol binding protein; sig = significant(ly); SRBC = sheep red blood cells; TWA = time weighted
average; TWE = cumulative exposure index; TLCO = carbon monoxide transfer factor; UK = unknown, document in retrieval; VC = vital capacity; VMD
= volume median diameter; wk = week; wt = weight; yr = years.
-------
1 Signs of renal damage have been observed in several studies of workers occupationally
2 exposed to cadmium (Chia et al., 1989; Blinder et al., 1985a, 1985b; Falck et al., 1983;
3 Kjellstrom et al., 1977; Mason et al., 1988; Smith et al., 1980; Thun et al., 1989). The
4 proteinuria caused by cadmium exposure is characterized by the presence in urine of a
5 number of low-molecular-weight proteins, including 62-microglobulin, lysozyme, and retinol
6 binding protein. These low-molecular-weight proteins are all readily filtered by the
7 glomerulus and are normally reabsorbed in the proximal tubule of the kidney. Therefore,
8 elevated urinary excretion of these proteins is symptomatic of proximal tubular damage.
9 Urinary excretion of high-molecular-weight proteins such as albumin also occurs in
10 occupationally exposed workers (Bernard et al., 1990; Blinder et al., 1985b; Mason et al.,
11 1988; Thun et al., 1989), but there is some debate as to whether this represents glomerular
12 damage (Bernard et al., 1990) or severe tubular damage (Blinder et al., 1985a; Mason et al.,
13 1988). The tubular proteinuria caused by cadmium exposure may be accompanied by
14 depressed tubular resorption of other solutes such as enzymes, amino acids, glucose,
15 calcium, copper, and inorganic phosphate (Blinder et al., 1985a,b; Falck et al., 1983; Mason
16 et al., 1988). The urinary concentrations of some of these compounds, particularly renal
17 enzymes, has been suggested to be more sensitive than low-molecular-weight proteins for
18 detecting tubular dysfunction in exposed humans. An additional renal effect seen in workers
19 after high levels of cadmium inhalation exposure is increased frequency of kidney stone
20 formation (Blinder et al., 1985a; Falck et al., 1983; Thun et al., 1989); likely secondary to
21 disruption of calcium metabolism due to kidney damage.
22 Tubular dysfunction generally develops only after cadmium reaches a minimum
23 threshold level or "critical concentration" in the renal cortex. The critical concentration of
24 cadmium in renal cortex associated with increased incidence of renal dysfunction in an adult
25 human population chronically exposed to cadmium has been estimated to be about 200 jig/g
26 wet weight by several investigators (Ellis et al., 1985; Roels et al., 1983).
27 Several quantitative evaluations of kidney toxicity have been performed using
28 cumulative dose (exposure duration times cadmium concentration) as the independent
29 variable. An early study found a, 19% prevalence of proteinuria after 6 to 12 year exposure
30 to 50 /ig/m3 (Kjellstrom et al., 1977), but a subsequent follow-up study found only a 4%
31 prevalence at about this level of exposure (Jarup et al., 1988). The definition of proteinuria
April 1995 11-204 DRAFT-DO NOT QUOTE OR CITE
-------
1 used in these studies is an excretion exceeding 95th percentile of a normal population. Thus
2 a prevalence of 5% or less can be considered unrelated to cadmium exposure. Among the
3 workers in the follow-up study, the prevalence of proteinuria was 9% at an average
4 cumulative exposure of 691 year x /ig/m3 (Jarup et al., 1988). Other recent analyses found
5 thresholds for proteinuria at 820 jig/m3 X year (Thun et al., 1989) or «1 mg/m3 x year
6 (Blinder et al., 1985b; Mason et al., 1988). In another cohort, with an average 30-year
7 exposure of 26 fig/m3, the average exposures of workers with and without proteinuria were
8 459 and 1,137 ^g/m3 x year, respectively (Falck et al., 1983).
9 Cessation of cadmium exposure generally does not lead to any decrease in proteinuria
10 in occupationally-exposed workers (Blinder et al., 1985b; Mason et al., 1988; Thun et al.,
11 1989), possibly because kidney cadmium levels decline very slowly postexposure. In fact,
12 recent evidence shows that kidney damage may be induced after exposure ceases. Blinder
13 et al. (1985b) observed the development of proteinuria in workers after exposure cessation.
14 The respiratory tract is also a major target of cadmium, with intense irritation resulting
15 from acute high-level exposure; lower-level chronic exposure produces dyspnea and
16 decreased lung function. Data on effects of acute inhalation exposure to cadmium are very
17 limited. However, based on secondary sources, World Health Organization (1987) reported
18 that chemical pneumonitis is expected at cadmium fume concentrations above 1,000 ^g/m3.
19 High levels of cadmium oxide fumes or dust are intensely irritating to respiratory tissue,
20 producing severe tracheobronchitis, pneumonitis, and pulmonary edema within several hours
21 (Beton et al., 1966). Repeated exposure within one to two days does not cause recurrent
22 symptoms; however, if the repeated exposure occurs several days later, symptoms may
23 reoccur (Barnhart and Rosenstock, 1984).
24 Emphysema and dyspnea are the major symptoms of chronic cadmium exposure
25 (Friberg, 1950). However, this study included no control for cigarette smoking. Some
26 recent studies that controlled for smoking have found that cadmium-exposed workers had
27 evidence of lung impairment in pulmonary function tests (Chan et al., 1988; Davison et al.,
28 1988; Smith et al., 1976), but similar studies have found no impairment (Edling et al.,
29 1986). One possible reason for the conflicting results is that lung injury caused by high-level
30 cadmium exposure may be partially reversible (Chan et al., 1988), so that several years after
31 exposures have been significantly reduced, lung function may be close to normal.
April 1995 H_205 DRAFT-DO NOT QUOTE OR CITE
-------
1 Although neurotoxicity is not generally associated with cadmium inhalation exposure,
2 few studies have specifically assessed neurological effects. A recent study found decreased
3 performance on measures of attention, psychomotor speed, and memory in a cohort with
4 high urinary cadmium, compared to a group with lower cadmium exposure (Hart et al.,
5 1989b).
6 The relationship between occupational exposure to cadmium and increased risk of
7 cancer (particularly lung and prostate cancer) has been explored in a number of
8 epidemiologic studies. The data are conflicting, and confounding factors such as exposure to
9 other metal carcinogens and smoking may explain observed increases in cancer rates.
10 Overall, the results provide weak evidence of an increased risk of lung cancer in humans
11 following prolonged inhalation exposure to cadmium.
12 Recent analyses of English and Swedish cohorts have found some increases in lung
13 cancer at levels >300 jtg/m3, but no clear relationship between lower levels and duration of
14 cadmium exposure and increased risk of lung cancer (Blinder et al.,, 1985c; Sorahan, 1987).
15 In an American cohort, a statistically significant 2.8-fold excess risk of lung cancer was
16 found in the highest exposure group (cumulative exposures greater than 8,000 jug/m3 x
17 years) and an exposure-related trend was observed (Thun et al., 1985). In the Swedish
18 study, some workers were also exposed to nickel, a known human lung carcinogen (Blinder
19 et al., 1985c). Smoking was not corrected for in the analysis of any cohort. A small excess
20 of prostate cancer has also been observed in studies of men occupationally exposed to
21 cadmium, but appears to be limited to groups with very high cadmium exposures (Blinder
22 etal., 1985c).
23
24 Laboratory Animal Data
25 Laboratory animal toxicity data are summarized in Table 11-27. Data from an early
26 animal study confirm that renal damage occurs following inhalation exposure to cadmium.
27 Rabbits developed proteinuria after 4 mo of inhalation exposure, and histologic lesions were
28 found after an additional 3 to 4 mo of exposure (Friberg, 1950). Subsequent studies that
29 assessed urinary protein levels found no effect, presumably because the exposure levels and
30 durations of follow-up prior to sacrifice were insufficient to produce a critical concentration
31 in the kidney (Glaser et al., 1986; Prigge, 1978a).
April 1995 11-206 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 11-27. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
p— »
h- »
1
3
o
>>
rfl
b
0
1
0
cj
O
w
0
n
Exposure
Concentration
Exposure Chemical
ppm fig Cd/m3 protocol form
Acute Studies
N/A 0 2hr CdCl2
250 aerosol
450
4,500
N/A 0 2hr CdO
250 aerosol
450
4,500
N/A 0 2hr CdCl2
250 aerosol
450
4,500
Particle size and
distribution
250:
MMAD=0.50,
ffg=2.07
480:
MMAD=0.63,
(jg=2.00
4,500:
MMAD=0.56,
ag=2.39
250:
MMAD = 1.28,
(jg=1.47
450:
MMAD = 1.33,
ffg=1.45
4,450:
MMAD = 1.56,
ag = 1.54
250
MMAD=0.50,
ffg=2.07
450:
MMAD=0.63,
ag=2.00
4,500:
MMAD=0.56,
ffg=2.39
Species,
Strain,
(Number) Sex
Rat, Crl:CD
(SD)BR
(16-20) M
Rat, Crl:CD
(SD)BR
(16-20) M
Rabbit, DLA:
(NZW)
(2-4) M
Assays performed: Effect(s)
HP of lung: At 4,500 /tg/m3, no lesions at 0 hr
post-exposure, but at 72 hr, pneumonitis
characterized by proliferation of Type II
epithelial cells, hemorrhage, edema, and inc
macrophage populations. Pneumonitis more
severe following CdO than CdCl2 exposure.
HP of lung: At 4,500 /*g/m3, no lesions at 0 hr
post-exposure, but at 72 hr, pneumonitis
characterized by proliferation of Type II
epithelial cells, hemorrhage, edema, and inc
macrophage populations. Pneumonitis more
severe following CdO than CdCl2 exposure.
HP of lung: At 4,500 /ig/m3, moderate
thickening of alveolar wall at 0 hr and mild
multifocal pneumonitis at 72 hr post-exposure.
Reference
Grose et al. (1987)
Grose et al. (1987)
Grose et al. (1987)
-------
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00
O
O
25
O
H
O
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i—i
3
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm
Cd/m3
Exposure Chemical
protocol form
Particle size and
distribution
Species,
Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
N/A
0 2hr
250
450
4,500
CdO
aerosol
250:
MMAD=0.50,
-------
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
1
»— '
£
8
o
>
6
o
1
o
a
0
3
Exposure
Concentration
ppm jig Cd/m3
N/A 0
10,000
N/A 0
1,100
10,100
N/A 0
88,000
N/A 0
110
190
Species,
~ Exposure Chemical Particle size and Strain,
protocol form distribution (Number) Sex
1 hr/d CdCl2 "mean diameter = Rat, UK
5-15 d form UK 3.5 jim" (8) M
ffgUK
30 min CdCl2 MMAD = 1.7 /xm Hamster,
aerosol ag = 1.7 Syrian
(8)NS
1 hr CdCl2 MMAD = 0.7 /im Mouse,
aerosol ag - 3.43 C57B1/6
(10) F
2hr CdCl2 > 99% of particles Mouse, CD-I
aerosol <3 /im (17) F
Assays performed: Effect(s) Reference
HP of lung: Acute vascular congestion, Snider et al. (1973)
alveolar hemorrhage, and PMN cell
proliferation. Granulation tissue response
resulted in fine scar tissue resembling human
centrilobular emphysema.
HP of lung, BAL fluid analysis: Inflammation Henderson et al.
(BAL showed inc nucleated cell number and AP (1979)
at both levels, ALKP activity at high level) at 2
hr to 3 wk post-exposure. HP (done only at
high level) showed nothing immediately, but
necrosis of bronchiolar epithelium at 1 d after
exposure. Also lymphatic infiltration of
bronchiolar walls) but no effect on alveoli.
Immune response: At 5-18 d post-exposure, dec Krzystyniak et al.
primary IgM response. Dec spleen cell (1987)
viability.
Immune response to SRBC injected 2 hr post Graham et al. (1978)
exposure: Dec IgM level in spleen cells at 4 d
post-exposure.
-------
> TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
g: CADMIUM AND COMPOUNDS
vo Exposure
S Concentration Species,
ppm /ig Cd/m3 protocol form distribution (Number) Sex
Assays performed: Effect(s) Reference
Subchronic and Chronic Studies
N/A 0 6hr/d CdCl2 300: VMD=0.66, Rat, F344
300 5d/wk aerosol ag = 1.10; (8) M, (8) F
1,000 62 d 1,000 and 2,000:
2,000 VMD=0.73,
1,600 5 d/wk aerosol diameter determined (15) M
0 1-6 wk by EM was 1.76
/im
particle size
O variability averaged
!* 7-10%
6
O
0
H
O
a
0
H
M
0
Organ wt, HP of lung, reproductive fitness Kutzman et al. (1986)
(exposed rats mated with unexposed rats 6 d
after last exposure): Hyperplasia of terminal
bronchioles, cell flattening, inflammation and
proliferation of fibroblasts at >300 /ig/m3. At
1,000 /ig/m3, also lymphoid hyperplasia,
microgranulomas, inc lung wt due to inc elastin
and collagen. All animals died at 2,000 /ig/m3.
No effect on viable embryos, late deaths,
resorptions, corpora lutea, preimplantation loss.
BAL, HP of lung: Lung damage indicated by Hart (1986)
cytologic and biochemical alterations in BAL
fluid (e.g., inc ALKP, AP, LDH, protein,
PMNs). Aggregates of PMNs in interstitium,
thickening of alveolar septa at 2 wks of
exposure. Effects peaked at 2 wks of exposure,
then decreased.
O
I—I
H
W
-------
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
1— »
£
Ul
£
to
>— k
O
J>
T1
o
o
H
O
H
m
0
Exposure
Concentration
ppm /xg Cd/m3
N/A 0
1,600
N/A 0
100
N/A 0
100
N/A 0
1,000
Exposure Chemical
protocol form
3 hr/d CdO
5 d/wk aerosol
4 wk
22 hr/d CdCl2
7 d/wk aerosol
30 d
22 hr/d CdO
7 d/wk aerosol
30 d
22 hr/d CdS
7 d/wk aerosol
30 d
Particle size and
distribution
Aerodynamic
diameter
determined by EM
was 1.76 ±0.04
/xm
MMAD = 0.29 jon
ag = 1.56
MMAD = 0.24 /on
<7g = 1.44
MMAD = 0.21 ^m
ag = 1.48
Species,
Strain,
(Number) Sex
Rat, Lewis
(20) M
Rat, Wistar
(6)M
Rat, Wistar
(6)M
Rat, Wistar
(6)M
Assays performed: Effect(s)
BAL analysis, HP of lung: Lung damage
indicated by cytologic and biochemical
alterations in BAL (e.g., inc Type 2
pneumocytes, lymphocytes, PMNs, nonprotein
sulfhydryl, inc ALKP, AP, LDH). No effect of
1,600 jig/m3 alone on HP, but pre-exposure dec
effects (diffuse alveolitis, edema) of challenge
with 8,400 /tg/m3. Hypothesized adaptive
synthesis of metallothionein. BAL changes in
challenged animals were lower in those that had
been pretreated. Note: measured effects after
single 3-hr challenge with to 8,400 /tg/m3.
BAL analysis, RBC count, serum alanine
aminotransferase levels, urinary protein: Inc
number and size of macrophages, returning to
normal 2 mo post-exposure. No effect on other
parameters.
BAL analysis, RBC count, serum alanine
aminotransferase levels, urinary protein: Inc
number and size of macrophages, returning to
normal 2 mo post-exposure. Inc serum alanine
aminotransferase. No effect on other
parameters.
BAL fluid analysis, RBC count, serum alanine
aminotransferase levels, urinary protein: Inc
number and size of macrophages, returning to
normal 2 mo post-exposure. No effect on other
parameters.
Reference
Hart et al. (1989a)
Glaser et al. (1986)
Glaser et al. (1986)
Glaser et al. (1986)
O
HH
3
-------
3.
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
1— '
Ul
H-
to
1— '
N)
O
g
(^
H
O
O
O
H
O
O
H
W
Exposure
Concentration
ppm /*g Cd/m3
N/A 0
25
50
100
N/A 0
4,100
5,700
N/A 0
400
Exposure Chemical Particle size and
protocol form distribution
23.5 hr/d CdCl2 Median
63-90 d aerosol aerodynamic
100 /xg/m3 diameter = 0.19
exposure jam
for 63d (rg = 1.5
3 hr/d Mostly =95% of particles
21-23 d/mo CdO dust <5 /tm, =55%
7-9 mo < 1 /tm
6 hr/d CdCl2 MMAD 0.5-1 /tm
5 d/wk aerosol
4-6 wk
Species,
Strain,
(Number) Sex Assays performed: Effect(s)
Rat, Wistar HP of lungs, liver, kidney; urinalysis,
(12) F hematology: Bronchiolar proliferation,
emphysematic areas, xanthoma cell areas,
histiocytic cell granulomas at all levels. Inc
hemoglobin and hematocrit at >50 /tg/m3. No
liver or kidney lesions or proteinuria Kidney
cadmium = 32.88 ppm wet wt at 100 /tg/m3.
Rabbit, UK HP of lung, kidney; urinalysis, hematology
(8-9) M, (4,100 /tg/m3 only): Concentration-related
(4) F incidence and severity of bronchitis, fibrosis,
edema, and emphysematous changes. Slight
anemia and eosinophilia at 4,100 /tg/m3.
Significant proteinuria after 4 mo exposure, with
histologic renal lesions (isolated foci, interstitial
infiltrates) at 7-9 mo. Note: Dust also
contained =20% iron and small amounts of Si
and Ni.
Rabbit, NS HP of lung: Inc lung wt, interstitial infiltration
(8) M of PMNs and lymphocytes, intra-alveolar
accumulation of large, vacuolated macrophages,
inc phospholipid content.
Reference
Prigge (1978a)
Friberg (1950)
Johansson et al.
(1984)
n
-------
> TABLE 11-27 (cont'd).
2.
vo Exposure
L» Concentration
ppm fig Cd/m3 protocol form
N/A 0 5 hr/d CdO
20 5 d/wk aerosol
160 5-6.5 mo
LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
Particle size and
distribution
MMAD <0.65 iim
99.2% of total
aerosol mass had
particle size <4.7
/un
Species,
Strain,
(Number) Sex Assays performed: Effect(s)
Rat, Wistar Behavioral tests of pups (forepaw muscle
(7-15) F strength, exploratory activity, conditioned
learning); pup viability: No effect on no.
pups/litter, but pup viability dec at 20 jtg/m3.
Dec exploratory activity in both sexes at
Reference
Baranski (1984)
H- N/A
0
20
160
1,000
5 hr/d CdO Fraction <5 ftm
5 d/wk aerosol was 98.3-99.4% of
4-5 mo total dust mass
160 /ig/m3, and in males at 20 /tg/m3.
Conditioned learning dec in females at
160 jig/m3 at 3 and 7 mo. Dec ambulation in
open field hi males at 160 /*g/m3.
Note: Dams exposed for 5 mo prior to mating,
during mating, and during gestation.
Rat, Wistar Developmental toxicity, including neurotoxiciry; Baranski (1985)
(5-16) F maternal toxicity: No effects on reproductive:
Delayed ossification at all levels. Dec
locomotor activity and conditioned reflex at up
to 4 mo of age at all levels. No effect on
reproductive success at <160 /tg/m3. At
1,000 /ig/m3, sig fewer pregnancies and inc
mortality. Note: Dams exposed for 4-5 mo
prior to mating, during mating and during
gestation
-------
3.
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
1— k
s
I— '
t— '
1
>— »
*.
0
^
3
^n
i
o
o
o
H
£
c
0
H
W
O
Exposure
Concentration
ppm ng Cd/m3
N/A 0
20
160
1,000
N/A 0
200
400
600
N/A 0
13.4
25.7
50.8
Exposure Chemical Particle size and
protocol form distribution
5 hr/d CdO Fraction <4.7 /un
5 d/wk aerosol was 98.3-99.4% of
20 wk total aerosol mass
24 hr/d CdCl2 Median
21 d aerosol aerodynamic
diameter = 0.6 /tm
ag = 1.6
23 hr/d CdCl2 MMAD = 0.55 fim
7 d/wk aerosol
-------
3.
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
vo Exposure
<~n Concentration
ppm
N/A
N/A
N/A
£
to
h- k
Lh
2 N/A
>
H
1
o
O
•2,
9
O
a
o
^g Cd/m3
0
30
90
0
90
0
90
270
810
2,430
0
30
90
— T-l ^"11_ * 1
Exposure Chemical
protocol form
22 hr/d CdCl2
7 d/wk aerosol
18 mo
(0.03)
or 6 mo
(0.09)
22 hr/d CdSO4
7 d/wk aerosol
18 mo
22 hr/d CdS
7 d/wk aerosol
18 mo
22 hr/d CdO
7 d/wk dust
18 mo
T» j,t* 1 " J
Particle size and
distribution
avg MMD of
0.2-0.5 /*m
°gNS
avg MMD of
0.2-0.5 j«m
°gNS
avg MMD of
0.2-0.5 ftm
agNS
avg MMD of
0.2-0.5 urn
agNS
Species,
f\. "
Strain,
(Number) Sex
Rat, Wistar
(20) M,
(20) F
Rat, Wistar
(20) M,
(20) F
Rat, Wistar
(20) M,
(20) F
Rat, Wistar
(20) M,
(20) F
Assays performed: Effect(s)
HP of lung: Lung tumors (bronchioalveolar
adenoma, adenocarcinoma, squamous cell
tumors) at >0.03 in both sexes. Note:
Exposure for only 6 mo at 90 /*g/m3 due to
toxicity. Animals observed for 12 (30 ftg/m3)
or 18 (90 /ig/m3) mo post-exposure.
HP of lung: Lung tumors (bronchioalveolar
adenoma, adenocarcinoma, squamous cell
tumors) in both sexes. Note: Animals observed
for 12 mo post-exposure
HP of lung: Lung tumors (bronchioalveolar
adenoma, adenocarcinoma, squamous cell
tumors) at 90 jig/m3 in both sexes and at 270,
810, and 2,430 for shorter durations (3-16 mo).
Note: Total exposure + post-exposure
observation time 27-30 mo.
HP of lung: Lung tumors (bronchioalveolar ,
adenoma, adenocarcinoma, squamous cell
tumors) at both levels in both sexes. Similar
tumors were also observed in animals exposed
40 hr/wk for 6 mo. Co-exposure to ZnO dust.
Note: In main exp, exp to 90 /ig/m3 for
7-11 mo. Exposure + post-observation time 31
mo.
Reference
Oldiges et al. (1989)
Oldiges et al. (1989)
Oldiges et al. (1989)
Oldiges et al. (1989)
O
HH
H
W
-------
3.
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
VO
Ul
H- »
1
Ni
o\
O
>
H
o
O
^
O
H
O
|
w
O
0
H
m
Exposure
Concentration
ppm /ig Cd/m3
N/A 0
10
30
N/A 0
30
90
N/A 0
30
90
N/A 0
90
270
1,000
N/A 0
10
30
90
Exposure
protocol
22 hr/d
7d/wk
18 mo
8 or, 19
hr/d
5d/wk
42-69 wk
8 or, 19
hr/d
5d/wk
95-96 wk
8 or, 19
hr/d
5d/wk
41-64 wk
8 or, 19
hr/d
5d/wk
98-105 wk
4"1 1* n. w* * n n 1
Chemical
form
CdO
fume
CdCl2
aerosol
CdSO4
aerosol
CdS
aerosol
CdO
fume
Species,
Particle size and Strain,
distribution (Number) Sex
"primary CdO Rat, Wistar
particles in the size (20) M,
range of 10 nm" (20) F
NS Mouse, Han:
NMRI
(82-89) F
NS Mouse, Han:
NMRI
(95-96) F
NS Mouse, Han:
NMRI
(71-101) F
NS Mouse, Han:
NMRI
(93-105) F
Assays performed: Effect(s)
HP of lung: Lung tumors (bronchioalveolar
adenoma, adenocarcinoma) at 30, but not at
10 /tg/m3 in both sexes. Note: Exposure +
post-exposure observation time 31 mo.
HP of lung: Inc incidence of alveolar
lipoproteinosis, interstitial fibrosis,
bronchoalveolar hyperplasia. No effect on lung
tumors, or on probability of dying with a lung
tumor in life table analysis to correct for shorter
lifespan of exposed animals.
HP of lung: Inc incidence of alveolar
lipoproteinosis, interstitial fibrosis,
bronchoalveolar hyperplasia. No effect on lung
tumors, or on probability of dying with a lung
tumor in life table analysis to correct for shorter
lifespan of exposed animals.
HP of lung: Inc incidence of alveolar
lipoproteinosis, interstitial fibrosis,
bronchoalveolar hyperplasia. No sig effect on
lung tumors. However, life table analysis to
correct for shorter lifespan of exposed animals
found inc probability of dying with a lung tumor
at 90 ftg/m3.
HP of lung: Inc incidence of alveolar
lipoproteinosis, interstitial fibrosis,
bronchoalveolar hyperplasia. Sig inc incidence
of lung tumors.
Reference
Oldiges et al. (1989)
Heinrich et al. (1989)
Heinrich et al. (1989)
Heinrich et al. (1989)
Heinrich et al. (1989)
-------
L/l
•fl
?
O
O
Z
s
O
I
w
O
90
O
HH
H
W
TABLE 11-27 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
CADMIUM AND COMPOUNDS
Exposure
Concentration
ppm
N/A
Hg Cd/m3
0
10
30
90
270
Exposure Chemical Particle size and
protocol form distribution
8 or, 19 CdO NS
hr/d dust
5d/wk
34-64 wk
Species,
Strain,
(Number) Sex
Mouse, Han:
NMRI
(86-107) F
Assays performed: Effect(s)
HP of lung: Inc incidence of alveolar
lipoproteinosis, interstitial fibrosis,
bronchoalveolar hyperplasia. Sig inc incidence
of lung tumors. Inc probability of dying with a
lung tumor in life table analysis.
Reference
Heinrich et al. (1989)
Abbreviations:
avg = average; AAP = alanine aminopeptidase (brush border enzyme); ALKP = alkaline phosphatase; AM = alveolar macrophages; AP = acid phosphatase;
B = both male and female; B-2m = B-2-microglobulin; 6-2m-uria = 6-2-microglobulinuria; BAL = bronchoalveolar lavage; Cd = cadmium; CdCl2 = cadmium
chloride; CdO = cadmium oxide; CdS = cadmium sulfide; CdSO4 = cadmium sulfate; cum = cumulative; d = day; dec = decreased; dep = depending; EM
= electron microscopy; exp = exposure; est = estimated; FEVj = forced expiratory flow in 1 second; FSH = follicle stimulating hormone; FVC = forced vital
capacity; GFR = glomerular filtration rate; geom = geometric; GFR = glomerular filtration rate; GOT = gamma glutamyltranspeptidase; HMW = high
molecular weight; hr = hour; HP = histopathology; inc = increased; LDH = lactate dehydrogenase; LH = luteinizing hormone; LMW = low molecular weight;
MEFR = maximal expiratory flow rate; MMAD = mass median aerodynamic diameter; mo = month; MMD = mass median diameter; N/A = not applicable;
NAA = neutron activation analysis; NAG = N-acetyl-D-glucosaminidase; NS = not specified; occup = occupational; PEFR = peak expiratory flow rate; PMN
= polymorphonuclear cells; ; ppm = parts per million; ; RBC = red blood cell; RBP = retinol binding protein; sig = significantly); SRBC = sheep red blood
cells; TWA = time weighted average; TWE = cumulative exposure index; TLCO = carbon monoxide transfer factor; UK = unknown, document in retrieval;
VC = vital capacity; VMD = volume median diameter; wk = week; wt = weight; yr = years.
-------
1 Other studies in animals confirm that inhalation exposure to cadmium leads to
2 respiratory injury. Acute exposure to cadmium oxide or cadmium chloride causes increased
3 lung weight, inhibition of macrophages, cytoplasmic swelling and edema of type I cells, and
4 eventually, replacement by type II cells (Boudreau et al., 1989; Buckley and Bassett, 1987;
5 Bus et al., 1978; Grose et al., 1987; Henderson et al., 1979; Palmer et al., 1989).
6 Intermediate-duration exposure causes similar respiratory toxicity (Glaser et al., 1986;
7 Johansson et al., 1984; Kutzman et al., 1986; Prigge, 1978a). However, some tolerance to
8 cadmium appears to develop, with lung lesions that develop after a few weeks of exposure
9 not progressing or even reversing after longer exposure (Hart, 1986; Hart et al., 1989a).
10 Multiple mechanisms appear to be responsible for this tolerance, including the synthesis of
11 lung metallothionein and an increase in type II cells (Hart et al., 1989a). Chronic inhalation
12 exposure to several forms of cadmium aerosols causes bronchioalveolar hyperplasia,
13 proliferation of connective tissue, and interstitial fibrosis in rats (Takenaka et al., 1983).
14 Two studies found that inhalation exposure to cadmium can suppress the primary
15 humoral immune response of mice, and cadmium can be cytotoxic to spleen cells (Graham
16 et al, 1978; Krzystyniak et al., 1987).
17 Developmental toxicity (delayed ossification, decreased locomotor activity, and
18 impaired conditioned learning) occurred in offspring of female rats exposed to cadmium
19 oxide (20 /-ig Cd/m3) for 4 to 5 mo prior to mating and during gestation (Baranski, 1984,
20 1985). Maternal weight gain and fetal weight were reduced in pregnant rats exposed to
21 cadmium chloride aerosols at concentrations of 200, 400, or 600 jug Cd/m3 during gestation
22 (Prigge, 1978b). The decrease in fetal weight was statistically significant only at 600 /xg/m3
23 (Prigge, 1978b). These studies indicate that cadmium is a developmental toxin in animals by
24 the inhalation route.
25 Decreased fertility was found in female rats exposed for 4 to 5 mo to 1,000 /ig Cd/m3;
26 however, this concentration also caused substantial maternal toxicity (Baranski, 1985). Male
27 and female rats exposed to cadmium concentrations of up to 1,000 /ng/m3 for 62 days and
28 subsequently mated with unexposed controls showed no decrement in reproductive success,
29 as measured by viable embryos and preimplantation losses (Kutzman et al., 1986).
30 Studies in rats demonstrate that chronic inhalation exposure to cadmium can cause lung
31 cancer (Oldiges et al., 1989; Takenaka et al., 1983). These studies reported primary lung
April 1995 11-218 DRAFT-DO NOT QUOTE OR CITE
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1 tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell tumors) following
2 exposure to cadmium chloride, cadmium sulfate, or cadmium sulfide aerosols, and cadmium
3 oxide dust or fumes. No lung cancers were produced in hamsters exposed under a similar
4 protocol (Heinrich et al., 1989), and only relatively weak evidence of association with lung
5 cancer was found among mice exposed to cadmium oxide dusts or cadmium oxide fumes
6 (Heinrich et al., 1989). In an abstract by Oberdorster et al. (1994) it was suggested that
7 mice may have increased resistance to cadmium-induced lung cancer compared to rats
8 because of their greater capacity for metallothionein induction. However, inflammation and
9 cell proliferation were greater in the mouse lung than in the rat lung.
10
11 11.6.6.4 Factors Affecting Susceptibility
12 No studies were located that specifically evaluated factors affecting susceptibility.
13 However, because the kidney and respiratory tract are targets of inhaled cadmium, people
14 with compromised function of these organs would be expected to be at increased risk.
15 Populations with decreased kidney function include diabetics and individuals with an age-
16 related decline in kidney function.
17 Although immune function has not been assessed in workers exposed to cadmium, two
18 studies in mice found decreased immune response following acute inhalation exposure to
19 cadmium (Graham et al., 1978; Krzystyniak et al., 1987). This suggests that people with a
20 compromised immune system may be at increased risk. Pregnant women may also have an
21 increased susceptibility, based on the finding of Prigge (1978b) that toxic effects were
22 observed in pregnant rats at lower concentrations than in nonpregnant female rats.
23 Laboratory animal studies also suggest that the developing fetus may be at increased risk
24 (Baranski, 1984, 1985).
25 Palmer et al. (1986) found that thyroidectomy results in increased injury from cadmium
26 inhalation as a result of a decreased repair response. Their observations of enhanced Type II
27 cell damage, decreased Type II cell proliferation, decreased macrophage levels, and
28 decreased antioxidant levels suggest that thyroidectomy results in reduced capacity for
29 efficient clearance of cell debris from the lungs. These results suggest that people with
30 reduced thyroid function may be more susceptible to the respiratory toxicity of cadmium.
31 These groups include the elderly and people with certain acute or chronic illnesses (such as
April 1995 11-219 DRAFT-DO NOT QUOTE OR CITE
-------
1 cirrhosis and diabetes). Major illnesses, malnutrition, glucocorticoids, and surgical trauma
2 may also affect the levels of thyroid hormones.
3 Individuals with a genetically-determined decreased metallothionein inducibility would
4 be less able to sequester cadmium, and thus would probably be more susceptible to cadmium-
5 related renal toxicity.
6
7 11.6.7 Chromium
8 11.6.7.1 Chemical and Physical Properties
9 Chromium is a metallic element and belongs to Group VI of the periodic system of
10 elements. Chromium forms compounds in oxidation states ranging from -2 to +6, of which
11 +2, +3 and +6 are the most common (Agency for Toxic Substances and Disease Registry,
12 1993; Page and Loar, 1993; U.S. Environmental Protection Agency, 1984). Chromium
13 forms both cationic and anionic salts (Hazardous Substances Data Bank [Data Base], 1995;
14 Westbrook, 1993). Divalent chromium [+2 or chromous; Cr(II)] is relatively unstable and
15 is readily oxidized to the chromium (+3) [Cr(III)] state. Trivalent chromium (+3 or
16 chromic) is the most stable oxidation state and tends to form kinetically inert hexacoordinate
17 complexes with water and other ligands. Cr (III) forms stable complexes with amino acids
18 and peptides. Hexavalent chromium [+6 or chromate; Cr(IV)], the second most stable
19 oxidation state, is rapidly reduced to Cr(III) after it penetrates biological membranes and in
20 the presence of organic matter (Agency for Toxic Substances and Disease Registry, 1993;
21 U.S. Environmental Protection Agency, 1984). The Cr(IV) oxidation state is also reduced to
22 Cr(III), since it is apparently an intermediate in the reduction of Cr(IV) to Cr (III) (Page and
23 Loar 1993). In solution, Cr(VI) exists as a complex anion.
24 Solubility in water is an important factor related to differential toxicologic effects of
25 chromium and its compounds. Elemental chromium and its Cr+3 and Cr+4 oxides (Cr2O3
26 and CrO2) are insoluble in water, as are zinc (ZnCrO4) and ferrochromate (FeCr2O4).
27 Several other chromium compounds are slightly to moderately soluble in hot water, such as
28 the Cr+6 oxide (CrO3), the trichloride (CrCl3), and potassium, sodium, calcium, and lead
29 chromates (K2Cr2O7, NaCrO4, CaCrO4, PbCrO4, respectively).
30
31
April 1995 11-220 DRAFT-DO NOT QUOTE OR CITE
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1 11.6.7.2 Pharmacokinetics
2 Hexavalent and trivalent chromium, the most common species of chromium in the
3 environment, have different patterns of absorption, distribution, metabolism, and excretion.
4 Generally, trivalent chromium [Cr(III)] is relatively non-toxic because it cannot cross
5 biological membranes. Exposure to hexavalent chromium [Cr(VI)], which is more soluble
6 and better absorbed, leads to documented toxicological and carcinogenic effects. However,
7 the ultimate carcinogen within the cell is suspected to be trivalent chromium, and possibly
8 tetravalent, pentavalent and radical chromium intermediates as well (Jones, 1990).
9 Accordingly, interaction between the kinetics and the oxidation state of chromium has
10 significant toxicological consequences.
11
12 Absorption and Distribution
13 The absorption of inhaled chromium compounds depends on several factors, including
14 the physical and chemical properties of the material (oxidation state, size, solubility, and the
15 activity of alveolar macrophages). The presence of chromium in the serum and urine of
16 workers occupationally exposed to chromium indicates that chromium can be absorbed from
17 the lungs (Foa et al., 1988; Gylseth et al., 1977; Lindberg and Vesterberg, 1983a; Minoia
18 and Cavalleri, 1988). Chromium (VI) compounds are usually much better absorbed than
19 chromium (III). There is no specific information available about the absorption of chromic
20 acid mist, a compound of particular toxicological concern.
21 Among rats exposed to aerosols of Cr (VI) as potassium dichromate or Cr (III) as
22 chromium trichloride, clearance was dependent on particle size, but Cr (VI) entered the
23 blood stream more rapidly and extensively than Cr (III) (Suzuki et al., 1984). Clearance of
24 Cr (VI) particles of 1.5 or 1.6 pm was biphasic, with half-lives of 31.5 h and 737 h. Cr
25 (VI) particles of 2 /*m followed a uniphasic clearance curve, with a half-life of 151-175 h.
26 The clearance curve for Cr (III) was uniphasic, with a half-life of 164 h. The study authors
27 calculated that the amount of Cr (VI) transferred to the blood was always at least three-fold
28 greater than the amount of Cr (III) transferred.
29 The absorption of CrCl3 [Cr(III)] and Na2CrO4 [Cr(VI)] were compared following
30 intratracheal administration to rabbits (Wiegand et al., 1984). Initially, whole blood
31 concentrations of the two compounds were similar, indicating comparable initial absorption
April 1995 11-221 DRAFT-DO NOT QUOTE OR CITE
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1 rates into the body. Subsequently, Cr(VI) was taken up more completely; at the end of the
2 experiment (4 h post-exposure), only 47% of Cr(VI) remained in the respiratory tract, while
3 85% of Cr(III) was found in the respiratory tract at that time. Further absorption of Cr(III)
4 may be forestalled by the formation of complexes within the respiratory tract.
5 Human data on chromium distribution following inhalation exposure are limited but
6 indicate that levels are highest in the lung (Gerhardsson et al., 1984). A study of Japanese
7 chrome platers and chromate refiners found that chromium levels in the hilar lymph node,
8 lung, spleen, liver, kidney, and heart were elevated compared to those of unexposed males
9 (Teraoka, 1981). In rats injected intratracheally with radiolabelled Na2Cr2O4 • 2H2O
10 [Cr(VI)], the percent of administered radioactivity in various tissues at 6 h was the
11 following: lung (42.9%), gastrointestinal tract (20.3%), residual carcass (10.4%), skin
12 (3.2%), liver (2.6%), kidney (2.3%), serum (1.8%), red blood cells (1.5%), and testis
13 (0.12%). After 40 days, the radioactivity was primarily found in the lung (12.3%) and
14 residual carcass (5.3%); all other tissues contained less then 0.75% of the administered
15 radioactivity (Weber, 1983). Following intratracheal administration to rabbits, absorption
16 into the blood was strictly compartmentalized; Cr(VI) absorbed by the blood was primarily
17 present in the erythrocytes, while Cr(III) was confined to the plasma (Wiegand et al., 1984).
18 There were no reliable data on whether inhaled chromium can cross the placenta.
19 Cr(VI) administered via the oral or injection routes can cross the placenta, while Cr(III)
20 crosses at much lower levels (Agency for Toxic Substances and Disease Registry, 1993).
21 The relevance of these findings to inhalation exposure is unclear.
22
23 Metabolism
24 Hexavalent and trivalent chromium form different complexes inside the body. The
25 metabolism of Cr(VI) includes its reduction to Cr(III) via Cr(V) and Cr(IV) species; there
26 are no known instances of biological oxidation of Cr(III). Because cellular membranes are
27 selectively permeable to Cr(VI), the locus of reduction has profound consequences for the
28 effect of chromium. Cr(VI) enters the cell and undergoes metabolic interactions, including
29 reduction, intracellularly. Cr(III), including extracellularly reduced Cr(VI), has more limited
30 metabolic interactions and toxicological consequences. The available information does not
31 describe reduction or metabolism of chromic acid.
April 1995 11-222 DRAFT-DO NOT QUOTE OR CITE
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1 Extracellular reduction of chromium has been noted primarily in the respiratory,
2 digestive, and urinary tracts. As reviewed by Jones (1990), reduction in the lungs is
3 mediated by the epithelial lining fluid, the pulmonary alveolar macrophages, the lung
4 peripheral parenchyma, and the bronchial tree. In a detailed examination of chromium
5 reduction in the epithelial lining fluid of rats that received intratracheal injections of Na2CrO4
6 [Cr(VI)], Suzuki and Fukuda (1990) found that approximately 80% of the chromium was
7 reduced in the lungs after 18 min. Ascorbic acid appeared to carry out most of the initial
8 reduction, with glutathione acting as the reducing agent after ascorbic acid levels were
9 depleted.
10 Reduction in the urinary tract is suggested by Minoia et al. (1983). In dichromate
11 workers who were mainly exposed to Cr(III) or Cr(VI) compounds, urinary chromium was
12 present only as Cr(III).
13
14 Elimination
15 Human (Foa et al., 1988; Gylseth et al., 1977; Lindberg and Vesterberg, 1983a;
16 Minoia and Cavalleri, 1988) and animal (Langard et al., 1978) data indicate that chromium is
17 eliminated in the urine, but there is little information on the rate. In addition, no studies
18 were located that assessed chromium in feces. Studies assessing urinary chromium following
19 occupational exposure were reported in the section on absorption. Elimination of chromium
20 was slow in rats exposed for 4 days to ZnCrO4 [Cr(VI)]. Chromium levels in the urine were
21 almost constant for 4 days postexposure, and then decreased, indicating that chromium bound
22 inside the erythrocyte is released slowly (Langard et al., 1978).
23
24 11.6.7.3 Health Effects
25 Human Data
26 No data were located on the effects in humans of acute inhalation exposure to
27 chromium. Longer term studies were generally limited to occupational case studies and
28 epidemiology studies. Based on these data, the respiratory tract is the primary target of
29 chromium inhalation. Renal effects have also been observed, as well as gastrointestinal
30 irritation, probably from swallowing chromium via mucociliary clearance. Exposure levels
31 reported in epidemiological studies, especially more recent ones, should be viewed with
April 1995 11-223 DRAFT-DO NOT QUOTE OR CITE
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1 caution, because levels of chromium dusts in the workplace have improved in recent years,
2 and some symptoms may have resulted from earlier, higher exposure levels. In addition,
3 nasal effects may have partially resulted from the transfer of chrome from the hands to the
4 nose by direct dermal contact. Human toxicity data are summarized in Table 11-28.
5 Workers in the chrome electroplate industry are frequently exposed to CrO3 (VI)
6 aerosols ("chromic acid mist"). The electroplating process results in the electrolysis of
7 water, and the hydrogen and oxygen produced cause the formation of a chromic acid aerosol.
8 Commonly observed upper respiratory symptoms include irritation and atrophy of nasal
9 mucosa, progressing to nasal ulceration and perforation at higher exposure levels and/or
10 durations. Other reported symptoms include epitaxis (nosebleeds) and rhinorrhea (nasal
11 discharge) (Cohen et al., 1974; Gomes, 1972; Kleinfeld and Rosso, 1965; Lucas and
12 Kramkowski, 1975; Royle, 1975). Effect levels can not be determined from these studies
13 because there was no stratification of exposure levels. No effects were observed in a group
14 of 32 chrome workers exposed to levels up to 6 /ig/m3 Cr(VI) as CrO3 (Markel and Lucas,
15 1973). Pulmonary function tests have found that chromium also can cause obstructive lung
16 disease. Respiratory effects of chromium are probably due to the direct action of chromium
17 at the site of contact.
18 Swedish chrome plating workers exposed to >2 /ig/m3 Cr(VI) as CrO3, had crusty,
19 atrophied nasal mucosa, but no nasal symptoms were reported in workers exposed to
20 < 1 /ig/m3. Also, slight statistically significant transient effects on forced vital capacity
21 (FVC) and forced expiratory volume in 1 second (FEVj) were observed at > 2 /ig/m3
22 (Lindberg and Hedenstierna, 1983). Emphysema and obstructive lung disease, characterized
23 by decreased FVC and FEVl5 were observed in a group of ferrochromium workers, exposed
24 to Cr(III) and Cr(VI) at total chromium levels of 20 to 190 /ig/m3 (Langard, 1980). Asthma
25 from chromium inhalation has been reported (Park et al. 1994), but the chemical form and
26 exposure levels were unknown. The pathogenic mechanism of chromium-induced asthma is
27 not known; data are conflicting regarding the existence of an IgE-mediated reaction.
28 Occupational inhalational exposure to chromium compounds has resulted in the early
29 signs of renal damage, as indicated by the presence of low molecular weight proteins in
30 urine. Franchini and Mutti (1988) reported increased levels of retinol binding protein and
31 tubular antigen in the urine of chromate and dichromate industry workers with > 15 /ig
April 1995 11-224 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-28. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM AND COMPOUNDS
K>
l/i
SB/
5
o
o
2
o
H
O
CJ
8
n
p— i
H
M
Exposure
Concentration
ppm pg Cr/m3
N/A 0
<2
(TWA)
2-20
(TWA)
peak 46
Exposure
protocol
0.2-23. 6 yr
(median
2.5) yr
occup
Chemical
form
CrO3
(VI)
mist
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s)
NS Human Respiratory symptoms, PF, changes in nasal mucosa (cluster
(NS) M,F exposure groups): Nasal mucosal atrophy and irritation in all
groups based on TWA. When classified by peak exposures,
no effects at 0.2-1.2 ftg/m3, but effects were seen in the
cohort with peak exposure at 2.5-11 /*g/m3, and in the highest
peak exposure group. Slight, transient dec. FVC, FEVj at 2-
20 |tg/m3. Severity correlated better with peak exposure
levels than with mean exposure. Subjects were divided into
"low exposure" (<2 /tg/m3, 16M, 5F), "high exposure"
(>2-20 /tg/m3, 21M, IF), and "mixed" (CrO3 and other
acids, metallic salts, 48 M, 13 F), and controls (119 M).
Reference
Lindberg and
Hedenstierna
(1983)
Note: 36 subjects were also divided into peak exposure
categories: 0.2-1.2 /*g/m3 (n=10); 2.5-11 /tg/m3 (n=12);
and 20-46 jtg/m3 (n= 14).
N/A
N/A
N/A
180-1,400
<52
52-100
110-160
160-210
310-360
>520
<1-20
mean = 4
2 wk-1 yr
occup
<1 yr
occup
3-16 yr
occup
ave 7.5 yr
Cr03 NS
(VI)
mist
Cr03 N/A
(VI)
vapor
CrO3 NS
(VI)
aerosol
Human
(9)M
Human
(258) NS
Human
(11) M
Respiratory symptoms: Septal perforation of nose, ulcerated
nasal septum, moderate injection of nasal septum, epitaxis.
Negative chest roentgenograms.
Nasal mucosa, dental effects, clinical signs: Nasal ulceration
and perforation, epitaxis, rhinorrhea at >52 /*g/m3.
Respiratory and GI clinical signs: Nasal septal ulceration and
perforation, epitaxis, rhinorrhea, stomach pain, duodenal
ulcers in exposed workers. Levels based on personal
monitoring. Pathology attributed to direct skin contact.
Kleinfeld and
Rosso (1965)
Gomes (1972)
Lucas and
Kramkowski
(1975)
-------
I
h-*
«o
VO
Ul
TABLE 11-28 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM AND C
Exposure
Concentration Exposure Chemical Particle size and Species, Strain,
ppm /ig Cr/m3 protocol form distribution (Number) Sex Assays performed: Effect(s)
N/A 5yr CrO3 NS Human Physical exam and questionnaire with emphasis on eye,
occup (VI) (32) NS nose, and throat: No effects observed. Nasal mucosal
mist inflammation was attributed to recent upper respiratory
tract infection.
IMPOUNDS
Reference
Market and
Lucas (1973)
N/A
N/A
0.1
7.1
Avg. Total
Cr. = .3
Avg. Cr
(VI) = 2.9
>52
0.3-132 mo CrO3
26.9 mo (VI)
ave
occup
NS
Human
(30) M, (7) F
<1 yr->5
yr
occup
CrO3
(VI)
NS
NS
Human
(997-1117)
M,F
Respiratory symptoms: nasal ulceration and perforation,
rhinorrhea, epitaxis in exposed workers.
Cohen et al.
(1974)
Respiratory symptoms: Inc prevalence of bronchial
asthma, exposure-duration-related inc in nasal perforations,
nasal ulcers in chrome platers. In 10/12 plants, level was
Royle (1975)
N/A NS
O
O
o
H
O
1
3-108 mo Cr dust NS
occup (com-
pound
NS)
Human Clinical symptoms, skin-prick test, BPT: Case study of 4
(4) M cases of occupational asthma caused by chromium. All
had positive response to Cr2(SO4)3 [Cr(III)] on skin prick
or patch test, and a positive response in BPT to Cr2(SO4)3.
Healthy controls and intrinsic asthmatics did not respond
on the BPT.
Note: All were smokers.
O
I-H
H
W
-------
I
VO
TABLE 11-28 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM AND COMPOUNDS
N>
-J
Exposure
Concentration
ppm ng Cr/m3
N/A 2-20
mean = 6
N/A 50-1,000
N/A 20-158
N/A 130-61
N/A 20-190
total Cr
N/A 0
10-1,350
Exposure
protocol
0.1-26yr
occup
ave 5.3 yr
avg 7 yr
occup
2-12 yr
occup
1-32 yr
avg 7 yr
occup
>15yr
occup
4-19 yr
occup
Chemical
form
CrO3
(VI)
NS
Cr03
(VI)
Cr203
(III)
Chromium
(0)
Ferro-
chromium
(III, VI)
dust
11-33%
Cr(VI)
PbCr04
and
ZnCrO4
(VI)
Particle size and Species, Strain,
distribution (Number) Sex
NS Human
(24-27) M
NS Human
(43) M
dust, not further Human
described (236) M
UK Human
(230) M
NS Human
(25-60) M
NS Human
(24) M
Assays performed: Effect(s)
Renal function: Inc. urinary beta-2-microglobulin at
0.002 among chrome platers. Increase not found in ex-
chrome platers. No effect on urinary albumin. Most of
the current workers had irritation of the airways; four had
ulcerated or perforated nasal septum.
Urinalysis: Dose-related increase in retinol binding
protein (RBP) and tubular antigen. No effect on RBP at
Cr levels < 15 jtg/g creatinine.
Note: Exposure usually <50 /*g/m3, sometimes as high
as l.OOOftg/m3.
Renal function: No effect on urinary albumin, renal
tubular epithelium antigens.
Urinalysis: No effect on excretion of urinary enzymes,
total protein, or B2-microglobulin in a well-designed
epidemiological study.
Pulmonary function, chest x-ray: Obstructive lung
disease, emphysema, dec FVC and FEVj in exposed
workers.
Lung cancer deaths: Three cases of bronchial carcinoma
observed, compared to 0.079 expected based on national
rates (SMR = 3,797). Exposure of the 3 affected
workers estimated at 500-1,500 for 6-9 yrs; 2 of the 3
were smokers.
Reference
Lindberg and
Vesterberg
(1983b)
Franchini and
Mutti (1988)
Foa et al. (1988)
Triebig et al.
(1987)
Langard (1980)
Langard and
Norseth (1975)
-------
TABLE 11-28 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM AND COMPOUNDS
N^
D.
£
to
00
o
^
2
0
2
o
H
O
c!
O
Exposure
Concentration Exposure
ppm fig Cr/m3 protocol
N/A 0 >3 yr
usually 10-30 occup
N/A 40-290 1-49 yr
occup
N/A 40-290 1-49 yr
occup
N/A <50 ftg/m3- NS
yr to occup
>6,000
jug/m3-yr
(Total Cr)
Chemical
form
ZnCrO4
(VI)
Ferro-
chromium
(Viand
III) dust
Ferro-
chromium
mix
(Viand
III)
Reported
only as
Insoluble
[Cr(III)]
and
Soluble
[Cr(VI]
Particle size and Species, Strain,
distribution (Number) Sex
NS Human
(24) M
NS Human
(976) M
NS Human
(976) M
NS Human
(332) M
Assays performed: Effect(s)
Lung cancer deaths: Inc lung cancer rate. Four new
cases of lung cancer were found among 133 workers,
with 3/4 in subcohort employed for >3 yrs before
exposure was reduced in 1973. O/E = 6/0.135, SMR =
4,444. Types of lung cancer: Highly differentiated
epithelial cell carcinoma, adenocarcinoma, anaplastic
small cell carcinoma, oat-cell carcinoma.
Note: Exposure levels had been higher previously.
Lung cancer incidence: 7 cases among study group.
Compared to local rate, risk ratio = 389 (p=0.06).
Compared to internal reference group, risk ratio = 850
(p =0.026). Perforation of nasal cavity hi 2 workers.
Cancer incidence: Inc in lung, prostate, and kidney
cancers that were not statistically significant. Incidence
ratios were 154, 151, and 273, respectively.
Note: Workers with first exposure <20 years prior to
study were excluded to allow for latent period for cancer
development.
Lung cancer deaths: Inc. lung cancer rate. The age-
adjusted lung cancer death rate due to Cr(III) was 0 at
<250 |tg/m3-year, and increased with exposure above
that level. Similarly, for total Cr, there were no lung
cancer deaths at <500 /*g/m3-year, and rate increased
with exposure. For Cr(VI), death rate inc with exposure,
but lung cancer deaths were observed at < 250 /tg/m3-yr.
A cohort of employees exposed hi 1931-1937 were
followed to 1974. Lung cancer deaths clustered at
27-36 years of observation.
Reference
Langard and
Vigander (1983)
(follow-up to
Langard and
Norseth, 1975)
Langard et al.
(1980)
Langard et al.
(1990)
Mancuso (1975)
n
H
W
-------
TABLE 11-28 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM AND COMPOUNDS
Lft
N>
VO
O
O
Exposure
Concentration
ppm ug Cr/m3
N/A 0
218,
413 "usual
cone of
Cr(VI)"
N/A >500-
> 2,000
Exposure
protocol
90 d-
>5yr
occup
1 mo-
29 yr
occup
Chemical
form
Mix
VI and III
PbCrO4
and
ZnCrO4
(VI)
dust
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s)
NS Human Lung cancer deaths: Inc lung cancer deaths. O/E =
(2101)NS 59/29.16, based on local population; SMR = 202
(p<0.01). Usual exposure estimated for earlier exposure
years; no data were available for later years. Cumulative
exposures were estimated to be 670 ptg Cr(VI)/m3-yrs for
short-term employees and 3,647 /ig Cr(VI)/m3-yrs for
long-term employees. Cr(III) levels not estimated.
Exposure dec in later years.
Note: Usual cone estimated as avg of mean annual air
concentrations for several years.
NS Human Cancer deaths: Significant trend for lung cancer with
(1879) M duration of employment, limited to those employed for
> 10 yrs and with >30 yr since initial employment (O/E
= 6/1.87; SMR = 321 for this group). Positive trend
for stomach cancer with duration of employment,
although no significant excess.
Note: Exposure levels determined only during "later
years".
Reference
Hayes et al.
(1979); Braver
et al. (1985)
Hayes et al.
(1989)
Abbreviations:
ALAT = alanine aminotransferase; AM = aveolar macrophage; AP = alkaline phosphatase; avg = average; BAL = bronchoalveolar lavage; BP =
bronchopulmonary lavage; BPT = bronchoprovocation test; BW = body weight; cone = concentration; CrO2 = chromium dioxide [chromium (IV) oxide]; Cr03
= chromic acid [chromium (VI) oxide]; Cr2O3 = chromium (III) oxide; d = day; dec = decreased; F = female; FVC = forced vital capacity; FEV, = forced
expiratory volume in 1 second; GI = gastrointestinal; h = hour; inc. = increased; M = male; N/A = not applicable; NS = not specified; occup = occupational
exposure; PbCrO4 = lead chromate; PF = pulmonary function; PMN = polymorphonuclear cells; ppm = parts per million; SMR = standard mortality ratio;
SRBC = sheep red blood cells; TWA = time-weighted average; wk = week; wt = weight; WBC = white blood cell count; yr = years; ZnCrO4 = zinc
chromate.
O
H- 1
3
-------
1 chromium/g creatinine in urine. Exposure was to 50-1,000 /*g/m3 Cr(VI) as CrO3 for an
2 average of 7 years. Levels of 6-2-microglobulin were elevated in the urine of chrome platers
3 exposed to 2-20 /-ig/m3 Cr(VI) as CrO3, but urinary albumin was unaffected (Lindberg and
4 Vesterberg, 1983b). The study found no effect in a group of ex-chrome platers, indicating
5 that elevated 6-2-microglobulin levels are reversible. There was no evidence of impairment
6 of renal function in ferrochromium workers exposed to up to 158 /xg/m3 Cr(III) as Cr2O3
7 (Foa et al., 1988), or in steel plant workers exposed to up to 610 /*g/m3 Cr(0) as metallic
8 chromium dust (Triebig et al., 1987). The renal toxicity of chromium is supported by
9 studies showing renal failure and necrosis of renal tubules following fatal or near-fatal oral
10 ingestion of chromium (Agency for Toxic Substances and Disease Registry, 1993).
11 Chromium inhalation may also result in gastrointestinal effects. Stomach pain and
12 duodenal ulcers were reported in a group of chrome platers exposed to an average of 4
13 Mg/m3 CrO3 (VI) (Lucas and Kramkowski, 1975); there was no control group. If these
14 effects are due to chromium, they probably result from mouth breathing and/or ingestion of
15 chromium removed from the lungs by mucociliary clearance.
16 There are numerous occupational epidemiology studies on the potential carcinogenicity
17 of chromium. Only the studies that are most appropriate for risk assessment or fill
18 qualitative data gaps are presented here. Overall, the data indicate that Cr(VI) can cause
19 lung cancer. Data on other cancers are less clear. Analysis of the data is confounded by the
20 high prevalence of smoking, but several of the authors used a control population matched for
21 percent smokers. Lung cancer deaths were increased (SMR = 202) in a cohort of 2,101
22 workers exposed to chromates at 410 /ig/m3 (Cr(VI), and risk increased in longer-term
23 employees (Braver et al., 1985; Hayes et al., 1979). In a study of 24 pigment workers
24 exposed to PbCrO4 and ZnCrO4 at 10-1,350 /xg/m3 Cr(VI), three cases of bronchial
25 carcinomas were observed, compared with 0.079 expected based on national rates (SMR =
26 3,797) (Langard and Norseth, 1975). In a followup study, three additional cases were
27 reported in this subpopulation (O/E = 6/0.135; SMR = 4,444), and one case in a larger
28 cohort that had been exposed after air concentrations of chromium were reduced (Langard
29 and Vigander, 1983). In a retrospective cohort study of chromate pigment workers, lung
30 cancer deaths were increased only in the subpopulation with >10 years exposure and >30
31 years since initial exposure (Hayes et al., 1989). In a cohort study of a ferrochromium plant
April 1995 11-230 DRAFT-DO NOT QUOTE OR CITE
-------
1 where exposure to a mixture of Cr(VI) and Cr(III) ranged from 40 to 290 jig/m3 total Cr, the
2 incidence of lung, prostate, and kidney cancers were increased above the general population,
3 but the increase was not statistically significant (Langard et al., 1990). In a group of
4 dichromate [Cr(VI)] producing workers, lung cancers were elevated (relative risk 1.8), and
5 two cases of nasal cancer were found (Alderson et al., 1981). Increased lung cancer risk has
6 also been reported for chromate workers (Taylor, 1966). Mancuso (1975) measured
7 exposure to both Cr(VI) and Cr(III) in a chromate plant, and calculated that the age-adjusted
8 death rate increased both with exposure to Cr(VI) and with exposure to Cr(III). However,
9 the association with Cr(III) exposure may have been due to the correlation between Cr(III)
10 and Cr(VI) exposure.
11
12 Laboratory Animal Data
13 Laboratory animal data support the respiratory tract as the main target of chromium
14 inhalation following either acute or chronic exposure. These data, summarized in
15 Table 11-29, indicate that all forms of chromium can result in mild irritation, increased
16 alveolar macrophage activity and/or accumulation of macrophages in the lung. However,
17 most respiratory tract tissue damage is attributed to Cr(VI) compounds.
18 In the one acute study analyzed, hamsters exposed to 900 to 25,000 pig/m3 Cr(III) as
19 CrCl3 for 30 min had increased acid phosphatase in bronchoalveolar lavage (BAL) fluid and
20 focal accumulation of macrophages. Rabbits exposed to chromium (0) dust at concentrations
21 up to 3,100 j^g/m3 for 4 weeks had increased alveolar macrophage activity, but no tissue
22 damage (Johansson et al. 1980). Similarly, in rabbits exposed to aerosols of Cr(NO3)3 at up
23 to 2,300 /ig/m3 Cr(III), effects were limited to accumulation of macrophages and decreased
24 macrophage response to stimulation (Johansson et al., 1986a,b, 1987). In the one study of
25 Cr(IV) toxicity, exposure of rats to CrO2 at 310 /xg Cr/m3 for 2 years resulted in dust-laden
26 alveolar macrophages and type II pneumocyte hyperplasia (Lee et al., 1988).
27 Respiratory effects of Cr(VI) compounds are consistent with an inflammatory reaction.
28 Increased macrophage levels in response to Cr(VI) have been observed in several studies
29 (Glaser et al., 1985, 1986; Johansson et al., 1986a,b). These changes can result in
30 granulomas, giant cells, and fibrosis (Steffee and Baetjer, 1965). The BAL fluid of rats
31 exposed to Na2Cr2O7 had increased percent lymphocytes and increased response to sheep red
April 1995 \\-23l DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 11-29. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
AND COMPOUNDS
\o Exposure
iS Concentration Exposure Chemical
ppm ftg Cr/m3 protocol
i— '
to
to
Acute Studies
N/A 0
900
25,000
Subchronic and
N/A 0
600
3,100
N/A 0
600
30 min
form
CrCl3
(HI)
aerosol
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s)
count median Hamster, Lung lavage (enzymes, cytology), lung HP: Inc. acid
diameter = 1.2 Syrian phosphatase in lavage fluid and lung tissue, focal
ftm (16) M, (16) F accumulation of MP and PMN cells at 900 and 25,000
T1
H
6
o
o
H
r*
O
M
N/A 0
900
N/A 0
600
2,300
6h/d
5 d/wk
4-6 wk
6h/d
5 d/wk
4 mo
Na2CrO4
(VI)
aerosol
Cr(N03)3
• 9H2O
(HI)
aerosol
MMAD - 1 fan Rabbit, NS
(8)M
MMAD - 1 fan Rabbit, NS
M
HP of lung by EM and light microscopy: Inc AM in
BAL fluid. Inc intraalveolar or intrabronchial
accumulation of macrophages, nodular accumulation of
macrophages. No epithelial destruction or abnormal
proliferation.
BAL, HP of lung by light microscopy and EM:
Increased levels of AM. Nodular accumulation of
macrophages in terminal airspaces, interstitial infiltration
of inflammatory cells at 600 and 2,300 ftg/m3.
Johansson et
(1986a,b)
Johansson et
(1987)
al.
al.
O
H-I
H
M
-------
t
I—'
VO
TABLE 11-29 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
AND COMPOUNDS
N)
O
O
o
d
s
w
o
ja
n
H
M
Exposure
Concentration
ppm
N/A
N/A
N/A
N/A
Hg Cr/m3
0
25
50
100
200
0
25
50
100
200
0
50
100
200
400
0
3,630
Exposure
protocol
22h/d
7d/wk
28 d
22h/d
7d/wk
90 d
22h/d
7d/wk
30-90 d
30 min/d
2d/wk
12 mo
Chemical
form
Na2Cr2O7
•2H2O
(VI)
aerosol
Na2Cr2O7
•2H20
(VI)
aerosol
Na2Cr2O7
•2H2O
(VI)
aerosol
CrO3
(VI)
aerosol
Particle size and
distribution
MM AD = 0.20
^tm
ffg = 1.5
MMAD = 0.20
/*m
ag = 1.5
50-100:
(MMAD =0.28
/on, ffg = 1.63)
200-400:
MMAD =0.39
/*m, Og=1.72
"mist size 10
/xm"
Species, Strain,
(Number) Sex
Rat, Wistar
(20) M
Rat, Wistar
(20) M
Rat, Wistar
(30) M
Mouse, ICR
(10-19) F
Assays performed: Effect(s) Reference
BW; HP of lung, stomach, liver; organ wt, blood Glaser et al.
biochem, BAL, immune function: Inc. lung, spleen wt at (1985)
>50 /ig/m3. HP normal. ALAT, AP, creatinine normal.
Response to SRBC and AM phagocytosis increased in
BAL fluid at all levels. Inc. percent lymphocytes in BAL
fluid at 25 and 50 /*g/m3.
BW; HP of lung, stomach, liver; organ wt, blood Glaser et al.
biochem, BAL, immune function: Inc. lung, spleen wt at (1985)
>50 pig/m3. HP normal. ALAT, AP, creatinine normal.
Response to SRBC increased at all levels. Macrophage
activity, percent lymphocytes in BAL fluid inc at 25 and
50, dec at 200 /*g/m3. Lung clearance dec at 200 /*g/m3.
Inc lung wt, serum phospholipids and triglycerides at
200 jig/m3.
Blood biochem, hemato., urinalysis, and BAL; gross and Glaser et al.
HP exam of upper airway epithelia, lung, kidneys: (1990)
Reversible inc. in WBC at > 100 /tg/m3 at 30 d and at
>50 jig/m3 at 90 d. At >50 Mg/rri3 and 30 d exposure,
lung wt inc, slight hyperplasia, macrophage infiltration.
Incidence declined with longer exposure, indicating
repair. Inc protein in BAL fluid.
HP of respiratory tract: Emphysema, nasal septum Adachi et al.
perforation. On epithelium of the trachea and bronchus, (1986)
loss of cilia, proliferation of goblet or basal cells, and
squamous metaplasia, with severity related to exposure
duration. Adenomas and adenocarcinomas observed.
-------
TABLE 11-29 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
AND COMPOUNDS
u>
H
6
o
2
o
H
O
c
I
o
?d
O
HH
a
Exposure
Concentration
ppm
N/A
N/A
N/A
N/A
jig Cr/m3
0
1,810
0
25
500
100
0
100
0
Avg. 1.600-
2,100
Exposure
protocol
120 min/d
2d/wk
12 mo
22h/d
7d/wk
18 mo
22h/d
7d/wk
18 mo
4-5 h/d
4d/wk
2yr
Chemical
form
CrO3
(VI)
aerosol
Na2Cr2O7
•2H2O
(VI)
aerosol
Na2Cr2O7
•2H2O
(VI):
Cr5012
(III)
3:2
mixture
Finely
ground
chromium
roast
(VI) and
K2Cr2O7
(VI)
dust
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s)
"mist size ~5 Mouse, C57BL Gross and HP of respiratory tract: Emphysema, nasal
^m-85%" (20-23) F septum perforation, lung metaplasia. In animals
sacrificed 6 mo after the last exposure, also hyperplasia
of larynx/trachea and papillomas of nasal epithelia.
MMAD = 0.36 Rat, Wistar Body wt, HP of lungs, liver, kidney, adrenals,
fj.m (20) M hematology, blood biochem, urinalysis: Lung and liver
a = 1.69 weight significantly increased at 100 /*g/m3. Weak
accumulations of pigmented macrophages hi alveolar
region of lung at 25 /xg/m3 and moderate levels at higher
exposure levels. Lung tumors (adenocarcinoma and
adenomas) and squamous cell carcinoma of pharynx at
100 fig/m3.
Cr(VI): Rat, Wistar Body wt, HP of lungs, liver, kidney, adrenals,
MMAD = 0.36 (20) M hematology, blood biochem, urinalysis: Lung wt
fim increased. Moderate accumulations of pigmented
a = 1.69; macrophages; focal thickened septa, bronchoalveolar
Cr(III): hyperplasia, and interstitial fibrosis. Hematocrit, Hb,
MMAD = 0.39 RBC, WBC, but not differential white blood cell counts
,uin were increased. Inc cholesterol. Lung tumor (adenoma).
ffg = 1.71
NS Rat, Wistar HP of lungs and tissues with gross lesions: Lung
(78) NS abscesses, bronchopneumonia, alveolar and interstitial
inflammation, giant cell, granulomatoma. No exposure-
related evidence of carcinogenesis. K2Cr2O7 was added
to chromate roast at a level of 1 % .
Reference
Adachi (1987)
Glaser et al.
(1986)
Glaser et al.
(1986)
Steffee and
Baetjer (1965)
-------
TABLE 11-29 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
AND COMPOUNDS
»
to
O
O
O
H
O
a
9
W
O
90
O
h-H
H
W
Exposure
Concentration
ppm
N/A
N/A
N/A
/tg Cr/m3
0
Avg. 1,600-
2,100
0
1,040-1,560
0
Avg. 1,600-
2,100
Exposure
protocol
4-5 h/d
4 d/wk
4.5 yr
4 h/d
5 d/wk
101 wk
4-5 h/d
4 d/wk
4.5 yr
Chemical
form
Finely
ground
chromium
roast
(VI) and
K2Cr2O7
(VI)
Mixed
chromium
dust
(VI)
13.7%
CrO3
6.9%
Cr203
Finely
ground
chromium
roast
(VI) and
K2Cr207
(VI)
Particle size and
distribution
NS
Mass median
diameter of
airborne particles
0.8 /xm
Distribution:
<0.5 /an, 23%;
0.5-1, 46%; 1-2,
14%; 2-3, 9%;
3-4, 4%; 4-5,
2%; >5, 5%
NS
Species, Strain,
(Number) Sex
Guinea pig
(50) M,F
Rat,
Wistar/Mc-
collum mix
(57) M, (53) F
Guinea pig, NS
(50) M,F
Assays performed: Effect(s)
HP of lungs and gross lesions: Inc incidence of
granulomata and inflammatory response. Alveolar and
interstitial inflammation, alveolar hyperplasia, interstitial
fibrosis. No evidence of carcinogenicity.
HP of lungs: Pneumonia, inflammation, consolidation,
and congestion of lungs. No statistically significant
effect on lung cancer incidence.
Note: Chromate dust obtained from a chemical plant.
HP of lungs and gross lesions: Inc incidence of
granulomata and inflammatory response. Alveolar and
interstitial inflammation, alveolar hyperplasia, interstitial
fibrosis. No evidence of carcinogenicity.
Reference
Steffee and
Baetjer (1965)
Baetjer et al.
(1959)
Steffee and
Baetjer (1965)
-------
> TABLE 11-29 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
U AND COMPOUNDS
o Exposure
<2 Concentration Exposure
ppm ng Cr/m3 protocol
N/A 0 4h/d
1,040-1,560 5d/wk
101 wk
Chemical
form
Mixed
chromium
dust
(VI)
13.7%
CrO3
6.9% Cr2O3
Particle size and
distribution
Mass median
diameter of
airborne particles
0.8 /un
Distribution:
<0.5 urn, 23%;
0.5-1,46%; 1-2,
14%; 2-3, 9%;
3.4, 4%; 4-5, 2%;
>5, 5%
Species, Strain,
(Number) Sex
Rat,
Wistar/Mc-
collum mix
(57) M, (53) F
Assays performed: Effect(s) Reference
HP of lungs: Pneumonia, inflammation, consolidation, Baetjer et al.
and congestion of lungs. No statistically significant (1959)
effect on lung cancer incidence.
Note: Chromate dust obtained from a chemical plant
N/A 0
E 4,300
OJ
ON
O
§>
T1
H
6
o
o
H
0
o
H
W
5 h/d CaCrO4 Size
5 d/wk (VI) (ftm)
18 mo dust
<0.1
<0.2
<0.3
<0.4
<0.5
<0.6
<0.7
<0.8
<0.9
<1.0
% Particles Mouse,
smaller than C57BL/6
(136) M, (136)
4.5 F
48.7
69.6
82.2
91.2
95.9
97.3
98.7
99.6
99.9
HP of heart, trachea, lung: Epithelial changes in Nettesheim et al.
bronchial tree ranging from epithelial necrosis and (1971)
atrophy to marked hyperplasia. Inflammatory
infiltration of subepithelial tissues. Bronchiolization of
alveoli, dilation of alveolar ducts, accumulation of
alveolar cells and foam cells. Increased incidence of
lung tumors. The tumors were identified as
alveologenic adenomas and adenocarcinomas.
Hyperplasia and atrophy of trachea! and submandibular
lymph nodes, occasional small ulcerations in stomach
and intestinal mucosa.
O
HH
H
M
-------
£ TABLE 11-29 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR CHROMIUM
2 AND COMPOUNDS
vo Exposure
S Concentration ExDOSUre Chemical
ppm jug Cr/m3 protocol form
N/A 0 6h/d CrO2
310 5 d/wk aerosol
15,500 2 yr (IV)
(0.31-
stabilized,
un-
stabilized;
15.5
stabilized)
~
Particle size and
distribution
Aerodynamic
diameter = 2.6-
2.8/im
-------
1 blood cells (Glaser et al., 1985) The incidence of macrophage infiltration declined with
2 longer exposures, suggesting that repair occurred (Glaser et al., 1990). Glaser et al. (1990)
3 also suggested that inflammation is essential for the induction of most chromium inhalation
4 effects and may influence the carcinogenicity of Cr(VI) compounds.
5 Respiratory tissue alterations have also been observed in animals. Lower levels, such
6 as up to 400 /xg/m3 Cr(VI) as Na2Cr2O7, result in hyperplasia (Glaser et al., 1990). Mice
7 exposed to 1,810 or 3,630 fig/m3 Cr(VI) as CrO3 for 1 year developed nasal septal
8 perforation, loss of cilia, and metaplasia of the lung, trachea, and bronchus (Adachi, 1987;
9 Adachi et al., 1986). Epithelial changes of the bronchial tree ranging from necrosis and
10 atrophy to hyperplasia were observed in mice exposed to 4,300 /ig Cr/m3 as CaCrO4 dust for
11 18 mo (Nettesheim et al., 1971).
12 Chromium can also act as a sensitizing agent. Miyamoto et al. (1975) sensitized guinea
13 pigs to chromium by repeated dermal painting and intradermal exposure to potassium
14 dichromate, and then exposed the animals via inhalation to an aerosolized solution of
15 potassium dichromate (concentration not specified) for 30-45 min. The inhalation challenge
16 elicited a stronger reaction in the lungs (edema, infiltration of lymphocytes into the
17 interstitial spaces) of actively sensitized guinea pigs than in control guinea pigs. The
18 observed changes were characterized as a delayed-type hypersensitivity reaction.
19 Few animal data are available on non-respiratory effects of chromium. However,
20 Glaser et al. (1986) reported increased liver weight in rats exposed to 100 jitg/m3 Cr(VI) as
21 Na2Cr2O7 for 18 mo.
22 Animal studies also support the carcinogenicity of Cr(VI). Rats treated with 100 /ig/m3
23 Cr(VI) as Na2Cr2O7 had adenocarcinoma and adenomas of the lung and squamous cell
24 carcinomas of the pharynx, but exposure-related tumors were not observed at lower levels
25 (Glaser et al., 1986). Lung tumors were also observed in mice treated with CaCrO4
26 (Nettesheim et al.. 1971).
27 No developmental effects were reported in rats exposed to 200 jwg/m3 Cr(VI) as sodium
28 dichromate for three generations (Glaser et al., 1984, as cited in Agency for Toxic
29 Substances and Disease Registry, 1993). Further experimental details were not available in
30 the secondary reference, and the original reference is in German. There were no other
31 studies on developmental toxicity by the inhalation route and no studies were located that
April 1995 11-238 DRAFT-DO NOT QUOTE OR CITE
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1 observed reproductive outcome in animals that inhaled chromium compounds. However,
2 there were no histological effects of the testes in rats exposed to 200 /ig/m3 Cr(VI) as sodium
3 dichromate for 28 or 90 days (Glaser et al., 1985) or 100 /^g/m3 Cr(VI) as sodium
4 dichromate for 18 mo (Glaser et al., 1986, 1988). Oral data indicate that Cr(VI) compounds
5 are reproductive and developmental toxicants, while Cr(III) compounds may cause
6 reproductive toxicity, but not developmental toxicity (Agency for Toxic Substances and
7 Disease Registry, 1993).
8
9 11.6.7.4 Factors Affecting Susceptibility
10 Because the respiratory system is a major target of chromium inhalation toxicity,
11 individuals with impaired respiratory function may have increased susceptibility to
12 chromium. The developing respiratory tract of children may also pose an increased
13 susceptibility. Repeated exposure to chromium may result in hypersensitivity (Miyamoto
14 et al. 1975), which can be manifested as increased respiratory toxicity. Differences in
15 chromium metabolism can also increase susceptibility. Individuals who reduce Cr(VI) in the
16 bloodstream to Cr(III) more slowly have been identified (Korallus 1986). Because Cr(III)
17 cannot cross biological membranes and is much less toxic than Cr(VI), slow reducers are
18 more likely to be adversely affected by chromium exposure. The ability to reduce Cr(VI) in
19 the bloodstream may be related to plasma ascorbic acid levels. Smokers may also be more
20 susceptible to lung cancer related to chromium exposure, since inhalation of cigarette smoke
21 may result in squamous metaplasia of the respiratory mucosa (Albert, 1991).
22 Since occupational studies have shown early signs of renal damage following inhalation
23 exposure to chromium (Franchini and Mutti, 1988; Lindberg and Vesterberg, 1983b),
24 individuals with pre-existing kidney dysfunction may be more susceptible to the nephrotoxic
25 effects of chromium.
26
27 11.6.8 Cobalt
28 11.6.8.1 Chemical and Physical Properties
29 Cobalt is a metallic element found in Group 8B of the periodic table. It exhibits the
30 valence states of 0, +1, +2, +3, +4, and +5. The common forms of cobalt in the 0
31 oxidation state are cobalt metal and the cobalt carbonyls (Agency for Toxic Substances and
April 1995 11-239 DRAFT-DO NOT QUOTE OR CITE
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1 Disease Registry, 1991). Most cobalt compounds are formed with cobalt in the +2 or +3
2 oxidation state, although cobalt(III) compounds tend to exist as complexes rather than as
3 simple salts. In aqueous solution, Co"1"2 is stable; however, Co"1"3, a strong oxidizing agent,
4 is reduced to Co+2 in aqueous solutions. Cobalt exists in the environment both as inorganic
5 salts, and as organocobalt compounds (Richardson, 1993). Elemental cobalt is insoluble in
6 water, as are cobalt (II) oxide (CoO) and cobalt (III) oxide (Co2O3), whereas cobalt (II)
7 sulfate (CoSO4) and cobalt (II) chloride (CoCl2) are moderately soluble in hot water (at ca.
8 80 to 100 °C).
9
10 11.6.8.2 Pharmacokinetics
11 Absorption and Distribution
12 No data were located regarding absorption of cobalt following inhalation or oral
13 exposure to cobalt powder, hard metal, or cobalt sulfate. However, the kinetics of cobalt
14 excretion in the urine suggest that there is a component that is absorbed rapidly (within
15 < 1 day) and a component that is absorbed over the course of at least several weeks
16 (Alexandersson, 1988; Roshchin et al., 1989). Based on lung activity levels on Days 15 and
17 80 post-exposure in workers who accidentally inhaled 60Co aerosol for 10 to 20 min, the
18 lung clearance half-time was in the range 25 to 78 days; only minor activity was in the liver
19 (Beleznay and Osvay, 1994). Hamsters exposed via inhalation to 12,200 ng cobalt/m3 as
20 cobalt oxide for 7 h/day for 2 days had virtually no cobalt in the lungs at 6 days post-
21 exposure. At 24 h post-exposure, most of the inhaled dose was detected in the
22 gastrointestinal tract (60%), with the lungs containing only approximately 3% of the dose,
23 the liver and kidney less than 1% each, and the remaining carcass 23% (Wehner and Craig
24 1972). Dogs administered a radiolabeled cobalt nitrate aerosol intratracheally rapidly
25 eliminated most of the dose from the lungs and body (Kreyling et al., 1986). However,
26 3% of the dose was retained in the lungs with a biological half-life of 400 days. The rapid
27 elimination of most of the cobalt nitrate is probably related to its hygroscopic (water
28 absorbing) properties.
29 Serum cobalt levels of 32 workers in a hard-metal factory showed a progressive
30 increase from the beginning to the end of the work week (Posma and Dijstelberger, 1985).
31 Cobalt levels in the air ranged from 12 to 2,550 ^ig/m3, depending on the work area, and
April 1995 11-240 DRAFT-DO NOT QUOTE OR CITE
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1 mean serum cobalt levels ranged from 2.0 to 18.3 pg/L, depending on the work area. Blood
2 cobalt levels in workers exposed to cobalt powder at concentrations ranging from 49 to
3 1,050 /ig/m3 were 4.9 to 47.9 /*g/L (Angerer et al., 1985). Elevated cobalt levels were
4 found in the lungs of copper smelter workers autopsied at least 5 years after retirement
5 (Gerhardsson et al., 1984), indicating that cobalt has a long half-life in the lungs. Neither
6 the form of cobalt nor the exposure level were reported. The mediastinal lymph nodes of
7 hard-metal workers have also been found to have elevated cobalt levels (Hillerdal and
8 Hartung, 1983). Elevated cobalt levels were found in a cobalt worker who died of
9 myocardial disease (Kennedy et al., 1981). The highest tissue levels of cobalt administered
10 intratracheally to albino rats (strain unspecified) as cobalt sulfate were observed within 24 h
11 of dosing, in the lungs, liver, and kidney (Roshchin et al., 1989). Cobalt accumulated in
12 myocardial tissue (the only tissue analyzed) of rats fed 0.2 mg/kg cobalt as cobalt sulfate for
13 8 weeks (Clyne et al., 1990).
14 Using leaching experiments on neutron-activated hard-metal dust, Edel et al. (1990)
15 found that cobalt is about 17% soluble in lung cytosol and about 12% soluble in plasma.
16 Three biochemical pools of cobalt were identified in the lung cytosol. About 56% of the
17 cobalt was associated with low molecular weight components, constituting the diffusible
18 cobalt pool, and about 34% was associated with proteins of molecular weight 70,000 to
19 80,000, which may include transferrin. A third pool ( = 8%) was associated with high
20 molecular weight components. These data are consistent with the immunology data
21 indicating that cobalt binds to proteins to form an allergen (Shirakawa et al., 1989).
22
23 Metabolism
24 Cobalt is an essential nutrient and is a constituent of cyanocobalamin (Vitamin B12).
25 Vitamin B12 plays an essential role in the maturation and development of erythrocytes and is
26 required for the action of several enzymes (Lehninger, 1975).
27
28 Excretion
29 Excretion of cobalt occurs primarily in the urine, although fecal excretion is also
30 significant in the first few days post exposure (Kreyling et al., 1986). Urinary cobalt levels
31 in four hard-metal workers at the end of a work week ranged from about 100 to about
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1 4,500 nmol/L (unexposed controls had 6.8 nmol/L), and correlated with exposure level
2 (Alexandersson, 1988). Blood cobalt levels measured Friday at the end of the shift were
3 178 nmol/L in workers exposed to about 90 ptg/m3, compared with 8.5 nmol/L in the
4 controls. The two subjects with the highest urinary cobalt levels exhibited biphasic
5 excretion. The decrease in urinary concentration was rapid for the first 24 hours and slower
6 for the next 46 hours. Even after a 4-week vacation, blood and urine levels (39 nmol/L and
7 83 nmol/L, respectively) in ten workers were elevated above the control values. Urinary
8 cobalt levels of 26 workers in a hard-metal factory correlated with exposure level and
9 showed a progressive increase from the beginning to the end of the work week (Scansetti
10 et al., 1985). By the third week after a vacation break, excretion over the weekend was not
11 sufficient to reduce levels to normal.
12 Cobalt sulfate administered intratracheally to rats was also eliminated in a biphasic
13 manner (Roshchin et al., 1989). Palmes et al. (1959) found that urinary cobalt rose rapidly
14 and declined rapidly in rats exposed via inhalation to mixed cobalt oxides; biphasic
15 elimination was observed, with a half-life of about 1 day for the rapid phase.
16
17 11.6.8.3 Health Effects
18 Human Data
19 The respiratory tract is the primary target of inhalation exposure to cobalt and its
20 compounds in humans, as summarized in Table 11-30. Much of the data on inhalation
21 exposure of humans to cobalt and its compounds come from studies of workers exposed to
22 hard-metal dust. Hard-metal contains 75 to 95% tungsten carbide, 5 to 20% cobalt as a
23 binder, and small amounts of other metals such as titanium, nickel, chromium, niobium,
24 vanadium, and tantalum (Shirakawa et al., 1989). The particles generated are <2.0 jum in
25 diameter. Although cobalt constitutes only 5 to 20% of the material, the respiratory effects
26 of hard-metal exposure are believed to be due to the cobalt, rather than the tungsten carbide
27 because: (1) these effects have been seen following exposure to cobalt in the absence of
28 tungsten carbide, and (2) laboratory animal studies indicate that tungsten carbide alone does
29 not produce these effects. However, data noted below from acute and intermediate-duration
30 animal studies indicate that the tungsten carbide exacerbates the toxic effects of cobalt
31 exposure. Data also come from studies of diamond polishers exposed to a mixture of cobalt
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TABLE 11-30. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COBALT AND COMPOUNDS
U>
O
O
Z
s
n
5
Exposure
Concentration Exposure Chemical Particle size and
ppm
Acute
N/A
Chronic
N/A
N/A
N/A
/ig Co/m3 protocol form distribution
avg 38 6h Hard-metal "75% of dust in
range 14- dust room was
76 respirable"
avg 126 10 yr Hard-metal "75% of dust in
range 6- occup dust room was
610 respirable"
17-32,470 17.3, 25 Hard-metal NS
mean of yr avg at dust
peak 2 plants
values occup
48 7 yr avg Hard-metal NS1
(mean occup dust
present
exp)
Species, Strain,
(Number) Sex
Human
(15) M
Human
(34-68) M,
(8-16) F
Human
(281) M,
(9)F
Human
(828) M,
(211)F
Assays performed: Effect(s) Reference
PF (e.g., FVC, FEVj, PF), clinical symptoms: Subjects Kusaka et al.
(all naive) were exposed in hard-metal factory. Sig dec in (1986)
FVC and nonsig dec in FEVj were observed, compared to
pre-exposure values. Coughing, expectoration, sore throat
reported, but not rales or wheezing.
PF (e.g., FVC, FEVj, PF), medical exam: No changes in Kusaka et al.
pulmonary function between pre- and post-shift values. (1986)
However, all measured ventilatory indices were lower than
those of the controls, and FEV1% was sig lower.
Note: Three of the exposed subjects had asthma related to
hard metal.
PF (FVC, FEVj), x-ray, complete physical of affected Sprince et al.
workers: Interstitial infiltrates in 9 of 290 subjects chosen (1984)
based on high exp or exp duration. Two subjects had
restriction and 2 had obstructive lung defects. Cough,
sputum, wheeze in some affected subjects. Symptoms
progressed with further exposure. Interstitial fibrosis in one
biopsy.
Cross sectional study; Medical history, PF (flow volume, Sprince et al.
DLCO), x-ray: Work related wheeze 9.2% at <50, 18.1% (1988)
at 50-100, 15.4% at >100 (p=0.016). DLcO correlated
with cumulative exp. Profusion observed in 2.6% of
subjects and interstitial lung disease (based on profusion,
FVC or DLCO, or FEVj/FVC) in 0.7%. Relative odds of
profusion 5.1 for avg lifetime exp > 100. Interstitial lung
disease also found in 3 workers with avg lifetime exp <8.
Suggests susceptible subpopulation.
-------
TABLE 11-30 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COBALT AND COMPOUNDS
~ Exposure
£ Concentration Exposure Chemical Particle size and
<•" ppm fig Co/m3 protocol form distribution
N/A 0, 1-19 yr Hard-metal NS1
5-10, occup dust
10,
60 (avg
exp in last
few yr)
Species, Strain,
(Number) Sex Assays performed: Effect(s)
Case-control study; Clinical exam, x-ray, dynamic
Human spirometry, Co hi urine and blood: No statistically sig
(30-60) B effect observed in 5-10 group. Inc chest tightness and
chronic bronchitis in 10 group. All groups showed dec
compared to controls in spirometry (FEVj, FEV%) Monday
morning before work; effect sig at 60 for FEVj. FVC not
affected. Effects indicate obstructive change. In 60 group,
dec FEVj correlated with yrs exp.
Note: Controls individually matched with regard to length
of employment, smoking. 60 /xg/m3 largest group,
strongest statistical power.
Reference
Alexandersson
and Swensson
(1979)
O
o
O
a
3
m
N/A 0 avg 13.2- Hard-
30-272 17.8 yr metal,
mean, dep occup "soft
on area powder"
NS
Human Cross sectional study; Medical history, bronchial
(69-351) M, hyperreactivity, PF (FEV, flow volume, CO): Cough and
(19-74) F sputum more frequent in exp workers. Inc incidence of
obstructive and restrictive syndrome, with larger effect in
women. Exposure-related changes in the steady state
carbon monoxide uptake (TCOSS). Marked inc hi bronchial
hyperreactivity in women. Slight abnormalities in x-rays
more frequent in men. Those with abnormal x-rays had
lower FVC, FEV^ CO indices.
Meyer-Bisch
et al. (1989)
N/A
4-55
NS
occup
Hard-metal
dust
NS1
Human
(3)NS
Case studies; BAL, lung biopsy, CS, lung function:
interstitial pneumonitis, interstitial fibrosis, dec FVC,
cough, dyspnea, inc macrophages in BAL fluid.
Barnhart
1991
et al.
o
-------
TABLE 11-30 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COBALT AND COMPOUNDS
to
ft
O
O
1
o
o
H
m
o
n
Exposure
Concentration
ppm /*g Co/m3
N/A 0
15.2, 136
(geom.
means)
range
6-2875
N/A 50-1000
N/A 1-57
Exposure
protocol
6 yr avg
occup
5-18 yr
occup
>6 mo
(case-
control)
7.3 yr
avg
(cross-
section-
al)
occup
Chemical
form
Cobalt/
diamond
dust
Cobalt/
diamond
dust
Cobalt
sulfate,
cobalt
metal
dust
Particle size and Species, Strain,
distribution (Number) Sex
NS Human
(11-34)M,
(12-14) F
NS Human
(2) F, (4) M
-25% of all Human
dust particles <3 (151, 224) B
/mi
Assays performed: Effect(s)
PF (e.g., FVC, FEVj, PEFR), urinary Co, resp symptoms:
Dec values of FVC, FEVlt MEF75; resp symptoms (cough,
sputum, dyspnea) more common in exposed group. Among exp
nonsmokers, higher urinary Co and lower PF values in those
exp >5 yr, compared to those exp <5 yr. Symptoms
compatible with moderate restrictive syndrome; obstructive
component also possible. Concomitant oral exp likely.
Medical history, lung function tests, bronchoscopy, chest x-rays;
BAL fluid analysis: All cases had tracheobronchitis, mild
increases in total cells in BAL fluid. Inc T-lymphocytes and
inversion of helper/suppressor ratio hi 3 cases. Cytology of one
worker with interstitial lung disease was comparable to that of 5
other "symptomless" workers among those with the longest
exposures.
Case-control study of asthma, cross-sectional study of chronic
bronchitis and decreased pulmonary capacity: Occupational
asthma (relative risk 4.1); symptoms reversed in most subjects
when exposure removed. 5/15 gave positive response when
challenged with cobalt chloride. In cross-sectional study,
symptoms of chronic bronchitis (cough, phlegm, and wheezing)
more elevated in cobalt workers who smoked than other
smokers. No evident effect on nonsmoking pop.
Note: Workers in 3 areas studied; in one, personal monitoring
was 1-57 /tg/m3. In second, it was 1.3-9.5 /tg Co/m3 as cobalt
sulfate on dust particles, and air in third had 10 to 100 /ng/m3
metallic cobalt. Concomitant to SO2 expos.
Reference
Gennart and
Lauwerys
(1990)
Mosconi et al.
(1991)
Roto (1980)
-------
TABLE 11-30 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COBALT AND COMPOUNDS
3.
VO
H
6
o
o
H
O
O
a
Exposure
Concentration
ppm pig Co/m3
N/A 100-3,000
N/A 49-1,046
N/A NS
Exposure
protocol
10.7 yr
avg
(range 2-
31 yr)
occup
11.3 yr
avg
occup
1-40 yr
occup
Chemical Particle size and
form distribution
cobalt NS
salts and
oxides
(not
further
described)
Cobalt NS
metal
powder
Cobalt NS
metal dust
cobalt
chloride
aerosol
Species, Strain,
(Number) Sex
Human
(46) M
Human
(40)NS
Human
NS
Assays performed: Effect(s)
Resp symptoms (questionnaire), PF (FEVj, FVC), chest x-ray:
No sig difference on any parameter.
Note: Two potentially sensitive workers had left work area
before the study and were not included. One had developed
asthma and the other had a positive cobalt skin patch test.
Note: Exposure based on personal monitoring; most exposure
-------
1 and diamond dust (Gennart and Lauwerys, 1990). Diamond polishing dust was analyzed by
2 Van den Oever et al. (1990) and found to contain no fibrinogenic materials and none of the
3 metals present in hard metal, except cobalt. In the one human epidemiological study of
4 exposure to cobalt metal dust, results of exposure to cobalt metal were reported together with
5 results for cobalt sulfate (Roto, 1980).
6 Human respiratory effects of cobalt inhalation are asthma and interstitial lung disease
7 (fibrosis). Symptoms related to interstitial lung disease include small opacities (indicative of
8 interstitial infiltrates) on radiographs, work-related wheeze, and reduced values of forced
9 expiratory volume in 1 s (FEVj), forced vital capacity (FVC), and diffusing capacity for
10 carbon monoxide (DLCO) (Sprince et al., 1984, 1988). Others have observed decreased
11 FEVj and FEV% (but unchanged FVC), indicating obstructive alterations (Alexandersson
12 and Swensson, 1979). Hard metal workers in Italy were found to have reduced carbon
13 monoxide diffusing capacity (Suardi et al., 1994). There are also data suggesting that certain
14 subpopulations may be more sensitive than others. Among a cohort of 1,039 tungsten
15 carbide workers, most of the affected workers experienced short-term exposures to cobalt
16 levels exceeding 300 /ig/m3, but three affected subjects were exposed to <50 p.g cobalt/m3
17 (Sprince et al. 1988).
18 Symptoms similar to those observed following exposure to hard-metal dust (dyspnea,
19 cough, and decreased FVC, FEV1; and mean expiratory flow at 75% of FVC [MEF75])
20 occurred in workers in a plant producing diamond-cobalt saws, where exposure was to
21 cobalt, without tungsten carbide (Gennart and Lauwerys, 1990). The study authors
22 concluded that the results were compatible with a moderate restrictive syndrome, but an
23 obstructive component could not be ruled out. Both obstructive (defined as normal vital
24 capacity with decreased FEVi or MMEF) and restrictive (defined as decreased VC and TLC,
25 with normal FEVj/VC ratio) syndromes were observed in a cross-sectional study of hard-
26 metal workers exposed to levels of 45 to 272 /*g cobalt/m3, or 30 to 210 /^g cobalt/m3,
27 depending on the factory. Cough, sputum, and bronchial hyperreactivity were also observed
28 (Meyer-Bisch et al., 1989).
29 There are several case studies of respiratory symptoms in workers occupationally
30 exposed to cobalt. Ohori et al. (1989) presented four case studies of giant-cell interstitial
31 pneumonia (characterized by decreased FVC and interstitial fibrosis) that developed in people
April 1995 H_247 DRAFT-DO NOT QUOTE OR CITE
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1 who had worked with hard metal for 3 to 13 years. No exposure levels were available, but
2 the particle size was described as less than 2.0 ptm in diameter. Symptoms of occupational
3 asthma (dyspnea and airway hyperresponsiveness) and interstitial lung disease (crackles and
4 leucocytosis following cobalt challenge) were found in a diamond polisher with a history of
5 dyspnea and chest tightness associated with exposure to diamond-cobalt disks (Van Cutsem
6 etal., 1987).
7 Asthma due to cobalt inhalation clearly has an immunological component. Cobalt-
8 specific antibodies and elevated immunoglobulin IgE levels have been detected in
9 occupational asthma, but no exposure levels were reported (Shirakawa et al., 1989). Cobalt
10 hypersensitivity is specific to the cobalt-sensitized population (Roto, 1980). In order to
11 provoke an antibody-mediated response, cobalt metal would have to be converted to ionized
12 cobalt on the bronchial mucosa to act as a hapten; the complete antigen would be formed by
13 complexing with host proteins (Shirakawa et al., 1988). Significantly elevated IgA levels
14 and slightly but significantly decreased IgE levels were reported in a study of 35 cobalt
15 production workers where exposure was not assessed (Bencko et al., 1986). The finding in
16 this study of elevated levels of serum proteins known as acute reactants (c^-antitrypsin, a2-
17 macroglobulin, transferrin, ceruloplasmin, and lysozyme) suggests that cell-mediated
18 immunity may also be involved. Irritation from cobalt particles probably contributes to
19 interstitial lung disease, but this effect may also have an immunotoxic component. Three
20 cases of diamond polishers with occupational asthma attributed to cobalt exposure had
21 positive cobalt inhalation challenge tests, and exposure to cobalt temporarily increased
22 nonspecific hyperreactivity (Gheysens et al., 1985). By contrast, the reaction to histamine
23 challenge in a control diamond polisher with documented asthma was unaffected by pre-
24 exposure to cobalt, indicating that the effect of cobalt was not due to nonspecific irritation.
25 Other studies have used bronchoalveolar lavage to study the possible role of allergic
26 mechanisms in respiratory symptoms related to cobalt exposure. Mosconi et al. (1991)
27 examined workers producing cobalt-diamond stone cutting who were exposed to 50 to 1000
28 /ig cobalt/m3. They found a marked increase in the levels of T lymphocytes, suggestive of
29 chronic hypersensitivity. In three of the workers, the helper/suppressor ratio was reversed.
30 In an abstract, Barnhart et al. (1991) reported pneumoconiosis, accompanied by elevated
31 macrophage and lymphocyte levels in bronchoalveolar lavage fluid, in hard-metal workers
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1 exposed to low cobalt levels (4 to 55 /ig cobalt/m3). Eosinophils were found in
2 bronchoalveolar lavage or in lung biopsies from case studies of hard-metal workers with
3 dyspnea, indicating that cell-mediated immunity plays a role in the toxic response to cobalt
4 (Davisonet al., 1983).
5 Workers exposed to hard-metal or cobalt dust developed acute hypersensitivity
6 pneumonitis, interstitial fibrosis, and multinucleated giant cell pneumonitis (Cugell et al.,
7 1990). Increases of lymphocytes and neutrophils in bronchoalveolar lavage fluid indicated
8 active alveolitis. A metal-coating worker developed shortness of breath and interstitial
9 fibrosis with numerous macrophages and multinucleated giant cells following exposure for 7
10 years (Beckett, 1992). Fischbein et al. (1986) described two cases of interstitial lung disease
11 in hard-metal workers. Clinical signs included dyspnea and a productive cough. Lung
12 biopsy found interstitial fibrosis and giant cell interstitial pneumonia. Interstitial lung disease
13 leading to death, possibly as a complication of oxygen therapy, was reported in a case study
14 of a diamond polisher (Nemery et al., 1990). Autopsy revealed pronounced mural fibrosis of
15 the lung with an active interstitial and intraalveolar inflammatory exudate and multinucleated
16 giant cells in the alveolar lumina.
17 Rubin et al. (1986) found no evidence of lung fibrosis in 315 employees of two hard-
18 metal factories. No data on exposure levels were provided. It is not clear why no effect
19 was observed, but it could be because sensitive workers had left the department. Morgan
20 (1983) found no x-ray changes or effect on lung function in 46 workers exposed to 100 to
21 3,000 fig cobalt/m3 in the manufacture of cobalt salts; most exposures were below 1,100 jig
22 cobalt/m3. The study did not include two affected workers (one with asthma and one with a
23 positive cobalt skin test) who had moved out of the work area prior to the study. Pulmonary
24 function tests and x-ray analysis revealed no respiratory effects on 40 workers who had been
25 exposed to cobalt powder for an average of 11.3 years (Angerer et al., 1985). Average
26 cobalt levels were 49 to 1,046 /*g/m3. No details of the physiological analysis were
27 reported. Small sample size or the removal of a sensitive subpopulation could account for
28 the lack of respiratory effects in the Morgan (1983) and Angerer et al. (1985) studies.
29 Alternatively, the latter study suggests that respiratory effects may not occur following
30 exposure to cobalt powder at cobalt levels that would produce fibrosis in populations exposed
31 to cobalt in hard metal.
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1 Cardiovascular effects of cobalt were first noticed following large oral doses of cobalt
2 (Morin et al., 1971), but there is evidence suggesting that inhalation exposure to cobalt can
3 also cause cardiovascular effects. Horowitz et al. (1988) found a weak correlation between
4 reduced left ventricular function and duration of cobalt exposure in 30 hard-metal workers
5 who had been exposed to undetermined cobalt levels for 10±5 years. This result was
6 attributed to early cor pulmonale related to hard-metal pneumoconiosis. Kennedy et al.
7 (1981) reported a case of fatal myocardial disease due to occupational exposure to cobalt
8 powder; elevated cobalt levels were found in the myocardium. Subsequent personal
9 monitoring of workers at the factory revealed cobalt levels "well in excess" of 100 /ig/m3.
10 The cardiotoxic effects of cobalt have been attributed to cobalt producing a biochemical block
11 at the same point in the myocardial metabolic pathway as where a thiamine deficiency would
12 be evident (Heggtveit et al., 1970). Another case of fatal cardiomyopathy due to
13 occupational cobalt exposure was described by Barborik and Dusek (1972).
14 In comparing 12 hard-metal workers with pulmonary symptoms and 26 controls, the
15 exposed workers had verbal memory and attention deficits (Jordan et al., 1990). No
16 exposure information was available and no tests were conducted to determine the hard metal
17 component responsible for observed effects. Meecham and Humphrey (1991) reported that a
18 worker exposed to cobalt powder for 20 mo developed optic atrophy and nerve deafness.
19 Both symptoms lessened after exposure stopped; 3 mo postexposure, blood cobalt was
20 234 fj.g/L (normal <2 /xg/L).
21 Mur et al. (1987) assessed the effect of exposure to cobalt metal dust and cobalt
22 chloride on cancer mortality in an electrochemical plant. Among exposed workers, the lung
23 cancer death rate was elevated (SMR = 4.66; P<0.05). In a small case-control study,
24 cobalt exposure was more common among the lung cancer deaths than in the general plant
25 population, but the effect was not statistically significant. In addition, there were
26 concomitant exposures to other chemicals, such as arsenic and nickel.
27 No studies were located on the reproductive or developmental effects in humans of
28 inhaled cobalt compounds.
29
30
April 1995 11-250 DRAFT-DO NOT QUOTE OR CITE
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1 Laboratory Animal Data
2 Inhalation toxicity data for laboratory animals are summarized in Table 11-31. Studies
3 in laboratory animals confirm the respiratory tract as the major target of cobalt toxicity.
4 Acute exposure to high levels have also found effects on the thymus and testes. Animal
5 studies differ from the available human studies in reporting effects on the upper respiratory
6 tract, including the nose and larynx, that were not reported in humans. This may be due to
7 the use of a soluble cobalt compound in the laboratory animal studies, to the greater
8 sensitivity of URT evaluation (e.g., histopathology) in laboratory animal studies, to
9 differences in URT dosimetry between laboratory animal species and humans, to the the high
10 exposures used in experimental studies, or to species sensitivity. Polycythemia (nonadverse
11 increases red blood cells) occurs at higher cobalt concentrations as a result of the role of
12 cobalt and vitamin B12 in hematopoiesis.
13 Only two studies were found on the effects of acute exposure of animals to cobalt
14 compounds. Rats exposed to mixed cobalt oxides at >7,000 /^g/m3 for 30 min had
15 pulmonary edema (Palmes et al., 1959). Bucher (1991) exposed rats and mice to 38, 190,
16 1,900, 19,000, or 76,000 /xg cobalt/m3 as cobalt sulfate for 6 hours/day, 5 days/week, for 16
17 exposures. Effects at <1,900 jug/m3 were poorly described, but red discoloration of the
18 lungs was reported at 1,900 jug/m3 in rats. Histopathological changes included inflammation
19 and necrosis of the respiratory epithelium of the larynx, trachea, brochioles, and respiratory
20 turbinates of the nose. These effects were seen at > 19,000 ^g/m3 in rats, and
21 >1,900 jug/m3 in mice, the only levels that were histologically analyzed.
22 In F344/N rats and B6C3Fj mice exposed to a cobalt sulfate aerosol at 0, 110, 380,
23 1,140, 3,800, or 11,400 /-ig/m3 for 6 hours/day, 5 days/week for 13 weeks, compound-
24 related lesions were limited to the respiratory tract (Bucher, 1991; Bucher et al., 1990). At
25 the lowest concentration, squamous metaplasia of the larynx and infiltration of histiocytes to
26 the alveolar space were observed in both rats and mice. Effects at higher concentrations
27 (>3,800 £ig/m3) included fibrosis, inflammation, and degeneration of the olfactory
28 epithelium, but no evidence of heart damage, based on histopathology or enzyme levels.
29 Among miniature swine exposed to pure cobalt metal powder to 100 or 1,000 pig/m3
30 for 6 hours/day, 5 days/week for 3 mo, total compliance and tidal volume were decreased,
April 1995 H_25i DRAFT-DO NOT QUOTE OR CITE
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.
TABLE 11-31. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR COBALT
AND COMPOUNDS
1
£
bl
N)
O
%
H
6
o
5/
0
H
O
Exposure
Concentration Exoosure
ppm pg Co/m3 protocol
Acute Studies
N/A 0 30 min
7000
26000
83000
90000
106000
116000
137000
179000
236000
N/A 0 6h/d
38 5 d/wk
190 16 exp
1900
19000
76000
Chemical
form
Cobalt
mixed
oxide,
cobalt
carbonate
dust
Cobalt
sulfate
(CoSO4 •
7H20)
aerosol
Particle size and Species, Strain,
distribution (Number) Sex
"the overall Rat, NS
median size was (5) NS
0.1 fj.m
diameter, or 0.3
/tm mass median
diameter. There
are many
particles of about
0.01 /*m
diameter. "
1 ura MMAD Rat, F344/N
range: 0.83- (5)M,
1.10/im (5)F
Assays performed: Effect(s)
Lung and body wt, gross necropsy: Pulmonary edema at 7000
and up. Gross damage (defined as "any one or more of
hemorrhage, edema, consolidation, congestion, pleuritis,
bronchiectasis, emphysema, or atelectasis") observed at all
levels. Animals were sacrificed 24 h postexposure.
Note: In a separate experiment, deaths were observed at
^78000 following a 30 min exposure.
Note: The exposure material was not well characterized, but
was produced as breakdown products of cobalt carbony 1.
Histology of major organs (3 top levels), wt gain, lethality: No
effect on wt gain or survival at <1900. Resp tract lesions
reported at 1900, but not further described, except "red
discoloration and increased firmness in the lungs." Survival dec
at > 19000 in males and at 76000 in females. HP described at
only at S 19000, and included (at both levels) inflammation and
necrosis of resp epithelium of larynx, trachea, bronchioles, and
respiratory turbinates of nose; degeneration of olfactory
epithelium of nose; squamous metaplasia of the larynx.
Hemorrhage into alveolar spaces at 76000. Also lymphoid
necrosis of thymus in animals that died, and atrophy of testis at
19000.
Reference
Palmes et al.
(1959)
Bucher (1991)
n
3
-------
TABLE 11-31 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR COBALT
AND COMPOUNDS
K>
Ui
u>
O
o
1
o
c
o
a
o
o
Exposure
Concentration
ppm /tg Co/m3
N/A 0
38
190
1900
19000
76000
Subchronic and
N/A 0
9000
N/A 0
400
2000
Exposure
protocol
6h/d
5 d/wk
16 exp
Chronic
7h/d
5 d/wk
3 mo
6h/d
5 d/wk
14-16 wk
Chemical
form
Cobalt
sulfate
(CoSO4 •
7H2O)
aerosol
Cobalt
mixed
oxides,
cobalt
carbonate
dust
Cobalt
chloride
Particle size and Species, Strain,
distribution (Number) Sex
1 /tm MMAD Mouse, B6C3F!
range: (5) M,
0.83-1. 10 /un (5)F
"the overall Rat, NS
median size was (41-75) NS
0.1 /xm
diameter, or 0.3
/xm mass median
diameter. There
are many
particles of about
0.01 /xm
diameter. "
MMAD -1/xm Rabbit, NS
ffg NS (8) M
Assays performed: Effect(s) Reference
Histology of major organs (3 top levels), wt gain, lethality: Bucher
Survival dec at > 19,000 /*g/m3. Animals also lost wt at 19,000 (1991)
/tg/m3. HP showed the following at > 1900: inflammation and
necrosis of the respiratory epithelium of larynx, trachea,
bronchioles, and respiratory turbinates of nose; degeneration of
olfactory epithelium of nose. At 19,000 /xg/m3, squamous
hyperplasia of the larynx and regeneration of the bronchiolar
epithelium in the lung. Animals that died also had lymphoid
necrosis of thymus, necrosis of hepatocytes.
Note: No HP done at 38 or 190 /xg/m3.
Body wt, gross necropsy, HP of major organs, hematology, Palmes et al.
urinary cobalt: Lung edema, nodules consisting of large (1959)
macrophages with foamy cytoplasm. Also moderate interstitial and
peribronchial fibrosis, mild emphysema, moderate penbronchial
lymphoid hyperplasia. Inc hemoglobin in exposed animals (not
necessarily adverse). No effect on organs other than lung.
Note: 1 1 deaths at beginning of experiment attributed to infection
weakening resistance to cobalt.
Note: The exposure material was not well characterized, but was
produced as breakdown products of cobalt carbonyl.
LM and EM of lung: Interstitial inflammation and abnormal Johansson et
accumulation of enlarged alveolar macrophages at both levels. al. (1987)
Also nodular aggregation of type II cells, and focal swelling of
type I and type II cells, with some type II cells missing microvilli.
Incidence and severity inc with exp concentration.
-------
TABLE 11-31 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR COBALT
AND COMPOUNDS
o
O
o
z
3
O
g
n
Exposure
Concentration
ppm /ig Co/m3
N/A 0
110
380
1140
3800
11400
N/A 0
110
380
1140
3800
11400
N/A 0
100
1000
Exposure
protocol
6h/d
5d/wk
13 wk
6h/d
5d/wk
13 wk
6h/d
5d/wk
3 mo
Chemical
form
Cobalt
sulfate
(CoSO4 -
7H20)
aerosol
Cobalt
sulfate
(CoSO4 •
7H20)
aerosol
Cobalt
metal
powder
Particle size and Species, Strain,
distribution (Number) Sex Assays performed: Effect(s)
1 /*m MMAD Rat, F344/N Histology of resp tract, hematology, thyroid function, urinalysis,
range: 0.83- (10) M, (10) F serum chemistry, sperm morphology, vaginal cytology, estrous
1.10 pm stage, wt. gain, lethality: Squamous metaplasia of the larynx,
infiltration of histiocytes to alveolar space at 110. More severe
effects on lung, nose, and larynx at higher levels. Inc relative
kidney and lung wt in males at all levels, and inc lung wt in
females at >380. No effects on sperm parameters or estrous
cycle.
Note: Total amount of Co in 16 h urine ranged from 2.5 to 105
jig in males and from 2.0 to 67 /ig in females (from low to high
exposure level).
1 p,m MMAD Mouse, B6C3F^ Histology of resp tract, hematology, thyroid function, urinalysis,
range: 0.83- serum chemistry, sperm morphology, vaginal cytology, estrous
1.10/tm (10) M, (10) F stage, wt. gain, lethality: Compound-related HP was limited to
resp tract and were concentration related. At 110, squamous
metaplasia of the larynx, infiltration of histiocytes to alveolar
space. Similar effects at 380. More severe effects on lung,
nose, and larynx at higher levels, including degeneration of
olfactory epithelium, squamous metaplasia of respiratory
epithelium of nose at >3800. Inc absolute and relative lung wt
at >3800. Dec epididymal wt in males at 11400, and sig dec
sperm motility at >1140. Estrous cycle sig longer at 11400.
size range 0.4 to Swine, PF, ECG, x-ray, biopsy, urinary Co: Dec compliance and tidal
3.6 pin Miniature volume at >100; cardiomyopathy; no visible effect on x-ray; no
ffg NS (5) NS interstitial fibrosis or alveolar exudate
Note: Exp for a week, not exp for 10 days to allow for the
development of sensitization, and then exp for 3 mo.
Reference
Bucher et al.
(1990); Bucher
(1991)
Bucher et al.
(1990); Bucher
(1991)
Kerfoot et al.
(1975)
-------
a
SO
to
T1
H
6
O
Z
O
H
O
TABLE 11-31 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR COBALT
AND COMPOUNDS
Exposure
Concentration
ppm jtg Co/m3
N/A 0
1000
N/A 0
500
2000
N/A 0
7,900
Exposure
protocol
6h/d
5d/wk
13 wk
6h/d
5d/wk
1-8 mo
7 h/day
5 days/week
14 mo
Chemical
form
Cobalt
dust
Cobalt
chloride
Cobalt
oxide
aerosol
Particle size and Species, Strain,
distribution (Number) Sex
MMAD = Rat, F344
~4.1/iin (24) M
trg = 1.9
NS Rabbit, NS
(NS)M
"Respirable" Hamster, Syrian
aerosol golden
(51) M
Assays performed: Effect(s)
PF (lung volume, static and dynamic mechanics, DLCO), HP
of lung: No effect on lung function. End-airway
inflammation, mild-to-moderate interstitial thickening.
Foamy macrophages, suggesting lipid accumulation.
Note: Observed HP more severe in combination with
15000 /ig/m3 tungsten carbide.
LM and EM of lung, morphology and function of alveolar
macrophages, phospholipid levels: Nodular proliferation of
type II alveolar cells and macrophage stimulation after 1 mo
of exposure at 500. At 4 mo, nodular hyperplasia of type II
cells, accumulation of enlarged macrophages, hyperreactive
type II cells, interstitial inflammation at >500.
HP: Pneumoconiotic lesions with emphysema component;
tumor incidence: No carcinogenic effects seen.
Note: Few study details available.
Reference
Costa et al.
(1990)
Johansson and
Camner (1986)
Wehner etal.
(1972)
Abbreviations:
avg = average; B = both male and female; BAL = bronchoalveolar lavage; Co = cobalt; CO = carbon monoxide; CS = clinical signs; d = day; dec =
decreased; dep = depending; DI^o = diffusing capacity for carbon monoxide; ECG = electrocardiogram; EM = electron microscopy; exp = exposure; F =
female; FEVj = forced expiratory flow in 1 second; FEV1% = forced expiratory flow at 1%; FVC = forced vital capacity; geom = geometric; h = hour; HP
= histopathology; inc = increased; LM = light microscopy; M = male; MEF75 = mean expiratory flow at 75%; MMAD = mass median aerodynamic diameter;
mo = month; N/A = not applicable; nonsig = nonsignificant; NS = not specified; occup = occupational; PF = pulmonary function; PEFR = peak expiratory
flow rate; pop = population; ppm = parts per million; resp = respiratory; sig = significantly); SMR = standard mortality ratio; TCOSS = steady state carbon
monoxide uptake; VC = vital capacity; wk = week; wt = weight; yr = years.
n
HH
H
W
-------
1 but there was no histological evidence of inflammation, interstitial pneumonitis, or fibrosis
2 (Kerfoot et al., 1975). Cardiomyopathy was observed at both levels.
3 Male rabbits exposed to 500 or 2,000 /*g/m3 cobalt as cobalt chloride for 6 hours/day,
4 5 days/week for 4 mo developed nodular hyperplasia of type II alveolar cells and
5 accumulation of enlarged macrophages in reactive areas (Johansson and Camner, 1986).
6 Evidence from several studies in animals suggests that the symptoms of hard-metal
7 disease are due to cobalt rather than tungsten carbide, but the presence of tungsten carbide
8 can exacerbate the respiratory effects of cobalt exposure. Costa et al. (1990) reported in an
9 abstract that end-airway inflammation and interstitial thickening was more severe in rats
10 exposed to 1,000 pig cobalt/m3 and tungsten carbide (15,000 pig/m3) than in rats exposed to
11 1,000 fig cobalt/m3 alone. Lasfargues et al. (1992) found higher mortality and more severe
12 lung inflammation in rats exposed by intratracheal installation to suspensions of tungsten
13 carbide-cobalt (cobalt dose 10,000 /*g/kg), compared with rats exposed to cobalt
14 (10,000 jug/kg) alone. Urinary cobalt was higher when the cobalt was co-administered with
15 tungsten carbide, suggesting that tungsten carbide may increase cobalt absorption. In an in
16 vitro study, Lison and Lauwerys (1990) found that adding tungsten carbide increased cobalt
17 uptake in mouse and rat macrophages, and increased the resulting cytotoxicity.
18 In the one study located that assessed the carcinogenicity of inhalation exposure to
19 cobalt, treatment of hamsters with 7,900 ptg cobalt/m3 as cobalt oxide for 7 h/day, 5
20 days/week for 14 mo did not increase the incidence of benign or malignant tumors; however,
21 pneumoconiosis with lung consolidation was seen in animals with increasing age and
22 exposure time (Wehner and Craig, 1972).
23 No studies were located on the reproductive or developmental effects in animals of
24 inhaled cobalt compounds.
25
26 11.6.8.4 Factors Affecting Susceptibility
27 Because the primary target of inhaled cobalt is the respiratory tract, individuals with
28 respiratory impairments may be at increased risk for toxic effects. Some cobalt-exposed
29 workers develop an immune reaction to cobalt that is associated with asthma (Roto 1980;
30 Shirakawa et al., 1988, 1989). People who have developed this hypersensitivity would be
31 expected to be affected by cobalt toxicity at much lower levels than others. The developing
April 1995 11-256 DRAFT-DO NOT QUOTE OR CITE
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1 respiratory tract of children may also pose an increased susceptibility. Sprince et al. (1988)
2 also reported that certain individuals were more sensitive than others to interstitial lung
3 disease resulting from cobalt exposure. Because some of the more sensitive workers were
4 not reported to have experienced previous exposure to a sensitizing concentration, it appears
5 that some unknown mechanism may account for their increased susceptibility. Two different
6 mechanisms may be operating to determine sensitive subpopulations for the two different
7 endpoints (asthma and interstitial lung disease).
8 Oral (Morin et al., 1971) and inhalation (Horowitz et al. 1988; Kennedy et al. 1981)
9 exposure to cobalt has been associated with cardiovascular effects. This suggests that people
10 with cardiovascular disease may have increased susceptibility to cobalt toxicity.
11
12 11.6.9 Copper
13 11.6.9.1 Chemical and Physical Properties
14 Copper is a reddish colored, malleable, ductile metal that has a bright metallic luster.
15 It may be found in nature in its elemental form. Copper is the first element of group 11 (IB)
16 of the periodic system of elements. Copper demonstrates four oxidation states, 0, +1, +2,
17 and +3, of which +1 and +2 are the most important (George, 1993; Hazardous Substance
18 Data Bank, 1995; Richardson, 1993). When elemental copper is exposed to water or moist
19 air, copper sulfides and oxides are initially formed. Further oxidation and reaction with
20 water yields basic copper sulfates, such as CuSO4 • Cu(OH)2 and CuSO4 • 3Cu(OH)2
21 (George, 1993). Copper(+l) disproportionates spontaneously in aqueous solutions to
22 elemental copper and copper(+2) (Richardson, 1993). Copper(+2) is the most stable
23 oxidation state (Brady and Humiston, 1986). Copper forms compounds with the anions of
24 both strong and weak acids (George, 1993). It also forms organometallic compounds
25 (Richardson, 1993). Elemental copper is insoluble in water, whereas copper (+1) chloride
26 (CuCl), copper (+2) chloride dihydrate (CuCl2 • 2H2O) and copper sulfate pentahydrate
27 (CuSO4 • 5H2O) are poorly soluble at low temperatures (ca 0 °C) and moderately soluble at
28 high temperatures (ca. 100 °C).
29
30
April 1995 i1.257 DRAFT-DO NOT QUOTE OR CITE
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1 11.6.9.2 Pharmacokinetics
2 There is limited information on the pharmacokinetic properties of copper following
3 inhalation exposure. There are no studies available regarding the rate and extent of
4 distribution or excretion of copper following inhalation exposure of humans or laboratory
5 animals. Most of the following information provided on copper absorption, distribution,
6 metabolism and excretion are based on oral exposure data.
7 Serum copper levels were reported in humans in the range of 100 to 220 j*g/dL in
8 humans following chronic occupational exposure to copper dust (Suciu et al., 1981).
9 Armstrong et al. (1983) reported human urinary copper levels ranging from <20 to
10 180 ug/L after acute exposure to copper fumes. In animals, Batsura (1969) reported that
11 copper oxide was observed in alveolar capillaries 3 h after rats were exposed to a welding
12 dust aerosol generated from pure copper wires.
13 According to oral exposure studies, absorbed copper loosely binds to and is transported
14 by plasma albumin (Marceau et al., 1970), or the plasma protein transcuprein (Weiss and
15 Under, 1985). At the liver it is incorporated into ceruloplasmin and released into the
16 plasma. Copper metabolism involves the transfer to and from various organic ligands, most
17 notably sulfhydryls and imidazole groups on amino acids and proteins. Copper is stored
18 bound to metallothionein and amino acids and in association with copper-dependent enzymes.
19 There are several studies that have shown an increase in metallothionein synthesis in animals
20 injected with copper compounds; however, metallothionein synthesis has not been
21 investigated following inhalation exposure (Mercer et al., 1981; Sugawara et al., 1991; Wake
22 and Mercer, 1985). Mehra and Bremner (1984) suggested that increased levels of
23 metallothionein may be associated with resistance to copper toxicity in pigs. Exposure to
24 high levels of dietary copper has also been shown to induce ceruloplasmin biosynthesis in the
25 liver (Haywood and Comerford, 1980). As previously stated, copper is incorporated into
26 ceruloplasmin in the liver and then released into the plasma. Bile is the major excretion
27 pathway for copper based on oral exposure studies. Oral administration of radioactive
28 copper, as copper acetate, resulted in 72% excreted in the feces (Bush et al., 1955).
29 Normally, 0.5 to 3.0% of daily copper intake is excreted into the urine (Cartwright and
30 Wintrobe, 1964). Biliary copper is associated with low molecular weight copper binding
April 1995 11-258 DRAFT-DO NOT QUOTE OR CITE
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1 components as well as macromolecular binding species (Gollan and Dellar, 1973). Fairer
2 and Mistilis (1967) reported that the reabsorption of biliary copper is negligible.
3
4 11.6.9.3 Health Effects
5 Human Data
6 The data on human exposure to copper by inhalation are limited. The major target
7 organ appears to be the respiratory system, but the data are limited to occupational studies.
8 Data are primarily based on subjective symptoms without indications of pulmonary function
9 changes as a result of occupational exposure as discussed in Table 11-32. The observed
10 symptoms may also be due to exposure to copper by both oral and inhalation routes since
11 exposures were confounded. The lack of control workers is also a limitation in evaluating
12 the human data available for copper exposure by inhalation.
13 Acute inhalation exposure to copper in humans has primarily resulted in a combination
14 of respiratory symptoms (Armstrong et al., 1983). Upper respiratory irritation has been
15 reported with exposure to copper fumes; however, exposure data were not provided
16 (American Conference of Governmental Industrial Hygienists, 1991). Armstrong et al.
17 (1983) reported the following symptoms (in order of number of workers affected): fever,
18 dyspnea, chills, headache, nausea, myalgia, cough, shortness of breath, a sweet metallic taste
19 and vomiting in factory workers accidentally exposed to copper fumes for 1 to 10 h as a
20 result of cutting pipes known to contain copper. These symptoms are consistent with metal
21 fume fever, an acute disease induced by inhalation of metal oxides that temporarily impairs
22 pulmonary function but does not progress to chronic lung disease (Stokinger, 1981).
23 Airborne copper concentration during the exposure period was not reported. It was reported
24 that 5 of 12 workers hospitalized following the acute exposure had urine copper levels
25 greater than 50 /*g/L. Since the major route of excretion of copper is biliary, the elevated
26 urine copper levels reported suggest that the exposure concentration was relatively high.
27 Copper levels were not determined for control workers in this study which limits the
28 interpretation of the urinary copper values as an indicator of copper inhalation exposure.
29 Armstrong et al. (1983) also reported evidence of minimal elevation of serum lactate
30 dehydrogenase (in 3 of 14 workers evaluated) and leukocytosis (in 21 of 24 workers
31 evaluated). Nonspecific complaints of discomfort and chills were reported among several
April 1995 H_259 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-32. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COPPER AND COMPOUNDS
&• Exposure Concentration Exposure Chemical
so ppm fig Cu/m3 protocol form
Particle size and
distribution
Species, Strain
(Number) Sex
Assays performed: Effect(s)
Reference
O
O
5*
O
H
O
s
H
W
Acute Studies
N/A
NS
1-10 h occup Cu fumes NS
Human
(26) NS
Subjective symptoms and clinical tests (CBC,
LDH determination, urinalysis) after outbreak of
metal fume fever: Fever, dyspnea, chills,
headache, nausea, myalgia, cough, shortness of
breath, sweet metallic taste, vomiting.
Leukocytosis, elevated LDH levels, 5/12 workers
had urine copper levels > 50 jtg/L.
Workers were cutting pipes known to contain
approx 90% Cu, 10% Ni, trace amounts of Zn.
Armstrong et
al. (1983)
N/A 75,000-
120,000
N/A NR
few weeks Cu dust "extremely fine" Human
occup (NS)
1-60 mo Cu(II) NS Human
occup dust (10) M
Subjective symptoms: Complaints of discomfort
similar to onset of common cold; chills or
warmth; stuffiness of the head.
Note: Actual exposures may have been higher
when work being carried out. Symtpoms ceases
when ventilation improved.
Nose and throat examinations, subjective
symptoms: 6/11 workers had nasal mucosa
characterized by increased vascularity and
superficial epistatic vessels. Symptoms included
runny nose and mucosal irritation in mouth and
eyes.
Gleason (1968)
Askergren and
Mellgren (1975)
Q
s
-------
TABLE 11-32 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR COPPER AND COMPOUNDS
Exposure
Concentration
ppm ng Cu/m3
Exposure Chemical Particle size and
protocol form distribution
Species, Strain
(Number) Sex,
Assays performed
: Effect(s)
Reference
Chronic Studies
N/A 464,000
(464,000 1st
4 year occup Cu dust NS
99.9%
Human
(75-100) NS
Annual examinations in the
categories:
following
Suciu et al.
(1981)
year;
132,000 2nd
year;
111,0003rd
year; NR
4th year)
Respiratory: Radiography showed linear
pulmonary fibrosis and in some cases
nodulation. Symptoms included coughing,
sneezing, yellowish-green expectoration, and
thoracic pain.
Gastrointestinal: Symptoms included anorexia,
nausea, and diarrhea.
Hepatic: Hepatomegaly (39% in first yr, 50%
in second yr, 70% in third yr, 56% in fourth
year).
Neurological: Symptoms in >17% included
headache, vertigo, drowsiness, polyneuritic
syndromes with subjective troubles of
sensitivity (paresthesia and spontaneous pains in
limbs), irritability, disturbances in motor
reactions, neurasthenic syndrome.
Serum copper levels in polyneuritic syndrome
were 100-180 ug/dL, in neurasthenic syndrome
they were 180-220 ug/dL.
Reproductive: Sexual impotence in 16% of
workers.
Abbreviations:
1st = first; 2nd = second; 3rd = third; 4th = fourth; approx = approximately; Cu = copper; CuSO4 = copper sulfate; CuCl2 = copper chloride; d = day;
dec = decreased; HP = histopathology; inc = increased; h = hour; LDH = lactate dehydrogenase; LM = light microscopy; M = male; |tg/m3 = micrograms
per cubic meter; MMAD = mass median aerodynamic diameter; mo = month; NA = not applicable; NET = nitroblue tetrazolium; Ni = nickel; NS = not
specified; occup = occupational exposure; ppm = parts per million; SEM = scanning electron microscopy;
-------
1 workers within a few weeks of beginning operation of a copper plate polishing operation.
2 Exposure levels of 75 to 120 pig/m3 were measured (Gleason, 1968).
3 In a epidemiological study by Suciu et al. (1981), factory workers exposed to copper
4 dust received annual physical and clinical examinations during a 4 year exposure period.
5 The reported air copper levels were not reported for the first year, were 464,000 /xg Cu/m3
6 in the second year; 132,000 /^g Cu/m3 in the third year; and 111,000 ^g Cu/m3 in the fourth
7 year. Although inhalation was considered to be the major route of exposure for these
8 workers, it was likely that a portion of the airborne copper was trapped in the upper
9 respiratory tract and swallowed. This assumption was made based on the gastrointestinal
10 effects that were observed in these workers in addition to the respiratory effects. Respiratory
11 effects reported included symptoms of coughing, sneezing, yellowish-green expectoration,
12 dyspnea, and thoracic pain. Radiography revealed linear pulmonary fibrosis and in some
13 cases nodulation. Gastrointestinal symptoms included anorexia, nausea and diarrhea.
14 Hepatic effects included hepatomegaly (39% in first year, 50% in second year, 70% in third
15 year and 56% in fourth year). Neurological symptoms in > 17% of the workers included
16 headache, vertigo, drowsiness, polyneuritic syndromes with subjective troubles of sensitivity
17 (parathesia and spontaneous pains in limbs), irritability, disturbances in motor reactions and
18 neurasthenic syndrome. Serum copper levels were also determined and were at levels of 100
19 to 180 /xg/dL in polyneuritic syndrome subjects, and 180 to 220 /xg/dL in neurasthenic
20 syndrome subjects. Sexual impotence was reported in 16% of workers examined.
21 Limitations of this study include the absence of a control group, poor description of study
22 design and the lack of statistical analysis of data.
23 Respiratory effects were also noted in a report by Askergren and Mellgren (1975).
24 Nose and throat examinations were performed in sheet-metal workers exposed to copper
25 dust. Six of 11 workers had nasal mucosa characterized by increased vascularity and
26 superficial epistatic vessels. This was accompanied by symptoms of runny nose and mucosal
27 irritation in the mouth and eyes.
28
29 Laboratory Animal Data
30 As with human exposure, the respiratory system appears to be the primary site of injury
31 following inhalation exposure to copper. Table 11-33 summarizes the available toxicity data
April 1995 11-262 DRAFT-DO NOT QUOTE OR CITE
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>
T3
2.
vo
to
O\
U)
TABLE 11-33. LABORATORY ANIMAL EXOPOSURE CONDITIONS AND EFFECTS FOR COPPER
AND COMPOUNDS
Exposure
Concentration
ppm
N/A
Hg Cu/m3
0
560
Exposure
protocol
3 h/day
Chemical
form
CuSO4
aerosol
Particle size and
distribution
MMAD =
0.54 urn
Species, Strain
(Number) Sex
Mouse, CD1
(23-100) B
Assays performed: Effect(s)
Tracheobronchial lavage for total and
differential cell count, viability and ATP
Reference
Drummond et al.
(1986)
1,210
3,300
<7g = 2.07
content, trachea! HP, tracheal cilia beating
frequency, subgroups simultaneously
challenged with Streptococcus zooepidemicus
aerosol to determine mean survival time,
subgroups simultaneously exposed to 35S-
Klebsiella pneumoniae aerosol to determine
pulmonary bactericidal activity: Dec mean
survival time >560 /tg/m3. Dec bactericidal
activity at 3,300 /*g/m3. No effect on lavage
parameters, tracheal cilia beating frequency or
histology.
N/A
0 3 h/day
1,210
3,300
CuSO4
aerosol
MMAD = 0.54
/im
ffg = 2.07
Hamster, Syrian
golden
(4)NS
Tracheal cilia beating frequency
Dec cilia beating frequency and
epithelium at 3,300 /*g/m3.
, tracheal HP:
abnormal
Drummond et al.
1986
O
O
Z
O
H
O
I
O
&
n
i—i
H
W
-------
a.
TABLE 11-33 (cont'd). LABORATORY ANIMAL EXOPOSURE CONDITIONS AND EFFECTS FOR
COPPER AND COMPOUNDS
Exposure
Concentration
ppm
N/A
Mg Cu/m3
0
120
130
Exposure
protocol
3 h/day
5 days/week
1-2 weeks
Chemical
form
CuS04
aerosol
Particle size and
distribution
MMAD = 0.54
af = 2.07
Species, Strain
(Number) Sex,
Mouse, GDI
(4)NS
Assays performed: Effect(s)
Respiratory tract HP (SEM), subgroups
simultaneously challenged with 5.
zooepidemicus aerosol to determine mean
Reference
Drummond et al.
(1986)
survival time, subgroups simultaneously
exposed to 35S-AT. pneumoniae aerosol to
determine pulmonary bactericidal activity:
Slight alveolar thickening and irregularities
after 5 exposures at 120 fig/m3, extensive
thickening with many walls fused into irregular
masses after 10 exposures at 130 fig/m3. Dec
mean survival time after 10 exposures at 130
/ig/m3. Dec bactericidal activity in both
exposure groups.
£ N/A
O
(* N/A
T1
H
6
o
0
H
O
d
o
0
120
130
0
600
3h/d
5d/wk
1-2 wk
6h/d
5d/w
1 mo
CuSO4
aerosol
CuCl2
aerosol
MMAD =
0.54 /im
ag = 2.07
MMAD range =
0.5-11 jon
Hamster, Syrian
golden
(4)NS
Rabbit, NS
(8)M
Respiratory tract HP (SEM), tracheal cilia
beating frequency: No change in frequency.
Normal epithelium.
Pulmonary lavage for number and variance of
macrophages, LM and SEM of alveolar
macrophages, oxidative metabolism determined
by ability to reduce NBT, macrophage bacterial
capacity: Slightly increased amount of
lamellated cytoplasmic inclusions.
Drummond et al.
(1986)
Johansson et al.
(1983)
0
-------
I
5
wi
TABLE 11-33 (conf
Exposure
Concentration Exposure
ppm /*g Cu/m3 protocol
N/A 0 6 h/d
600 5 d/wk
4-6 wk
d). LABORATORY ANIMAL EXOPOSURE CONDITIONS AND EFFECTS FOR
COPPER AND COMPOUNDS
Chemical
form
CuCl2
aerosol
Particle size and Species, Strain
distribution (Number) Sex, Assays performed: Effect(s) Reference
NS Rabbit, NS Microscopy: Minor lymphocytic or eosinophilic Johansson et
(8) M inflammatory infiltrates noted, however, (1984)
incidence was similar to controls. Volume
density of alveolar type II cells increased
slightly.
al.
to
N/A 0
600
6 h/d CuCl2 NS
5 d/wk aerosol
4-6 wk
Rabbit, NS
(8)M
Lysozyme (muramidase) concentration and
number of alveolar macrophages: No effect.
Lundborg and
Camner (1984)
Abbreviations:
B = both males and females; Cu = copper; CuSO4 = copper sulfate; CuCl2 = copper chloride; d = day; dec = decreased; HP = histopathology; inc =
increased; h = hour; LDH = lactate dehydrogenase; LM = light microscopy; M = males; jtg/m3 = micrograms per cubic meter; MMAD = mass median
aerodynamic diameter; mo = month; NA = not applicable; NET = nitroblue tetrazolium; Ni = nickel; NS = not specified; ppm = parts per million; SEM
= scanning electron microscopy; a. = geometric standard deviation of distribution; wk = week; yr = years; Zn = zinc.
S
o
d
o
H
M
O
90
n
-------
1 for laboratory animals. Drummond et al. (1986) reported a decrease in tracheal cilia beating
2 frequency following a single exposure to 3,300 /xg Cu/m3 (as a copper sulfate aerosol) in
3 hamsters, but not in mice exposed to the same level. This respiratory effect was not seen
4 with repeated exposures at lower levels. Histological examination of the trachea revealed
5 abnormal epithelium in hamsters at 3,300 /zg Cu/m3, supporting the observation of decreased
6 Cu/m3 or 10 exposures at 130 /xg Cu/m3) led to alveolar thickening and respiratory tract
7 irregularities, which worsened with increased duration of exposure, cilia beating frequency.
8 In mice repeatedly exposed to copper sulfate (5 exposures at 120 /ug
9 Immunological effects were observed in mice (Drummond et al., 1986) and in rabbits
10 (Johansson et al., 1983) exposed to copper sulfate aerosols. Mice exposed to either a single
11 concentration of 560 /xg Cu/m3 or 10 exposures to 130 ^ig Cu/m3, and simultaneously
12 challenged with an aerosol of Streptococcus zooepidemicus had decreased survival time
13 (Drummond et al., 1986). Decreased bactericidal activity was also observed in mice after
14 exposure to an aerosol of Klebsiella pneumonia after single or repeated exposures to copper
15 sulfate aerosols (Drummond et al., 1986), suggesting that copper can inhibit the function of
16 alveolar macrophages. After inhalation exposure, Johansson et al. (1983) also observed a
17 slight increase in the amount of lamellated cytoplasmic inclusions in alveolar macrophages.
18 Exposures of rabbits to copper chloride aerosols for 4 to 6 weeks resulted in a minor
19 increase in volume density of alveolar Type 2 cells and minor levels of lymphocytic or
20 eosinophilic inflammatory infiltrates (Johansson et al., 1984).
21
22 11.6.9.4 Factors Affecting Susceptibility
23 Because the respiratory system is a target of inhaled copper (Armstrong et al., 1983;
24 Suciu et al., 1981), individuals with respiratory impairments may be at increased risk, and
25 the developing respiratory tract in children may also be more susceptible.
26 Other information on factors increasing susceptibility to copper are limited to data from
27 oral exposure, but many of these factors may be relevant for inhalation as well, since several
28 inhaled copper compounds are absorbed from the lungs. For example, patients with
29 Wilson's disease (hepatolenticular degeneration) have an impaired ability to maintain copper
30 homeostasis, and so are highly susceptible to copper toxicity. Wilson's disease is an
31 autosomal recessive disorder characterized by increased retention of hepatic copper,
April 1995 11-266 DRAFT-DO NOT QUOTE OR CITE
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1 decreased biliary copper excretion, decreased plasma ceruloplasmin, and hypercupruria
2 (Schroeder et al., 1966).
3 Because of the liver's key role in copper storage, ceruloplasmin synthesis, and copper
4 excretion into bile, metabolic or pathologic dysfunction would probably disrupt copper
5 homeostasis, thus making persons with liver damage more susceptible to copper toxicity.
6 Similarly, homeostasis is maintained by increasing urinary copper excretion when copper
7 intake is high, such that people with impaired renal function might have difficulty in
8 increasing renal copper excretion to handle a high copper intake; but it is dubious that
9 environmental inhalation exposure to copper would be high enough for these issues to be a
10 factor.
11 Infants under one year of age have increased susceptibility to copper toxicity because
12 they have not yet developed the homeostatic mechanisms for clearing copper from the body
13 and preventing its entry via the intestine. This was seen in a study where two infant siblings
14 exposed to high levels of copper in tap water developed hepatosplenomegaly, but no effects
15 were observed in an older sibling or the parents (Mueller-Hoecker et al., 1988). Also, those
16 with inherited deficiency of the enzyme glucose-6-phosphate dehydrogenase are likely to be
17 more susceptible to toxic effects of oxidative stressors such as copper (Calabrese and Moore,
18 1979). The threshold for copper toxicity may be lower for such individuals with this
19 deficiency (Chugh et al., 1975).
20
21 11.6.10 Iron
22 11.6.10.1 Chemical and Physical Properties
23 Pure elemental iron is silvery-white or gray and a relatively soft, ductile, malleable
24 metal (Knepper, 1981). Elemental iron is rarely found in nature because it readily combines
25 with other elements such as oxygen and sulfur (Knepper, 1981). Iron is in Group VIII of the
26 periodic system of elements. Oxidation states of iron may range from -4 to +6, of which
27 +2 (ferrous) and +3 (ferric) are the most important (McArdle, 1981). Iron forms a large
28 number of inorganic compounds (e.g., oxides, carbonates, sulfates, chlorides, and sulfides)
29 and some carbonyls, e.g., iron pentacarbonyl (Blinder, 1986). In aqueous solutions,
30 iron(+2) ions are oxidized to iron(+3). Iron(+3) ions hydrolyze in solution to form aquo
31 species (Knepper, 1981). In dry air, elemental iron is stable but readily oxidizes in moist air
April 1995 11-267 DRAFT-DO NOT QUOTE OR CITE
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1 forming "rust" which is mainly hydrated iron oxide (Budavari, 1989). Elemental iron and its
2 most common compound, ferric oxide (Fe2O3), are insoluble in water, as is ferric or iron
3 pentacarbonyl, FeC5O5 or Fe(CO)5. Certain other iron compounds, e.g., ferric chloride
4 (FeCl3), ferric sulfate Fe^SO^, and ferric nitrate Fe(NO3)3 are water soluble.
5
6 11.6.10.2 Pharmacokinetics
7 No quantitative data were located on absorption of iron from the lungs of humans.
8 In rats, lung clearance of deposited iron oxide particles is slow after inhalation of iron oxide
9 (mass median aerodynamic diameter [MMAD] of 0.3 /mi) (Blinder, 1986). Creasia and
10 Nettesheim (1974) also reported increased iron accumulation in lungs after repeated exposure
11 of hamsters to ferric oxide.
12 The body normally contains about 3-5 grams of iron. Two-thirds of the iron in the
13 body are bound to hemoglobin in red blood cells. Therefore, whole blood concentration of
14 iron is directly proportional to the hemoglobin concentration. Approximately 10% of iron in
15 the body is found in myoglobin and iron-requiring enzymes. The remaining is bound to iron-
16 storage proteins (ferritin and hemosiderin) found mainly in the liver, bone marrow, and
17 spleen (Blinder, 1986). In tissues, the highest concentrations of iron are found in liver and
18 spleen, followed by kidney, heart, and skeletal muscle.
19 Transferrin, a j8rglobulin, is important in the metabolism of iron as it binds to iron and
20 transports iron in the plasma to storage tissues (e.g., bone marrow) (Blinder, 1986). Iron
21 can exist in two stable oxidation states, ferrous Fe(II) and ferric Fe(III). In most biological
22 fluids, Fe(II) is rapidly oxidized to its thermodynamically stable form, Fe(III), which forms
23 insoluble Fe(III) hydroxide complexes. These redox reactions are important in iron
24 metabolism because iron shuttles continuously between its ferrous and ferric state during
25 storage and transport processes (Marx, 1984). Iron is eliminated primarily in the urine and
26 feces (Blinder, 1986). Iron can also be eliminated via sweat, hair, and nails.
27
28 11.6.10.3 Health Effects
29 Human Data
30 Most of the available human inhalation data on iron are based on occupational
31 exposures to iron oxide, with effects limited to respiratory symptoms and dysfunction. There
April 1995 11-268 DRAFT-DO NOT QUOTE OR CITE
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1 are no acute human inhalation data on the effects of iron exposure. Health effects
2 information via inhalation route is limited on iron pentacarbonyl. No information was
3 located on the soluble iron salts including ferric chloride, ferric nitrate, and ferric sulfate.
4 Inhalation toxicity information on humans is summarized in Table 11-34.
5 Occupational exposure occurs from mining of iron ores, consisting mainly of oxide
6 forms. During the mining and during smelting and welding process, workers are often
7 exposed to dust containing iron oxides and silica, as well as other metals and substances. It
8 is known that exposure to iron oxides results in roentgenological changes in the lung due to
9 deposition of inhaled iron particles (Doig and McLaughlin, 1936; Musk et al., 1988;
10 Plamenac et al., 1974), designated variously as siderosis, iron pneumoconiosis, hematite
11 pneumoconiosis, iron pigmentation of the lung, and arc welder lung (Blinder, 1986).
12 Siderosis is prevalent in 5 to 15% of iron workers exposed for more than 5 years (Buckell
13 et al., 1946; Schuler et al., 1962; Sentz and Rakow, 1969). Exposure levels were reported
14 to exceed 10,000 ^ig iron/m3 by Sentz and Rakow (1969); but no exposure data were
15 presented for the other studies. A Romanian study (Teculescu and Albu, 1973) reported a
16 34% prevalence of siderosis in workers exposed to ferric oxide dust (3,500 to
17 269,000 /ig/m3); but radiological evidence of lung fibrosis was not observed. Complaints of
18 chronic coughing were reported by 80% of the workers. Morgan (1978) found a male
19 subject exposed chronically to ferric oxide (magnetite; Fe3O4) had symptoms of coughing and
20 sputum for 8-9 years and exhibited an abnormal chest x-ray, but pulmonary function tests
21 revealed no abnormalities. Stokinger (1984) reviewed the literature on occupational exposure
22 to iron oxide fumes, and concluded that most investigators considered the roentgenological
23 pulmonary changes, secondary to inhalation of iron dust (i.e., siderosis), as benign and did
24 not suspect them to progress to fibrosis. Although several case reports have described iron
25 oxide workers, with coughing and shortness of breath, exhibiting diffuse fibrosis in their
26 chest x-rays (Charr, 1956; Friede and Rachow, 1961; Stanescu et al., 1967), concurrent
27 exposure to other chemicals may have contributed to this finding (Chan-Yeung et al., 1982;
28 Sitasetal., 1989).
29 Several studies report high incidence of lung cancer mortality among workers exposed
30 to iron oxide in mines and smelters; but, in all cases, there was simultaneous exposure to
31 other potentially carcinogenic substances (Boyd et al., 1970; Faulds, 1957). Improvements
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TABLE 11-33. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR IRON AND COMPOUNDS
3.
h-*
°"
^
£>
^
o
§
H
6
o
x^
o
H
O
r^^
1
O
Exposure
Concentration
Exposure Chemical Particle size and
ppm /*g Fe/m3 protocol form distribution
Chronic Human
NA > 10,000 2mo-12yrlron NR
(occup) oxide
fume
NA NS >6yr Iron NR
(occup) oxide and
metallic
iron dust
NS >7yr Iron NR
(occup) oxide
dust
Species, Strain,
(Number) Sex
Human
(73) M
Human
(138) M,
(33) F
Human
(13) M (control)
(16) M (exposed)
Assays performed: Effect(s) Reference
Subjective symptoms, chest x-ray: Sentz and
Siderosis in 3 males. Note: Rakow (1969)
concurrent exposure to several other
chemicals; exposure characterized
after plant levels reduced; workers
from 5 different plants.
Occupational history, subjective Buckell et al.
symptoms, chest x-ray: Siderosis in (1946)
15 individuals, of which 1 complaint
of shortness of breath and 6 of
cough. Note: Concurrent exposure
to HC1, silica, and combustible
matter (carbon, oil, fiber).
Clinical exam, medical and work Stanescu et al.
history questionnaire, lung function (1967)
tests: Slight dyspnea (7 cases) and
cough (3 cases) in exposed group.
Significant decrease in static and
functional compliance. Note:
Welders may have been exposed to
other chemicals in metallurgical
plant.
-------
K)
-j
O
O
Z
s
O
C
O
H
M
O
90
n
TABLE 11-34 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR IRON AND COMPOUNDS
Exposure
Concentration
ppm
NA
NA
/zg Fe/m3
3,500-
269,000
3,500-
269,000
Exposure Chemical
protocol form
10 yr (avg) Iron
(4-13 yr) oxide
(occup) dust
10 yr (avg) Iron
(4-13 yr) oxide
(occup) dust
Particle size and
distribution
< 1 fj.m - 30%
1-3 /mi -45%
3-5 /mi -23%
5-10 /mi - 2%
< 1 /mi - 30%
1-3 pirn - 45%
3-5 /mi -23%
5-10 /mi - 2%
Species, Strain,
(Number) Sex
Human
(113) M
Human
(14) M
Assays performed: Effect(s)
Medical history and physical exam,
chest x-ray: 34% prevalence of
siderosis; complaints of chronic
coughing and breathlessness. No
evidence of fibrosis.
Medical history and physical exam,
chest x-ray, pulmonary function test:
siderosis; 64% of workers had
chronic cough. No evidence of
fibrosis. Normal pulmonary
function. Note: 4 smokers,
3 ex-smokers.
Reference
Teculescu and
Albu (1973)
Teculescu and
Albu (1973)
Abbreviations:
avg = average; d = day(s); h = hours; MMAD = mass median aerodynamic diameter; NA = not applicable; NK = not known, waiting for study retrieval;
NR = not reported; NS = not specified; occup = occupational; yr = years.
-------
1 in dust control and ventilation of mines after 1967 have also resulted in reduction of lung
2 cancer mortality in iron ore mine workers (Kinlen and Willows, 1988). It is hard to draw
3 definite conclusions about the role of iron oxide particles in development of lung cancer in
4 humans (Blinder, 1986). Stokinger (1984) concluded that when confounding factors
5 (smoking, concurrent exposure to other chemicals) are considered, there is no evidence that
6 inhaled iron oxides might be a human carcinogen.
7 No studies were located regarding the reproductive and developmental effects of iron
8 oxides in humans.
9
10 Laboratory Animal Data
11 As shown in Table 11-35, two acute inhalation studies reported clinical signs relating to
12 respiratory distress in rats exposed to iron pentacarbonyl for 4 h or 1 mo (BASF
13 Corporation, 1991; Bio/Dynamics Incorporated, 1988). However, histopathology was not
14 performed on the lungs. Acute exposure of rats to 500,000 pg iron/m3 as iron oxide for
15 greater than 30 min also resulted in coughing, respiratory difficulties, and nasal irritation
16 (Hewitt and Hicks, 1972 as cited in Blinder, 1986) and histopathology of the lungs revealed
17 iron oxide particles in macrophage cells. Ten intratracheal installations of ferric oxide to
18 hamsters produced loss of ciliated cells, and hyperplasia and proliferation of non-ciliated
19 epithelial cells in the lungs (Port et al., 1973). At a longer duration of 1 mo, hamsters
20 inhaling 14,000 jig iron/m3 as ferric oxide dust (MMAD of 0.11 /xm) revealed respiratory
21 tract cell injury and alveolar fibrosis (Creasia and Nettesheim, 1974).
22 Carcinogenicity of iron in animals was reported in an early study by Campbell (1940).
23 Mice inhaling iron oxide at unspecified concentrations for 10 mo developed lung tumors
24 (32.7% versus 9.6% in controls); however, study details were limited (Campbell, 1940), and
25 this finding has not been confirmed in later studies in hamsters (Creasia and Nettesheim,
26 1974). Iron oxide may serve as a carcinogenic cofactor either by retarding clearance of
27 inhaled carcinogens or by inducing cytopathological changes that make the cells of the
28 respiratory tract more prone to develop cancer when exposed to carcinogenic substances.
29 There was a lack of animal information on the effect of iron exposure on other systemic
30 organs including the reproductive system.
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3.
Ul
TABLE 11-35. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR IRON
AND COMPOUNDS
Exposure
Concentration
ppm pig Fe/m3
NA 500,000
Exposure
protocol
> 30 min
Chemical
form
Iron oxide
Particle size and
distribution
NK
Species, Strain,
(Number) Sex
Rats, NS
(NS)
Assays performed: Effect(s)
Clinical signs: Coughing,
respiratory difficulties, nasal
Reference
Hewitt and
Hicks, (1972)
NA 14,000 1 mo
Iron oxide MMAD
0.11
Hamsters, NS
(NS)
irritation
Histopathology: Respiratory tract
cell injury (not specified), alveolar
fibrosis
as sited in
Blinder (1986)
Creasia and
Nettesheim
(1974)
0 0
0.02 200
0.08 700
0.28 2,300
0.9 6,800
2.8 22,000
0 0
2.1 17,000
7 55,000
11 87,000
23 182,000
6 h/d Iron NA
5 d/wk pentacarbonyl
4 wk vapor
4 h Iron NA
pentacarbonyl
vapor
Rats, Wistar
(10) NS
Rats, S-D
(5)M,
(5)F
Clinical signs: Impaired respiration,
blood nasal discharge at two highest
concentrations only.
Clinical signs, gross examination:
Labored breathing, rales,
lacrimation, nasal discharge at three
highest concentrations. Red lungs
and turbinates; however, findings are
equivocal on basis of gross
examination only.
BASF
Corporation
(1991)
Bio/Dynamics
Incorporated
(1988)
Abbreviations:
d = day(s); h = hours; MMAD = mass median aerodynamic diameter; NA = not applicable; NK = not known, waiting for study retrieval; NR = not reported;
NS = not specified; occup = occupational; wk = week(s).
-------
1 11.6.10.4 Factors Affecting Susceptibility
2 Individuals with preexisting respiratory conditions would likely be more susceptible to
3 iron oxide because human and laboratory animal studies indicate that the respiratory system
4 is the major target organ for iron toxicity. The developing respiratory tract of children may
5 also pose increased susceptibility. There may be other factors affecting susceptibility to iron;
6 but there is a lack of data to determine other such factors.
7
8 11.6.11 Mercury
9 11.6.11.1 Physical/Chemical Properties
10 Mercury is a liquid metal found in Group 2B of the periodic table. It exhibits three
11 valence states, 0, +1, and +2, and readily forms compounds in the +1 and +2 states
12 (Singer and Nowak, 1981). Many mercury compounds are unstable, and are easily reduced
13 to metallic mercury and compounds of lower oxidation state (Singer and Nowak, 1981).
14 Metallic mercury, the most reduced form of mercury, is stable at ordinary temperatures, and
15 does not react with air or oxygen (Drake, 1981). In its gaseous form, it constitutes over
16 95% of the mercury found in the atmosphere (Agency for Toxic Substances and Disease
17 Registry, 1994). Mercury exists in the environment as both inorganic salts and
18 organomercurial compounds (Singer and Nowak, 1981). Elemental mercury is insoluble, as
19 is mercuric sulfide (HgS). Mercuric compounds slightly to moderately soluble, depending on
20 temperature, include, for example, mercuric (HgCl2) and mercurous (Hg2Cl^) chloride and
21 mercuric acetate, Hg (C2H3O2)2-
22
23 11.6.11.2 Pharmacokinetics
24 Elemental mercury and inorganic mercury compounds (mercuric chloride) are most
25 likely inhaled by humans. Inhalation exposure to organic mercury compounds is low.
26 Therefore, data on the pharmacokinetics and health effects of mercury are focused primarily
27 on elemental mercury vapors and inorganic mercury compounds.
28
29 Absorption and Distribution
30 Elemental mercury is highly lipophilic and absorption of the inhaled vapor is
31 substantial, followed by rapid diffusion across the alveolar membranes of the lungs into
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1 blood. Studies indicate that following exposure to 100 to 200 jug/m elemental mercury
2 vapor, approximately 74 to 80% of inhaled elemental mercury vapor is retained in human
3 tissues (Hursh et al., 1976; Teisinger and Fiserova-Bergerova, 1965). Indirect evidence of
4 rapid absorption was provided by elevated mercury levels found in red blood cells, plasma,
5 and excreta of five volunteers who inhaled radiolabeled mercury for 14 to 24 min (Cherian
6 et al., 1978). Elevated blood levels of mercury were also observed in humans following a
7 brief occupational exposure (3 days) to > 100 /-tg/m3 elemental mercury vapor (Barregard
8 etal., 1992).
9 There are few reports regarding the respiratory absorption of elemental and inorganic
10 mercury compounds in animals. Elevated levels of mercury were detected in blood and
11 tissues of pregnant or nursing guinea pigs after short-term exposure (2 to 2.5 h) to elemental
12 mercury vapors (6,000 to 10,000 ^g/m3) (Yoshida et al., 1989, 1992). Following repeated
13 exposure (5 weeks) of rats to mercury vapor (1,000 />ig/m3), high levels were detected in the
14 blood and brain (Warfvinge et al., 1992).
15 Elemental mercury distributes throughout the body due to its lipophilic nature, crossing
16 blood-brain and placental barriers with ease (Clarkson, 1989; Dencker et al., 1983; Yoshida
17 et al., 1992). Mercury distributes to all tissues and reaches peak levels within 24 h, except
18 in the brain where peak levels are achieved within 2 to 3 days (Hursh et al., 1976). The
19 longest retention of mercury after inhalation of mercury vapor occurs in the brain.
20 A 4-h exposure of mice to elemental mercury vapor produced the highest mercury
21 retention in the brain compared to other organs (Berlin et al., 1966). Mercury was found
22 primarily in the neocortex, basal nuclei, and the cerebellar Purkinje cells (Warfvinge et al.,
23 1992). After 12 to 14 h of exposure of rats to a relatively small amount of elemental
24 mercury vapor (550 pig/m3), accumulation of mercury was observed within all cell types
25 examined (ganglion cells, satellite cells, fibroblasts, and macrophages).
26 The kidney is the major organ of mercury deposition after inhalation exposure to
27 elemental mercury vapor. Mercury concentrations in the kidney are orders of magnitude
28 higher than in other tissues (Rothstein and Hayes, 1964). The kidney contains
29 metallothionein, a metal-binding protein that is also found in fetal and maternal livers. In the
30 kidney, the production of metallothionein is stimulated by exposure to mercury. The
31 increased levels of metallothionein increase the amount of mercuric ion binding and
April 1995 H_275 DRAFT-DO NOT QUOTE OR CITE
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1 accumulation in the kidney (Piotrowski et al., 1973). Three classes of sulfhydryl groups
2 have been identified in the kidney, with the metallothionein having the greatest affinity for
3 mercury (Clarkson and Magos, 1966). Low-molecular-weight complexes of mercury have
4 been identified in the urine, suggesting that they may exist in the kidney and contribute to the
5 kidney's accumulation of mercury (Piotrowski et al., 1973).
6 After exposure to mercury vapor, mercury is distributed throughout the body in
7 different chemical and physical states. Elemental mercury dissolves in the blood upon
8 inhalation; mercury concentration in red blood cells is twice that measured in the plasma
9 (Cherian et al., 1978). Elemental mercury in the blood is oxidized to its divalent form hi the
10 red blood cells. The divalent cation exists as a diffusible or nondiffusible form. The
11- nondiffusible form is mercuric ions that bind to proteins (albumin and globulins) and are held
12 in high-molecular-weight complexes, existing in equilibrium with the diffusible form.
13
14 Metabolism
15 Metabolism of all forms of mercury is similar for humans and animals. Once
16 absorbed, elemental and inorganic mercury enter an oxidation-reduction cycle. Elemental
17 mercury is oxidized to the divalent inorganic cation in the red blood cells and lungs of
18 humans and animals. Evidence from animal studies suggests the liver as an additional site of
19 oxidation. Absorbed divalent cation from exposure to mercuric mercury compounds can, in
20 turn, be reduced to the elemental or monovalent form and released as exhaled elemental
21 mercury vapor. In the presence of protein sulfhydryl groups, mercurous mercury (Hg2++)
22 disproportionates to one divalent cation (Kg2"1") and one molecule at the zero oxidation state
23 (Hg°). The conversion of methylmercury or phenylmercury to divalent inorganic mercury
24 can probably occur soon after absorption, also feeding into the oxidation-reduction pathway.
25 Elemental mercury vapor is inhaled through the lungs and rapidly enters the
26 bloodstream. The dissolved vapor can undergo rapid oxidation, primarily in the red blood
27 cells, to its inorganic divalent form by the hydrogen peroxide-catalase pathway (Clarkson,
28 1989). It is believed that the rate of oxidation is dependent on: (1) concentration of catalase
29 in the tissue; (2) endogenous production of hydrogen peroxide; and (3) availability of
30 mercury vapor at the oxidation site (Magos et al., 1978). In red blood cells in vivo,
31 hydrogen peroxide production is probably a rate-determining step because Nielsen-Kudsk
April 1995 11-276 DRAFT-DO NOT QUOTE OR CITE
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1 (1973) found that stimulation of hydrogen peroxide production in red cells increased the
2 uptake of mercury vapors in red cells. At low doses, the percent of dose in the blood is
3 higher than after a high dose, indicating that a higher proportion of the dose is oxidized by
4 blood (Magos et al., 1989). The hydrogen peroxide-catalase pathway in red cells may
5 become saturated at higher dose levels (Magos et al., 1989).
6 The oxidation of elemental mercury may also occur in the brain, liver (adult and fetal),
7 lungs, and probably all other tissues to some degree (Clarkson, 1989; Magos et al., 1978)).
8 In rat liver homogenates, hydrogen peroxide catalase is the predominant oxidative pathway in
9 tissues. Its capacity is very high. Unlike oxidation in red cells, the rate-limiting step in
10 in vitro oxidation in the liver is dependent on the rate of mercury delivery to the enzyme
11 (Magos et al., 1978). Unoxidized elemental mercury can still reach the brain because the
12 oxidation of elemental mercury is a slow process compared with the circulation time from the
13 lung to the brain. Once in the brain, elemental mercury can be oxidized to the divalent
14 form. Because the oxidized form does not readily cross the blood-brain barrier, mercury can
15 be trapped in the brain. Autoradiographic studies suggest that mercury oxidation also occurs
16 in the placenta and fetus (Dencker et al., 1983), although the extent of oxidation is not
17 known. Based on the fact that the rate of oxidation in red cells is non-linear (i.e., can
18 become saturated at higher doses) (Magos et al., 1989), it is assumed that the rate of
19 distribution of elemental mercury to the brain and fetus is probably nonlinear.
20 High affinity binding of divalent mercuric ion to thiol or sulfhydryl groups of proteins
21 is believed to be a key underlying mechanism for biologic activity of mercury (Clarkson,
22 1972). However, since proteins containing sulfhydryl groups are rather ubiquitous,
23 occurring in both extracellular and intracellular membranes and organelles, and most
24 sulfhydryl groups play an integral part in the structure or function of many proteins, the
25 precise intracellular target for mercury is not easily determined. Possible mechanisms
26 include inactivation of various enzymes, structural proteins, or transport processes.
27 There is evidence to suggest that the divalent inorganic mercury cation is reduced by
28 mammalian tissue to elemental mercury after its oxidation. Rats and mice pretreated
29 parenterally with mercuric chloride exhale elemental mercury vapor (Clarkson and Rothstein,
30 1964). Liver and kidney homogenates in animals also release mercury vapor after exposure
31 to mercuric chloride.
April 1995 H_277 DRAFT-DO NOT QUOTE OR CITE
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1 Excretion
2 The urine and feces are the main excretory pathways of mercury in humans, with a
3 body burden half-life of approximately 1 to 2 mo (Clarkson, 1989). After an acute mercury
4 exposure hi humans, urinary excretion accounts for 13% of the total body burden. After
5 long-term exposure, urinary excretion increases to 58%. Humans inhaling mercury vapor
6 for less than an hour expired approximately 7 % of the retained dose of mercury (Cherian
7 et al., 1978; Hursh et al., 1976). The half-life for this elimination pathway was 14 to 25 h;
8 therefore, excretion via expired air is negligible by 5 to 7 days after exposure (Cherian
9 et al., 1978). Using a two-compartment model, elimination half-lives in urine of workers
10 exposed for 20 to 45 h to > 100 /ig/m3 elemental mercury vapor were estimated to be 28 and
11 41 days for a fast and slow phase, respectively (Barregard et al., 1992). For high level
12 exposure to inorganic divalent mercury, the urine is probably the major elimination route
13 with a half-life similar to that of elemental mercury (Clarkson, 1989). An elimination half-
14 life from urine was estimated to be 25.9 days following an acute exposure to a high level of
15 mercuric chloride (13,8000 jig/kg) (Suzuki et al., 1992). Exhalation in the lungs and
16 secretion in saliva, bile, and sweat may also contribute a small portion to the excretion
17 process (Joselow et al., 1968b). There was no human data on the elimination of mercury in
18 the feces.
19 The overall elimination rate of inorganic mercury from the body is the same as the rate
20 of elimination from the kidney, where most of the body burden is localized. Inorganic
21 mercury is also readily cleared from the lung. Elimination from the blood and the brain is
22 thought to be a biphasic process with an initial rapid phase in which the decline in the body
23 burden is associated with high levels of mercury being cleared from tissues, followed by a
24 slower phase with mercury clearance from the same tissues (Takahata et al., 1970). An even
25 longer terminal elimination phase is also possible because of accumulation or persistence of
26 mercury, primarily hi the brain (Takahata et al., 1970).
27 Data are limited on elimination of elemental and inorganic mercury in animals. Initial
28 excretion of mercury is predominantly in the fecal matter following inhalation of elemental
29 mercury vapor, but as mercury concentrations increase in the kidney, urinary excretion
30 increases (Rothstein and Hayes, 1964). After inhalation of elemental mercury for 8 weeks,
April 1995 11-278 DRAFT-DO NOT QUOTE OR CITE
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1 approximately 10 to 20% of the total excreted mercury is by exhalation (Rothstein and
2 Hayes, 1964).
3
4 11.6.11.3 Health Effects
5 Inhalation of elemental mercury vapor has been associated with systemic toxicity in
6 both humans and animals. At low levels of exposure, the major target organs of elemental
7 mercury induced toxicity are the kidneys and the central nervous system. At high exposure
8 levels, respiratory, cardiovascular, and gastrointestinal effects also occur. It should be noted
9 that the temperature at which exposure occurs affects the vapor pressure and presence of
10 condensed droplets which, in turn, influence the primary route by which exposure occurs
11 (Milne et al., 1970). Inhaled droplets, for example, are more likely to be ingested instead of
12 inhaled. This is due to particles cleared from the upper respiratory tract by mucociliary
13 action which are swallowed and absorbed via the gastrointestinal route.
14 A great deal of the information on effects associated with inhalation exposure to
15 elemental mercury vapor comes from studies conducted several decades ago, when methods
16 for determining exposure levels were less precise than current methods. No studies were
17 located concerning effect levels following inhalation exposure to inorganic salts of mercury
18 (e.g., mercuric or mercurous salts, oxides, etc.). Information on inhalation exposure to
19 organic mercury compounds (e.g., alkylmercury compounds) in humans is limited to case
20 reports and includes only qualitative data on gastrointestinal, renal, muscular, and
21 neurological effects. In many cases, it is difficult to determine whether effects observed in
22 exposed persons were directly attributable to mercury exposure.
23 The central nervous system is probably the most sensitive target organ for elemental
24 mercury vapor exposure. Nervous system disorders following exposure to elemental
25 mercury vapors are both consistent and pronounced. Short- and long-term exposures elicit
26 similar neurological effects. Symptoms intensify and may become irreversible as exposure
27 duration and/or concentration increases. Most occupational studies discuss chronic exposure
28 to a time-weight average concentration or a concentration range (i.e., subjects are not
29 grouped by exposure levels), thereby preventing the assessment of dose-response
30 relationships within the populations studied. However, the average exposure levels for
31 affected groups are similar in many of these studies. There are a large group of studies that
April 1995 H_279 DRAFT-DO NOT QUOTE OR CITE
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1 reported urinary and/or blood mercury levels, but did not monitor air mercury levels in the
2 occupational settings. It should also be noted that mercury vapor concentrations in the
3 general work environment may be lower than those in the microenvironment immediately
4 surrounding workers (Stopford et al., 1978); therefore, actual exposure levels may be higher
5 than the estimated air mercury values.
6
7 Human Data
8 The human toxicity data are summarized in Table 11-36. Several case studies have
9 reported adverse neurological effects following acute inhalation of high concentrations of
10 mercury vapor. A wide variety of cognitive, personality, sensory, and motor disturbances
11 have been reported. The most prominent symptoms include tremors (initially affecting the
12 hands and sometimes spreading to other parts of the body), emotional lability (characterized
13 by irritability, excessive shyness, confidence loss, and nervousness), insomnia, memory loss,
14 neuromuscular changes (weakness, muscle atrophy, muscle twitching), headaches,
15 polyneuropathy (paresthesia, stocking-glove sensory loss, hyperactive tendon reflexes, slowed
16 sensory and motor nerve conduction velocities), and performance deficits in tests of cognitive
17 function (Hallee, 1969; Jaffe et al., 1983; Karpathios et al., 1991; Lilis et al., 1985;
18 McFarland and Reigel, 1978; Snodgrass et al., 1981). In case reports of individuals exposed
19 to inorganic mercury vapor for 1 to 6 mo, similar effects were reported (Fagala and Wigg,
20 1992; Friberg et al., 1953; Sexton et al., 1978; Taueg et al., 1992). Effects included
21 dizziness, joint pains, weakness, insomnia, numbness and tingling in her palms, decreased
22 pinprick and vibration sensations in the lower extremities, intention tremor, a slowing of the
23 background rhythms on electroencephalograms, irritability, outbursts of temper, shyness,
24 sensitivity, auditory hallucinations, and photophobia, personality change, insomnia,
25 headaches, and weakness.
26 Information on the neurological effects in humans from chronic mercury vapor
27 exposure is available primarily from occupational studies. Chronic-duration exposures to
28 elemental mercury vapor have resulted in tremors (which may be mild or severe depending
29 on degree of exposure), unsteady walking, irritability, poor concentration, short-term
30 memory deficits, tremulous speech, blurred vision, performance decrements in psychomotor
31 skills (e.g., finger tapping, reduced hand-eye coordination), paresthesias, and decreased
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TABLE 11-36. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR MERCURY AND COMPOUNDS
5
VD
i—"
i
to
oo
I— '
M
1
H
6
o
i
o
H
0
a
o
^^
tn
O
90
Q
H
tn
Exposure
Concentration
Exposure
ppm ng Hg/m3 protocol
0.001- 10-50 NS
0.006 (occup)
0.005 41a NS
(urine) (occup)
0.005 41a NS
(urine) (occup)
0.006- 50-1,000 3.5, 21 yr
0.12 (occup)
0.012 100 l->10yr
0.02 180 (avg)
(occup)
0.003 25 > 1 yr (avg)
(occup)
0.007 59 7.9 yr (avg)
(occup)
Chemical Particle size Species, Strain,
form and distribution (Number), Sex
Hg vaporb NA Human
(21) NS
Hg vapor NA Human
(63) NS
Hg vapor NA Human
(20) NS
Hg vapor NA Human
(101-111) M
Hg vapor NA Human
(567) NS
Hg vapor NA Human
(9-10) M,
(60-62) F
Hg vapor NA Human
(53-77) M
Assays performed: Effect(s)
Urinary protein: Inc proteinuria.
Renal function parameters, urinary protein: Renal
dysfunction (increased /32-microglobulin, inc high
molecular weight proteins).
BML: 50 /*g/g creatinine; 30 fig/L blood.
Inc urinary brush border proteins.
BML: >50 /ug/g creatinine.
Subjective symptoms, physical examination: No
effect.
Subjective symptoms, tremors: Insomnia,
nervousness, weight loss, objective tremors at
180 /*g/m3.
Subjective symptoms, psychometric tests, tremor: Inc
tiredness, memory disturbance.
Nerve conduction test: Altered sensory nerve
conduction and visual evoked response.
Reference
Stewart et al.
(1977)
Buchet et al.
(1980)
Mutti et al. (1985)
Bunn et al. (1986)
-
Smith (1970)
Langworth et al.
(1992a)
Ellingson et al.
(1993)
-------
TABLE 11-36 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR MERCURY AND COMPOUNDS
—
$
oo
Exposure
Concentration
ppm
0.18-
0.4
0.004
(0.001-
0.01)
0.002-
0.05
0.012-
0.12
0
0.013-
0.095
Exposure Chemical
/ig Hg/m3 protocol form
1,500- 389min/d Hg vapor
3,300 duration NS
(occup)
330 (avg) 10.4 yr Hg vapor
(8-850) (avg)
(occup)
20-450 8-9 mo Hg vapor
(case
report)
100-1,000 51-176 d Hg vapor
(case
report)
0 NS Hg vapor
106-783 (occup)
Particle size and Species, Strain,
distribution (Number), Sex
NA Human
(76-1 17) M
NA Human
(19) M,
(69) F
NA Human
(DM
NA Human
(5)M,
(6)F
NA Human
(41-55) M
Assays performed: Effect(s)
Subjective symptoms; objective neurobehavior and
psychomotor function tests; biochemical
measurements for blood, liver, and kidney functions:
Lower scores than controls for motor coordination,
reaction time, and short-term memory.
Subjective symptoms; neurobehavioral tests: Fatigue
and confusion; impaired performance on tests.
Clinical signs: Fatigue, irritability.
Signs and symptoms: Nervousness, insomnia,
inattentiveness, altered EEGs and personality
changes.
Blood chemistry, serum immunoglobin levels: Inc
a-2-macroglobulin and ceruloplasmin; dec IgG and
increased IgA and IgM.
Note: No information on employment duration,
daily exposure, or confounding factors; exposure
measured just before study, and not during time of
exposures.
Reference
Kishi et al. (1993)
Liang et al. (1993)
Friberg et al. (1953)
Sexton et al. (1978)
Bencko et al. (1990)
-------
TABLE 11-36 (cont'd). EXPOSURE CONDITIONS AND EFFECTS FOR MERCURY AND COMPOUNDS
3.
»— t
Exposure
Concentration
u« Exposure Chemical Particle size and Species, Strain,
i
00
w
O
>
H
6
o
H
O
G
O
H
w .
O
JO
Q
H
W
ppm ng Hg/m3
0.003 26
(TWA)
0.002 14 (avg)
(0.001- (8-49)
0.006)
0 0
0.009 76 (avg)
(0.003- (25-270)
0.03)
0.007- 630
0.36
0.0004 3.3 (blood)
0.006 46 (urine)3
0.003 25 (blood)"
protocol form distribution
1-41 yr (avg Hg vapor NA
= 15.3 yr)
(occup)
0.7-24 yr Hg vapor NA
(occup)
1-5 yr Hg vapor NA
(occup)
NS Hg vapor NA
(occup)
10 yr (avg) Hg vapor NA
(occup)
15.6 yr (avg) Hg vapor NA
(occup)
(Number), Sex
Human
(25-26) M
Human
(27-60) M,
(27-38) F
Human
(79-84) M
Human
(81) NS
Human
(36) M
Human
(41) M
Assays performed: Effect(s)
Hand tremor measurements: Inc
frequency of mild intention tremors with
weight load (neurophysiological
impairment) (related to duration).
Neurobehavioral and intelligence tests:
Impaired performance on neurobehavioral
tests (finger tapping, trail making, symbol
digit, digit span, logical memory recall,
visual reproduction recall, Bender gestalt
time scores).
Questionnaire, subjective symptoms,
neurological examination: Difficulty with
heel-to-toe gait (15%), static tremor
(19%), symptoms (metallic taste and
difficulty sleeping).
Plasma /3-galactosidase, /3-glucuronidase,
/3-N-acetylglucosaminidase, and /3-
glucosidase levels: Proteinuria (15/81).
Clinical and neurological status, EEG,
cognitive tests: Dec verbal intelligence
and memory.
BML: 15 ftg/L urine; 56 /ig/L blood
EEG: 15% had slower and attenuated
EEGs.
Reference
Fawer et al. (1983)
Ngim et al. (1992)
Ehrenberg et al. (1991)
Foa et al. (1976)
Piikivi et al. (1984)
Piikivi and Toulonen
(1989)
-------
%
3.
H- »
VO
s
1— '
K>
2
O
!>
•n
i— j
™
0
0
0
H
o
a
TABLE
Exposure
Concentration
ppm /ig Hg/m3
0.003 =25
(blood)3
0.005 =30
(blood)2
0.003 =25
(urine)2
0.006 =46
(urine)2
0.007 =59
(urine)a
0.007 =55
(urine)2
11-36 (cont'd). EXPOSURE CONDITIONS AND
Exposure
protocol
14 yr (avg)
(occup)
15.6 yr (avg)
(occup)
13. 7 yr (avg)
(occup)
5.5 yr (avg)
(occup)
7.9 yr (avg)
(occup)
8 yr (avg)
(occup)
Chemical Particle size and Species, Strain,
form distribution (Number), Sex
Hg vapor NA Human
(60) M
Hg vapor NA Human
(41) M
Hg vapor NA Human
(60) M
Hg vapor NA Human
(62) M
Hg vapor NA Human
(58) NS
Hg vapor NA Human
(100) M
EFFECTS FOR MERCURY AND COMPOUNDS
Assays performed: Effect(s)
BML: 19.3 /ig/L urine; 11.6 /ig/L blood
Subjective symptoms, psychological
performance tests: Inc in subjective measures
of memory disturbances and sleep disorder;
anger, fatigue, and confusion also reported.
BML: 17 /ig/L urine; 10 /tg/L blood
Subjective and objective symptoms of
autonomic function, EEG: Inc subjective
symptoms of cardiovascular dysfunction and
slight decrease hi pulse rate variations
(cardiovascular reflex response).
BML: 19.3 /ig/L urine; 11.6 /tg/L blood
Urinary albumin and N-acetyl-beta-
glucosaminidase (NAG): No effects.
BML: 17 /ig/L urine; 14 /ig/L blood
Serum and urinary proteins: No effects.
BML: 56 /tg/g creatinine
Renal function: No effects.
BML: 72 /ig/g creatinine
Renal function: No effects.
Reference
Piikivi and Hanninen
(1989)
Piikivi (1989)
Piikivi and Ruokonen
(1989)
Lauwerys et al. (1983)
Bernard et al. (1987)
Stonard et al. (1983)
s
n
-------
TABLE 11-36 (cont'd). EXPOSURE CONDITIONS AND EFFECTS FOR MERCURY AND COMPOUNDS
& Exposure
^ Concentration
55 ppm /tg Hg/m3 Exposure Chemical
protocol form
0.005 =41 5 yr (avg) Hg vapor
(urine)3 (occup)
0.007 =58 Syr (avg) Hg vapor
(urine)3 (occup)
0.006 =52 7.7 yr (avg) Hg vapor
(urine)3 (occup)
0.0035 =29 0.5-19 yr (avg) Hg vapor
(urine)3 (occup)
0.006- 50-100 2->10yr Hg vapor
£ 0.012 (blood and (avg)
££ urine)c (occup)
<~r>
O
i>
H
Particle size and Species, Strain,
distribution (Number),
NA Human
(43) M
NA Human
(43) M
NA Human
(54) M
NA Human
(21) M
NA Human
(38) M,
(4)F
^L Extrapolated from blood or urine levels based on conversion factor from Roels
O bElemental mercury.
^ cExtrapolated from blood and urine levels based
O
Abbreviations:
Sex Assays performed: Effect(s) Reference
BML: 67 /xg/g creatinine Roels et al. (1982)
Clinical examination, psychomotor tests: preclinical
psychomotor dysfunction.
BML: 50 /ig/g creatinine; 10-20 /xg/L blood Roels et al. (1982)
Clinical examination, /32-microglobulin in urine and
serum, serum protein: Proteinuria and albuminia.
BML: 71 /xg/g creatinine; 21 itg/L blood Roels et al. (1989)
Hand tremor tests: Postural and intentional tremor.
BML: 63 /ig/g creatinine; 24 /xg/L blood Verberk et al.
Postural tremor of the finger: Inc tremor (1986)
parameters with urinary excretion of Hg.
BML: 35 /ig/g creatinine Rosenman et al.
Symptoms questionnaire, neurological performance (1986)
tests, nerve conduction test, saccadic eye movement,
opthalomogic examination, urinary NAG:
Subjective neurological symptoms; numbness or pain
in extremities; decreased motor nerve condutction
velocity; inc NAG levels. BML: 100-250 /xg/L;
2.8-5 /ig/L blood
et al. (1987).
on conversion factors from Rosenman et al. (1986).
^ avg = average; BML = biological monitoring level; dec = decreased; EEG =
O inc = increased; M = males; NAG = Jv"-acetyl-/3-glucosaminidase; NA = not
fd average.
electroencephalography; F = females; Hg = mercury; Ig = immunoglobulin;
applicable; NS = not specified; occup = occupational; TWA = time weighted
O
El
-------
1 nerve conduction (Albers et al., 1988; Chaffin et al., 1973; Fawer et al., 1983; Kishi et al.,
2 1993; Langolf et al., 1978; Langworth et al., 1992a; Liang et al., 1993; Piikivi et al., 1984;
3 Smith et al., 1970). The majority of studies suggest that motor system disturbances are
4 reversible upon exposure cessation, while cognitive impairments, primarily memory deficits,
5 may be permanent (Chaffin et al., 1973).
6 Several studies have shown significant effects on tremor or cognitive skills at low
7 exposure levels (Ehrenberg et al., 1991; Fawer et al., 1983; Piikivi et al., 1984; Piikivi and
8 Hanninen, 1989; Piikivi and Toulonen, 1989; Roels et al., 1982,, 1989; Rosenman et al.,
9 1986; Verberk et al., 1986). Decreases in performance on tests that measured intelligence
10 (similarities test) and memory (digit span and visual reproduction tests) were observed in
11 chlor-alkali workers exposed for an average of 16.9 years to low levels of mercury when
12 compared to an age-matched control group (Piikivi et al., 1984). Dentists with an average of
13 5.5 years of exposure to low levels of mercury showed impaired performance on several
14 neurobehavioral tests (Ngim et al., 1992). Difficulty with heel-to-toe gait was observed in
15 thermometer plant workers subjected to mean personal breathing zone air concentrations of
16 76 /ig/m3 (range of 25 to 270 ^g/m3) (Ehrenberg et al., 1991). Chlor-alkali workers
17 exposed to low air levels of inorganic mercury reported an increase in memory disturbances,
18 sleep disorders, anger, fatigue, confusion, and hand tremors compared to the controls (Piikivi
19 and Hanninen, 1989).
20 Peripheral nerve function has generally been reported to be affected at higher exposure
21 levels. Changes include progressive sensory loss and diminished sensation reflexes in the legs
22 (Ellingsen et al., 1993; Shapiro et al., 1982), prolongation of brainstem auditory evoked
23 potentials (Discalzi et al., 1993), and prolonged somatosensory evoked potentials (Langauer-
24 Lewowicka and Kazibutowska, 1989).
25 The kidney is a sensitive target organ of toxicity following inhalation exposure to
26 elemental mercury. This sensitivity may be, in part, because of the relatively high
27 accumulation of mercury in the kidney. Acute high-concentration inhalation exposure in
28 humans has resulted in effects ranging from mild transient proteinuria or slight changes in
29 urinary acid excretion (Bluhm et al., 1992), to frank proteinuria, hematuria, and/oliguria
30 (Campbell, 1948; Bailee, 1969; Snodgrass et al., 1981), and acute renal failure with
April 1995 11-286 DRAFT-DO NOT QUOTE OR CITE
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1 degeneration or necrosis of the proximal convoluted tubules (Campbell, 1948; Jaffe et al.,
2 1983; Kanluen and Gottlieb, 1991; Rowens et al., 1991).
3 The results from a number of studies show renal toxicity in workers chronically
4 exposed to mercury vapor (Barregard et al., 1988; Bernard et al., 1987; Buchet et al., 1980;
5 Cardenas et al., 1993; Ehrenberg et al., 1991; Foa et al., 1976; Kazantis et al., 1962;
6 Langworth et al., 1992b; Piikivi and Ruokonen, 1989; Roels et al., 1982; Stewart et al.,
7 1977; Stonard et al., 1983; Tubbs et al., 1982). Effects include proteinuria, proximal
8 tubular and glomerular changes, albuminuria, glomerulosclerosis, and increased urinary
9 A/-acetyl-/3-glucosaminidase. Gstraunthaler et al. (1983) has suggested that epithelial cell
10 damage in the kidney is the result of enhanced free radical formation and lipid peroxidation.
11 Attempts to define threshold levels for effects have had mixed results. Urinary excretion of
12 albumin, /32-microglobulin, or retinol binding protein were not affected at 72 jtig mercury/g
13 creatinine (Bernard et al., 1987). However, other studies have shown increases in urinary
14 albumin with urinary mercury levels greater than 50 /ig mercury/g creatinine (Buchet et al.,
15 1980) and increases in urinary Af-acetyl-/?-glucosaminidase at urinary mercury levels of
16 greater than 50 or 100 /ig mercury/g creatinine.
17 Respiratory symptoms are a prominent effect of acute-duration high level exposure to
18 elemental mercury vapors. The most commonly reported symptoms include cough, dyspnea,
19 and chest tightness or burning pains in the chest (Hallee, 1969; Kanluen and Gottlieb, 1991;
20 King, 1954; Lilis et al., 1985; McFarland and Reigel, 1978; Milne et al., 1970; Rowens
21 et al., 1991; Snodgrass et al., 1981; Taueg et al., 1992). In the more severe cases,
22 respiratory distress, pulmonary edema (alveolar and interstitial), lobar pneumonia, fibrosis,
23 and desquamation of the bronchiolar epithelium have been observed. The ensuing
24 bronchiolar obstruction by mucus and fluid results in alveolar dilation, emphysema,
25 pneumothorax, and possibly death (Campbell, 1948; Jaffe et al., 1983; Kanluen and Gottlieb,
26 1991; Taueg et al., 1992). Little information is available regarding exposure levels resulting
27 in the above symptoms. At chronic exposures, no respiratory symptoms and no
28 abnormalities were noted upon examining chest X-rays or the results of pulmonary function
29 tests in a group of chlor-alkali workers exposed for an average of greater than 6 years to low
30 levels of mercury (Smith et al., 1970).
April 1995 11-287 DRAFT-DO NOT QUOTE OR CITE
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1 Exposure to mercury vapors has resulted in cardiovascular effects (increased heart rate
2 and blood pressure) following acute inhalation exposure to high concentrations of elemental
3 mercury vapor (Haddad and Sternberg, 1963; Hallee, 1969; Snodgrass et al., 1981).
4 Exposures of longer durations due to spills or occupational exposures have also been reported
5 to result in increased blood pressure (Fagala and Wigg, 1992; Friberg et al., 1953;
6 Karpathios et al., 1991; Taueg et al., 1992) and increased heart rate (Fagala and Wigg,
7 1992). Chronic-duration occupational exposures, however, have given mixed results
8 regarding effects on blood pressure and heart rate. Two studies of workers exposed to
9 relatively low levels of mercury showed no effects on blood pressure or electrocardiography
10 (Smith et al., 1970). In contrast, workers exposed to lower concentrations of mercury
11 vapors for at least 5 years reported an increased incidence of palpitations and cardiovascular
12 reflex responses were slightly reduced compared to unexposed matched controls (Piikivi,
13 1989). These studies are limited, however, because exposure to other chemicals may have
14 contributed to the effects observed and other risk factors were not consistently considered.
15 Gastrointestinal effects have been reported in humans after acute-duration exposure to
16 high concentrations of elemental mercury vapors. Stomatitis (inflammation of the oral
17 mucosa), abdominal pains, nausea and/or vomiting, and diarrhea (Kanluen and Gottlieb,
18 1991). A correlation was also observed between mercury exposure levels and unspecified
19 oropharyngeal symptoms in workers from a chlor-alkali plant (Smith et al., 1970).
20 Initial exposure to high concentrations of elemental mercury vapors produces a
21 syndrome similar to "metal fume fever", an acute disease induced by intense inhalation of
22 metal oxides, that temporarily impairs pulmonary function but does not progress to chronic
23 lung disease. This disease is characterized by fatigue, fever, chills, and elevated leukocyte
24 count. Evidence of moderate-to-high leukocytosis with neutrophilia was reported following
25 acute inhalation exposure to elemental mercury vapor (Campbell, 1948; Hallee, 1969; Jaffe
26 et al., 1983; Lilis et al., 1985; Rowens et al., 1991), as well as subacute or chronic
27 exposures (Fagala and Wigg, 1992). In volunteers with dental amalgam, significantly
28 decreased hemoglobin and hematocrit, and increased mean corpuscular hemoglobin
29 concentration were found compared to controls without dental amalgams (Siblerud, 1990).
30 6-Aminolevulinic acid dehydratase activity in erythrocytes was decreased in workers exposed
31 to elemental mercury in the manufacture of tungsten rods (Wada et al., 1969). In workers
April 1995 11-288 DRAFT-DO NOT QUOTE OR CITE
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1 exposed to 106 to 783 /ig/m3 mercury vapors, there was a significant increase in
2 a2-m3Lcrog\db\ilm anc* ceruloplasmin (an a-globulin protein active in storage and transport of
3 copper) compared to unexposed workers (Bencko et al., 1990).
4 The immune reaction to mercury exposure appears to be idiosyncratic, with either
5 increases or decreases in immune activity depending on a genetic predisposition. Therefore,
6 it is not surprising that several studies of workers exposed to elemental mercury vapor have
7 failed to show marked changes in immune function parameters in large populations. For
8 example, no effect on serum immunoglobulins (IgA, IgG, or IgM) and no increase in
9 autoantibody liters were observed in a group of chlor-alkali workers exposed for an average
10 of 13.5 years (Langworth et al., 1992b). Similarly, no increases in antilaminin antibodies
11 were observed in workers exposed for an average of 7.9 years (Bernard et al., 1987), and no
12 increase in antiglomerular basement membrane antibodies or IgE was seen in workers
13 exposed for between 1.5 and 25 years (Cardenas et al., 1993). Slight decreases in IgA and
14 IgG were observed in workers after more than 20 years of exposure to elemental mercury
15 vapors when compared to unexposed controls (Moszczynski et al., 1990).
16 Evidence for a human autoimmune response has been obtained in a few studies.
17 Examination of the kidneys of two workers with proteinuria revealed granular deposition of
18 IgG and the C3 complement factor in the glomeruli (Tubbs et al., 1982). One of 89 workers
19 examined by Langworth et al. (1992b) showed a weak reaction to antiglomerular basement
20 membrane, and 8 of 44 workers examined by Cardenas et al. (1993) showed an abnormally
21 high anti-DNA antibody titer. Increases in IgA and IgM were observed in workers in a
22 mercury refinery (Bencko et al., 1990) and increases in anti-DNA antibodies were observed
23 in workers from a chlor-alkali plant (Cardenas et al., 1993).
24 Epidemiological studies have found no evidence indicating that inhalation of elemental
25 mercury produces cancer in humans (Cragle et al., 1984; Kazantzis, 1981).
26 Several studies evaluated fertility (i.e., ability to conceive within a year; number of
27 children conceived with correlation to age of parents) following subchronic or chronic
28 inhalation exposure to elemental mercury in humans (Alcser et al., 1989; Lauwerys et al.,
29 1985); no effects were observed compared to unexposed control groups. Although no effect
30 on fertility was observed in exposed workers, the rate of spontaneous abortions was
31 correlated with increased mercury concentrations in the urine of fathers exposed before the
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1 pregnancy to elemental mercury in chlor-alkali plants (Cordier et al., 1991). In addition,
2 women occupationally exposed to elemental mercury vapors (dentists and dental assistants,
3 factory workers) had more reproductive failure (spontaneous abortions, stillbirths, congenital
4 malformations) and irregular, painful, or hemorrhagic menstrual disorders than a control
5 group of women not exposed to mercury (Sikorski et al., 1987) and complications of
6 parturition (toxicosis, abortions, prolonged parturition, hemorrhagic parturition) (Mishonova
7 et al., 1980). However, these studies lacked adequate information regarding exposure
8 concentrations and durations.
9
10 Laboratory Animal Data
11 In laboratory animals, as in humans, adverse neurological and behavioral effects are
12 prominent following inhalation exposure to elemental mercury vapor. However, animals
13 appear to be less sensitive than humans. Table 11-37 summarizes the laboratory animal data.
14 Marked cellular degeneration and widespread necrosis were observed in the brains of rabbits
15 following exposures to elemental mercury vapor at 28,800 pig/m3 for durations ranging from
16 2 to 30 h (Ashe et al., 1953). With longer exposures (1 to 13 weeks) and lower
17 concentrations, rabbits exhibited effects ranging from mild, unspecified, pathological changes
18 to marked cellular degeneration and some necrosis in the brain (Ashe et al., 1953), and slight
19 tremors and clonus (Fukuda, 1971). Rats exhibited a decline in conditioned avoidance
20 response (reversible) with exposure to 3,000 /xg/m3 for 12 to 42 weeks; however, no
21 histopathological changes were evident (Kishi et al., 1978). Mice exposed to an unspecified
22 concentration of elemental mercury vapor intermittently for over 3 weeks exhibited
23 progressive neurological dysfunction (i.e., wobbling and unresponsiveness to light),
24 beginning 22 days after initial exposure, and died 4 days postexposure (Ganser and
25 Kirschner, 1985). No studies were conducted using standard battery of tests on neurological
26 endpoints (e.g., functional and observational neurological changes).
27 Respiratory effects in laboratory animals have been observed following acute inhalation
28 exposure of elemental mercury vapors. Rats exposed to 27,000 /xg/m3 of elemental mercury
29 vapors for 2 h displayed dyspnea and death due to asphyxiation (Livardjani et al., 1991).
30 Respiratory tract lesions included lung edema, necrosis of the alveolar epithelium, and
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TABLE 11-37. LABORATORY ANIMAL EXPSOURE CONDITIONS AND EFFECTS FOR MERCURY
VAPOR AND COMPOUNDS
Exposure
Concentration
ppm fj.g Hg/m3
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number), Sex
Assays performed: Effect(s)
Reference
Animal Acute Studies
to
0
3.3
0
27,000
1 or 2 hr
Hg vapor NA
Livardjani et al. (1991)
3.5 28,800 1-30 hr
Hg vapor NA
Rats, Wistar Clincal observations, superoxide dismutase
(4) M activity, histopathology of major organs
(stated in summary only): Death by
asphyxiation, respiratory effects (lung
edema, hyaline membranes, necrosis of
alveolar epithelium).
Note: Air continuously recycled in
chamber.
Rabbits, NS Clinical signs, histopathology: Cellular Ashe et al. (1953)
(1-2) NS degeneration (not specified) and necrosis in
lungs, heart, colon, liver, kidney, and
brain.
Note: Data not presented in detail.
O Subchronic and Chronic Animal
> 0.73 6,000 7 hr/d Hg vapor NA
3 5 d/wk
jL, 1-1 1 wk
\*/
0
25
O
0
H
W
O
o
H
w
Rabbits, NS Clinical signs, histopathology: Cellular Ashe et al. (1953)
(1-3) NS degeneration and ncrosis in liver, necrosis
in kidneys, unspecified histopathological
changes in lungs, heart, colon, and brain.
Note: Data not presented in detail.
-------
t
TABLE 11-37 (cont'd). LABORATORY ANIMAL EXPSOURE CONDITIONS AND EFFECTS FOR MERCURY
VAPOR AND COMPOUNDS
to
VO
to
O
O
25
O
H
I
H
W
8
O
h-1
3
Exposure
Concentration
ppm
0.105
0.012
0.012
0.012
0
0.37
0
0.5
Exposure
pg Hg/m3 protocol
860 7 hr/d
5d/wk
12 wk
100 7 hr/d
5d/wk
72 wk
100 7 hr/d
5d/wk
72 wk
100 7 hr/d
5 d/wk
72 wk
0 3 hr/d
3,000 5 d/wk
12-42 wk
0 6 hr/d
4,000 4 d/wk
13 wk
Chemical Particle size and Species, Strain,
form distribution (Number), Sex
Hg vapor NA Rabbits, NS
(1-4) NS
Hg vapor NA Rat, NS
(1-2) NS
Hg vapor NA Rabbit, NS
(1-4) NS
Hg vapor NA Dog, NS
(2)NS
Hg vapor NA Rats, NS
(7)M
Hg vapor NA Rabbits, NS
(6)M
Assays performed: Effect(s)
Clinical signs, histopathology: Unspecified
histopathological changes (transient) hi heart,
kidney, and brain. Clinical signs not
reported.
Note: Data not presented hi detail.
Clinical signs, histopathology of kidneys:
No effects.
Clinical signs, histopathology of kidneys:
No effects.
Clinical signs, histopathology of kidneys:
No effects.
Behavioral tests; histopathology of lung,
liver, kidney, brain, spinal cord, and sciatic
nerve: Irritability; dense deposits in tubular
cells and lysosomal inclusions in renal
cortex; decline hi conditioned avoidance
response; tremor. No histopathological
changes in the brain.
Clinical signs, electromyographic recording:
tremors and clonus.
Reference
Ashe et al. (1953)
Ashe et al. (1953)
Ashe et al. (1953)
Ashe et al. (1953)
Kishi et al. (1978)
Fukuda (1971)
-------
3.
TABLE 11-37 (cont'd). LABORATORY ANIMAL EXPSOURE CONDITIONS AND EFFECTS FOR MERCURY
VAPOR AND COMPOUNDS
1— »
£
>o
1
w
o
&
H
6
o
z
H
0
0
Exposure
Concentration
Exposure Chemical
ppm /xg Hg/m3 protocol form
0 0 6 or 24 hr/d Hg vapor
0.12 1,000 5wk
00 1 or 4h/d Hg vapor
0.006 50 7d
ppdll-17
00 6 hr/d Hg vapor
0.3 2,500 5 d/wk
3 wk
(prior to
mating and Gd
7-20)
Mercuric Chloride
NA NS 1 h/d HgCl2
4 d/wk aerosol
2 mo
Particle size and Species, Strain,
distribution (Number), Sex
NA Rat, Brown
Norway
(3-4/sex)
NA Rats, Sprague-
Dawley
(6)M
NA Rat, NS
(24) F
NS Brown, Norway
Rat/5B
Assays performed: Effect(s)
Serum IgE concentration, anti-laminin
antibody titer, urinary protein: Inc serum
IgE; anti-laminin autoantibody titer, IgG
deposits along glomerular capillary walls.
Spontaneous motor activity (at 2 and 4 mo of
age) and spatial learning tasks (at 6 mo):
impaired spatial learning (radial arm maze),
increased locomotor activity.
Maternal, reproductive, and developmental
parameters: Dec number of live pups/litter;
death of remaining infants by postpartum day
6; maternal toxicity (spasms, tremor, death,
decreased milk production).
Immunomorphological studies, indirect
immunofluorescent studies, proteinuria:
Proteinura and autoimmune effect in kidney,
lung, and spleen (linear pattern of fixation of
the fluorescinated anti-rat IgG antiserum
along glomerular capillary wall and
mesangium in kidneys, lung vessels and
interstitium, and/or white pulp of spleen).
Reference
Hua et al. (1993)
Fredriksson et al. (1992)
Baranski and Szymczyk
(1973)
Bernaudin et al. 1981
O
HH
H
W
-------
o
o
25
O
H
O
TABLE 11-37 (cont'd). LABORATORY ANIMAL EXPSOURE CONDITIONS AND EFFECTS FOR MERCURY
VAPOR AND COMPOUNDS
Exposure
Concentration
Exposure
ppm ng Hg/m3 protocol
NA 0 4 h/d
0.17 4d
1.6 Gd 9-12
Chemical Particle size and Species, Strain,
form distribution (Number), Sex Assays performed: Effect(s)
HgCl2 NS CFLP Mice/ Reproductive and developmental parameters:
aerosol F NS Inc dead or resorbed fetuses; delayed
ossification at 0.17 jig/m3.
Limitation: Data reported as number of
embryos only, not as number of affected
litters; no statistical analysis; aerosol
exposure not well characterized; maternal
toxicity not evaluated.
Reference
Selypes et al. 1984
Elemental mercury.
Abbreviations:
avg = average; d = day(s); dec = decreased; ppd = post partum day; F = females; Gd = gestational day; Hg = mercury; HgCl2 = mercuric chloride;
h = hours; Ig = immunoglobulin; inc = increased; M = males; NAG = AT-acetyl-jS-glucosaminidase; NA = not applicable; NS = not specified; ppd = post
partum day; TWA = time weighted average; yr = years.
O
O
HH
a
-------
1 hyaline membranes, and occasional lung fibrosis. Longer exposure to mercury vapor (1 to
2 20 h) produced effects ranging from mild to moderate pathological changes (unspecified)
3 (Ashe et al., 1953). Congested lungs were observed in rats exposed to 1,000 /ig/m3
4 elemental mercury vapors for 6 weeks (continuously for 100 h/week) (Gage, 1961).
5 However, in rats exposed to 3,000 /^g/m3 mercury vapor for 12 to 42 weeks (intermittently
6 for 3 h/day), pathological examination revealed no significant changes in the respiratory
7 system (Kishi et al., 1978).
8 The study by Ashe et al. (1953) has also reported cardiovascular and liver effects in
9 animals following acute and subchronic exposures; however, pathological lesions in the liver
10 and heart tissues were not specified. The study was not well conducted, was deficient in
11 quantitative data, and used a small number of animals.
12 Increased serum IgE, anti-laminin autoantibody titer, and IgG deposits along glomerular
13 capillary walls were observed in Brown Norway rats exposed to 1,000 jug/m3 mercury vapor
14 for 5 weeks (Hua et al., 1993). Inhalation exposure to mercuric chloride aerosol for 2 mo
15 also resulted in proteinuria and autoimmune effects in the kidney, lung, and spleen in Brown
16 - Norway rats (Bernaudin et al., 1981).
17 In rats, exposure to elemental mercury vapor for 21 days caused prolongation of the
18 estrous cycle (Baranski and Szymczyk, 1973). The study authors speculated that the effects
19 on the estrous cycle were caused by the action of mercury on the central nervous system
20 (i.e., damage to the hypothalamic regions involved in the control of estrous cycling).
21 Reproductive and developmental effects in rats exposed .to elemental mercury are
22 indicated by Baranski and Szymczyk (1973). Adult female rats were exposed to mercury
23 vapor at 2,500 /xg/m3 for 3 weeks prior to fertilization and during gestational days 7 to 20.
24 A decrease in the number of living fetuses was observed in these dams compared to
25 unexposed controls, and all pups born to the exposed dams died by the 6th day after birth.
26 However, no difference in the occurrence of developmental abnormalities was observed
27 between exposed and control groups. The cause of death of the pups in the mercury-exposed
28 group was unknown, although an unspecified percentage of the deaths was attributed by the
29 authors to a failure of lactation in the dams. Death of pups was also observed in another
30 experiment in which dams were only exposed prior to fertilization to the same dose level,
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1 supporting the conclusion that high mortality in the first experiment was due, at least in part,
2 to poor health of the mothers (Baranski and Szymczyk, 1973).
3 Neurodevelopmental effects have also been reported with exposure to elemental
4 mercury vapor in rat; subtle behavioral changes (delayed spatial learning, lower locomotor,
5 rearing, and total activity) when the rats were tested at 4 and 6 mo of age (Fredriksson
6 et al., 1992). Offspring of rats exposed for 1 h/day showed increases in the time necessary
7 to finish a task in the radial arm maze (spatial learning). Offspring of rats exposed for
8 4 h/day showed increases in both the time to finish the task and in the number of errors
9 committed. When tested for locomotor activity at 2 mo, an increase in rearing was observed
10 in the 4 h/day group, but repeat testing at 4 mo showed lower locomotor, rearing, and total
11 activity than controls. The 1 h/day exposure group showed no difference from controls at
12 2 mo, and increased activity and decreased rearing at 4 mo when compared to controls. An
13 inhalation developmental study in rats (Selypes et al., 1984) reported increased dead or
14 resorbed fetuses and delayed ossification following in utero exposure to mercuric chloride
15 during gestational day 9-12. However, the study had several limitations, including lack of
16 information regarding maternal toxicity, number of affected litters, statistical analysis, and
17 aerosol characterization.
18
19 11.6.11.4 Factors Affecting Susceptibility
20 Because the kidney, respiratory tract, and nervous system are targets of mercury
21 toxicity following inhalation exposure, individuals with functional impairments of these
22 tissues are considered to be at greater risk of suffering from the toxic effects of mercury.
23 Inhalation and oral laboratory animal studies (Aten et al., 1992; Bernaudin et al., 1981;
24 Druet et al., 1978; Hultman and Enestrom, 1992) and limited human data (Lindqvist et al.,
25 1974; Tubbs et al., 1982) also indicate that there may be persons with a genetic
26 predisposition to develop an autoimmune glomerulonephritis upon exposure to mercury.
27 In this form of renal toxicity, proteinuria is observed following the reaction of autoantibodies
28 with renal tissues and deposition of immune material (i.e., IgG and complement C3) in the
29 renal mesangium and glomerular blood vessels. Both susceptible and resistant mice and rat
30 strains have been identified, and susceptibility appears to be governed by both major
31 histocompatibility complex (MHC) genes and nonMHC genes (Aten et al., 1991; Druet
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1 et al., 1978; Hultman and Enestrom, 1992; Hultman et al., 1992; Michaelson et al., 1985;
2 Sapinetal., 1984).
3 Other data on factors affecting susceptibility are from oral and dermal exposures.
4 Metabolism of mercury is expected to be similar after absorption for all exposure routes, and
5 as such, the following information on susceptibility may be relevant for the inhalation route.
6 Individuals with a dietary insufficiency of zinc, glutathione, antioxidants, or selenium, or
7 those who are malnourished may be more susceptible to the toxic effects of mercury
8 poisoning because of the diminished ability of these substances to protect against mercury
9 toxicity.
10 Probably the most widely recognized form of hypersensitivity to mercury poisoning is
11 the uncommon syndrome known as acrodynia, also called erythredema polyneuropathy and
12 pink disease (Warkany and Hubbard, 1953). Infantile acrodynia was first described in 1828,
13 but many adult cases have since been reported. While acrodynia is seen in a small number
14 of children (0.1%) after short-term exposures and with urine levels of 50 /xg/L or more,
15 there are some cases in the literature in which mercury exposure was known to have
16 occurred, but without elevated (above background) Hg levels in urine. There could be many
17 reasons for this, but the most likely is that urine levels are not a simple measure of body
18 burden or of target tissue, i.e., brain levels. Acrodynia is characterized by itching, flushing,
19 swelling, and/or desquamation of the palms of the hands or soles of the feet, morbiliform
20 rashes, excessive sweating and/or salivation, tachycardia, elevated blood pressure, insomnia,
21 weakness, irritability, fretfulness, and peripheral sensory disturbances (Warkany and
22 Hubbard, 1953). The occurrence of acrodynia was determined to be an idiosyncratic
23 reaction to mercury exposure. Despite widespread exposure of children to mercury-
24 containing laxatives, antiascariasis medications, and teething powders in the 1940s and
25 1950s, only a few children developed acrodynia. The basis for this hypersensitivity and
26 methods for identifying the susceptible population are unknown, although the lack of
27 stabilized thermoregulatory and other homeostatis in neonates is suspected.
28 Neonates may also be especially susceptible to mercury toxicity. Both inorganic and
29 organic forms of mercury are excreted in the milk (Sundberg and Oskarsson, 1992; Yoshida
30 et al., 1992). Furthermore, suckling rats exhibit a very high absorption of inorganic
31 mercury as a percentage of the diet (30-40%) compared to adult rats, which absorb ca. 1%
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1 of inorganic mercury from the diet (Kostial et al., 1978). The highest oral toxicity to
2 inorganic mercury as expressed by the LD50 was for 2-week-old rats; by 3 to 6 weeks of
3 age, rats showed a dramatic drop in sensitivity to inorganic mercury poisoning (Kostial et
4 al., 1978). The transfer of mercury to suckling rats via milk was found to result in greater
5 concentrations of the metal in brains of the offspring than in the mother (Yang et al., 1973).
6
7 11.6.12 Manganese
8 11.6.12.1 Physical and Chemical Properties
9 Manganese (Mn) is a reddish-gray or silver-colored metal with an atomic weight of
10 54.94, a melting point of 1244°C, and a density of 7.20 at 20°C (Sax and Lewis, 1987).
11 Although widely distributed in the earth's crust, ranking as the twelfth most abundant
12 element and the fifth most abundant metal, manganese does not occur naturally as the pure
13 metal. Oxides, carbonates, and silicates are the most important manganese-containing
14 minerals. Manganese is mainly used in metallurgical processes but has various other uses
15 (e.g., in dry-cell batteries, glass, leather, textiles, fertilizers). Organic carbonyl compounds
16 are used as fuel-oil additives, smoke inhibitors, and anti-knock additives in gasoline (U.S.
17 Environmental Protection Agency, 1984, 1994).
18 Crustal manganese enters the atmosphere by a number of natural and anthropogenic
19 processes, which include wind erosion and the suspension of road dusts by vehicles. The
20 resulting mechanically generated aerosols consist primarily of coarse particles >2.5 pm mass
21 median aerodynamic diameter (MMAD). The smelting of natural ores and the combustion of
22 fossil fuels also result in injection of crustal manganese into the atmosphere in the form of
23 fume or ash in the fine-particle range (<2.5 /xm MM AD). Nearly one-half of all industrial
24 and combustive emissions of manganese are from ferroalloy manufacture and about one-tenth
25 from fossil-fuel combustion.
26 The most common forms of manganese compounds in coarse particles of crustal origin
27 are oxides or hydroxides of oxidation state +2, +3, or +4, and manganese carbonate. The
28 manganese emitted by metallurgical processes consists of oxides. The manganese from
29 combusted methylcyclopentadienyl manganese tricarbonyl (MMT), used in some countries as
30 a fuel additive, is emitted primarily as Mn3O4 particles < 1 /mi MM AD. Minute amounts of
31 organic manganese compounds such as MMT may be present in ambient air under certain
April 1995 11-298 DRAFT-DO NOT QUOTE OR CITE
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1 conditions. However, MMT itself is rapidly photodegraded to inorganic manganese in
2 sunlight. The estimated half-tune is 10 to 15 seconds (U.S. Environmental Protection
3 Agency, 1984).
4 Background concentrations of manganese have been reported as 0.05 to 5.4 ng/m3 over
5 the Atlantic Ocean (Duce et al., 1975) and 0.01 ng/m3 at the South Pole (Zoller et al.,
6 1974). For the period of 1979 to 1983, the median ambient concentration of paniculate
7 manganese with an MMAD < 10 /*m for sites in the U.S. Environmental Protection Agency
8 (EPA) Inhalable Particulate Network was approximately 20 ng/m3, with a 10th percentile
9 level of 10 ng/m3 and a 99th percentile value of over 200 ng/m3 (U.S. Environmental
10 Protection Agency, 1994).
11 The size of manganese particles in the atmosphere varies from place to place,
12 depending on the dominant sources in an area. Based on dichotomous sampler data for
13 22 sites in the United States (Davis et al., 1984), the proportion of paniculate matter
14 < 10 fj,m MMAD (PM10) manganese that was in the fine-mode (<2.5 ^m MMAD) ranged
15 from 3 to 66%.
16
17 11.6.12.2 Pharmacokinetics
18 Quantitative pharmacokinetic data directly comparing different routes of exposure for
19 manganese are not available, but several experimental studies have demonstrated that tissue
20 manganese levels are well regulated when the exposure is by ingestion. Very few cases of
21 manganese toxicity by ingestion have been observed. However, when inhaled, manganese
22 that enters the bloodstream passes first by the brain, before being processed by the liver.
23 Depending on its ability to cross the blood brain barrier, this manganese may reach areas of
24 the central nervous system (CNS) and produce the characteristic neurotoxic effects of
25 manganese. Although manganese is eliminated primarily by biliary excretion, it appears that
26 inhaled manganese may not be as well regulated by this mechanism as is ingested
27 manganese.
28 The water-solubility of a manganese compound appears to affect the time course of
29 respiratory tract absorption but not necessarily the amount ultimately absorbed. Mena et al.
30 (1969) observed no difference between the absorption of 1 /mi particles of MnCl2 and Mn2O3
31 in healthy adults. Drown et al. (1986) found that following intratracheal instillation of
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1 MnCl2 and Mn3O4 in rats, the soluble chloride cleared four times faster than the insoluble
2 oxide from the respiratory tract; however, despite this initial difference, after 2 weeks the
3 amounts of labeled Mn in the respiratory tract were similar for the two compounds.
4 Extrathoracic deposition is another possible route of exposure. Studies such as those of Perl
5 and Good (1987) and Evans and Hastings (1992) have indicated that neurotoxic metals such
6 as aluminum and cadmium can be directly transported to the brain olfactory bulbs via nasal
7 olfactory pathways.
8 Experimental studies using radiolabeled manganese indicate that the metal is eliminated
9 more slowly from the brain than from most other organs or the body as a whole.
10 Pharmacokinetic analyses based on inhalation of manganese chloride by macaque monkeys
11 (Newland et al., 1987) indicated that clearance from the brain was slower than from the
12 respiratory tract and that the rate of clearance depended on the route of exposure. Brain
13 half-times were 223 to 267 days after inhalation versus 53 days following subcutaneous
14 administration (Newland et al., 1987) or 54 days in humans given manganese intravenously
15 (Cotzias et al., 1968). These long half-times were thought to reflect both slower clearance of
16 brain stores and replenishment from other organs, particularly the respiratory tract. In rats,
17 Drown et al. (1986) also observed slower clearance of labeled Mn from the brain than from
18 the respiratory tract. Several occupational physicians have reported large individual
19 differences in workers' susceptibility to manganese intoxication, which Rodier (1955)
20 speculated might be due in part to differences in the ability to clear particulate manganese
21 from the lung. However, large differences between individuals in their absorption of
22 ingested manganese have also been noted (Davidsson et al., 1991). The basis for the wide
23 range in individual susceptibility to manganese toxicity remains to be elucidated.
24 Some experimental evidence suggests that the mechanisms of manganese toxicity may
25 depend on the oxidation state of manganese. However, both the trivalent form (Mn3+) and
26 the divalent form (Mn2+) have been demonstrated to be neurotoxic. Also, both forms of
27 manganese can cross the blood-brain barrier, although research suggests that Mn3+ is
28 predominantly transported bound to the protein transferrin (Aschner and Gannon, 1994),
29 whereas Mn2+ may enter the brain independently of such a transport mechanism (Murphy
30 etal.,1991).
31
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1 11.6.12.3 Health Effects
2 The toxicity of manganese varies according to the route of exposure. By ingestion,
3 manganese has relatively low toxicity at typical exposure levels and is considered a
4 nutritionally essential trace element. However, by inhalation, manganese has been known
5 since the early 1800s to be toxic to workers. Manganism is characterized by various
6 psychiatric and movement disorders, with some general resemblance to Parkinson's disease
7 in terms of difficulties in the fine control of some movements, lack of facial expression, and
8 involvement of underlying neuroanatomical and neurochemical factors. Respiratory effects
9 (e.g., pneumonitis) and reproductive dysfunction (e.g., reduced libido) are also frequently
10 reported features of occupational manganese intoxication. The available evidence is
11 inadequate to determine whether or not manganese is carcinogenic; some reports suggest that
12 it may even be protective against cancer. Based on this mixed but insufficient evidence, the
13 U.S. Environmental Protection Agency (IRIS, 1988) has placed manganese in a Group D
14 weight-of-evidence category, which signifies that it is not classifiable as to human
15 carcinogenicity.
16
17 Human Data
18 Various epidemiological studies of workers exposed to manganese at average levels
19 below the current American Conference of Governmental Industrial Hygienists Threshold
20 Limit Value (TLV) (5 mg/m3)1 have shown neurobehavioral, reproductive, and respiratory
21 effects, both by objective testing methods and by workers' self-reported symptoms on
22 questionnaires (e.g., Roels et al., 1987, 1992; Iregren, 1990; Mergler et al., 1994).
23 Neurobehavioral effects generally have reflected disturbances in the control of hand
24 movements (e.g., tremor, reduced hand steadiness) and/or the speed of movement (e.g.,
25 longer reaction time, slower finger-tapping speed). Reproductive effects have included
26 a decrease in the number of children born to manganese-exposed workers (compared to
27 matched controls) and various self-reported symptoms of sexual dysfunction. In recent
28 studies at low to moderate occupational exposure levels, respiratory effects have been
29 reflected primarily in self-reported symptoms of respiratory tract illnesses rather than in
30 lrThe American Conference of Governmental Industrial Hygienists (1992) has given notice of intent to lower the
31 TLV to 0.2 mg/m3.
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1 differences between objective spirometric measurements in manganese-exposed and control
2 workers. However, the lack of studies using more sensitive investigational methods and the
3 existence of some limited evidence from an epidemiological study of school children
4 (Nogawa et al., 1973) raise a degree of concern about pulmonary function effects in relation
5 to lower level manganese exposure.
6 Several epidemiological studies of workers have provided consistent evidence indicating
7 that neurotoxicity is associated with low-level occupational manganese exposure. Roels et al.
8 (1992) conducted a cross-sectional study of neurobehavioral and other endpoints in a group
9 of 92 male alkaline-battery plant workers exposed to MnO2 dust and compared their
10 performance to a matched control group of 101 male workers without industrial manganese
11 exposure. The geometric mean occupational-lifetime integrated respirable dust concentration
12 was 793 /xg Mn/m3 x years (range: 40 to 4433). The equivalent value for total dust was
13 3505 /*g Mn/m3 X years (range: 191 to 27,465). The authors noted that the monitored
14 concentrations were representative of the usual exposures of the workers because work
15 practices had not changed during the preceding 15 years of the plant's operation. Because
16 the respirable fraction (5 ^m MM AD) is more representative of the lexicologically significant
17 particles (i.e., the smaller particles that are inhaled and deposit predominantly in the lower
18 respiratory tract), the respirable dust measurements were considered to be more accurate than
19 total dust as an indicator of exposure in relation to the observed health effects.
20 According to the 1992 report of Roels et al., manganese-exposed workers performed
21 significantly worse than matched controls on several measures of neurobehavioral function,
22 particularly eye-hand coordination, hand steadiness, and visual reaction time. Similar
23 neurobehavioral impairments were also found in an earlier study by Roels et al. (1987) of a
24 different occupational population exposed to mixed manganese oxides and salts at
25 approximately the same levels of total dust (respirable dust was not measured). A recent
26 study of manganese workers in Canada by Mergler et al. (1994) also indicated that, among
27 other effects, performance on tests of the ability to make rapid alternating hand movements,
28 to maintain hand steadiness, and to perform other aspects of fine motor control was
29 significantly worse, compared to matched controls. Workers in that study were exposed to
30 an average respirable manganese dust concentration of 35 ^ig/m3 at the time of the study, but
31 earlier exposure levels had been somewhat higher (Mergler et al., 1994). In addition,
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1 reports of a Swedish study of manganese-exposed steel workers (Iregren, 1990; Wennberg
2 et al., 1991, 1992) provided compelling evidence of comparable neurobehavioral
3 impairments, including slower reaction time and finger-tapping speed. The median total dust
4 concentration in the Swedish study was 140 ^g Mn/m3, with respirable dust reported as
5 constituting 20 to 80% of individual workers' total dust exposures. Thus, the lowest-
6 observed-adverse-effect level (LOAEL) from this study would presumably be somewhat
7 lower than that from Roels et al. (1992), but the exposure histories in the Swedish study are
8 less fully characterized.
9 None of the investigators in the above studies have reported a no-observed-adverse-
10 effect level (NOAEL). If the period of occupational manganese exposure in the Roels et al.
11 (1992) study had been longer than the relatively short average duration of only 5.3 years and
12 if the age of the workers had been greater than the relatively young average of 31.3 years, it
13 is possible that the observed effects would have occurred at even lower levels of exposure.
14 Some reports in the literature indicate that manganese toxicity may not be clinically evident
15 until some years after exposure occurred or terminated (e.g., Cotzias et al., 1968; Rodier,
16 1955), and other reports point to a greater sensitivity of elderly persons, compared to middle-
17 aged or young adults, for acute as well as chronic manganese toxicity (e.g., Kawamura
18 et al., 1941). It is possible that the compensatory or reserve capacity of certain neurological
19 mechanisms may be stressed by manganese exposure earlier in life, with manifestations of
20 impairments only becoming evident much later, perhaps at a geriatric stage. One reason for
21 the latter concern is that Parkinson's disease is typically a geriatric disease in which
22 symptoms are only seen when the loss of brain cells that produce dopamine (which is also
23 apparently involved in manganese toxicity) reaches 80% or more. Indeed, some neurologists
24 think that a long latency period of perhaps several decades may precede various parkinsonian
25 syndromes. These points lead to a concern that if manganese reduces the compensatory or
26 reserve capacity of the nervous system, parkinsonian-type effects might occur earlier in life
27 than they would otherwise.
28
29 Laboratory Animal Data
30 Evidence from several laboratory animal studies supports findings in
31 manganese-exposed humans. For example, inhaled manganese has been shown to produce
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1 significant alterations in dopamine levels in the caudate and globus pallidus of Rhesus
2 monkeys (Bird et al., 1984) and behavioral changes in mice (Morganti et al., 1985).
3 However, species differences may complicate interpretation of certain neurobehavioral
4 findings in laboratory animals. Unlike primates, rodents do not have pigmented substantia
5 nigra, which is a brain region of relatively high manganese uptake and involvement in
6 consequent neurobehavioral dysfunction. Nevertheless, rodent and primate studies show
7 various neurochemical, neuropathological, and neurobehavioral effects resulting from
8 manganese exposure. However, because most laboratory animal studies of manganese
9 neurotoxicity involve exposure by routes other than inhalation, they are not described here
10 (see U.S. Environmental Protection Agency, 1984).
11 Other endpoints of manganese toxicity have also been investigated with laboratory
12 animal models of inhalation exposure. Experimental animal data qualitatively support human
13 study findings in that manganese exposure results in an increased incidence of pneumonia in
14 rats exposed to 43,000 to 139,000 fig Mn/m3 as MnO2 (mean MMAD = 0.76 /mi; mean ag
15 = 2.28) for 2 weeks (Shiotsuka, 1984), pulmonary congestion in monkeys exposed to 700 or
16 3,000 fig Mn/m3 as MnO2 (80% < 1 /mi) for 5 mo (Nishiyama et al., 1977), pulmonary
17 emphysema in monkeys exposed to 700 to 3,000 fig Mn/m3 as MnO2 (80% < 1 /mi) for
18 10 mo (Suzuki et al., 1978), and bronchiolar lesions in rats and hamsters exposed to 117 fig
19 Mn/m3 as Mn3O4 (0.29 /mi) for 56 days (Moore et al., 1975). Also, Lloyd-Davies and
20 Harding (1949) induced bronchiolar epithelium inflammation, widespread pneumonia, and
21 granulomatous reactions in rats administered 10,000 /ig MnO2 (80% < 1 /mi) by
22 intratracheal injection, and pulmonary edema in rats administered 5,000 to 50,000 /ig MnCl2
23 (as a 5% solution in saline) in the same fashion. However, no significant pulmonary effects
24 were detected in other studies of rats and monkeys exposed to as much as 1,150 /xg Mn/m3
25 as Mn304 (equivalent aerodynamic diameter « 0.11 /mi; ag = 3.07) for 9 mo (Ulrich et al.,
26 1979a,b,c) and rabbits exposed to as much as 3,900 /tg Mn/m3 as MnCl2 (MMAD = 1 /mi)
27 for 4 to 6 weeks (Camner et al., 1985).
28 Laboratory animal studies have also shown that inhaled manganese may increase
29 susceptibility to infectious agents such as Streptococcuspyogenes in mice (Adkins et al.,
30 1980), Enterobacter cloacae in guinea pigs (Bergstrom, 1977), Klebsiella pneumonia in mice
31 (Maigetter et al., 1976), and Streptococcus hemolyticus in mice (Lloyd-Davies, 1946).
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1 In general, manganese concentrations were relatively high (> 10,000 /xg/m3) in these studies.
2 However, Adkins et al. (1980) concluded that, based on the regression line of the
3 relationship between concentration and mortality in manganese-exposed mice, exposure to
4 620 /tg/m3 would result in a mortality rate at least 10% greater than the control rate.
5 The developmental effects of manganese have been investigated primarily from the
6 viewpoint of the nutritional role of this element and therefore have generally involved oral
7 exposure. Some studies indicate that neonates of various species have a greater body burden
8 of manganese than mature individuals have, possibly because neonates do not develop the
9 ability to eliminate manganese (and thereby maintain manganese homeostasis) until some time
10 after birth (Miller et al., 1975; Cotzias et al., 1976; Wilson et al., 1992). Moreover, some
11 evidence suggests that the neonate's inability to maintain manganese homeostasis is due to a
12 limitation in the elimination of manganese rather than in its gastrointestinal absorption (Bell
13 et al., 1989), which would suggest a potentially greater vulnerability of young individuals to
14 excessive manganese exposure regardless of the route of exposure.
15 Several studies have demonstrated neurochemical alterations in young rats and mice
16 exposed postnatally to manganese by routes other than inhalation (e.g., Kontur and Fechter,
17 1988; Seth and Chandra, 1984; Deskin et al., 1981; Cotzias et al., 1976). The only
18 inhalation study of the developmental toxicity of manganese appears to be that of Lown et al.
19 (1984). Female HA/ICR mice were exposed to MnO2 7 h/day, 5 days/week for 16 weeks
20 prior to conception and between gestational days 1 and 18. For the first 12 weeks, the air
21 concentration was 49,100 pig Mn/m3; all later exposures were at 85,300 pig Mn/m3.
22 To separate prenatal and postnatal exposure effects, a cross-fostering design was used.
23 Although mothers exposed to MnO2 prior to conception produced significantly larger litters,
24 prenatally exposed offspring showed reduced scores on various neurobehavioral activity
25 measures and retarded growth that persisted into adulthood. Balance and coordination were
26 affected by either gestational or post-partum exposure to MnO2.
27
28 11.6.12.4 Comparative Toxicity
29 The neuropathological bases for manganism have been investigated by many researchers
30 and have indicated the involvement of the corpus striatum and the extrapyramidal motor
31 system (e.g., Archibald and Tyree, 1987; Donaldson and Barbeau, 1985; Eriksson et al.,
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1 1987, 1992). Neuropathological lesions have generally been associated with the basal
2 ganglia, with neuronal degeneration in the putamen and globus pallidus (e.g., Newland et al.,
3 1987; Yamada et al., 1986). The substantia nigra, a pigmented area of the midbrain with
4 connections to the striatum and globus pallidus, contains dopamine cells that project to the
5 striatum and play an important role in the control of movement. Manganese tends to
6 accumulate in the substantia nigra and the basal ganglia and damage dopamingergic neurons
7 in those structures (Bird et al., 1984). Rodents lack the degree of melanin pigmentation that
8 characterizes the substantia nigra of humans and nonhuman primates, and thus rodents are
9 not thought to be as susceptible to the neurotoxic effects of manganese as are humans.
10 However, this difference between rodents and humans is not a qualitative difference, and
11 rodents do show various effects indicative of manganese neurotoxicity.
12 In terms of the neurochemistry of manganese toxicity, several studies have shown that
13 dopamine levels are affected by manganese exposure in humans, monkeys, and rodents, with
14 various indications of an initial increase in dopamine followed by a longer term decrease
15 (e.g., Cotzias et al., 1976; Bird et al., 1984; Barbeau, 1984). Some theories of manganese
16 neurotoxicity have focused on the role of excessive manganese in the oxidation of dopamine
17 resulting in free radicals and cytotoxicity (e.g., Donaldson et al., 1982; Barbeau, 1984).
18 In addition, the fundamental role of mitochondrial energy metabolism in manganese toxicity
19 has been indicated by the studies of Aschner and Aschner (1991), Gavin et al. (1990), and
20 others. Brouillet et al. (1993) have suggested that the effects of manganese on mitochondrial
21 function result in various oxidative stresses to cellular defense mechanisms (e.g., GSH) and,
22 secondarily, free radical damage to mitochondrial DNA. In view of the slow release of
23 manganese from mitochondria (Gavin et al., 1990), such an indirect effect would help
24 account for a progressive loss of function in the absence of ongoing manganese exposure
25 (Brouillet et al., 1993), as manganese toxicity may continue or progress in humans despite
26 the termination of exposure (Cotzias et al., 1968; Rodier, 1955).
27 Because of the involvement of the dopaminergic system and extrapyramidal motor
28 system in both Parkinson's disease and manganism, symptoms of the two diseases are
29 somewhat similar, and several writers have suggested the possibility of a common etiology;
30 however, many neurological specialists make a clear distinction in the etiologies and clinical
31 features of Parkinson's disease and manganism (Barbeau, 1984; Langston et al., 1987).
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1 11.6.12.5 Factors Affecting Susceptibility
2 Epidemiological studies of workers and experimental studies laboratory animals exposed
3 to manganese have shown neurobehavioral, reproductive, and respiratory effects. People
4 with impairments in the function or reserve capacity of these systems are potentially
5 susceptible to the effects of manganese toxicity. Some reports in the literature indicate that
6 manganese toxicity may not be clinically evident until some years after exposure occurred or
7 terminated (Cotzias et al., 1986; Rodier, 1955). It is possible that the compensatory or
8 reserve capacity of certain neurological mechanisms may be stressed by manganese earlier in
9 life, with manifestations of impairments only becoming evident much later, perhaps at a
10 geriatric stage. The neurobehavioral effects of manganism are characterized by various
11 psychiatric and movement disorders that resemble Parkinson's disease, a disease that is
12 typically a geriatric disease. If manganese reduces the compensatory or reserve capacity of
13 the nervous system, then Parkinsonian-type effects might occur earlier in life or be
14 exacerbated later in life. Because the epidemiologic studies only investigated healthy
15 working adult males, there is concern that the effects of manganese on the developing
16 nervous system have not been adequately investigated, and suggests that the prenatal and/or
17 postnatal populations may be at increased risk. People with iron or calcium deficiencies and
18 individuals with liver impairment may also have an increased potential for excessive
19 manganese body burdens due to increased absorption or altered clearance mechanisms.
20
21 11.6.13 Magnesium
22 11.6.13.1 Chemical and Physical Properties
23 Magnesium is a metallic element in Group 2A of the periodic table. It forms all of its
24 compounds in the +2 oxidation state. Upon exposure to air, the surface of magnesium metal
25 is oxidized from its elemental valence of 0 to form magnesium oxide. This magnesium oxide
26 film protects the metallic magnesium from further oxidation. In water, under ordinary
27 atmospheric conditions, metallic magnesium is oxidized as well to form magnesium
28 hydroxide [Mg(OH)2] (Lockwood et al., 1981). Magnesium exists in the environment as
29 both inorganic salts, and organomagnesium compounds (Copp and Wardle, 1981). Elemental
30 magnesium is insoluble in cold water and decomposes in hot water to magnesium hydroxide,
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1 Mg (OH)2, whereas two of its more common compounds, i.e., magnesium oxide (MgO) and
2 magnesium carbonate (MgCO3) are slightly soluble in water.
3
4 11.6.13.2 Pharmacokinetics
5 Data on the absorption, distribution, metabolism, and excretion of inhaled magnesium
6 compounds are limited. However, the observation of increased serum magnesium levels in
7 workers exposed to magnesium oxide dust (Pleschitzer, 1936) indicates that some of the
8 magnesium is absorbed, either directly following deposition in the lung, or from the
9 gastrointestinal tract following clearance from the lung. Any magnesium oxide that is
10 absorbed is hydrated to magnesium hydroxide (American Conference of Governmental
11 Industrial Hygienists, 1991). Lung deposition of magnesium carbonate and magnesium
12 carbonate dusts has been observed in animals following prolonged exposure at high
13 concentrations; further experimental details were not available (Zeleneva, 1970).
14 Further data on magnesium toxicokinetics are limited to information from oral dosing.
15 Absorbed magnesium is distributed throughout the body. A normal adult body contains a
16 total of about 21 g of magnesium, of which about 11 g are in the skeleton, 9.5 g are in the
17 cells, and 0.5 g are in extracellular water (Wacker and Vallee, 1958). Magnesium is an
18 essential element and is a cofactor in many enzymatic reactions. It is associated with
19 metabolically active ATP, and so is essential to such functions as muscle contraction, nerve
20 conduction, carbohydrate utilization, and macromolecule synthesis. Absorbed magnesium is
21 excreted in the urine, but absorption from the intestine is poor, leading to elimination in the
22 feces (Aikawa et al., 1958). The kidney plays a key role in maintaining magnesium
23 homeostasis (Labeeuw and Pozet, 1988).
24
25 11.6.13.3 Health Effects
26 Limited data are available regarding the health effects in humans or laboratory animals
27 of inhalation exposure to magnesium compounds. Data are available only on magnesium
28 oxide fume and magnesite. Magnesium oxide occurs as a powder at room temperature, but
29 magnesium oxide fume results when magnesium is burned at high temperatures. Magnesite
30 is the mineral magnesium carbonate; roasting magnesite produces magnesium oxide.
31
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1 Humans
2 Toxicity data for humans are summarized in Table 11-38. Data on acute magnesium
3 inhalation are limited to one study in which volunteers inhaled freshly generated magnesium
4 oxide fume at 246,000, 252,000, 258,000, or 348,000 ^g magnesium/m3 for 1 to 9 min
5 (Drinker et al., 1927). The total amount inhaled was estimated at 15,000 to 29,000 /xg.
6 Less than 10 min after exposure, body temperature rose slightly, followed 5 to 6 h later by
7 fever and elevated white blood cell counts; recovery was complete by the next morning. The
8 response was considered milder than that observed with zinc oxide fume, but the authors
9 suggested that more prolonged exposures would lead to more severe symptoms. This study
10 appears to be the basis for the statement in Stokinger (1981) that the TCLO for magnesium
11 oxide is 400,000 /-ig/m3 (238,000 /xg magnesium/m3). The mechanism for the development
12 of fever following exposure to magnesium oxide is not known, but it has been compared to
13 metal fume fever from zinc oxide exposure, which is attributed to an immune response (see
14 zinc section below).
15 Among workers exposed to magnesium oxide dust, symptoms were limited to
16 conjunctivitis and nasal catarrh (Pleschitzer, 1936). Blood magnesium levels were elevated
17 up to twice normal levels, but exposure levels were not available. Serum calcium was also
18 elevated in 70% of those examined. Details on parameters assessed and exposure conditions
19 were not reported in the secondary references available.
20 There are a few epidemiological studies of chronic exposure to magnesium carbonate
21 dusts; because all were in Russian, this description is based on a secondary reference
22 (American Conference of Governmental Industrial Hygienists, 1991). Pneumoconiosis was
23 reported in these studies, but appears to be due to coexposure to other materials, such as
24 silica or asbestos. Thus, the severity of pneumoconiosis has been reported to be related to
25 the crystalline silica (Tokmurzina and Dzangosina, 1970) or asbestos content (Keane and
26 Zavon, 1966) of the dust. Pneumoconiosis was reported in 2.1% of a cohort of 619 workers
27 exposed for 6 to 20 years to "high concentrations" of crude magnesite (magnesium
28 carbonate) or roasted magnesite (magnesium oxide). The magnesite also contained 1 to 3%
29 silicon dioxide (Zeleneva, 1970). Most of the cases were among the workers exposed to
30 roasted (calcined) magnesite; actual exposure levels were not reported. A "benign
31 pneumoconiosis," often associated with bronchitis and emphysema, was suggested by the
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> TABLE 11-38. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR MAGNESIUM AND COMPOUNDS
T3
^ Exposure
Jo Concentration
<•" ppm /*g Mg/m
Exposure
protocol
Chemical
form
Particle size and Species.Sex,
distribution Strain Assays performed: Effect(s)
Reference
Acute Studies
NA 246,000
252,00
258,000
348,000
1-9 min
MgO
fume
UK Human CS, white blood cell count: Slight rise in
UK temperature at 10 min; fever and elevated white
blood cell counts at 5-6 hr postexposure.
Complete recovery by the next morning.
Drinker et al. (1927)
Chronic Studies
NA "high
concen-
trations"
6-20 yr
occup
MgC03,
MgO
dust
UK Human Medical exam, x-ray: Pneumoconiosis, often
(619) UK associated with bronchitis and emphysema in
2.1% of cohort.
Zeleneva (1970)
Note: Most cases were among those exposed to
magnesium oxide. The magnesium carbonate
contained 1-3% silicon dioxide.
Abbreviations:
3
O
I
CS = clinical signs; hr = hour; Mg = magnesium; MgO = magnesium oxide; MgCO3 = magnesium carbonate;
min = minutes; NA = not applicable; occup = occupational; yr = years.
8
w
n
i— i
H
W
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1 clinical phenomena and latent periods. Toxic effects outside the respiratory system have not
2 been reported following human exposure to magnesium carbonate dusts (American
3 Conference of Governmental Industrial Hygienists, 1991).
4 Heldaas et al. (1989) investigated cancer mortality in a group of magnesium metal
5 workers exposed to various magnesium compounds (magnesium oxide, magnesium metal
6 dust, and magnesium chloride). Elevated cancer incidences were observed for cancer of the
7 lip (6 observed versus 2.3 expected), stomach (21 observed versus 12.8 expected), and lung
8 (32 observed versus 18.2 expected). The rate of lung cancer and all cancers increased with
9 increased duration of employment and for lung cancer was statistically significant for all
10 employment periods. However, the relevance of this study to magnesium carcinogenicity is
11 unclear, since there were confounding exposures to coal tar, asbestos, and hexachlorobenzene
12 and other chlorinated aromatics. Magnesium has been proposed to antagonize the
13 tumorigenic potential of nickel and lead, based on the results of intraperitoneal injection of
14 magnesium along with either of the other two compounds (Poirier et al., 1984).
15
16 Laboratory Animal Data
17 The limited toxicity data for laboratory animals are summarized in Table 11-39.
18 A reaction similar to metal fume fever was observed in cats that inhaled freshly formed
19 magnesium oxide fume for 15 min to 3 h (Drinker and Drinker, 1928). Carbon dioxide was
20 included at 10% to stimulate deep respiration. Exposure levels were not reported, but the
21 estimated amount of inhaled magnesium ranged from 21,000 /^g to 156,000 ^ig (apparently
22 for a single exposure level of varying durations). After 3 h of exposure, symptoms included
23 dyspnea and lethargy, and the animals were cold to the touch. The animals rapidly returned
24 to normal after exposure; necropsy of one cat showed normal lungs. This is an old study,
25 conducted prior to development of standard toxicological methods and few experimental
26 details are available; still, the reaction described is similar to that with zinc, but milder. It is
27 unclear why hypothermia was found in cats and fever in humans.
28 Intratracheal installation of finely divided metallic magnesium particles in a salt solution
29 in guinea pigs resulted in a slight pneumonic reaction that was attributed to the fluid rather
30 than the administered magnesium (Gardner and Delahant, 1943). Microscopic vacuoles in
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TABLE 11-39. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
U MAGNESIUM AND COMPOUNDS
vo Exposure
<^i Concentration
Me/m3 Exposure Chemical Particle size and Species, Sex,
protocol form distribution Strain Assays performed: Effect(s)
NA NS 15 min- MgO fume UK Cat, NS CS, necropsy (lungs): Uniform, but slight
3 hr (UK) hypothermia. After 3 h exposure, dyspnea and
lethargy; animals were cold to the touch. The
animals rapidly returned to normal. Necropsy of
one cat showed normal lungs.
Reference
Drinker and Drinker
(1928)
TJ
?
o
o
z
s
o
a
I
i
n
Note: Exposure was apparently to one
concentration for varying durations. Total
amount magnesium inhaled estimated at 21,000-
156,000 ftg.
Note: Symptoms were described as milder than
those in animals exposed to zinc oxide fume.
Abbreviations:
CS = clinical signs; hr = hour; MgO = magnesium oxide; min = minutes; NA = not applicable; NS = not specified in the literature reviewed;
-------
1 the cytoplasm of mononuclear cells lining the alveolar walls were also observed, and were
2 attributed to the liberation of hydrogen. Healing and resolution occurred within 6 weeks,
3 with no residual fibrosis.
4 Studies on the effects hi laboratory animals of magnesite dust are limited to reports in
5 Russian (Katsnel'son et al., 1964; Zeleneva, 1970), and experimental details are lacking.
6 Slight fibrosis was observed in animals exposed via inhalation to magnesium oxide or
7 magnesium carbonate dusts, although magnesium oxide dust was more fibrogenic. The
8 report implied that the experimental procedure involved prolonged exposure at high levels
9 (American Conference of Governmental Industrial Hygienists, 1991).
10 Chronic data on the effects in laboratory animals of magnesium oxide were limited to a
11 single carcinogenicity study of intratracheal instillation. Elevated levels of hystiocytic
12 lymphomas compared with historical control levels were observed in hamsters that were
13 administered 1,200 /*g magnesium per week as magnesium oxide dust for 30 weeks
14 (Stenbacket al., 1973).
15
16 11.6.13.4 Factors Affecting Susceptibility
17 Based on the limited data in humans and laboratory animals suggesting that the
18 respiratory tract is a target of magnesium inhalation, individuals with a compromised
19 respiratory tract may be at increased risk from magnesium inhalation toxicity. The
20 developing respiratory tract of children may also pose an increased susceptibility.
21 Other information on factors affecting susceptibility is based on general information on
22 magnesium toxicity, and relates only to absorbed magnesium. The relevance of these data to
23 magnesium inhalation would depend on the absorption of the magnesium compound of
24 interest. People with reduced renal function, have reduced magnesium excretion and may
25 develop hypermagnesemia. This population may include those with renal failure, as well as
26 the elderly, since the elderly may have an age-related decrease in renal clearance (Beliles
27 1994; Ratzan et al. 1980).
28
29
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1 11.6.14 Molybdenum
2 11.6.14.1 Chemical and Physical Properties
3 Molybdenum, a silvery-gray metal or grey-black powder, belongs to Group VIB of the
4 periodic system of elements (Barr, 1981; Friberg and Lener, 1986). Molybdenum forms
5 compounds in the valence states of 0, +2, +4, +5, or +6, of which +6 is the most stable
6 valence state (Barr, 1981; Barry, 1981). Molybdenum does not occur naturally in the native
7 state (Friberg and Lener, 1986). Over fifty inorganic molybdenum compounds are known
8 and organomolybdenum compounds also exist (Friberg and Lener, 1986). Molybdenum
9 compounds may disproportionate to mixtures in which molybdenum occurs in different
10 oxidation states (Barry, 1981). Molybdenum is resistant to oxidation at temperatures up to
11 about 1650 °C (Barr, 1981). Budavari (1989) reports that molybdenum is slowly oxidized to
12 the trioxide in the presence of steam but is not attacked by water. Elemental molybdenum
13 and its dioxide (MoO2) are insoluble in water, whereas the trioxide (MoO3) is slightly
14 soluble in water at 18 °C and moderately soluble at 70 °C. Other compounds also vary in
15 their solubility. Ammonium molybdate (NH4)2 MoO4, decomposes in water, but ammonium
16 paramolybdate, (NH4)6 MO7O24, is fairly water soluble as is sodium molybdate, Na2M04.
17 Both molybdenum disulfide (or molybdenite, MoS2) and calcium molybdate (CaMoO4), on
18 the other hand, are insoluble.
19
20 11.6.14.2 Pharmacokinetics
21 Molybdenum is an essential micronutrient and acts as a cofactor for three enzymes:
22 xanthine oxidase (which affects uric acid formation), aldehyde oxidase, and sulfite oxidase
23 (Friberg and Lener, 1986).
24 Indirect evidence for absorption of molybdenum following inhalation exposure comes
25 from studies showing increased molybdenum concentrations in plasma (0.9 to 36.5 /ig/
26 100 mL versus 0 to 3.4 jug/100 mL for controls) and urine (120 to 11,000 jug Mo/L versus
27 20 to 230 /xg Mo/L for controls) of workers at a molybdenum roasting plant exposed to
28 concentrations of soluble molybdenum dusts (mainly MoO3 and other molybdenum oxides)
29 ranging from 100 to 4500 j*g Mo/m3 (8-h tune-weighed average = 9500 fig Mo/m3)
30 (Walravens et al., 1979). Following inhalation exposure of Guinea pigs to molybdenum
31 compounds, tissue levels indicated that absorption was limited for all tested compounds
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1 (Fairhall et al., 1945). The major portion of molybdenum was found in the lungs following
2 exposure to molybdenum sulfide (286,000 jug Mo/m3) and calcium molybdate
3 (159,000 jig Mo/m3) with minute amounts in the liver, kidney, spleen, and bones. Exposure
4 to molybdenum trioxide dust (205,000 /xg Mo/m3) resulted in similar low levels in the lungs
5 and other organs. Levels in all tissues were negligible following exposure to molybdenum
6 trioxide fume (191,000 or 53,000 pig Mo/m3). No studies were found on metabolism or
7 excretion of molybdenum or molybdenum compounds in humans or animals following
8 inhalation exposure. Orally administered hexavalent molybdenum is readily absorbed (Van
9 Campen and Mitchell, 1965) and is distributed to the kidneys, liver, and bone (Huber et al.,
10 1971; Robinson et al., 1964). Excretion is mostly in the urine (Neilands et al., 1948)
11 although biliary excretion in the feces has also been reported (Lener and Bibr, 1979).
12
13 11.6.14.3 Health Effects
14 There are few studies on health effects in humans or laboratory animals of inhalation
15 exposure to molybdenum compounds, and those that do exist were generally not conducted
16 according to modern toxicology standards. The major toxic endpoint for such inhalation
17 exposure in humans and laboratory animals is the respiratory system.
18
19 Human Data
20 Inhalation toxicity data for humans are summarized in Table 11-40. No studies were
21 located on the acute inhalation toxicity of molybdenum compounds in humans. Walravens
22 et al. (1979) conducted an occupational survey of 25 workers in a molybdenum-roasting plant
23 in Colorado, where exposure was to molybdenum oxides. The 8-h time weighted average
24 exposure was approximately 9,500 /xg Mo/m3, and the average length of worker exposure
25 was 4.0 years (range 0.5 to 20 years). Clinical findings included elevated serum
26 ceruloplasmin (average 50.47 mg/100 mL versus 30.50 mg/100 mL for controls) and smaller
27 increments in serum uric acid concentrations. Although hyperuricosuria (indicative of gout-
28 like symptoms) was not seen, high employee turnover could have removed workers sensitive
29 to the gout-causing action of molybdenum. Nonspecific worker complaints included joint
30 pains, headaches, backaches and hair and skin changes.
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> TABLE 11-40. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR MOLYBDENUM AND COMPOUNDS
— Exposure
!^ Concentration
<-" ppm /*g Mo/m3
NA 9,500
(8 h TWA)
Exposure
protocol
4.0 yr avg
(range
0.5-20 yr)
occup
Chemical
form
Soluble Mo
oxides dust
(mainly
Mo03)
Particle size and Species, Sex,
distribution Strain
"respirable dust less Human
than 10 /xm (25) M
diameter"
Assays performed: Effect(s)
BC, subjective symptoms on medical
questionnaire: Inc serum ceruloplasmin and
serum uric acid, inc Mo in plasma and
urine. No Mo-induced gout reported.
Reference
Walravens et al.
(1979)
o\
O
O
2
O
H
O
§
w
O
NA
670-12,700 4-7 yr
occup
Mo trioxide
dust
UK
Human
(19) B
NS
<600,000 NS
occup
Molybdenu UK
m, form
UK
Human
(500) UK
Note: Soluble Mo in total dust was TWA
exposure of 9,500 ng/m3; Mo in respirable
dust was 1,000-4,500 /ig/m3.
Note: High employee turnover.
Case study, subjective symptoms, chest x-
ray: Pneumoconiosis in 3 workers. 1
female, difficulty breathing, general
weakness, dizziness; one male, dry cough;
second male, difficulty breathing, pain in
chest, expectoration.
Medical exam: nonspecific symptoms and
CNS changes.
Note: Concomitant exposure to copper dust,
possibly to radon in mine.
Mogilevskaya (1963)
Eolayan (1965)
Abbreviations:
avg = average; BC = blood chemistry; BW = body weight; cardio = cardiovascular; CS = clinical signs; d = day; dec = decreased; est = estimated; F =
female; h = hour; HP = histopathology; inc = increased; M = male; Mo - molybdenum N/A = not applicable; NS = not specified in the literature reviewed;
occup = occupational; UK = unknown, original reference in retrieval; wk = week; wt = weight; yr = years.
-------
1 In a Russian study of, 19 workers exposed to molybdenum compounds, three subjects
2 showed signs of pneumoconiosis upon x-ray examination. Exposure in all cases was
3 primarily to molybdenum trioxide dust. A female exposed to 670 to 2,000 pig Mo/m3 (with
4 occasional excursions to > 16,700 pig Mo/m3) for 5 years had difficulty breathing, general
5 weakness, and dizziness; a male exposed to 4,000 to 12,700 pig Mo/m3 as molybdenum
6 trioxide aerosol for 4 years experienced a dry cough. Another male worker who was
7 exposed to the same levels of molybdenum (not stated whether dust or aerosol) for 7 years
8 had difficulty breathing, pain in the chest, and morning expectoration; this worker had also
9 suffered from a pulmonary hemorrhage at an earlier unspecified time (Mogilevskaya, 1963).
10 A Russian occupational survey of 500 workers from a molybdenum and copper mine
11 where molybdenum concentrations could have been as high as 60,000 to 600,000 pig Mo/m3
12 reported nonspecific symptoms and some central nervous system changes (Eolayan, 1965);
13 however, the exact form of molybdenum and specific symptoms are not available.
14 In workers at a copper-molybdenum factory (exposure to both molybdenum and copper),
15 toxic effects were reported in the liver, based on serum biochemistry (Avakyan et al., 1978).
16 The observed effects were attributed to a disruption of the balance between copper and
17 molybdenum. Further study details will require translation of the article.
18 Although the exact mechanism of molybdenum is not known, it is believed that
19 molybdenum forms a complex with copper that reduces the bioavailability of copper.
20 Tetrathiomolybdate reduces the activity of ceruloplasmin, a copper-containing enzyme
21 (Winston, 1981). The gout-like symptoms reported in some Armenian residents may be the
22 result of increased xanthine oxidase activity in response to increased molybdenum levels.
23 The xanthine oxidase may then cause increased uric acid levels which are the primary cause
24 of gout (Yarovaya, 1964).
25 Oral exposure to high levels of molybdenum has been reported to cause gout-like
26 symptoms. This has been seen in residents of Armenia where the soil is rich in molybdenum
27 (77,000 pig Mo/kg) and copper (39,000 pig Cu/kg). Intake levels via food have been
28 estimated to be 10,000 pig molybdenum (compared with 1,000 to 2,000 pig in control areas)
29 (Koval'skiy et al., 1961; Koval'skiy and Yarovaya, 1966; Yarovaya, 1964). Some exposure
30 via inhalation of soil cannot be ruled out, although the symptoms reported did not include
31 any pulmonary effects.
April 1995 H_317 DRAFT-DO NOT QUOTE OR CITE
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1 No studies were located regarding reproductive or developmental effects in humans of
2 inhalation exposure to molybdenum compounds.
3
4 Laboratory Animal Data
5 The toxicity data for laboratory animals are summarized in Table 11-41. In a series of
6 4-h rat inhalation studies, rats were exposed to technical grade molybdenum trioxide
7 (2,610,000 /*g Mo/m3), pure molybdenum trioxide (3,890,000 /zg Mo/m3), ammonium
8 dimolybdate (1,160,000 j*g Mo/m3), or sodium molybdate (899,000 /xg Mo/m3) (Barltrop,
9 1991). The dust level for pure molybdenum trioxide was so high that the animals were not
10 visible. Clinical signs for all but ammonium dimolybdate were limited to partial or complete
11 closing of the eyes, which was attributed to the high dust level. Other clinical signs of
12 discomfort observed with ammonium dimolybdate (wetness around the mouth, restlessness,
13 and hunched posture) molybdic may also have been a result of the high dust levels. Systemic
14 effects were limited to decreased body weight losses for the first 3 days postexposure.
15 Respiratory effects were limited to one male exposed to sodium molybdate that had an
16 increased lung to body weight ratio and congested lungs. This study indicates that acute
17 exposure to very dust levels of these molybdenum compounds is minimally toxic.
18 Effects on cellular respiration of the respiratory tract mucosa were reported in rats in a
19 Russian abstract (Georgiadi, 1978). Further details were not available in English.
20 A study of rats receiving a single intratracheal dose (0.5 mL) of a 2% solution of LPA
21 (55% cobalt, 35% molybdenum, and 10% silicon) showed weight loss for 3 to 4 days post-
22 exposure after which weight gain was normal. Transient histopathological signs included
23 peribronchial or peribronchiolar pneumonia with edema. Alveolar lesions, including
24 epithelialization, bronchiolar proliferation and atelectasis and minimal fibrosis were reversible
25 with time (Du Pont, 1971). Diffuse pneumoconiosis with interstitial pneumonia was seen in
26 rabbits 9 mo after receiving powdered molybdenum as intratracheal doses of 70,000 to
27 80,000 ^g/kg (Mogilevskaya, 1963, Dzukaev, 1970).
28 A Russian study of the comparative toxicity of four molybdenum dusts to rats after 1 h
29 of exposure found no effects (unspecified) during a 4-week observation period for metallic
30 molybdenum (25,000,000 to 30,000,000 fig Mo/m3), molybdenum dioxide (7,500,000 to
31 9,000,000 jug Mo/m3), or molybdenum trioxide (8,040,000 to 10,050,000 /xg Mo/m3).
April 1995 11-318 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-41. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
MOLYBDENUM AND COMPOUNDS
VO
•O
H-
^
I—"
O
j*
^
H
6
o
o
H
O
c^
H
W
Exposure
Concentration
ppm /igMo/m3 Exposure Chemical
protocol form
Acute Studies
NS 0 4 h Mo trioxide
2,610,000 (technical)
dust
NS 0 4h Mo trioxide
3,890,000 (pure)
dust
NS 0 4 h Ammonium
1,160,000 dimolydbate
dust
"56.4% Mo-
Particle size and
distribution
36% by wt
<3.5jtm
MMAD=4.2/xm
ffg=2.19
72% by wt
<3.5/im
MMAD=2.9Mm
ffg = 1.83
23 % by wt
<3.5/im
MMAD=6.3 Atm
-------
TABLE 11-41 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
MOLYBDENUM AND COMPOUNDS
Exposure
Concentration
ppm »g Mo/m3 Exposure Chemical Particle size and Species,Sex,
protocol form distribution Strain
Assays performed: Effect(s)
Reference
NS
0
899,000
4h
Sodium 26% by wt <3.5/xm Rat, SD
molydbate MMAD=6.9/*m (5) M,
dust
<7g=2.71
(5)F
CS, BW, food/water consumption, gross Barltrop (1991)
necropsy, HP of lungs: No deaths, transient
clinical signs (partial closing of eyes). Both
sexes lost wt until day 3, then gained at
normal rate. Food intake dec days 2-3. One
exposed male had inc lung:bw ratio and
congested lungs, but no HP. No effects on
other animals. Closing of eyes due to high
dust levels.
NS 70,000- single dose Powdered UK
80,000 (intra- Mo
i— '
to
0
O
>
6
o
1
'c
o
H
O
i
trachea!)
NS 25 to 30 1 h
NS 7.5 to 9.0 1 h
NS 8.0 to 10.0 1 h
NS 2.4 to 4.0 1 h
Chronic Studies
NS 12 to 15 1 h/d
30 d
NS 6 to 7.5 1 h/d
30 d
Mo metal UK
dust
Mo dioxide UK
dust
Mo trioxide UK
dust
Ammonium UK
paramolyb-
date dust
Mo metal UK
dust
Mo dioxide UK
dust
Rabbits, UK
(NS)
Rat, UK
(UK)
Rat, UK
(UK)
Rat, UK
(UK)
Rat, UK
(UK)
Rat, UK
(UK)
Rat, UK
(UK)
HP: Diffuse pneumoconiosis with interstitial
pneumonia after 9 mo observation.
CS: No effect.
CS: No effect.
CS: No effect.
CS: Irritation of upper respiratory passages
and conjunctivae.
CS, HP: Slight growth depression, dust
deposits in lungs, thickening of intraalveolar
septa.
CS, HP: Slight growth depression, dust
deposits in lungs, thickening of intraalveolar
septa.
Mogilevskaya (1963)
Mogilevskaya (1963)
Mogilevskaya (1963)
Mogilevskaya (1963)
Mogilevskaya (1963)
Mogilevskaya (1963)
Mogilevskaya (1963)
-------
TABLE 11-41 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
u
MOLYBDENUM AND COMPOUNDS
\o Exposure
L/I Concentration
i— »
T
to
O
?3
H
^n
i
o
0
H
C
O
H
M
ppm
NS
NS
NS
NS
NS
NS
fig Mo/m3
5.4 to 6.7
40,000-
200,000
286,000
(avg)
205,000
53,000
191,000
159,000
Exposure Chemical
protocol form
1 h/d
30 d
1 h/d
30 d
Ih/d
5 d/wk
5 wk
Ih/d
5 d/wk
5 wk
Ih/d
5 d/wk
5 wk
Ih/d
5 d/wk
5 wk
Mo trioxide
dust
Ammonium
paramolyb-
date dust
Mo disulfide
dust
Mo trioxide
dust
Mo trioxide
fume
Calcium
molybdate
dust
Particle size and Species, Sex,
distribution Strain
UK Rat, UK
(UK)
UK Rat, UK
(UK)
NS Guinea pig, NS
(25) M
"Average 1.63 /mi" Guinea pig, NS
(51) M
"Average 1.55 /mi" Guinea pig, NS
(12) M
NS Guinea pig, NS
(24) M
Assays performed: Effect(s) Reference
CS, HP: Dec weight gain (by 28%), Mogilevskaya (1963)
macroscopic hemorrhage, perivascular
edema, alveolar hemorrhage.
CS, HP: All animals died, severe dust Mogilevskaya (1963)
deposits in lungs, thickening of intraalveolar
septa.
CS: One death, all other animals appeared Fairhall et al. (1945)
"normal," except for inc respiratory rate.
CS, HP: Weight loss, loss of appetite, Fairhall et al. (1945)
diarrhea, muscular incoordination, loss of
hair and 50% mortality; alveolar and
bronchial exudate; some swelling and
vacuolization of hepatic cells.
CS: One death at 191,000 /xg Mo/m3, no Fairhall et al. (1945)
other toxic effects at either concentration.
CS: 20% mortality, no other toxic effects. Fairhall et al. (1945)
Abbreviations:
avg =
female;
occup :
average; BC =
= blood
chemistry; BW =
h = hour; HP = histopathology; inc =
= occupational
; SD =
Sprague-Dawley;
body weight; cardio = cardiovascular;
CS = clinical signs; d = day; dec = decreased; est = estimated; F =
increased; M = male; Mo - molybdenum N/A = not applicable; NS = not specified in the literature reviewed;
UK = unknown, original reference in
retrieval; wk = week; wt = weight; yr = years.
n
-------
Exposure to 240,000 to 400,000 ^g Mo/m3 ammonium paramolybdate resulted in irritation of
the upper respiratory passages and conjunctivae (Mogilevskaya, 1963).
A study with Guinea pigs exposed to various molybdenum compounds for 1 h/day,
5 days/week for 5 weeks was conducted by Fairhall et al. (1945). Molybdenum disulfide
dust (286,000 fjLg Mo/m3 average concentration) caused death in 1/25 animals within 3 days,
despite normal appearance of other animals in the group. Exposure of 51 guinea pigs to
205,000 /*g Mo/m3 as molybdenum trioxide dust resulted in the most severe symptoms, with
a loss of weight, loss of appetite, diarrhea, muscular incoordination, loss of hair and a 50%
mortality rate, with histopathologic signs in the lung showing alveolar and bronchial exudate.
Molybdenum trioxide fumes (either, 191,000 or 53,000 /*g Mo/m3) caused significantly
fewer effects than the dust, with only 1/12 animals at the higher exposure dying and no other
toxic effects seen in the other animals at either concentration. Guinea pigs exposed to
159,000 /ig Mo/m3 as calcium molybdate had a 20% mortality rate among the 24 exposed
animals but no other adverse effects.
In a subchronic study by Mogilevskaya (1963), rats were exposed to metallic
molybdenum (12,000,000 to 15,000,000 /zg Mo/m3), molybdenum dioxide (6,000,000 to
7,500,000 /*g Mo/m3), molybdenum trioxide (5,360,000 to 6,700,000 fig Mo/m3), or
ammonium paramolybdate (40,000 to 200,000 /xg Mo/m3)] for 1 h/day for 30 days. These
levels were slightly lower than those used in the acute study in the same paper. Metallic
molybdenum and molybdenum dioxide produce no adverse effects, except for a slight growth
depression; examination of the lungs revealed dust deposition and thickening of the
intraalveolar septa. Molybdenum trioxide exposure resulted in decreased weight gain (28%
of control) with histopathologic examination of the lung revealing macroscopic hemorrhage,
marked perivascular edema and hemorrhage into the alveolar space. Ammonium
paramolybdate had high toxicity (all animals died) with severe dust deposits in the lungs and
thickening of the intraalveolar septa, which contained connective tissue fibers.
No studies were located regarding reproductive or developmental effects in animals of
inhalation exposure to molybdenum compounds.
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11.6.14.4 Factors Affecting Susceptibility
No data were located that addressed populations especially sensitive to the effects of
inhaled molybdenum compounds. However, since the respiratory tract is the major target of
molybdenum inhalation, individuals with impaired respiratory function would be expected to
be at increased risk. The developing respiratory tract of children may also pose an increased
susceptibility.
Other susceptible populations can be hypothesized based on the mechanism of toxicity
of absorbed molybdenum. Since molybdenum decreases the bioavailability of copper
(Winston, 1981), people with impaired copper metabolism, such as those with Wilson's
disease, would be expected to be at increased risk. Similarly, since high levels of
molybdenum can cause gout-like symptoms, individuals with pre-existing gout may have an
increased susceptibility. However, it is unclear if absorption of molybdenum from
inhalational exposure to environmental levels would be high enough to affect these two
groups.
11.6.15 Nickel
11.6.15.1 Physical/Chemical Properties
Nickel is a metallic element belonging to transition Group 8B of the periodic table.
It forms compounds in which the nickel atom has oxidation states of —1, 0, +1, +2, +3,
and +4. Under environmental conditions, the +2 state is the only one of importance; other
oxidation states occur in special complexes and oxides (Agency for Toxic Substances and
Disease Registry, 1992). Nickel is stable in air at ordinary temperatures, but can burn in
oxygen, forming nickel(+2) oxide (Windholz, 1983). Nickel exists in aqueous solutions as
the hexahydrate ion [Ni(H2O)6]2+. In alkaline solutions, nickel(+2) hydroxide can be
oxidized to nickel(+4) oxide (Agency for Toxic Substances and Disease Registry, 1992).
Nickel exists in the environment as both organic and inorganic compounds (Antonsen, 1981).
Elemental nickel, nickel oxide (NiO), and nickel subsulfide (Ni3S2) are all insoluble in water,
whereas nickel chloride (NiCl2) and nickel sulfate (NiSO4) are both relatively water soluble.
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11.6.15.2 Pharmacokinetics
Absorption and Distribution
Respiratory tract deposition and uptake of nickel is dependent on particle size and
solubility (Grandjean, 1974). In humans, 30 to 35% of inhaled nickel is retained in the the
respiratory tract, of which only a portion (~ 20% of inhaled) will be absorbed into the
bloodstream (Bennett, 1984; Grandjean, 1984; Sunderman and Oskarson, 1991). The
remainder is either swallowed or expectorated. Absorption is evident from nickel in the urine
of exposed workers (Bernacki et al., 1978; Torjussen and Andersen, 1979). Higher
concentrations of urinary nickel were found in workers exposed to soluble nickel compounds
(nickel chloride, nickel sulfate) compared to insoluble nickel compounds (nickel oxide, nickel
subsulfide), indicating that the soluble compounds were more readily absorbed from the
respiratory tract (Bernacki et al., 1978; Torjussen and Andersen, 1979). The nickel content
of the nasal mucosa in workers exposed to insoluble nickel compounds was higher than the
content in workers exposed to soluble nickel compounds, again suggesting greater absorption
of the soluble compounds (Torjussen and Andersen, 1979).
Data in rats and mice indicate that insoluble nickel compounds are retained in the lungs
in greater amounts and for a longer period of time than soluble nickel compounds (Benson
et al., 1987, 1988; Dunnick et al., 1989; English et al., 1981; Tanaka et al., 1985). The
lung burden of nickel in these rodents increase with increasing particle size (Tanaka et al.,
1985, 1988). Nickel retention was about 6 times (mice) to 10 times (rats) greater in animals
expose to insoluble nickel subsulfide compared to soluble nickel sulfate (Benson et al., 1987,
1988). Elimination half-times from the lung of rats were calculated to be 7.7, 11.5, and 21
mo for nickel oxide with mass median aerodynamic diameters (MMADs) of 0.6, 1.2, and
4.0 fj,m, respectively (Tanaka et al., 1985, 1988). In addition, the lung burdens of nickel
generally increased with longer exposure duration and higher levels of the various nickel
compounds (Dunnick et al., 1988, 1989).
Slow clearance of nickel oxide from the lungs was observed in hamsters (Wehner and
Craig, 1972). The retention was not dependent on the duration of exposure or exposure
concentration. Approximately 20% of the inhaled concentration of nickel oxide (30 to
130 mg Ni/m3) was retained in the lungs 3 days after a 3-week exposure. By 45 days after
the last exposure to nickel oxide, 45% of the initial lung burden was still present in the lungs
April 1995 11-324 DRAFT-DO NOT QUOTE OR CITE
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(Wehner and Craig, 1972). First-order clearance kinetics were reported for nickel in mice
lungs after a 2-h exposure (Graham et al., 1978). After 4 days of exposure, 72% of the
deposited fraction was cleared from the lungs.
The clearance of nickel compounds from lungs was also studied following intratracheal
administration (Carvalho and Ziemer, 1982; Valentine and Fisher, 1984). Nickel subsulfide
was cleared from lungs in two phases, an initial half-time of 1.2 days (38% of dose cleared)
followed by a half-time of 12.4 days (42% of dose). After 35 days, 10% remained in the
lungs (Valentine and Fisher, 1984). Soluble nickel chloride is cleared from lungs more
rapidly than nickel subsulfide, with 71% of the initial nickel chloride dose cleared by 24 h
and 0.1% remaining after 21 days (Carvalho and Ziemer, 1982).
Once absorbed, nickel is transported in the bloodstream. Soluble nickel ion (Ni[II])
forms complexes with water or with water and other ligands. These complexes can be
rapidly translocated into different tissues. In plasma, about 75% of nickel is bound to high
molecular weight proteins (e.g., a2"macrogl°bulin, gamma-globulin, transferrin, albumin)
(Coogan et al., 1989). Elevated serum nickel levels have been found in occupationally
exposed individuals compared to nonexposed controls (Angerer and Lehnert, 1990; Elias
et al., 1989; Torjussen and Andersen, 1979). Levels were higher in workers exposed to
soluble nickel compounds compared to workers exposed to insoluble nickel compounds
(Torjussen and Andersen, 1979).
Nickel has been detected primarily in the lungs of exposed individuals, with much
lower levels of nickel in the liver and kidneys (Resuke et al., 1987; Sumino et al., 1975).
Nickel has also been found in the nasal mucosa of exposed workers, with higher levels found
in workers exposed to insoluble nickel compounds (Torjussen and Andersen, 1979).
In rats exposed to nickel oxide, the lung burden of nickel increased with longer
exposures and increasing particle size (Kodama et al., 1985; Tanaka et al., 1985). Nickel
was found in the liver, kidney, and spleen following exposure to nickel oxide, nickel
subsulfide, and nickel sulfate; however, these levels were very low compared to lung content
(Benson et al., 1987, 1988; Tanaka et al., 1985).
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Metabolism
The metabolism of nickel consists of ligand exchange reactions (Coogan et al., 1989).
In humans and laboratory animals, nickel binds to albumin, L-histidine, and
a-2-macroglobulin in the serum. The principal binding locus of nickel to serum albumins in
humans, rats, and bovines is the histidine residue at the third position from the amino
terminus. Dogs do not seem to have this binding locus, and most of the nickel (> 85%) in
the serum was not bound to protein (Agency for Toxic Substances and Disease Registry,
1992). A proposed transport model involves the ability of L-histidine to remove nickel from
albumin via a ternary complex composed of albumin, nickel, and L-histidine. The
low-molecular weight L-histidine nickel complex can then cross biological membranes
(Coogan et al., 1989). Once inside the cell, nickel interacts with deoxyribonucleic acid
(DNA), resulting in crosslinks and strand breaks.
Excretion
Absorbed nickel is excreted in the urine, regardless of the route of exposure (Angerer
and Lehnert, 1990; Bernacki et al., 1978; Elias et al., 1989; Hassler et al., 1983; Torjussen
and Andersen, 1979). A half-life of 17 to 53 h has been reported in exposed welders
(Onkelinx and Sunderman, 1980). A two-compartment model has been developed for the
whole-body kinetics of nickel(II) (Onkelinx and Sunderman, 1980); the model consists of a
rapid clearance phase, followed by a slow clearance phase. In nickel-exposed workers, an
increase in urinary nickel excretion was found from the beginning to the end of the shift,
indicating a fraction that was rapidly eliminated. An increase in urinary excretion was also
found as the week progressed, indicating a fraction that was excreted more slowly (Ghezzi
et al., 1989). Higher nickel levels were found in the urine of workers exposed to soluble
nickel compounds, indicating that the soluble compounds are more readily absorbed than
insoluble compounds (Bernacki et al., 1978; Torjussen and Andersen, 1979). Nickel has
also been excreted in the feces of nickel workers, but this was most likely due to mucociliary
clearance of nickel from the respiratory system to the gastrointestinal tract (Hassler et al.,
1983).
In laboratory animals, the route of excretion following intratracheal administration of
nickel depends on the solubility of the nickel compound. In rats given soluble nickel chloride
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or nickel sulfate, =70% of the given dose was excreted in the urine within 3 days (Carvalho
and Zeimer, 1982; Clary, 1975; English et al., 1981; Medinsky et al., 1987). By day 21,
96.5% of the given dose of nickel chloride had been excreted in the urine (Carvalho and
Zeimer, 1982). Following intratracheal administration of less soluble compounds (nickel
oxide, nickel subsulflde), a greater fraction of the dose is excreted in the feces as a result of
mucociliary clearance. Following administration of nickel oxide to rats or nickel subsulfide
to mice, approximately equal amounts of the initial dose were excreted in the urine and the
feces (English et al., 1981; Valentine and Fischer, 1984). A total of 90% of the initial dose
of nickel subsulfide was excreted within 35 days, and 60% of the initial dose of nickel oxide
was excreted within 90 days. This is consistent with nickel oxide being less soluble and not
as rapidly absorbed as nickel subsulfide (English et al., 1981; Valentine and Fischer, 1984).
11.6.15.3 Health Effects
Both soluble and insoluble nickel compounds, as well as elemental nickel, can produce
toxicity in humans following inhalation exposure. Generally, soluble nickel compounds
(nickel chloride, nickel sulfate, and nickel nitrate) are considered more toxic than the
insoluble nickel compounds (nickel oxide and nickel subsulfide). The respiratory system is
the primary target of nickel toxicity following inhalation exposure. The potential for
respiratory carcinogenicity is evident in both human and laboratory animal studies.
Human Data
Most human data on respiratory effects of nickel are based on occupational or chronic
duration studies. Human toxicity data are summarized in Table 11-42. Asthma induced by
occupational exposure to nickel has been documented (Dolovich et al., 1984; McConnell
et al., 1973; Novey et al., 1983). The asthma can result from either primary irritation or
from an allergic response. Reduced vital capacity and expiratory flows were observed in
stainless steel welders (Kilbam et al., 1990); alveolar volume and total thoracic gas volume
were unaffected. Because the welders were also exposed to high levels of chromium, the
role of nickel in the etiology of the impaired lung function is not known. In addition, no
quantitative exposure information is available from these studies.
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TABLE 11-42. EXPOSURE CONDITIONS AND EFFECTS FOR NICKEL AND COMPOUNDS
Exposure
Concentration
ppm fig Ni/nr
Exposure
protocol
Chemical
form
Particle size
and
distribution
Species, Sex,
Strain
(Sample or group size)
Assays performed: Effect(s)
Reference
K)
00
O
NA 0
80-310
NA NR
(occup) Ni NR
1-16 years aerosol
(occup) Ni
>5 years dust
NR
Human
(821) M,
(758) F
Human
(845) M
Clinical examination including pulmonary x-ray, ECG,
lung function tests, and blood count, hospital records of
birth data and congenital defects: Increased abortions
(relative risk 1.8) and increased incidence of
malformations (16.9% versus 5.8% in controls) occurred.
Deaths recorded for men who died before 1967, and
causes of deaths identified: Of 482 men that died,
113 had lung cancer and 39 nasal cancer. More observed
deaths compared to expected deaths for both types of
cancers, particularly nasal sinus cancer, in those workers
who were first employed before 1925 but not in workers
first employed in 1925-1944. The higher incidences may
be attributed to various reasons: high exposures to dust,
more smokers, and older workers employed prior to
1925. Also, between 1920-1925, personal protection for
workers against dust was introduced into the plant, which
may have attributed to the decreased number of cancers.
Chashschin et al.
(1994)
Doll et al.
(1970)
Abbreviations:
I
D ECG = electrocardiogram; F = females; LM = light microscopy; M = males; mo = months; NA = not applicable; NR = not reported; occup = occupational;
u SMR = standard mortality ratio; wt = weight.
S
O
cj
O
a
i
n
-------
1 The carcinogenic effect of nickel has been well documented in occupationally exposed
2 workers (Chovil et al., 1981; Doll et al., 1977; Magnus et al., 1982). Lung and nasal
3 cancer (primarily squamous cell carcinomas) were the predominant cancers in the exposed
4 workers. Respiratory cancers were related primarily to exposure to soluble nickel
5 compounds at concentrations > 1,000 ^tg Ni/m3 and to exposure to less soluble compounds at
6 concentrations >10,000 /tg Ni/m3 (primarily oxidic and sulfidic compounds) (Doll, 1990).
7 A higher incidence of respiratory tract cancer was observed among workers exposed to both
8 soluble and less soluble nickel compounds compared to those exposed to less soluble nickel
9 compounds alone, suggesting compound interaction. There was no evidence suggesting that
10 metallic nickel causes respiratory tract cancer (Doll, 1990).
11 In a cohort of 2,247 refinery workers, an excess of lung cancer was found by 3 to
12 14 years after first employment, while an increase in nasal cancer was not observed until
13 15 to 24 years after first employment (Magnus et al., 1982). The risk of respiratory tract
14 cancers markedly decreased when the date of first exposure was later than «1930 (Doll
15 et al., 1970, 1977; Pedersen et al., 1973). This was a result of reducing nickel dust
16 exposure by altering the machinery used in the refining process and by the use of cotton face
17 pads by the workers (Doll et al., 1977). The interaction between smoking and nickel
18 exposure for the development of respiratory tract cancer was found to be additive rather than
19 multiplicative (Magnus et al., 1982). Nevertheless, the workers in these studies were
20 exposed to a variety of other metals, including uranium, iron, lead, and chromium, so it
21 cannot be concluded that nickel was the sole causative agent.
22 Immunological, renal, and dermal effects have also been observed in refinery workers
23 exposed to nickel. Significant increases in levels of immunoglobulin G (IgG), IgA, and IgM,
24 respectively, and a significant decrease in IgE levels were observed in workers exposed to
25 nickel (compound not specified) (Bencko et al., 1983, 1986). A significant increase in other
26 serum proteins that may be involved in cell mediated immunity (including a-antitrypsin,
27 a-2-macroglobulin, ceruloplasmin) also were observed. The increase in immunoglobulins
28 and serum proteins indicated that the immune system was stimulated by nickel exposure.
29 Increased urinary /3-2-microglobulin levels in the kidneys has been observed in exposed
30 individuals (Sunderman and Horak, 1981). Contact dermatitis is one of the most prevalent
31 effects of nickel exposure. Immunological studies indicated that the dermatitis is an allergic
April 1995 11-329 DRAFT-DO NOT QUOTE OR CITE
-------
1 response to nickel. The contact dermatitis may be the result of dermal contact with airborne
2 nickel or a response to inhaled nickel in individuals sensitized to nickel (Agency for Toxic
3 Substances and Disease Registry, 1992).
4 In a cross-sectional study of 821 male and 758 female workers in a nickel refinery
5 plant, increased abortions (relative risk of 1.8) and increased incidence of malformations
6 (musculoskeletal system and cardiovascular defects) (16.9% versus 5.8% in unexposed
7 controls) occurred in the exposed workers (Chashschin et al., 1994).
8
9 Laboratory Animal Data
10 As in humans, the respiratory tract is the major target organ of nickel toxicity in
11 laboratory animals following inhalation exposure. The laboratory animal toxicity data are
12 summarized in Table 11-43. Acute duration studies are limited; studies evaluated effects
13 following at least 2 wks of exposure to nickel oxide (Lovelace, 1986a,b). Rats and mice
14 inhaling nickel oxide developed respiratory effects including hyperplasia of alveolar
15 macrophages, inflammation, and interstitial infiltrates. At exposures of longer duration,
16 bronchial gland hyperplasia was observed 20 mo after a 1-mo exposure to 500 /ig Ni/m3 as
17 nickel oxide (Horie et al., 1985). Chronic inflammation, fibrosis, macrophage hyperplasia,
18 interstitial inflammatory infiltrates, and increased lung weight occurred in rats and mice
19 following exposure to nickel sulfate hexahydrate, nickel subsulfide or nickel oxide for
20 16 days or 13 weeks (Benson et al., 1987, 1988, 1989, 1990; Dunnick et al., 1988, 1989).
21 Olfactory epithelial atrophy of the nose also occurred with exposure to nickel sulfate and
22 nickel subsulfide, but not nickel oxide, in both species (Benson et al., 1990). Rats appeared
23 to be more sensitive than mice to nickel toxicity (Benson et al., 1990; Lovelace, 1986a,b).
24 The toxicity depended on the solubility of the compounds and not on lung burden, since the
25 compound with the lowest toxicity (nickel oxide) had the highest lung burden. The studies
26 indicate the following toxicity ranking: nickel sulfate > nickel subsulfide > nickel oxide.
27 Enzyme changes were observed in alveolar macrophages of rats exposed to nickel oxide
28 or nickel chloride aerosols for 18 days (Murthy et al., 1983). Biochemical (altered
29 lysozyme, alkaline phosphatase, and /3-glucuronidase activities) and morphological alterations
30 (hyperplasia and lamellated material in the cytoplasm) in alveolar macrophages were
31 associated with impaired cellular function in rabbits exposed to metallic nickel or nickel
April 1995 11-330 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 11-43. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
I—*
<$
1— '
1— '
1
u>
o
|>
H
6
o
i^
3
O
c!
0
Exposure
Concentration
ppm /tg Ni/m3
Acute Studies
NA 0, 100
250, 350
500
NA 0
900
2,000
4,000
7,800
23,600
NA 0
900
2,000
4,000
7,800
23,600
Exposure Chemical Particle size and Species, Sex,
protocol form distribution Strain Assays performed: Effect(s)
2 hr NiCl2 99% <3 ^m Mouse, Swiss Hemolytic plaque technique to determine number
aerosol (14-29) F of specific antibody-producing spleen cells:
Immunosuppression was observed at >250 pg/m3.
6 hr/d NiO MM AD = 3 /xm Rats, F344 Clinical signs, gross and histopathology
5 d/wk aerosol ag = 1.9 (5/sex) examination: Lung lesions occurred at 2,000
12 d Mg/ni3 and above, increasing in severity with each
level. At 2,000 /xg/m3, hyperplasia of alveolar
macrophages in 3/10 animals. At 4,000 jtg/m3
and above, effects included hyperplasia of alveolar
macrophages, focal inflammation in alveoli and
alveoli septa, focal interstitial infiltrate,
hyperplasia of peribronchial lymphoid tissue,
enlarged and vacuolated Type II cells. At high
level, thymus lesions were reported (degeneration
with debris laden macrophages).
6 hr/d NiO MMAD = /*m Rats, F344 Clinical signs, body wt, gross and histopathology
5 d/wk aerosol crg = 1.9 (5/sex) examination: Lung lesions occurred at the two
12 d highest levels. At 9,000 fig/m3, mild hyperplasia
of alveolar macrophages. At highest level,
decreased body wt and moderate lung effects
occurred (hyperplasia of alveolar macrophages,
inflammation, focal interstitial infiltrates, necrotic
or vacuolated macrophages.
Reference
Graham et al. (1978)
Lovelace (1986a)
Lovelace (1986b)
n
i—i
H
W
-------
1
t— *
§
t— k
1
Ni
O
5
H
^^
i
O
O
2
O
H
O
d
g
H
M
O
Q
H
W
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
Exposure Concentration
nnm n o Ni /m
LJLslll r*o ^ ' '•' *^
Subchronic and Chronic
NA 0
2,000 (SD = 1)
NA 130
NA 0
1,700
NA 0
600
NA 0
230
300
430
NA 0
120
NA 0
109
• Exposure
protocol
Studies
6hr/d
5d/wk
4.5 wk
6hr/d
5d/wk
4 or 8 mo
6hr/d
5d/wk
1 mo
6hr/d
5d/wk
1 mo
6hr/d
5d/wk
4 wk
12 hr/d
6d/wk
>2 wk
8hr/d
5d/wk
18 d
Chemical
form
Ni
dust
metallic Ni
dust
metallic Ni
dust
NiCl2
aerosol
NiCl2
aerosol
NiCl2
aerosol
NiCl2
aerosol
Particle size and
distribution
NR
NR
Unspecified size, but 40%
respirable, i.e., penetrated
a preseparator
MMAD = 1 A*m
4% >8 fj.m
1%4-8/im
9% 2-4 urn
32% 1-2 nm
49% 0.1-1 Atm
4% 0.25-0.5 urn
1% <0.25 Atm
MMAD = 0.32 /xm
ag = 1.51
o
MMAD = 0.32 fim
Species, Sex,
Strain
Rabbit, NS
(8)M
Rabbit, NS
(6)
Rabbit, NS
(8)M
Rabbit, NS
(8)M
Rabbit, NS
(4-8) M
Rat, Wistar
(10) M
Rat, Wistar
(>3)M
Assays performed: Effect(s)
Lung weight, AM function and size:
Inc lung weight and AM activation.
EM and LM of lavaged AM,
phagocytic function and activity:
Inc volume density of Type II cells
and impaired AM function occurred,
but AM activity was not affected.
Morphometric measurements Inc
volume density of Type II alveolar
epithelial cells in lungs.
Fibronectin and lysozyme in lung
lavage fluid: Dec fibronectin
concentration and lysozyme activity.
LM and EM of lungs, bactericidal
and phagocytic activities of AM:
Inc number of AM in lavage fluid,
laminated structures and active cell
surface in AM, decreased
bactericidal capacity.
Lavaged AM, HP of lungs:
Hyperplastic bronchial epithelium,
lymphocytic infiltration.
Enzyme activities in AMs and
lavage fluid: Inc AM acetylesterase
and dec lysozyme activities; inc
alkaline phosphate in lavage fluid.
Reference
Jarstrand et al. (1978)
Johansson et al. (1983)
Johansson and
Camner, (1980)
Berghem et al. (1987)
Wiernik et al. (1983)
Bingham et al. (1972)
Murthy et al. (1983)
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
vo Exposure Concentration
^ Ppm
NA
NA
p— »
OJ
O
§ NA
H
O
o
H
O
g
§
/tg Ni/m3
0
130
0
110
220
440
880
1,800
0
110
220
440
880
1,800
protocol form
6 hr/d NiCl2
5 d/wk dust
4-6 wk
(3 d post)
6 hr/d Ni3S2
6 d/wk aerosol
13 wk
6 hr/d Ni3S2
6 d/wk aerosol
13 wk
Particle size and Species, Sex,
distribution Strain Assays performed: Effect(s)
MMAD = 0.5-1 /tm Rabbits, NS Macrophage concentration and
(6) M lysozyme activity in lung lavage
fluid: Inc lavaged AMs, dec
lysozyme activity hi lavage fluid and
hi lavaged AMs.
MMAD = 2.16-2.71 /tm Rat, F344 Body wt gain, CS, HP mortality,
erg = 1.99-2.7 (10/sex) sperm morphology and vaginal
cytology: Labored respiration at
1,800 /tg/m3; Inc lung wt at 110
/tg/m3; lung lesions (chronic
inflammation, goblet cell
hyperplasia, inc number of
vacuolated AMs) at 440 /tg/m3;
thinning of olfactory epithelium at
220 /tg/m3; enlarged bronchial and
mediastinal lymph nodes draining
the lungs due to inc number of
lymphocytes within cortex of nodes
at all levels.
MMAD = 2.16-2.71 /tm Mouse, Body wt gain, CS, HP mortality,
Og = 1.99-2.7 B6C3F1 sperm morphology and vaginal
(10/sex) cytology: Inc lung wt at 440
/tg/m3; lung lesions (AM
hyperplasia at 220 /tg/m3, then
inflammation, fibrosis, lymphoid
hyperplasia at higher cone.);
olfactory epithelial atrophy at
440 /tg/m3.
Reference
Lundborg and
Camner, (1984)
Benson et al. (1990)
Benson et al. (1990)
O
H
W
-------
3.
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
to Exposure Concentration
VO T^ y^i : i r* ..:_i_ _: a
ppm ug Ni/m . ,. ,. ., .
rr ° protocol form distnbution
NA 0 6 H/d Ni3S2 MMAD = 2.4 f*m
1 10 5 d/wk aerosol ag = 2.2
450 65 d
1,800
i— »
Oi
£ NA 0 6 hr/d NiSO4 MMAD = 2.3 /*m
27 5 d/wk aerosol ag = 2.4
110 65 d
0 45°
§
>
0
O
H
O
0
H
W
Species, Sex,
Strain Assays performed: Effect(s)
Mouse, Alveolar macrophages, antibody-
B6C3F1 forming cell response, spleen cell
(40) F proliferative response, NK cell
activity, host resistance to B16F10
tumor: Inc number of lung-
associated lymph nodes (LALN),
increased nucleated cells in LALN
(1,800 /tg/m3) and lavage fluid (450
Hg/m3); increased Ab-forming cells
in LALN (1,800); dec mixed
lymphocyte response (1,800 /tg/m3);
dec AM phagocytic activity of AMs
(450 /ig/3); dec NK cell activity of
spleen (1,800 ftg/m3).
Mouse, Alveolar macrophages, antibody-
B6C3F1 forming cell response, spleen cell
(40) F proliferative response, NK cell
activity, host resistance to B16F10
tumor: Inc number of lung-
associated lymph nodes (LALN) at
450 ftg/m3; increased Ab-forming
cells in LALN (450 fig/m3).
Reference
Haley et al. (1990)
Haley et al. (1990)
n
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
to Exposure Concentration
^0
^ ppm
NA
NA
i— >
t— »
i
bi
O
& NA
1
O
O
25
o
H
O
O
H
W
0
*
Q
H
W
T^ ~ /"M_ • 1 n _*• 1 • J
protocol form distribution
0 7 hr/d NiO MMAD = 0.3 jim
53,200 ± 5 d/wk aerosol ag = 2.2
11,100 lifespan
0 6 hr/d Ni3S2 MMAD = 2.4 pan
110 5 d/wk aerosol
-------
I
TABLE 11-43 (cont
to Exposure Concentration
*•* ™,m
ppm
NA
NA
I— »
E
u>
o\
„_ XT; /***3
Jig lNl/m
0
020
050
100
200
400
0
020
050
100
200
400
protocol
6hr/d
5d/wk
13 wk
6hr/d
5d/wk
13 wk
'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
Chemical Particle size and
form distribution
NiSO4 MMAD = 2.3 /im
aerosol
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
Exposure Concentration
ppm fig Ni/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species,Sex,
Strain
Assays performed: Effect(s)
Reference
O
O
O
B
i
n
i— i
H
W
NA
NA
0
400
900
1,800
3,600
7,300
0
400
900
1,800
3,600
7,300
6hr/d
5d/wk
16 days
Ni3S2
aerosol
6hr/d
5d/wk
16 days
Ni3S2
aerosol
AVG: MMAD=2.8, Rat, F344/N
-------
00
O
o
2
o
H
O
CJ
s
w
Exposure Concentration
ppm
NA
NA
NA
NA
/ig Ni/m3
0
700
0
200
100
400
0
400
1,800
0
20
100
400
u.A.^uauit< \^u&iiuuoi f aiu^it; diz*& aim
protocol form distribution
6 hr/d Ni3S2 diameter
5 d/wk aerosol 70% < 1 /mi
78 wk 25% 1-1. 5 ftm
(30 wk post)
6 hr/d NiSO4 MM AD = 1.9^1"
5 d/wk aerosol 0. = 2.1
13 wk
6 hr/d Ni3S2 MMAD = 2.8 urn
5 d/wk aerosol ag = 2.2
13 wk
6 hr/d NiSO4 MM AD =1.9 /*m
5 d/wk aerosol ag = 2.1
13 wk
Species, Sex,
Strain
Rat, F344
(22-32) M
Rat, F344/N
(6/sex)
Rat, F344/N
(6/sex)
Mouse,
B6C3F1
(8/sex)
Assays performed: Effect(s)
Body wt, HP in major organs:
Reduced body wt, inc lung lesions
(pneumonitis, atelectasis, bronchitis,
bronchiectasis, emphysema), inc
incidence of lung tumors (adenomas,
adenocarcinomas, squamous cell
carcinomas).
Biochemical and cytological
evaluation of BAL fluid, necropsy
of lungs: Inflammation suggested
by inc LDH, b-glucuronidase, and
total protein at 100 |tg/m3.
Biochemical and cytological
evaluation of BAL fluid, necropsy
of lungs: Inc LDH, b-
glucuronidase, and total protein;
inflammation, macrophage
hyperplasia, and interstitial
infiltrates at 400 /tg/m3.
Biochemical and cytological
evaluation of BAL fluid, necropsy
of lungs: Inflammation suggested
by inc LDH and b-glucuronidase,
macrophage hyperplasia and
interstitial infiltrates at 100 /tg/m3;
chronic inflammation and fibrosis at
400 /tg/m3.
Reference
Ottolenghi et al.
(1974)
Benson et al. (1989)
Benson et al. (1989)
Benson et al. (1989)
G
s
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
Co Exposure Concentration
\O n ^-11 : i n t:_i_ _: i
ppm /tg Ni/nr rt , , ,. . .. ..
protocol form distnbution
NA 0 6 hr/d Ni3S2 MMAD = 2.8 jim
400 5 d/wk aerosol ^ = 22.
1,800 13 wk
NA 0 6 hr/d NiSO4 MMAD = 1.9/un
800 5 d/wk • 6H20 ag = 2.2
1,600 16 d aerosol
3,300
£ 6,700
E 13,300
VO
o
TJ
H
6
o
o
H
O
H
w
o
5S
O
Species.Sex,
Strain Assays performed: Effect(s)
Mouse, Biochemical and cytological
B6C3F1 evaluation of BAL fluid, necropsy
(8/sex) of lungs: Inc LDH, b-
glucuronidase, and total protein at
400; chronic inflammation and
fibrosis at 1,800 and macrophage
hyperplasia and interstitial infiltrates
at 400 jig/m3.
Rat, F344/N Clinical signs, body wt gain,
(5/sex) mortality, NK cell activity, gross
necropsy, histopathology: Labored
respiration, emaciation, lethargy,
reduced body wt gain, inc lung wt,
lung inflammation, degeneration in
bronchiolar mucosa (less vacuolation
of epithelial cells, goblet cell
hypertrophy), nasal lesions
(degeneration of respiratory
epithelium and atrophy of olfactory
epithelium) at 800; lymphoid
hyperplasia in lymph nodes at
800 and lymphocyte depletion in
cortex at 6,700; testicular
degeneration at 13,300 jig/m3.
Reference
Benson et al. (1989)
Benson et al. (1988)
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
Exposure Concentration
ppm
NA
NA
NA
/tg Ni/m3
0
800
1,600
3,300
6,700
13,300
0
120
0
400
900
2,000
3,900
7,900
- Exposure Chemical Particle size and
protocol form distribution
6 hr/d NiSO4 MMAD = 1.9/*m
5 d/wk • 6H20 ffg = 2.2
16 d aerosol
12 hr/d NiO MM AD = 0.25 ^m
6 d/wk aerosol 2 wk
6 hr/d NiO MMAD = 2.8 jim
5 d/wk aerosol ag = 1.8
13 wk
Species.Sex,
Strain
Mouse,
B6C3F1
(5/sex)
Rat, Wistar
(10) M
Rat, F344/N
(10/sex)
Assays performed: Effect(s)
Clinical signs, body wt gain,
mortality, NK cell activity, gross
necropsy, HP: Emaciation,
lethargy, reduced body wt gain,
decreased lung wt. Due to high
mortality, only 0, 800, and 1,600
groups had HP exam: Lung
inflammation and atrophy of
olfactory epithelium at 800; spleen
and thymus atrophy due to lymphoid
depletion at 1,600 (in mice that died
only); testicular degeneration at
Lavaged alveolar macrophages,
histopathology of lungs: Inc
number of alveolar macrophages,
macrophage accumulation in
alveolar spaces, thickening of
alveolar wall with dec lymphocyte
infiltration.
Body and organ wts, clinical signs,
histopathology: Inc lung weight in
all males and at >900 in females;
alveolar macrophage hyperplasia at
all levels and chronic inflammation
at ^3,900 /ig/m3.
Reference
Benson et al. (1988)
Bingham et al. (1972)
Dunnick et al. (1989)
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
vp
Exposure Concentration
ppm
NA
NA
NA
NA
Hg Ni/m3
0
400
900
2,000
3,900
7,900
0
120
0
800
1,600
3,200
0
200
400
800
Euijnntuic uicuiittu raiuwc size auu
protocol form distribution
6 hr/d NiO MMAD = 2.8 ftm
5 d/wk aerosol ag = 1.8
13 wk
8 hr/d NiO MMAD = 0.25 (an
5 d/wk aerosol
18 d
continuously NiO NR
on aerosol
gdl-21
continuously NiO NR
for 28 days aerosol
Species, Sex,
Strain
Mouse,
B6C3F1
(10/sex)
Rat, Wistar
(^3) M
Pregnant Rat,
Wistar
(10-13) F
Rat, Wistar
(10) F
Assays performed: Effect(s)
Body and organ wts, clinical signs,
histopathology: increased lung
weight in 3,900 (females); AM
hyperplasia at all levels chronic
inflammation at ^7,900 /ig/m3.
Enzyme activities in AMs and
lavage fluid: inc. acetylesterase and
decreased lysozyme activities and
inc. acetylesterase, alkaline
phosphatase, b-glucuronidase, and
lysozyme activities in lavage fluid.
Body wt; wt change and HP on
lung, liver, and kidney; hematology:
Maternal effects decreased (11%)
body wt gain, inc. lung wt,
increased leukocytes at 800 /ig/m3;
fetal effects-decreased wt, increased
leukocytes and serum urea at 1,600
Body wt; HP on lung, liver, and
kidney; hematology: Lungs-
thickened septa, macrophage foci,
emphysema, peribronchial
Reference
Dunnick et al. (1989)
Murthy et al. (1983)
"
Weischer et al. (1980)
Weischer et al. (1980)
infiltration of round cells, edema;
kidney-tubular degeneration; dec
body wt gain and kidney wt at 800;
inc lung wt and alkaline phosphatase
at 200; inc SGOT activity at 400;
inc RBC at 800 jtg/m3.
-------
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
to Exposure Concentration
^O
^ ppm
NA
NA
i— »
i
6
NA
o
11
H
b
0
z
0
H
0
c!
O
/ig Ni/m3
0
400
2,000
7,900
0
400
2,000
7,900
0
200
900
_H__ f?vtt/icilf*A f'Vipfnir'Ql Portii^lA 0171* HTi/4
^^^ CApusure i^ncmicai t^anicie size
-------
.
TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
NICKEL AND COMPOUNDS
to Exposure Concentration
vo
°* ppm
NA
£ NA
i
6
O
•n
H
O NA
O
§
N**'
H
O
c^
H
W
/xg Ni/m3
0
900
2,000
3,900
7,900
23,600
0
900
2,000
3,900
7,900
23,600
0
500
1,100
5,100
5,500
6,300
Y"* _ _ __ yii_ _~_ * 1 T» L • i • j e* * f*
exposure tjiemicai ranicie size ana opecies^ex,
protocol form distribution Strain Assays performed: Effect(s)
6 hr/d NiO MMAD = 3 pm Rat, F344/N Body wt and organ wts, mortality,
5 d/wk aerosol ag = 1.9 (5/sex) clinical signs, microscopic
16 d pathology: Inc lung wt at 7,900;
hyperplasia of alveolar
macrophages, focal suppurative
inflammation, focal interstitial
cellular infiltrate and particles in
alveoli and alveolar macrophages at
900; atrophy of olfactory epithelium
and atrophy of thymus and
hyperplasia of lymph nodes at
23,600 fig/m3.
6 hr/d NiO MMAD = 3 /*m Mouse, Body wt and organ wts, mortality,
5 d/wk aerosol og = 1.9 B6C3F1 clinical signs, microscopic
16 d (5/sex) pathology: Lung lesions at
7,900 (focal mixed inflammatory
cell infiltrate, bronchial epithelium
hyperplasia, diffuse alveolar
macrophage hyperplasia); atrophy of
thymus and hyperplasia of lymph
nodes at 23,600 ftg/m3.
6 hr/d NiO MMAD = 1.2 /im Rat, Wistar Histopathology (up to 20 mo
5 d/wk aerosol crg = 2.2 (2-5) M postexposure): Bronchial gland
1 mo hyperplasia at 20 mo at 500 and
6,300 /ig/m3.
Reference
Dunnick et al. (1988)
Dunnick et al. (1988)
Horie et al. (1985)
O
s
-------
£• TABLE 11-43 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
S. NICKEL AND COMPOUNDS
S Exposure Concentration
\& T" x-n_ • i
DDI11 USL IN I/ HI * -
vv ** protocol form
NA 0 continuously NiO
25-818 for aerosol
4 wk or
4 mo
NA 0 6hr/d NiO
470 5 d/wk aerosol
2,000 65 d
7,900
£
i
£
Particle size and Species, Sex,
distribution Strain Assays performed: Effect(s)
MMAD = 0.41-0.49 /tm Rat, Wistar Alveolar macrophage analysis;
-------
1 chloride for 1 to 8 mo (Berghem et al., 1987; Jarstrand et al., 1978; Johansson and Camner,
2 1980, 1986; Johansson et al., 1983; Lundborg and Camner, 1984; Wiernik et al., 1983).
3 Increase in volume density of alveolar Type 2 cells was also seen after 1 mo exposure.
4 Acute to subchronic exposures have resulted in immunological changes in rats, mice,
5 and rabbits. Immunosuppression was observed in mice exposed to nickel chloride for 2 h
6 (Graham et al., 1978). Longer-term exposure caused effects in respiratory macrophages
7 (Haley et al., 1990; Spiegelberg et al., 1984). A decrease in alveolar macrophage
8 phagocytic activity was observed in mice exposed to nickel subsulfide, nickel sulfate, or
9 nickel oxide for 65 days (Haley et al., 1990). A decrease in natural killer cell activity was
10 observed in the mice exposed to nickel subsulfide. Atrophy of lymphoid organs (spleen and
11 thymus) and lymphoid hyperplasia in bronchial and mediastinal lymph nodes were observed
12 in rats and mice exposed for 16 days to nickel sulfate, nickel subsulfide, and nickel oxide
13 (Benson et al., 1987, 1988: Dunnick et al., 1988). A decrease in the number of alveolar
14 macrophages and in the humoral response was observed in rats after < 4 mo of exposure to
15 nickel oxide, indicating that inhalation exposure to nickel may make animals more susceptible
16 to infection (Spiegelberg et al., 1984). The increase in susceptibility was also exhibited by
17 rabbits exposed to metallic nickel for 3 to 6 mo (Johansson et al., 1981). All of the animals
18 exposed for 6 rno had foci of pneumonia, which may have resulted from an impaired
19 function of the alveolar macrophages. The inhibitory effects of nickel on the cellular
20 immune response may be related to the development of nickel-induced tumors in animals, as
21 well as to the high risk of lung cancer in nickel-exposed workers (Shen and Zhang, 1994).
22 After a 12-mo exposure, bronchial epithelial metaplasia were observed in rats exposed
23 to nickel oxide (Tanaka et al., 1988). An increase in respiratory lesions (pneumonitis,
24 atelectasis, bronchitis, bronchiectasis, and emphysema), compared to controls, was observed
25 in rats exposed to nickel subsulfide for 78 weeks, followed by a 30-week observation period
26 (Ottolenghi et al., 1974). Alveolar proteinosis and marked lung enlargement were observed
27 in rats exposed chronically to 60 /*g Ni/m3 as nickel oxide (Takenaka et al., 1985). At the
28 end of the experiment, two animals also had focal fibrosis. Pneumoconiosis was observed in
29 hamsters following a lifetime exposure to 42,000 \t.g Ni/m3 as nickel oxide alone or in
30 combination with cigarette smoke (Wehner, 1986; Wehner et al., 1975, 1979). The
31 pneumoconiosis was characterized by lung changes of interstitial pneumonitis, diffuse
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1 granulomatous inflammation, bronchial and bronchiolar epithelial hyperplasia, fibrosis of the
2 alveolar septa, bronchiolization of the alveolar epithelium, and emphysema and/or atelectasis.
3 Despite the high lung burden of nickel, pneumoconiosis was not observed initially, indicating
4 the low acute toxicity of nickel oxide. The pneumoconiosis increased in severity as a
5 function of exposure time and age. Emphysema was observed in the animals that died before
6 developing pneumoconiosis.
7 Nickel has been shown to be carcinogenic in animals, with nickel subsulfide being the
8 most potent (Coogan et al., 1989). Lung cancer was found in rats exposed chronically to
9 nickel subsulfide (Ottolenghi et al., 1974). Tumors included adenomas, adenocarcinomas,
10 squamous cell carcinomas, and fibrosarcoma. Lung tumors were not observed in rats
11 following exposure to nickel oxide ((Horie et al., 1985); however, the exposure duration
12 (1 mo) was not sufficient to evaluate the potential for carcinogenicity.
13 Other systemic changes associated with nickel inhalation exposure have included
14 decreased body weight gain, decreased liver weight, and altered serum glucose in rats
15 exposed to nickel oxide for less than a month (Weischer et al., 1980). Atrophy of the liver
16 was observed in mice and rats exposed to nickel subsulfide for 16 days (Benson et al., 1987).
17 A decrease in fetal body weight was observed in the offspring of rats exposed to nickel
18 oxide on gestation days 1-21 (Weischer et al., 1980). No effects on the number of fetuses or
19 on the number and weight of placentas were observed. Testicular degeneration was observed
20 in rats and mice exposed to nickel sulfate and nickel subsulfide for 16 days (Benson et al.,
21 1987, 1988). No exposure-related effects were seen in sperm number, motility, or
22 morphology, or on the length of the estrous cycle in rats or mice exposed nickel for
23 13 weeks (Dunnick et al., 1989). Higher exposure concentrations were used in the 16-day
24 studies, which explains why testicular effects were observed after 16 days but not 13 weeks
25 of exposure.
26
27 11.6.15.4 Factors Affecting Susceptibility
28 Individuals with respiratory difficulties may have greater susceptibility to the toxicity of
29 inhaled nickel, since pulmonary dysfunction and asthmatic symptoms have been shown to
30 occur in exposed workers (Dolovich et al., 1984; Kilbam et al., 1990; McConnell et al.,
31 1973; Novey et al., 1983). The developing respiratory tract of children may also pose an
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1 increased susceptibility. Data have suggested that smoking and nickel exposure may have an
2 additive effect on the development of respiratory tract cancer (Magnus et al., 1982).
3 Greater susceptibility to nickel toxicity may result in individuals with comprised
4 immunological systems. Human and animal data have shown that nickel can cause changes
5 in immunoglobulin levels (Bencko et al., 1983, 1986) and immunosuppression (Benson et al.,
6 1987, 1988; Dunnick et al., 1988, Haley et al., 1990).
7 Individuals sensitized to nickel may be unusually susceptible, because exposure to
8 nickel by any route may trigger an allergic response (Dolovich et al., 1984; McConnell et
9 al., 1973; Novey et al., 1983). Epidemiology studies indicate that blacks have a higher
10 nickel sensitivity than whites and that women of either racial group have higher reaction rates
11 (Nethercott and Holness, 1990; Prystowsky et al., 1979). The incidence of reactions may be
12 higher in women because they wear more metal jewelry than do men.
13 A relationship between human lymphocyte antigens (HLA-DRw6) and nickel sensitivity
14 was observed in patients who had a contact allergy and positive results in a patch test for
15 nickel only (Mozzanica et al., 1990). The patients had no occupational exposure history.
16 The nickel-sensitive group had a significant elevation in HLA-DRw6 antigen, compared to
17 normal controls. The relative risk for patients with DRw6 to develop a sensitivity to nickel
18 was approximately 1:11. The presence of DRw6 may be monitored to determine the
19 potential risk of individuals to become sensitized to nickel.
20
21 11.6.16 Potassium
22 11.6.16.1 Chemical and Physical Properties
23 Potassium is one of the alkali metals in Group 1A of the periodic table. It forms
24 compounds in the +1 oxidation state, and is never found free in nature. Metallic potassium
25 is rapidly oxidized in air, and decomposes in water with the evolution of hydrogen (Weast,
26 1989). Potassium is unique among alkali and alkaline-earth metals in forming the superoxide
27 KO2 in air. This compound is unstable in contact with molten potassium, and will react to
28 yield K2O. Potassium can react to form inorganic salts and organopotassium compounds
29 such as KCO (Greer et al., 1982). Potassium dichromate (K2Cr2O7) is moderately soluble in
30 water.
31
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1 11.6.17.2 Pharmacokinetics
2 Serum potassium concentration was unaffected in six atopic subjects after a single
3 inhalation of 10% potassium chloride from an ultrasonic nebulizer (Dixon et al., 1989).
4 However, due to the large potassium content in the body, it is unclear if a change in serum
5 levels would have been detected, even if the entire amount sprayed from the nebulizer were
6 deposited in the lungs and absorbed into the blood.
7 No other data were located on the pharmacokinetics of potassium following inhalation
8 exposure to potassium compounds. Therefore, this discussion is based on general principles
9 of chemistry and biochemistry (Mudge, 1985). Many potassium compounds are soluble in
10 water and would be expected to be absorbed from the lungs. Potassium is an essential
11 element. It is found throughout the body as the intracellular cation and in the extracellular
12 compartment. An active ion transport system using magnesium-adenosine triphosphate (Mg-
13 ATP) as the energy source (see the section on magnesium) maintains a potassium gradient
14 across the plasma membrane. This gradient plays a crucial role in nerve conduction and
15 muscle action. Orally administered potassium is completely absorbed from the
16 gastrointestinal tract and excreted in the urine. The kidney plays a major role in the
17 maintenance of potassium homeostasis. The body responds to increased potassium by
18 increasing excretion and by increasing tissue uptake, thereby returning extracellular
19 potassium levels to normal.
20
21 11.6.16.3 Health Effects
22 Data on the effects of inhalation exposure to potassium are summarized in Table 11-44.
23 The one study that investigated the health effects of inhaled potassium compounds was an
24 abstract that investigated the effects of inhaling potassium chloride and sodium chloride in
25 6 male atopic subjects with increased nonspecific bronchial reactivity (Dixon et al., 1989).
26 In a randomized double-blind study, the subjects inhaled 10% potassium chloride on one day
27 and 0.9% sodium chloride on a different day using an ultrasonic nebulizer. Cardiovascular
28 parameters and vital capacity were measured at intervals from 1 to 150 breaths after
29 exposure. All subjects coughed and bronchoconstricted after potassium chloride dosing, but
30 there was no cough and less bronchoconstriction after sodium chloride. Partial flow at 30%
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I
TABLE 11-44. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR POTASSIUM AND COMPOUNDS
Exposure
Concentration
ppm /ig K/m3
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number) Sex
Assays performed: Effect(s)
Reference
&
NA See See comments KC1
comments
NR
Human Cardiac output, heart rate, stroke volume,
(6) M ventricular ejection time, oxygen saturation, serum
'K, vital capacity: Cough only after KC1, not after
NaCl. Bronchoconstriction (40% fall hi Vp30) was
observed with KC1, but not 0.9% or 10% NaCl.
Serum K+ and cardiovascular parameters
unaffected, suggesting direct effect on respiratory
tissue. Effect attributed to KC1, not nonspecific
osmotic effect.
Note: Subjects were atopic, with increased non-
specific bronchial reactivity.
Note: Exposure was double-blinded and
randomized, with subjects exposed to 10% KC1 or
0.9% NaCl by ultrasonic nebulizer on separate days.
Exposure to 10% NaCl was in a separate
experiment.
Dixon et al.
(1989)
Abbreviations:
K+ = potassium ion; KC1 = potassium chloride; M = male; min = minute; NA = not applicable; NaCl = sodium chloride; NR = not reported; ppm = parts
per million; Vp30 = partial flow at 30% vital capacity.
-------
1 vital capacity (Vp30) was decreased by >40% after potassium chloride exposure, but not
2 after sodium chloride. Plasma potassium levels, oxygen saturation, and cardiovascular
3 parameters were unaffected. The abstract further states that a second randomized double-
4 blind study was conducted with the same subjects inhaling "0.9% sodium chloride or 10%
5 sodium chloride." However, since the next statement is "all subjects coughed and
6 bronchoconstricted after potassium chloride; there was no cough and less bronchoconstriction
7 after sodium chloride," it appears that the second study may actually have been conducted
8 with 0.9% potassium chloride and 10% sodium chloride. Thus, the second study would have
9 assessed whether the observed effects could have been attributed to potassium, or
10 nonspecifically to inhaled salts. Based on the observed results, the authors concluded that
11 hyperreactive subjects bronchoconstrict in response to potassium, and the effect cannot be
12 explained by osmotic challenge alone.
13 A Russian study assessed the effects on the upper respiratory tract of workers at a plant
14 that produced nitrogen-phosphorus-potassium fertilizer; further details were not available
15 (Kilin, 1972).
16 A study in Russian reported embryotoxic effects (apparently in animals) following
17 inhalation exposure to potassium ferricyanide; no English-language abstract was included
18 (Besedina and Grin, 1987). However, the observed embryotoxicity is likely to be due to the
19 ferricyanide ion, rather than to potassium ion.
20 Other reports on the effects on inhalation exposure to potassium are limited to studies in
21 which potassium was the counter-ion used for assessing the toxicity of specific anions.
22 Studies on potassium dichromate are discussed in the section on chromium, and a study on
23 potassium bromate is discussed in the section on bromine.
24 Sudden increases in oral or intravenous potassium intake can cause hyperkalemia.
25 Because of the role of potassium in nerve conduction and muscle contraction, the primary
26 effect of hyperkalemia is on the electrical activity of the heart (Mudge, 1985). Although
27 similar effects could theoretically result from inhalation exposure, one would expect the
28 required exposure concentrations to be quite high, due to the large amount of total body
29 potassium and the significant daily throughput via the oral route.
30
31
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1 11.6.16.4 Factors Affecting Susceptibility
2 Because the data on potassium inhalation toxicity are quite limited, only limited
3 hypotheses can be made regarding susceptible subpopulations. The finding of increased
4 cough and bronchoconstriction among atopic subjects who inhaled a potassium chloride
5 aerosol (Dixon et al., 1989) suggests that this group may be at increased risk of respiratory
6 toxicity following potassium inhalation. However, the tested concentration was much higher
7 than levels likely to be involved in environmental exposure.
8 Because the kidney is important in maintaining potassium homeostasis, individuals with
9 impaired kidney function may be less able to adjust to an increased potassium body burden if
10 large amounts of potassium are absorbed from the lung. In addition, hyperkalemia may
11 occur as a result of conditions such as acidosis, untreated Addison's disease, and
12 hyperglycemia in diabetic patients who are deficient in aldosterone (Mudge, 1985). People
13 with such conditions may be more susceptible to systemic effects of inhaled potassium
14 compounds. Because the heart is the primary target of hyperkalemia (Mudge, 1985), people
15 with cardiovascular disease may also be more susceptible to increased systemic levels of
16 potassium. However, because of the homeostatic balances on potassium levels, such
17 systemic increases would likely be limited to individuals with altered potassium metabolism.
18
19 11.6.17 Selenium
20 11.6.17.1 Chemical and Physical Properties
21 According to Elkin (1982), selenium belongs to Group 16 (VIA) of the periodic system
22 of elements and most of its chemical properties are very similar to sulfur. Solid elemental
23 selenium has several allotropic forms: amorphous, crystalline or red, and gray or metallic.
24 The gray form is stable at ordinary temperatures. Liquid selenium is brownish red and
25 produces dark red vapors when it boils. The important oxidation states of selenium are -2,
26 0, +2, +4, and +6. The +2 state is not known to occur in nature. Selenium reacts with
27 active metals and gains electrons to form ionic compounds containing the selenide ion Se2".
28 Selenium forms covalent compounds, including organoselenium compounds, with most other
29 substances. Crystalline selenium does not react with water, even at high temperatures, and is
30 generally stable in water over a wide range of pH values and mildly oxidizing to reducing
31 conditions (Agency for Toxic Substances and Disease Registry, 1989; Elkin, 1982). Strong
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1 oxidants convert selenium dioxide and its derivatives to the hexavalent state. Hydrogen
2 selenide is highly reactive in air and is rapidly oxidized to elemental selenium and water;
3 however, the gas may build up to hazardous levels in confined areas despite oxidative losses
4 (Agency for Toxic Substances and Disease Registry, 1989). Elemental selenium is insoluble,
5 but several selenium compounds are moderately to highly water soluble, including: selenium
6 dioxide (SeO2), hydrogen selenide (SeH2), selenic acid (SeH4O4) and selenious acid
7 (SeH203).
8
9 11.6.17.2 Pharmacokinetics
10 There is a lack of pharmacokinetic data following the inhalation of selenium and
11 selenium compounds in humans and laboratory annuals. Data presented hi this section are
12 based primarily from other routes of exposure.
13
14 Absorption and Distribution
15 Information on absorption of selenium following inhalation exposure is limited to
16 occupational studies. Glover (1970) examined urinary selenium levels of workers employed
17 in a selenium rectifier plant. Workers exposed to high levels of unspecified selenium
18 compounds hi the air excreted higher levels of selenium hi their urine than workers employed
19 hi other areas of the plant with lower concentrations of selenium in the air. Although the
20 study indicates that selenium compounds were absorbed from the lungs of the workers, the
21 lack of exposure information does not permit an estimate of the extent or rate of absorption
22 from the lungs.
23 Studies hi dogs and rats indicate that absorption of selenium following inhalation
24 exposure is extensive, although the rate of absorption was dependent on the administered
25 selenium compound. In rats (Medinsky et al., 1981b) and dogs (Weissman et al., 1983), the
26 absorption of selenious acid aerosol was approximately twice as rapid as the absorption of
27 elemental selenium aerosol following inhalation exposure. Medinsky et al. (1981b) also
28 found that, for both compounds, most of the selenium was absorbed after 4 days, and that
29 the distribution of selenium in the body tissues was identical, suggesting that selenium
30 entered the same body pool following absorption.
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1 No studies were located concerning the distribution of selenium in humans following
2 inhalation of elemental selenium or selenium compounds. The only laboratory animal
3 distribution data were reported by Weissman et al. (1983) in which selenium concentrated in
4 the liver, kidney, spleen, and lung of dogs following inhalation exposure to selenious acid or
5 elemental selenium aerosols.
6 Once absorbed, selenium is transported throughout the body in the blood. Selenium in
7 the blood is found in plasma and erythrocytes in a dose-related manner, with higher levels in
8 the plasma (Cikrt et al., 1988).
9 There is no evidence that the tissue distribution of selenium was dependent on route of
10 administration; however, tissue distribution differences appear to exist among the various
11 selenium compounds (Agency for Toxic Substances and Disease Registry, 1989; Ben-Porath
12 and Kaplan, 1969; Cantor et al., 1975). Selenium from selenomethionine has been observed
13 to concentrate in the pancreas of humans and rats following intravenous administration and in
14 the pancreas of chicks following oral administration (Ben-Porath and Kaplan, 1969; Cantor
15 et al., 1975; Lathrop et al., 1972). Selenium from sodium selenite and sodium selenate, on
16 the other hand, is found in the highest concentrations in the liver and kidney of humans and
17 animals following oral administration or injection (Cikrt et al., 1988; Jereb et al., 1975;
18 Sohn et al., 1991; Styblo et al., 1991). Selenium can also readily transfer into fetuses as
19 shown by elevated selenium levels in fetal tissues following exposure to sodium selenite
20 (Archimbaudetal., 1992).
21
22 Metabolism
23 Metabolic studies in humans are limited. Humans accidentally or occupationally
24 exposed to selenium have been reported to have a noticeable garlic odor of the breath,
25 probably due to excretion of dimethyl selenide in expired air (Bopp et al., 1982; Glover
26 et al., 1970; Holness et al., 1989).
27 Medinsky et al. (1981b) reported that in rats exposed via ingestion or inhalation to
28 elemental selenium or selenious acid aerosols, both selenium compounds were likely to enter
29 the same metabolic pool once absorbed into the general circulation.
30 In rats, dimethyl selenide has been identified as the primary respiratory metabolite
31 following injection of sodium selenite or sodium selenate (Hirooka and Galambos, 1966) and
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1 appears to be produced in the liver (Nakamuro et al., 1977). In mice, dimethyl selenide and
2 dimethyl diselenide have been detected in expired air following addition of unspecified
3 amounts of sodium selenite, DL-selenomethionine, or DL-selenocystine to their drinking
4 water (Jiang et al., 1983). A third unidentified volatile selenium compound was detected in
5 expired air of the mice following DL-selenomethionine administration (Jiang et al., 1983).
6 In rats, the trimethylselenonium ion has been identified as the predominant urinary
7 metabolite following intraperitoneal administration of sodium selenite (Byard and Baumann,
8 1967) or oral administration of sodium selenate, selenomethionine, selenocystine, selenium-
9 methylselenocysteine, or seleniferous wheat (Palmer et al., 1970). Another major selenium
10 metabolite that appeared in the urine more slowly than the trimethylselenonium ion was
11 identified chromatographically but not structurally (Palmer et al., 1970).
12 The metabolic pathways for the conversion of selenite to dimethyl selenide has been
13 studied in rodents. The reduction of selenite to dimethyl selenide requires glutathione and
14 the methylating agent S-adenosylmethionine. NADPH, coenzyme A, ATP, and
15 magnesium(II) salts are also required to provide optimal conditions for this reaction
16 (Ganther, 1979). Ganther (1971) and Hsieh and Ganther (1975) found that selenite initially
17 reacts nonenzymatically with glutathione to form a selenotrisulfide derivative. The
18 selenotrisulfide derivative is then reduced nonenzymatically, in the presence of excess
19 glutathione or by glutathione reductase in the presence of NADPH, to a selenopersulfide
20 (GSSeH). GSSeH is unstable and decomposes to glutathione and selenium or is
21 enzymatically reduced by glutathione reductase in the presence of NADPH to hydrogen
22 selenide (Ganther, 1971; Hsieh and Ganther, 1975). Hydrogen selenide can then be
23 methylated by S-adenosylmethionine in the presence of selenium methyltransferase.
24 Selenate apparently is not converted to dimethyl selenide as readily as is selenite.
25 Studies of selenate metabolism are limited in mammals, but studies using bacteria indicate the
26 selenate must be activated prior to conversion to selenite (Bopp et al., 1982; Dilworth and
27 Bandurski, 1977). Dilworth and Bandurski (1977) demonstrated that in the presence of ATP,
28 magnesium(II) salts, and ATP-sulfurylase, yeast could convert selenate to adenosine-5'-
29 selenophosphate and proposed that the latter compound reacts with glutathione to eventually
30 yield selenite.
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1 No studies were located that indicate how the trimethylselenonium ion is derived, but
2 injection of rats with trimethylselenonium chloride results in demethylation to dimethyl
3 selenide (Obermeyer et al., 1971), indicating that trimethylselenonium is not a product of the
4 methylation of dimethyl selenide.
5
6 Excretion
1 In humans and in laboratory animals, excretion of selenium occurs in the urine, feces,
8 and expired air (Griffiths et al., 1976; Lathrop et al., 1972; McConnell and Roth, 1966;
9 Medinsky et al., 1981a; Sohn et al., 1991; Styblo et al., 1991; Thomson, 1974). The initial
10 rate of excretion appears to be dose-dependent (Griffiths et al., 1976; Lathrop et al., 1972;
11 McConnell and Roth, 1966; Thomson and Stewart, 1974). Urinary and fecal excretion of
12 selenium are similar, each representing approximately 50% of the total output (Stewart et al.,
13 1978). At high selenium exposure levels, excretion of selenium in expired air becomes more
14 important (McConnell and Roth, 1966).
15 Following acute exposures to selenium compounds, humans excrete some of the
16 absorbed dose in the expired air as demonstrated by the odor of garlic in the breath (Glover,
17 1970). However, there were no studies located that quantified the rate of excretion or
18 identified the selenium compounds in the exposure air of humans.
19
20 11.6.17.3 Health Effects
21 Human Data
22 The selenium compounds that are most likely to be encountered in occupational settings
23 are dusts of elemental selenium, hydrogen selenide, and selenium dioxide, although other
24 volatile selenium compounds (e.g., dimethyl selenide, dimethyl diselenide) might also be
25 encountered in some situations. The largest number of reported human exposures has
26 occurred in industries that extract, mine, treat, or process selenium-bearing minerals and in
27 industries that use selenium or selenium compounds in manufacturing. In humans, the
28 respiratory tract is the primary site of injury after inhalation of selenium dust or selenium
29 compounds, but gastrointestinal and cardiovascular effects and irritation of the skin and eyes
30 also occur. Little of the available information for humans, however, relates health effects to
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1 measured concentrations of the selenium dust or compounds in the air. Toxicity data for
2 humans are summarized in Table 11-45.
3 Hydrogen selenide, a highly poisonous selenium compound, is a gas at room
4 temperature, with a density much higher than that of air. Irritation of mucous membranes,
5 pulmonary edema, severe bronchitis, and bronchial pneumonia have been observed in
6 humans following acute exposure to this gas (Buchan, 1947). Acute industrial inhalation
7 exposure to elemental selenium dust, possibly including some selenium dioxide, has irritated
8 mucous membranes in the nose and throat, produced coughing, nosebleed, and loss of
9 olfaction and, in heavily exposed workers, dyspnea, bronchial spasms, bronchitis, and
10 chemical pneumonia (Clinton, 1947; Hamilton, 1949).
11 Selenium dioxide is formed when selenium is heated in air. Selenium dioxide forms
12 selenious acid on contact with water, including perspiration, and causes severe irritation.
13 Acute inhalation of large quantities of selenium dioxide powder can produce pulmonary
14 edema due to the local irritant effect on alveoli (Middleton, 1947; Pringle, 1942). Bronchial
15 spasms, symptoms of asphyxiation, and persistent bronchitis have been noted in workers
16 briefly exposed to high concentrations of selenium dioxide (Wilson, 1962). An abstract by
17 Kinnigkeit (1962) reported that selenium dioxide concentrations of 7 to 50 ^g selenium/m3 in
18 a selenium rectifier plant produced slight tracheobronchitis in 9 out of 62 exposed workers.
19 Gastrointestinal distress, including indigestion and nausea, were observed in humans
20 following inhalation of selenium, selenium dioxide, or hydrogen selenide (Glover, 1967,
21 1970). Wilson (1962) reported that following an acute episode of exposure to selenium
22 dioxide fumes, several workers had lower blood pressure but an elevated pulse rate, which
23 normalized within 3 h. Brief exposure to clouds of elemental selenium dust ("red fumes")
24 resulted in lacrimation, irritation, and redness of the eyes (Clinton, 1947) and acute exposure
25 to selenium dioxide burned the eyes, conjunctiva, and skin upon contact (Middleton, 1947;
26 Pringle, 1942). The dermal and ocular effects most likely are due to direct contact with
27 selenium particles.
28 Information concerning possible neurological effects caused by inhalation of selenium
29 or selenium compounds is limited. Headaches, dizziness, and malaise were reported by
30 workers following acute occupational exposures to hydrogen selenide or to clouds of fine
31 elemental selenium dust or selenium dioxide (Clinton, 1947; Glover, 1970).
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TABLE 11-45. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR SELENIUM AND COMPOUNDS
21 Exposure
to Concentration
w» Exposure
ppm ng Se/m3 protocol
NA 40-3,600 8 h/d
5d/wk
NS
(occup)
NA 5-36 8 h/d
5d/wk
NS
(occup)
? NA 0 NS
£ >200 (occup)
Chemical
form
Elemental
selenium,
selenium
dioxide
dust
(assumed)
Selenium
dioxide
NS
NS
Particle size and Species, Strain,
distribution (Number) Sex
NS Human
(<100)B
NS Human
(62) NS
NS Human
(40) NS
Assays performed: Effect(s)
Clinical signs, urinalysis: No effects.
Testing once every 3 months for 5 years.
Clinical signs: Slight tracheobronchitis
reported hi 9 workers.
Questionnaire, skin biopsy, biochemistry,
pulmonary function, urinalysis: Clinical
Reference
Glover (1967)
Kinnigkeit (1962)
Holness et al. (1989)
. nose and eye irritation,
indigestion, stomach pain, fatigue, muscle joint
pain, and sputum. Spirometry and ECG
readings were normal. Anemia occurred, but
iron levels were normal. Subjects also
reported garlic-like bream odor.
Note: Concurrent exposure to copper, nickel,
silver, and trace levels of lead and arsenic.
Abbreviations:
B = both males and females; d = day; ECG = electrocardiogram; h = hours; NA = not applicable; NS = not specified;
occup = occupational; wk = week; wt = weight, occup = occupational; wk = week.
-------
1 No studies were located regarding reproductive or developmental effects in humans
2 following inhalation exposure to selenium or selenium compounds.
3 There are no epidemiological data that support a causal association between the
4 inhalation of elemental selenium dusts or selenium compounds and the induction of cancer in
5 humans (Gerhardsson et al., 1986; Wester et al., 1981). In a study by Gerhardsson et al.
6 (1986), samples were collected postmortem from copper smelter workers who were exposed
7 to several different airborne compounds, including selenium compounds. Samples from lung
8 cancer cases had lower concentrations of selenium in lung tissue than samples from controls
9 or from workers who had died from other causes. In another autopsy study of smelter
10 workers, Wester et al. (1981) found that the selenium concentrations in kidney tissues from
11 workers who had died of malignancies were lower than the selenium concentrations in kidney
12 tissues from workers who died of other causes.
13
14 Laboratory Animal Data
15 Toxicity data for laboratory animals are available only for acute exposures and are
16 summarized in Table 11-46. The respiratory tract is also the primary site of injury in
17 experimental laboratory animals following inhalation exposure to selenium dust and hydrogen
18 selenide. Hematological and hepatic effects have also been noted in animals.
19 Rats exposed to selenium dust at levels of 30,000 pg selenium/m3 for 8 h experienced
20 severe respiratory effects, including hemorrhage, edema, and chronic interstitial pneumonitis
21 in the lungs (Hall et al., 1951). Rabbits and Guinea pigs inhaling selenium dust at similar
22 concentrations for 8 days developed mild interstitial pneumonitis, vascular lymphocytic
23 infiltration, increased number of alveolar macrophages, and slight emphysema (Hall et al.,
24 1951).
25 Exposure to hydrogen selenide for 4 h produced respiratory irritation, diffuse
26 bronchopneumonia, and pneumonitis in Guinea pigs (Dudley and Miller, 1941). Histologic
27 examination of guinea pigs that had died following exposure to higher concentrations
28 (21,450 /Kg/m3) for 30 min revealed thickening of the alveolar walls and congestion of
29 alveolar capillaries (Dudley and Miller, 1937).
30 Mild hepatic effects have been observed in animals following acute inhalation exposure
31 to elemental selenium dust, hydrogen selenide, or dimethyl selenide vapor. One month after
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> TABLE 11-46. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS
a FOR SELENIUM AND COMPOUNDS
\o Exposure Concentration
ppm /ig Se/m3 protocol
Chemical Particle size and Species, Strain,
form distribution (Number) Sex Assays performed: Effect(s)
Reference
Acute Studies
NA 30,000 8 h
Elemental MMAD = 1.2 Rat, NS Body wt, organ wt, gross and histopathology
selenium /*m (20) F examination: Increased relative lung wt and
dust pulmonary hemorrhage in two animals that
died. After 3 wk postexposure, slight
interstitial infiltration of lymphocytes and
intraalveolar foci of large macrophages
consistent with chronic interstitial
pneumonitis. At 4 wk postexposure, slight
liver congestion, with central atrophy. Note:
No controls used.
Hall et al. (1951)
NA
31,000
4h/2d
8d
Elemental
selenium
dust
MMAD = 1.2
Guinea pig, NS
(10) M
Body wt, clinical signs, histopathology: After Hall et al. (1951)
1 or 3 wk postexposure, respiratory effects
included mild chronic interstitial pneumonitis,
pulmonary congestion, vascular lymphocytic
infiltration, alveolar infiltration of large
macrophages, and slight emphysema. Liver
effects were congestion, central atrophy, and
fatty metamorphosis. The spleen was
congested, with fissuring of red pulp, and
increased number of polymorphonuclear
leukocytes. Note: No controls used.
-------
3.
£
TABLE 11-46 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS
FOR SELENIUM AND COMPOUNDS
Exposure Concentration
ppm
Se/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species, Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
u>
8
NA
31,000
4h/2d
8d
Elemental MMAD = 1.2
selenium /urn
dust
Rabbit, NS
(6)F
0
1607
4499
8034
NA
0 1 h
5,190,000
14,540,000 (nose-only)
25,960,000
Dimethyl NA
selenide
vapor
Rats, F344
(20) M
7,800
4h
(1 h-60 d
postexposure)
Hydrogen
selenide
NS
Guinea pig, NS
(16) NS
NA
21,450
30 min
Hydrogen NS
selenide
Guinea pig, NS
(80) NS
Body wt, clinical signs, histopathology: After Hall et al. (1951)
1 or 3 wk postexposure, respiratory effects
included mild chronic interstitial pneumonitis,
pulmonary congestion, vascular lymphocytic
infiltration, alveolar infiltration of large
macrophages, and slight emphysema. No
other effects were reported. Note: No
controls used.
Body and organ wts, microscopic examination Al-Bayati et al. (1992)
of lung, liver, kidney, spleen, thymus, lymph
nodes, pancreas, and adrenal gland:
Increased relative lung wt at low and high
concentrations and increased liver wt at two
highest concentrations.
Histopathology: Fatty metamorphosis and
increased weight in liver were reported.
Respiratory effects included pneumonitis,
diffuse bronchopneumonia, and irritation.
Spleen effects included lymphoid hyperplasia
and delayed increase in reticuloendothelial
tissue. Note: No controls used.
Clinical signs, organ HP: Death in 47 of 80
animals. Examination of these animals
indicated increased liver and spleen wts, fatty
metamorphosis of kidney and liver,
centrilobular atrophy of liver, and increased
reticuloendothelial tissue in splenic pulp.
Respiratory effects included thickening of
alveolar wall and congestion of alveolar
capillaries.
Dudley and Miller (1941)
Dudley and Miller (1937)
-------
t
I— '
Ui
ON
O
§>
b
o
z
3
0
s
TABLE 11-46 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS
FOR SELENIUM AND COMPOUNDS
Exposure Concentration
ppm [ig Se/m3
NA 0 4
6,000
7,000
12,000
15,000
44,000
NA 0 8
1,000
4,000
6,000
7,000
41,000
NA 0 2
6,000
12,000
13,000
20,000
33,000
35,000
Abbreviations:
B = males and females; d =
occup = occupational; wk
Exposure Chemical Particle size and Species, Strain,
Protocol form distribution (Number) Sex
h Hydrogen NS
selenide
h Hydrogen NS
selenide
h Hydrogen NS
selenide
= day; h = hours; F = female;
= week; wt = weight; wk =
Guinea pig, NS
(16) NS
Guinea pig, NS
(16) NS
Guinea pig, NS
(16) NS
Assays performed: Effect(s)
Clinical signs and body wt: Slight nasal
discharge occurred at <20 /*g/kg, and nose
and eye irritation and breathing difficulties at
>20 pg/kg.
Clinical signs and body wt: Slight nasal
discharge occurred at <20 /*g/kg, and nose
and eye irritation and breathing difficulties at
>20 /ig/kg.
Clinical signs and body wt: Slight nasal
discharge occurred at <20 /*g/kg, and nose
and eye irritation and breathing difficulties at
>20 jig/kg.
MMAD = mass median aerodynamic diameter; M = male; NA = not applicable;
week; wt = weight.
Reference
Dudley and Miller (1941)
Dudley and Miller (1941)
Dudley and Miller (1941)
NS = not specified;
n
-------
1 an 8-h exposure to elemental selenium dust at a concentration of 30,000 ^g selenium/m3, rats
2 exhibited slight liver congestion and a few exhibited mild central atrophy of the liver (Hall
3 et al., 1951). Three weeks following acute exposure to higher concentration of elemental
4 selenium dust for 8 days, guinea pigs had slight hepatic congestion with mild central atrophy
5 and fatty metamorphosis (Dudley and Miller, 1941). Exposure to hydrogen selenide
6 (7,800 jitg selenium/m3) for 4 h in guinea pigs produced mild fatty metamorphosis in the liver
7 (Dudley and Miller, 1941). Al-Bayati et al. (1992) reported increased liver weight in rats
8 exposed to high concentrations of dimethyl selenide vapor (> 14,540,000 /xg selenium/m3)
9 for an hour; however, no histopathological changes were exhibited in the liver.
10 In Guinea pigs, splenic effects (congestion, fissuring red pulp, and increased
11 polymorphonuclear leukocytes) has been observed following acute exposure to elemental
12 selenium dust (Hall et al., 1951).
13 There were no studies available on the reproductive or developmental effects of
14 selenium in laboratory animals following inhalation exposure. Cancer data in laboratory
15 animals are also lacking for selenium.
16
17 11.6.17.4 Factors Affecting Susceptibility
18 Data concerning human subpopulations with unusual susceptibility to the toxic effects of
19 selenium were not located. It is likely that individuals with preexisting respiratory conditions
20 would be more susceptible than the healthy individuals to the respiratory tract effects (e.g.,
21 irritation, bronchitis) of selenium (Middleton 1947; Pringle 1942; Wilson 1962). The
22 developing respiratory tract of children may also be more susceptible.
23 Pregnant women and their fetuses might be at greater risk of adverse health effects
24 from excess selenium exposure than the general population. Doses of 500 /xg
25 selenium/kg/day have been reported to reduce birthweight in mice (Schroeder and Mitchener
26 1971) without producing signs of maternal toxicity.
27
28 11.6.18 Tin
29 11.6.18.1 Chemical and Physical Properties
30 Tin, a metallic element, is a member of Group 4A of the periodic table. It exhibits
31 three valence states, 0, +1, and +2 and readily forms compounds in both the stannous(+2)
April 1995 11-362 DRAFT-DO NOT QUOTE OR CITE
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1 and stannic(+4) states (Agency for Toxic Substances and Disease Registry, 1992). When
2 metallic tin (oxidation state 0) is exposed to oxygen or dry air, a thin oxide film forms on its
3 surface. This oxidation process is accelerated in the presence of heat (Gitlitz and Moran,
4 1983). In environmental waters, tin may exist as either Sn2"1" or Sn4+, with the stannous tin
5 (Sn2+) ion dominating in oxygen poor water (Agency for Toxic Substances and Disease
6 Registry, 1992). Tin occurs naturally in the environment in both inorganic compounds, and
7 in organotin compounds, the oxidation state of the tin species in the latter almost always
8 being +4 (Gitlitz and Moran, 1983). Elemental tin is insoluble in water, as are both of its
9 oxides: stannic oxide (SnO2) and stannous oxide (SnO).
10
11 11.6.18.2 Pharmacokinetics
12 Inorganic Tin
13 Very little information was located regarding the absorption, distribution, metabolism,
14 and excretion of inhaled tin in humans or animals. However, studies on the health effects of
15 tin inhalation show that inhaled tin accumulates in the lungs. There was no clear evidence
16 regarding whether tin is absorbed from the lungs into the bloodstream, but since tin and its
17 oxides are insoluble, any absorption would be expected to be minimal. Teraoka (1981)
18 observed that chromium refining and chromate refining workers had higher levels of tin in
19 the lungs and hilar lymph nodes than did normal controls. Neither the source nor level of tin
20 exposure were reported. In an early case study of stannosis (tin-associated pneumoconiosis),
21 tin levels were highest in the lungs (Dundon and Hughes, 1950). Tin concentrations were
22 higher in the spleen and liver than in the bone. Oral data indicate that tin is either poorly
23 absorbed or rapidly excreted in the feces (Galloway and McMullen, 1966).
24 In a study of about 160 human maternal-fetal pairs, tin levels were slightly higher in
25 the cord blood and placenta than in maternal blood, indicating that tin can cross the placenta
26 (Creason et al., 1976). Levels in scalp and pubic hair ( = 1 ptg/g) were higher than in
27 maternal and cord blood («5 /ig/mL).
28
29 Organic Tin
30 Data are also limited regarding the pharmacokinetics of inhalation exposure to organotin
31 compounds. Although no human or animal data were located regarding the rate or extent of
April 1995 H_363 DRAFT-DO NOT QUOTE OR CITE
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1 absorption of organotin compounds, the observation of urinary tin and nervous disorders in
2 workers exposed to a mixture of di- and trimethyltin chloride (Rey et al., 1984) indicates that
3 tin is absorbed from the lung to some degree. Similarly, the observation of systemic effects
4 in animals following inhalation exposure to organotin compounds (Gohlke et al., 1969;
5 Igarashi, 1959; Iwamoto, 1960) indicates that these compounds are absorbed from the lung.
6 No other data regarding the distribution, metabolism, or excretion of absorbed organotin
7 compounds were located. Data from other routes of exposure indicate that absorbed
8 organotin compounds accumulate to some degree in the kidney, liver, and brain; metabolism
9 may occur via oxidative mechanisms (Agency for Toxic Substances and Disease Registry,
10 1992; Iwai, 1981).
11
12 11.6.18.3 Health Effects
13 Inorganic Tin
14 Human Data. The primary health effect of inhalation exposure to tin or its oxide is
15 stannosis, a rare pneumoconiosis characterized by dense mottling of the lungs. These effects
16 are summarized in Table 11-47. Slightly more than 150 cases have been reported in the
17 world literature, of which only five were in the United States (American Conference of
18 Governmental Industrial Hygienists, 1991). Investigations of stannosis are limited to case
19 studies, mostly from the 1940s and 1950s. Exposure levels were reported in only two
20 studies (Cutter et al., 1949; Oyanguren et al., 1958). Because many studies reported the
21 form of tin only as tin oxide, it is unclear whether stannosis results only from stannic oxide
22 exposure or also from exposure to stannous oxide. Both fumes and dust of tin oxide can
23 cause stannosis.
24 Most cases of stannosis are reported as asymptomatic, although dyspnea has been
25 reported in a few cases (Cole et al., 1964; Spencer and Wycoff, 1954). Fibrosis has never
26 been reported, and respiratory impairment is generally mild, so this disease is referred to in
27 the literature as a "benign pneumoconiosis." However, mild adverse health effects as a
28 result of employment were more acceptable at the time of these reports than in today's
29 society. Therefore, while severe impairment clearly did not occur in the reported stannosis
30 cases, any observed mild impairments might be given more weight today. In particular,
April 1995 11-364 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-47. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR TIN AND COMPOUNDS
Exposure
Concentration
ppm /ig Sn/m3
Exposure
protocol
Chemical Particle size and
form distribution
Species, Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
Inorganic Tin
N/A 8,600,
14,900
N/A 8- >50
mp/cf
<3 to >12
yr
occup
20-24 yr
occup
Tin oxide NS
fume, dust
58.4%
metallic Sn,
0.07% soluble
Sn, 9.7% Fe
2.0% S, 1.0%
SiO2, 28%
unidentified
96-98% SnO2, <2 /mi, "but there
0.4% SiO2 was a strong
Human (19) M
Human
(2)M
Case studies; x-ray, lung function, urinalysis,
hematology, ECG: Based on x-ray findings, 8/9
subjects exposed <3 yr had suspected stannosis.
Longer exposures led to stage 1 through stage 3
stannosis. No effect on resting ventilation, VC,
maximum breath capacity, or ventilation
reserve. No other findings.
Note: Workers selected based on exposure to
tin oxide fumes and dust.
Case study; x-ray: No respiratory symptoms.
Pulmonary nodulation. Expiratory rales in one
Oyanguren
al. (1958);
et
Schuler et al.
(1958)
Cutter et al
(1949)
dust
tendency toward
agglomeration, so
some particle
groups > 10 /an"
other area-99%
<3 pirn
subject.
Note: Reported exposure on weighted average
basis. Higher levels were at earlier periods.
Concentration reported as dust counts.
3 N/A NS
\
O
O
2
3
o
o
w
0
0
H
M
>3 yr "Cassiterite, "EM shows a small Human
occup mainly tin size and denseness (215) M
oxide" of particles"
dust;
fume- SnO2
Physical exam, x-ray, chest expansion and VC
measurement: Radiological changes found in
121/215 exposed workers. Changes range from
faint mottling to gross dense modulation. Fewer
opacities in those with shorter or lower
exposure. No clinical signs referable to
pneumoconiosis. Changes found in those
exposed to only dust or only fume.
Note: Sampling of particles in air <5 /mi
showed dust was > 33 % metallic tin.
Robertson and
Whitaker
(1954);
Robertson
(1960)
-------
£
>-i
TABLE 11-47 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR TIN AND COMPOUNDS
Exposure
Concentration
ppm ng Sn/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species, Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
N/A NS
ll-46yr
occup
Tin oxide
dust,
SnO2 fume
NS
Human
(7) M
Case studies; HP of lung, clinical signs of
respiratory impairment: Radiological evidence
of pneumoconiosis in all. Films of those
exposed mostly to SnO2 fume showed nodular
appearance with opacities. Dust foci were dense
aggregates of dust-laden macrophages
surrounding the respiratory bronchioles or lying
free in alveoli. No fibrous nodules.
Note: Analysis of dust from ashed lungs
showed particles of 0.1-0.5 /tin, resembling
furnace fume.
Robertson et al.
(1961)
N/A NS
O
O
z
O
H
O
I
M
O
*
O
i
18 yr
occup
SnO2
fume, dust
NS
Human
(DM
N/A NS
15-26 yr
occup
SnO2 fumes NS
Human
(2)M
N/A NS
15 yr
occup
Tin oxide
dust
NS
Human
(DM
Case study; x-ray, physical exam, HP of lung:
Mottling of lung fields, incident of epigastric
pain and vomiting, sharp chest pain on deep
inspiration, dec VC (85% normal). No
evidence of enlarged hilar lymph nodes, no
subjective respiratory complaints. Pigment-
choked lymphatic channels.
Note: 1,100 jtg Sn/g wet lung tissue.
Case studies; x-ray, lung function, lung biopsy:
Numerous small nodules in lung, no effect on
FVC or FEVj. Focal aggregations of
macrophages containing dust particles in
perivascular and peribronchiolar connective
tissue.
Case study; x-ray: Discrete densities in both
lungs, opaque material hi hilar lymph nodes, no
fibrous tissue.
Dundon and
Hughes (1950)
Sluis-Cremer et
al. (1989)
Pendergrass and
Pryde (1948)
-------
£
n.
s
vO
| .
i— '
ON
^
O
»
>
3
6
o
z
TABLE 11-47 (cont'd). HUMAN EXPOSURE
Exposure
Concentration Exposure
ppm jug Sn/m3 protocol
N/A NS 15-60 yr
occup
Organic Tin
N/A 200 "short-
term"
occup
N/A 190, NS
290 occup
Chemical Particle size and
form distribution
"Tin oxide" NS
form, valence
NS
Organotin UK
corn-pounds
(not further
specified)
Bis(tributyl UK
tin) oxide
CONDITIONS
Species, Strain,
(Number) Sex
Human
(10) M
Human
(UK)
Human
(UK)
AND EFFECTS FOR TIN AND COMPC
Assays performed: Effect(s)
X-ray, clinical exam, HP of lung; case reports
of stannosis victims: Micronodular opacities or
other dense opacities hi all cases. Honeycomb
lung (hi one case), dyspnea. HP of one case
found dilation of the bronchia and bronchioles,
black dust-pigmented interstitial fibrosis, and
squamous hyperplasia and metaplasia of
bronchial and bronchiolar epithelium.
Carcinoma hi one case.
Note: Fibrosis was found in one man, but he
may have been exposed to other types of dust.
Headaches, upper respiratory tract irritation.
Irritation of the upper respiratory tract and eyes
of 70% of exposed workers.
>UNDS
Reference
Cole et al.
(1964)
American
Conference of
Governmental
Industrial
Hygienists
(1991)
National
Institute for
Occupational
Safety and
Health (1976)
O
I-H
H
W
'Not identified; presumably million particles per cubic foot.
Presumably reported as concentration of tin.
Abbreviations:
dec = decreased; ECG = electrocardiogram; EM = electron microscopy; Fe = iron; FEV: = forced expiratory flow in 1 second; FSH = follicle stimulating hormone; FVC = forced vital capacity;
; HP = histopathology; N/A = not applicable; NS = not specified; occup = occupational; S = sulfur; SiO2 = silicon dioxide; Sn = tin; SnO2 = stannous oxide; UK = unknown, not reported in
available secondary source; VC = vital capacity; yr = year
-------
1 choking of the lymphatic channels (Dundon and Hughes, 1950) might exacerbate infectious
2 respiratory disease. Stannosis has not been reported to progress or to be reversible.
3 Stannosis is usually identified by chest x-rays performed on workers in tin foundries or
4 other places where they work with tin or its dusts. Robertson and Whitaker (1954) reported
5 asymptomatic radiological changes in the chests of 121 of 215 tin refinery workers and
6 retirees. The physical examination included chest expansion and vital capacity
7 measurements, and was conducted on >95% of the people who had worked at the refinery
8 for at least 3 years. The radiological changes were characterized by small dense opacities.
9 The degree of pneumoconiosis correlated with the dustiness of the job held and the duration
10 of exposure, but no measurement was made of exposure level (Robertson, 1960). Analysis
11 of the dust particles small enough to be inhaled into the alveoli (< 5 microns) determined that
12 they contained no silica and >33% metallic tin. In spite of the marked radiological changes,
13 there was no increase in absences due to chest illness, sensitivity to tuberculosis, and no
14 effect was observed in the clinical examination. The possibility of a delayed effect was also
15 discounted but not eliminated, since the study group included workers with gross radiological
16 changes who had been retired for >20 years. The study authors noted that the high atomic
17 weight of tin (118.7) makes it very radio-opaque, so that inhalation of relatively small
18 amounts is radiologically detectable. Histological analysis of the lungs of two tin workers
19 who died of unspecified (but apparently unrelated) causes showed alveoli filled with dust
20 cells, but no evidence of fibrosis. The results from the autopsies of seven workers suggested
21 that the extent of radiological change in the lung correlated with the amount of tin dioxide in
22 the lung (Robertson et al., 1961).
23 Schuler et al. (1958) observed pneumoconiosis in 10/19 workers exposed to tin oxide
24 fumes or dust at a tin foundry. No adverse effects were observed on vital capacity,
25 maximum breath capacity, ventilation reserve, or resting ventilation. The most severe cases
26 of Stannosis occurred in workers exposed to tin oxide fumes, but it is not clear if they were
27 exposed for more years. No personal monitoring was done, but levels of tin fumes measured
28 in two work areas were 14,900 and 8600 //g/m3, respectively (Oyanguren et al., 1958).
29 Small amount of lead, zinc, and iron fumes were also present.
30 Ten cases of Stannosis in hearth tinners, who are exposed only to tin fumes, and not tin
31 dust, were reported by Cole et al. (1964). The subjects had worked as tinners for 15-60
April 1995 11-368 DRAFT-DO NOT QUOTE OR CITE
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1 years. Although no respiratory disablement was reported for most of the cases, pulmonary
2 lesions were reported in three cases. A man who had worked as a tinner for 19 years had
3 honeycomb lung. Prior to death, he suffered from dyspnea. Post-mortem examination
4 revealed dilation of the bronchia and bronchioles, black dust-pigmented interstitial fibrosis,
5 and squamous hyperplasia and metaplasia of bronchial and bronchiolar epithelium. Fibrosis
6 was found in a second man, but he may have been exposed to other types of dust. One man
7 who worked for 50 years as a tinner developed carcinoma of the lung. Honeycomb lung is
8 not commonly associated with stannosis, and was not observed by Robertson and Whitaker
9 (1954) in 121 stannosis cases.
10 Pendergrass and Pryde (1948) reported one of the earliest cases of stannosis, in a man
11 who had bagged tin oxide for 15 years. Although the study authors stated that there was no
12 disability associated with the radiographic abnormalities, they also reported that the domes of
13 the diaphragm scarcely moved. No silica was found in the tin oxide dust. Cutter et al.
14 (1949) reported asymptomatic stannosis in both of the employees performing dusty work in a
15 tin oxide recovery plant. Both workers had been exposed for about 20 years, but the subject
16 with the heavier deposits had lower total exposure, although he may have been exposed to a
17 higher percentage of tin as fumes. Time-weighted average exposure was estimated at
18 8 mp/cf (presumably million particles per cubic foot) per 8-h day for the previous few years,
19 and >50 mp/cf in prior years.
20 Asymptomatic stannosis was reported in a worker exposed for 18 years to tin oxide
21 fumes and dust (Dundon and Hughes, 1950). Dry lung tissue contained 1.15% tin, about
22 2500 times the normal level. X-ray diffraction analysis confirmed that tin was the only metal
23 or mineral present. Lymphatic channels were choked with pigment. No recent reports of
24 stannosis cases in the United States were located. However, a recent article reported two
25 cases of radiologically-diagnosed stannosis in South Africa (Sluis-Cremer et al. 1989). One
26 man was exposed to tin fumes and coal dust for 15 years, the other to tin fumes for 26 years.
27 There was no effect on the forced vital capacity or the forced expiratory volume of the first
28 second (FEVj). Basal crackles on auscultation and a minor cough were present, although
29 they may have resulted from the exposure to coal dust. Dust deposits in the air spaces of a
30 biopsied lung sample were not associated with collagen deposition.
April 1995 11-369 DRAFT-DO NOT QUOTE OR CITE
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1 Extensive fibrosis (dense mottling) may occur together with only mild functional
2 impairment. A worker who was exposed to tin oxide as a smelter and a bagger for 22 years
3 developed slight dyspnea and slightly impaired vital capacity (70% of normal) (Spencer and
4 Wycoff, 1954).
5 No data were located regarding reproductive, developmental, or carcinogenic effects of
6 inorganic tin in humans.
7
8 Laboratory Animal Data. As a crude animal model of stannosis, 50,000 /xg of tin dust
9 in saline was injected into the trachea of an unspecified number of rats and "blown into their
10 lungs" (Robertson, 1960). No other experimental details were provided. The dust was
11 collected from the sampling room of a tin smelter, and sized to contain only particles < 5
12 microns. The lungs of the rats resembled the lungs of the tin workers, with small, high-
13 density foci. Histological examination revealed dust cells lining alveoli, and phagocytes
14 containing tin particles. Tin particles were also found in the subpleural lymphatics and the
15 mediastinal lymph glands. No other pathology or histopathology data were reported. Tin
16 particles were found in the lungs, spleen, and liver of mice injected intravenously with 5000
17 jwg/animal tin dust. Pendergrass and Pryde (1948) injected a branch artery to one lobe of a
18 freshly excised dog lung with a saline suspension of tin oxide, and observed discrete
19 opacities similar to those seen in a worker with tin pneumoconiosis. These experiments
20 show that tin oxide alone can cause the radiographic abnormalities characteristic of stannosis.
21 No data were located regarding reproductive, developmental, or carcinogenic effects of
22 inorganic tin in animals.
23
24 Organic Tin
25 Human Data. Limited data suggest that the nervous system, liver, and kidney are the
26 major targets of organotin inhalation in humans; higher levels also affect the lungs. Data are
27 limited to a few case reports. Nervous symptoms (headache, tinnitus, deafness, impaired
28 memory, disorientation, "dreamy [epileptic equivalent] attacks," and loss of consciousness)
29 were observed after a latent period of 1 to 3 days in a group of 6 chemical workers exposed
30 to a 50 to 50 mixture in air of di- and trimethyltin chloride (Rey et al., 1984). Exposure
31 levels were not determined, but the maximal exposure duration was reported as nine 10-min
April 1995 11-370 DRAFT-DO NOT QUOTE OR CITE
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1 exposures in 3 days. Respiratory depression was reported in the most severe cases.
2 Elevated levels of serum transaminases, indicative of liver damage, were also reported in the
3 more severe cases. Urinary tin correlated with the severity of symptoms. Anuria was
4 reported in one patient who died; histological analysis revealed fatty degeneration and
5 necrosis of liver cells, shock kidneys (i.e., proximal tubule degeneration), and cerebral
6 edema. Nervous symptoms continued for at least 6 mo postexposure in the two highest-
7 exposed workers who survived.
8 In another case report, two chemists exposed to di- and trimethyltin chloride over a
9 3-mo period also reported nervous system symptoms, including seizures, headaches, memory
10 defects, and loss of vigilance (Fortemps et al., 1978). Breathlessness and anorexia were also
11 reported. Full recovery required approximately one year after exposure ceased.
12 American Conference of Governmental Industrial Hygienists, (1991) described two
13 unpublished reports of organotin exposure concentrations resulting in symptoms. The first
14 report was described by the National Institute for Occupational Safety and Health, (1976),
15 and reported irritation of the upper respiratory tract and eyes in 70% of workers exposed to
16 bis(tributyltin) oxide at 190 to 290 /ig tin/m3 at two buffing operation sites. A letter to
17 ACGIH reported headaches and respiratory tract irritation following "short-term" exposures
18 to organotin compounds at levels above 200 ^ig/m3. In another case report, inhalation
19 exposure to tributyltin oxide at undetermined levels resulted in asthma; a controlled challenge
20 experiment confirmed the relationship to tin exposure (Shelton et al., 1992).
21
22 Laboratory Animal Data. Laboratory animal data, Table 11-48, support the hepatic,
23 renal, and respiratory systems as targets of organotin toxicity. Data are too limited to make
24 comparisons between the inhalation toxicity of different organotin compounds. However,
25 oral data suggest that once organotin compounds are absorbed, toxicity within a class of
26 compounds is higher for lower homologs, e.g., among trialkyltin compounds, trimethyltin
27 and triethyltin are the most toxic (American Conference of Governmental Industrial
28 Hygienists, 1991). Experimental details are also lacking for most organotin inhalation
29 studies, because they were published in foreign languages, and only summaries from
30 secondary sources are available.
April 1995 11.371 DRAFT-DO NOT QUOTE OR CITE
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TABLE 11-48. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR TIN AND COMPOUNDS
2.
VO
8
h-*
U)
N>
o
c
3
D1
0
|
j
o
0
H
W
Exposure
Concentration
ppm /jig Sn/m
Organic Tin
0 0
0.44 2,120
1.2 5,650
0 0
0.41 2,000
0 0
0.30 1,460
0.45 2,190
0 0
0.41 2,000
Abbreviations:
Exposure Chemical Particle size and Species, Strain,
protocol form distribution
7 h/d Tributyltin bromide UK
6 d (1.1 ppm),
dibutyltin bromide
(0.06 ppm)
5 h/d Tributyltin UK
10-80 d dibromide (0.39
ppm),
dibutyltin bromide
(0.02 ppm)
6 h/d Tributyltin chloride UK
95 d
5 h/d Tributyltin UK
10 d dibromide (0.39
ppm),
dibutyltin bromide
(0.02 ppm)
(Number) Sex Assays performed: Effect(s) Reference
Mouse, UK HP of kidney, brain: Slight degenerative changes in Igarashi (1959)
(UK) the glomeruli, convoluted tubules, and collecting
tubules, as well as extramedullary hematopoiesis.
No brain histopathology.
Rat, UK (UK) HP of lungs, heart, liver, kidney, spleen, Iwamoto
reproductive organs; reproductive function: At 80 d, (1960)
severe bronchitis and vascular and alveolar edema of
lungs observed in exposed animals. Also observed
at this sacrifice time: mycardial atrophy, atrophy
and necrosis of liver, extensive congestion and
swelling of the renal tubular epithelium, and splenic
hyperplasia and thickened sheaths. Pregnancy rate
also reduced after 4 wk-3 mo of exposure (other
measure of reproductive success not reported).
Atrophy of glandular uterus at 14 d.
Rat, Albino HP of lung, liver: At low level, lung hyperemia, Gohlke et al.
(10) NS catarrhal bronchitis, minor fatty degeneration of the (1969)
liver. Also inflamed eyes, and nostrils, probably
due to direct contact.
Rat, UK Reproductive function: 40% dec in "reproduction" Iwamoto
(UK) (not further defined). (1960)
d = day(s); dec = decrease; HP = histopathology; UK = unknown, not reported in available secondary source.
n
i—i
3
-------
1 Inflammatory changes (hyperemia and bronchitis) were observed in the respiratory
2 system of rats exposed to 1,460 to 2,190 /ig tin/m3 as tributyltin chloride for 95 days
3 (Gohlke et al., 1969). In an experiment where rats were exposed for 80 days to 2,000 /zg
4 tin/m3 (0.41 ppm) as a mixture of tributyltin dibromide (0.39 ppm), dibutyltin bromide
5 (0.02 ppm), and hydrocarbon impurities, histopathological changes were reported as severe
6 bronchitis and vascular and alveolar edema (Iwamoto, 1960).
7 Gohlke et al. (1969) also observed histological changes of the liver, consisting of fatty
8 degeneration, in the experiment described above. Iwamoto (1960) reported atrophy and
9 slight necrosis of the liver in rats exposed to 2,000 /zg tin/m3 as di- and tributyltin
10 dibromide. Atrophy increased with exposure duration and some recovery occurred if
11 exposure was stopped prior to sacrifice.
12 Mice exposed to 5,650 /tg tin/m3 as a mixture of tributyltin bromide (1.1 ppm),
13 dibutyltin bromide (0.06 ppm), and hydrocarbon impurities for 7 h/day over 6 days had
14 pathological changes in the kidney (Igarashi, 1959). The changes consisted of slight
15 degenerative changes in the glomeruli, convoluted tubules, and collecting tubules, as well as
16 extramedullary hematopoiesis. More extensive kidney damage (extensive congestion and
17 swelling of the renal tubular epithelium) was observed in rats exposed to 2,000 /Ltg tin/m3 for
18 80 days, as described above (Iwamoto, 1960).
19 No studies that conducted standard neurological tests on animals exposed to organotin
20 compounds were located. There was no evidence of histopathology in the brains of mice
21 exposed for 6 days to 2,120 ^g tin/m3 as a mixture of di- and tributyltin bromide (Igarashi,
22 1959).
23 Reproductive data are limited to one study in which rats were exposed to 2000 /xg
24 tin/m3 as a mixture of tributyltin bromide and dibutyltin dibromide (Iwamoto, 1960). A
25 reversible decrease in pregnancy rates was observed after 4 weeks to 3 mo of exposure.
26 Histologically, atrophy of the glandular uterus was observed as early as 14 days of exposure.
27 No further reproductive data were provided. No studies were located that assessed
28 developmental effects of the inhalation of organotin compounds in laboratory animals.
29
30
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1 11.6.18.4 Factors Affecting Susceptibility
2 The limited inhalation data available on inorganic tin suggest that the respiratory tract is
3 the target organ and therefore, individuals with respiratory system impairments may be at
4 greater risk for toxicological effects. The developing respiratory tract of children may also
5 pose an increased susceptibility. The limited data do not provide indications of any other
6 susceptibility factors for inorganic tin.
7 The inhalation of organic tin may affect not only the respiratory tract, but also the
8 nervous, hepatic, and renal systems, as well as causing teratogenic effects. Therefore,
9 individuals with respiratory impairment, liver disease, kidney disease, or neurological
10 disorders may be at greater risk for adverse health effects following the inhalation of organic
11 tin compounds. The developing respiratory tract of children may also pose an increased
12 susceptibility. In addition, limited animal data (Iwamoto, 1960) suggest that pregnant women
13 and their fetuses may also be at greater risk for toxicological effects.
14
15 11.6.19 Titanium
16 11.6.19.1 Chemical and Physical Properties
17 Titanium, a dark gray lustrous metal, is the first member of Group IVB of the periodic
18 system of elements. It has three valence states, +2, +3, and +4, of which titanium(+4) is
19 the most stable (Hazardous Substances Data Bank [Data Base], 1995; Whitehead, 1983).
20 The lower valence states of +2 and +3 are less common and are readily oxidized to the
21 tetravalent state by air, water, and other oxidizing agents (Whitehead, 1983). Titanium
22 forms organometallic compounds primarily in the tetravalent state. Trivalent titanium
23 organic compounds and complexes are stable at room temperature, although most of them are
24 attacked by oxygen and moisture (Rondestvedt, 1983). Titanium(+2) organic compounds are
25 less common, and both titanium(+2) and titanium(O) organic compounds are potent reducing
26 agents (Rondestvedt, 1983). Upon contact with moist air, titanium tetrachloride hydrolyzes
27 with fuming to form a vapor of hydrochloric acid, titanium dioxide, and titanium oxychloride
28 (Whitehead, 1983; Wilms et al., 1992). Elemental titanium is insoluble in water, as are the
29 dioxide (TiO2) and disulfate Ti(SO4) O2 compounds. Titanium tetrachloride (TiCl4) is
30 soluble in cold water, but decomposes in hot water, whereas titanocene dichloride, (C5H5)2
April 1995 11-374 DRAFT-DO NOT QUOTE OR CITE
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1 TiCl is sparingly soluble in water and tetrabutyl titanate, Ti(C4H10), reacts with water to
2 form butanol and TiO2.
3
4 11.6.19.2 Pharmacokinetics
5 Few studies were located regarding absorption, distribution, metabolism, or excretion
6 of titanium or titanium compounds in humans or laboratory animals following inhalation
7 exposure. The titanium compounds with the most toxicity data available are titanium dioxide
8 and titanium tetrachloride. Titanium dioxide has low solubility and is deposited in the lung
9 upon inhalation. Titanium tetrachloride hydrolyzes upon contact with moist air to form a
10 vapor of hydrochloric acid, titanium dioxide, and titanium oxychloride (Whitehead, 1983;
11 Wilms et al., 1992). The major route of exposure for titanium tetrachloride is by inhalation,
12 and the major target organ is the lung. Particles of metallic titanium have been found in the
13 lungs of occupationally exposed individuals (Elo et al., 1972; Ophus et al., 1979; Redline
14 etal.,1986).
15
16 Titanium Dioxide
17 Titanium dioxide (as ultrafme particles of « 20 ran) may enter the pulmonary interstitial
18 space of the lungs and elicit an inflammatory response as a result of phagocytosis by alveolar
19 macrophages. This in turn, may attract polymorphonuclear neutrophils to the interstitium.
20 Within 24 h of titanium dioxide inhalation, the titanium particles are contained in the
21 phagocytes and are transported by mucociliary action in the lungs; within 25 days after
22 exposure, the phagocytes contain only a very few titanium particles and approximately 40%
23 of the initial deposition is removed from the lungs via the airway (Ferin, 1976). Titanium
24 dioxide deposited in the lungs is not translocated to other tissues even after 25 days (Ferin,
25 1976). Data from exposure of rats to 57,000 /xg/m3 titanium dioxide for 2 h showed that
26 titanium dioxide concentrations increased in the lungs throughout the exposure period and
27 slowly decreased thereafter (Ferin, 1970).
28 Following chronic inhalation exposure to titanium dioxide, metallic particulates have
29 been found in lysosomes of phagocytes within the alveolar lumen (Elo et al., 1972). Rats
30 exposed to titanium dioxide (concentration unspecified) for 2 h showed no titanium in the
April 1995 11.375 DRAFT-DO NOT QUOTE OR CITE
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1 blood, heart, liver, kidney or spleen; titanium found in the gastrointestinal tract was related
2 to the titanium content of the food (Ferin, 1970).
3
4 Titanium Tetrachloride
5 The pharmacokinetics of titanium tetrachloride are largely determined by its chemical
6 properties and by the pharmacokinetics of its hydrolysis products. Titanium tetrachloride is
7 rapidly hydrolyzed upon contact with moisture because of its instability in the presence of
8 water and heat. One hydrolysis product, hydrochloric acid, is largely responsible for the
9 corrosive effects observed following exposure to titanium tetrachloride. Because the
10 mechanism of action of titanium tetrachloride is so closely tied to its pharmacokinetics, both
11 topics will be discussed in this section.
12 A study comparing the effects of titanium tetrachloride and hydrochloric acid in mice
13 after acute inhalation exposure found that the active component in both cases was
14 hydrochloric acid, and that effects were more severe following titanium tetrachloride
15 exposure than following hydrochloric acid exposure (Mezentseva et al., 1967). The
16 difference in severity is thought to be due to the high solubility of hydrochloric acid, which
17 dissolves in the moisture of the nasopharynx and trachea and thus penetrates into the lungs to
18 only a very limited extent. Because titanium tetrachloride is less soluble, it penetrates deeper
19 into the lungs before being hydrolyzed. Titanium tetrachloride hydrolysis occurs via a two-
20 stage exothermic reaction. First, titanium tetrachloride condenses into fine droplets that form
21 a highly dispersed paniculate smoke. This hygroscopic smoke then reacts with the moisture
22 in the air to form secondary smoke, which contains various hydrolytic products of titanium
23 tetrachloride (e.g., hydrochloric acid, titanium oxychloride, and titanium dioxide). One
24 hydrolysis product, titanium oxide hydrate, is a paniculate that adsorbs some of the
25 hydrochloric acid vapors generated during hydrolysis and carries them into the deeper parts
26 of the lungs. In the lungs, the hydrolysis process is repeated with the further release of
27 hydrochloric acid, ultimately resulting in a larger amount of hydrochloric acid being carried
28 deeper into the lungs and alveoli (Mezentseva et al., 1967). Titanium tetrachloride is not
29 dermally absorbed; rather it hydrolyzes upon contact with the skin with the hydrochloric acid
30 causing burns.
31
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1 11.6.19.3 Health Effects
2 Studies regarding the effects on humans and animals following inhalation to titanium
3 and titanium compounds were largely limited to exposure to titanium dioxide and titanium
4 tetrachloride. The major toxicity endpoint for titanium exposure in humans and laboratory
5 animals appears to be the respiratory system. Inhalation toxicity data for humans are
6 summarized in Table 11-49. The laboratory animal data are summarized in Table 11-50.
7
8 Titanium Dioxide
9 Human Data. Occupational exposure to titanium dioxide has been linked to
10 pneumoconiosis in workers. Of 197 workers in a titanium dioxide plant assessed
11 spirometrically, 47% had some level of airway obstruction. Furthermore, 38% of those who
12 had never smoked and had more than 20 years of exposure had airflow impairment. Of the
13 201 workers who were examined radiologically, 13% had irregular or nodular interstitial
14 opacities. These data suggest that radiologic signs of pneumoconiosis from titanium are less
15 sensitive than measures of pulmonary function (Daum et al., 1977).
16 An epidemiologic study of 1,576 active and terminated workers exposed to titanium
17 dioxide for more than one year assessed the incidence of various types of cancer and of
18 chronic respiratory disease. Exposure was estimated and subjects were grouped by
19 cumulative exposure indices. Chest roentgenograms of 398 active workers showed that
20 titanium dioxide exposure was not associated with pleural thickening or plaques; no
21 pulmonary fibrosis was seen among the exposed workers. There was no correlation between
22 incidence of chronic respiratory disease or pleural thickening and cumulative exposure index.
23 There was also no relation between exposure and total cancer or lung cancer incidence, and
24 no increase in cancer compared to the expected values for the general company cohort or for
25 the general population (Chen and Fayerweather, 1988).
26 In a study of three workers who worked for 9 to 10 years in a titanium dioxide
27 processing factory, electron microscopy and spectrometric and spectrographic analyses of
28 lung tissue showed the presence of considerable amounts of titanium (Elo et al., 1972).
29 Electron microscopy first identified 0.1 to 0.4 pirn diameter black particles in the lysosomes
30 of phagocytic cells filling the alveolar lumen. Large quantities of titanium were also present
31 in the lymph nodes.
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TABLE 11-49. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR TITANIUM AND
I-
1— *
s
1— '
h- *
1
-J
oo
o
§
fe
Exposure
Concentration Exposure
ppm ng Ti/m3 protocol
Acute Studies
NS NS Single
exposure
accident
Chronic Human
NA 0-1,000 >lyr
1,000-4,000 occup
4,000-9,000
9,000-20,000
> 20,000
(est)
TITANIUM COMPOUNDS3
Chemical Particle size and Species, Strain,
form distribution (Number) Sex Assays performed: Effect(s)
TiCl4 NS Human CS: Case study of accidental spraying of TiCl4 over
vapor (1) M head, chest, neck and back; CS: 25% second and
third degree burns over chest, back, abdomen, arms,
scalp due to dermal exposure. Erythema of tongue,
pharynx, and conjunctivae; shallow breathing,
agitation, confusion, upper airway stridor. Within 48
h of exposure, progressive hypoxia and diffuse
pulmonary infiltrates characteristic of resp distress
syndrome. Fiberoptic bronchoscopy revealed
erythema of entire bronchial tree with 35-40 fleshy
polypoid lesions.
TiO2 NS Human Medical history, chest x-ray, lung cancer incidence
dust (1,576) M and mortality, incidence of total and other individual
cancers: No association between exposure and
increased cancer, chronic respiratory disease, or
pleura! thickening/plaques.
Reference
Park et al.
(1984)
Chen and
Fayerweather
(1988)
O
o
o
H
O
I
M
n
i—i
H
M
NA NS
9-10 yr TiO2 dust NS
Human
(3)M
HP of lung, CS: Recurrent bronchitis, dyspnea. HP Elo et al. (1972)
showed carbon-like, birefractive pigment
aggregations forming extensive patches under the
pleura. Pigment-containing phagocytes filled some of
the alveolar lumina; dense pigment accumulation
present in perivascular and peribronchial sites; slight
inc in connective tissue hi pleura, subpleural, and
alveolar septa. Lysosome-filled phagocytes within
alveolar lumen containing black (0.1-0.4/tm diameter)
particles.
-------
£• TABLE 11-49 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR TITANIUM AND
3: TITANIUM COMPOUNDS3
S Exposure
ui Concentration
ppm /xg Ti/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species, Strain,
(Number) Sex Assays performed: Effect(s)
Reference
NS NS
Syr
TiO, dust NS
Human
NS NS
NS
occup
Mixture of
Ti, TiCl4,
TiO2, HC1,
NaCl vapor
and
particulates
Ti02
particulates
200-
2,800 /*g/m3
Human
(209) M
Case study: Death by lung metastases from Ophus et al.
undifferentiated tumor in right ileal bone. Large (1979)
amounts of white, birefractive pigments in all parts of
lungs without obvious flbrotic changes, accumulated
Ti-rich material in the perivascular areas of lung,
crystal modification of titanium in form of rutile
(biologically inert crystalline modification of
Ti/TiO2).
Cough, phlegm production, chronic bronchitis, Garabrant et al.
wheezing with dyspnea. Reduced pulmonary capacity (1987)
of 24 ml/yr of occupational exposure, pleural disease
(pleura! plaques and diffuse pleural thickening). Data
suggest no clear association between pleural
thickening and reduced ventilatory capacity.
Abbreviations:
avg = average; BC = blood chemistry; BW = body weight; cardio = cardiovascular; CS = clinical signs; d = day; est = estimated; F = female; G6P =
glucose-6-phosphate dehydrogenase; gastro = gastrointestinal; h = hour; hemat = hematological; HP = histopathology; inc = increase; M = male; MMAD
= mass median aerodynamic diameter; mo = month; musc/skel = musculoskeletal; N/A = not applicable; NS = not specified in the literature reviewed; occup
= occupational; PF = pulmonary function; PMN = polymorphonuclear neutrophils; resp = respiratory; SD = Sprague-Dawley; sig = significant; UA =
urinalysis; Ti = titanium; TiO2 = titanium oxide; TiCl4 = titanium tetrachloride; TiH2 = titanium hydride; wk = week; yr = years.
-------
3.
s
TABLE 11-50. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR TITANIUM AND
TITANIUM COMPOUNDS8
00
o
O
H
O
O
3
o
o
M
Exposure
Concentration
ppm /*g Ti/m3
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number) Sex
Assays performed: Effect(s)
Reference
Acute Studies
NS 370,000
1,290,000
1,900,000
2,900,000
10 min TiCl4 NS Rat, SD
aerosol (NS) F
HP, CS: Nasal discharge, dyspnea, swollen eyelids at
370; discrete inflammatory residue in the lungs,
coarsened alveolar septa at 1290. Signs disappeared
with 48-72 h following exposure. HP of lungs was
normal when examined 7 days post exposure.
Karlsson
et al.
(1986)
Chronic Studies
NS 0
60
600
6,000
NS 0
60
600
6,000
6 h/d TiCl4 vapor "Fine, round Rat, CR
5 d/wk particles < 1 urn (100) M, (100) F
2 yr in diameter and
large aggregated
particles up to
400 /*m in
diameter"
6 h/d TiCl4 vapor NS Rat, CR-CD
5 d/wk (100) M, (100) F
2yr
HP, CS: No changes in CS, BW, or excess mortality.
Tracheitis and rhinitis at 0.06; increased incidence of
foamy lung macrophages with increased TiCl4 dust
deposition at 0.6. Squamous cell carcinoma in lungs
of 2/69 males and 3/74 females at 6. Pneumocyte
hyperplasia in alveoli adjacent to alveolar ducts. No
reported abnormal HP (lungs, trachea, thyroid, adrenal
glands, testes, kidneys and other organs — not
specified).
HP of respiratory tract: Differentiated squamous cell
carcinoma in lungs of 3/150, keratinized squamous cell
carcinoma hi lungs of 2/150 at 10. Alveolar cell
hyperplasia and paniculate dust deposition in the
alveoli and tracheobronchial lymph nodes at 1 and 10.
Du Pont
(1986);
Lee et al.
(1986)
Du Pont
(1984)
-------
a.
oo
TABLE 11-50 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR TITANIUM AND
TITANIUM COMPOUNDS3
Exposure
Concentration
ppm fig Ti/m3
NS 0
60
6,000
30,000
150,000
Exposure Chemical Particle size and Species, Strain,
protocol form distribution (Number) Sex Assays performed: Effect(s)
6 h/d TiO2 Dust: 1.5-1.7 /xm Rats, Crl:CD CS: No change in body weight, morbidity, mortality
5 d/wk MMAD; 84% <13 (400) M, (400)F at any concentration. Lung weights increased at
2 yr jim 30,000 at 6 mo and at 3 mo at 150,000 /xg/m3. Gross
pathology: few white foci in lung at 6,000 /ig/m3,
number increased with increasing concentration,
tracheobronchial lymph nodes were white, chalky, dry.
Microscopic: lungs contained dust laden macrophages
in alveoli at 6,000 /xg/m3, hyperplasia. At
30,000 /xg/m3 foamy macrophages with cholesterol
granuloma, thickened alveolar wall, fibrosis, and
bronchiolarization and alveolar proteinosis. At
150,000 /xg/m3, bronchioloalveolar adenomas and
cystic keratinizing squamous carcinomas, no metastasis
was seen.
Reference
Lee et al.
(1986a)
NS 31,100-38,500 4 h/d
(avg. 34,500 30 d
Titan dust Dust: <2/mi (5.7%), Rat
(48.9% 2-4 jtin (10.9%), (10) M
HP of respiratory tract: Cell infiltration in alveoli Shirakawa
with pigmentation. No other histopathological changes (1985)
2 a*511)
I
O
O
O
H
O
Ti) 4-6 /xm (26.7%), were seen. Dust also contained iron, silicon,
6-8 ion (16.6%), magnesium and other elements.
8-10 fim (12.4%),
10-12 /xm (7.2%),
12-14 itm (7.2%),
14-16 /xm (3.7%),
16-18 /xm (3.6%),
18-20 /xm (1.3%),
>20 /tm(4.5%)
3
M
n
h-4
H
W
-------
a-
TABLE 11-50 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR TITANIUM AND
TITANIUM COMPOUNDS3
VO
S
Exposure
Concentration
ppm /tg Ti/m3
NS 492,000-
523,000
Exposure
protocol
4h/d
286 d
Chemical
form
TiH2
(507,000 avg)
i
ex
to
O
>
H
b
o
^
0
H
O
c|
O
H
W
O
NS 10,800 (avg)
NS 228 (avg)
Abbreviations:
avg = average; BC
glucose-6-phosphate
2h/d
7-10 mo
4h/d
7 mo
Titan dust
(48% Ti)
Titan dust
(48% Ti)
= blood chemistry; BW
dehydrogenase; gastro =
= mass median aerodynamic diameter; mo =
= occupational; PF
= pulmonary
urinalysis; Ti = titanium; TiO2 =
function;
Particle size and
distribution
Dust: < 1 /tm
(37.4%),
1-2 m 44.6%),
2-3 /tm (8.5%),
3-4 /tm (3.4%),
4-6 /tm (3.0%),
6-23 /tm (3.1%)
Dust: <1
/im (17.3%),
1-2 m (26.7%),
2-3 /tm (21. 3%),
3-4 /tm (10.1%),
4-5 /tm (3.0%),
5-6 /tm (2.4%),
>6/tm(19.2%)
Fine dust,
<325 mesh
Species, Strain,
(Number) Sex
Rabbits
(4) M/(4) F
Rat
(9)M
Rabbit
(8)M
Rat
(9)M
Rabbit
(8)M
Assays performed: Effect(s)
HP of respiratory tract: Changes in lung with
accumulation of phagocytes and macrophages,
proliferation of connective tissue in alveolar wall,
deposition of dust in lymph nodes and formation of
irreversible dust foci. Reticulonodular shadowing
evident at 5 mo.
HP of respiratory tract: Moderate punctiform
opacities indicative of pneumoconiosis seen in rabbits
at 4-5 mo and in rats at 6 mo. Histopathology:
increased phagocytes and macrophages containing
dust particles, epithelial cell proliferation, hyperplasia
of alveolar connective tissue, and dust foci. Similar
changes seen in rats but with less dust in cells.
Radiography of respiratory tract: nodular shadows
seen in rabbits at 1 mo and in rats at 3 mo.
Retention of dust in alveoli and lymph nodes,
proliferation of alveolar walls, hyperplasia of
connective tissue, adsorption of dust particles by
phagocytes and macrophages
= body weight; cardio = cardiovascular; CS = clinical signs; d = day; est = estimated; F
= gastrointestinal; h
month; musc/skel
= hour; hemat =
= musculoskeletal
Reference
Shirakawa
(1985)
Shirakawa
(1985)
Shirakawa
(1985)
= female; G6P =
: hematological; HP = histopathology; inc = increase; M = male; MMAD
; N/A = not applicable; NS = not specified in the literature reviewed; occup
PMN = polymorphonuclear neutrophils; resp = respiratory; SD = Sprague-Dawley; sig =
titanium oxide; TiCl4 = titanium tetrachloride;
TiH2 = titanium hydride; wk = week; yr = years.
significant; UA =
0
-------
1 Similar findings were made in the case of a 55-year-old man who worked for three
2 years in a titanium pigment processing factory and died of lung metastasis from an
3 undifferentiated tumor in the right ileal bone (Ophus et al., 1979). Macroscopic and
4 microscopic examinations revealed large amounts of white, birefractive pigment in all parts
5 of the lungs without obvious fibrotic changes. Further analysis confirmed the presence of
6 titanium and occasionally iron, and also showed that the crystal modification of titanium was
7 in the form of rutile, a mineral of titanium dioxide that also contains iron. An increased
8 concentration of titanium dust particulates was found in the right middle lobe (43.3-49%)
9 and lower lobe (39.2 to 47%), compared to <0.2% in the controls.
10 Redline et al. (1986) reported a case study of a 45-year-old man with granulomatous
11 lung disease, who worked for 13 years as a furnace feeder in an aluminum smelting
12 company. Scanning electron microscopy and energy dispersive x-ray analysis showed that
13 the lung tissue biopsy from the lower right lobe contained 1.39 x 109 exogenous particulates
14 per cm3 of tissue (including titanium). Lymphocyte proliferative response indicated a
15 sensitivity to titanium. This finding confirms the possibility of titanium deposition in the
16 lung tissue following titanium dioxide inhalation and, in this case, supports the association of
17 granulomatous lung disease with metallic particle deposition.
18 These studies indicate that titanium dioxide can be deposited in the lungs of
19 occupationally exposed workers, and that these deposits do not necessarily cause
20 histopathological changes. However, these deposits may cause local pulmonary tissue
21 irritation, which may progress to pneumonocoisis.
22 No studies were located regarding reproductive or developmental effects in humans of
23 inhalation exposure to titanium compounds.
24
25 Laboratory Animal Data. A study of rats receiving a single intratracheal dose of
26 ultrafme (= 20 nm) titanium dioxide particles in saline indicated that these ultrafine particles
27 enter the interstitial spaces of the lungs, whereas larger particles ( = 250 nm) do not.
28 Inflammatory responses in the lung as evidenced by increased polymorphonuclear neutrophils
29 and increased lavage proteins were greater for the fine particles, probably as a result of
30 phagocytosis by alveolar macrophages (Oberdorster et al., 1992).
April 1995 H-383 DRAFT-DO NOT QUOTE OR CITE
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1 Rats exposed via inhalation to titanium dioxide dust for 2 years showed lesions only in
2 the respiratory tract and thoracic lymph nodes. At a titanium dioxide dust concentration of
3 6,000 fig Ti/m3, pathological and microscopic changes that occurred in the alveoli included
4 the presence of white foci, alveolar macrophages and hyperplasia. At doses of 30,000 ^g
5 Ti/m3 or greater, lung weights increased. At a maximum concentration of 150,000 pig
6 Ti/m3, lung adenomas were seen in alveoli showing hyperplasia of Type II pneumocytes, and
7 cystic keratinizing squamous carcinomas were also observed. Dust particle retention
8 increased progressively at the highest dose throughout the 2-year exposure period, indicating
9 that the lung clearance capacity of the lung was overwhelmed (Lee et al., 1986b).
10 Rats receiving intratracheal instillations of 5 mg of titanium dioxide dust showed that
11 although polymorphonuclear leucocytes counts were increased 24 h after administration,
12 values had returned to control levels by 100 days post exposure (Sykes et al., 1982).
13
14 Titanium Tetrachloride
15 Human Data. Only epidemiological reports of occupational exposure and case reports
16 of accidental exposure were found on effects on humans of inhaling titanium tetrachloride.
17 In both types of studies, the exact exposure levels were not known, and inhalation exposure
18 frequently occurred simultaneously with dermal exposure. Therefore, some of the effects
19 reported below may be partially due to dermal exposure to titanium tetrachloride.
20 Case studies of humans acutely exposed by inhalation to titanium tetrachloride fumes
21 indicate the irritant nature of chemical. Although the degree of pulmonary injury varies,
22 inhalation exposure results in an intense chemical bronchitis or pneumonia (Lawson, 1961).
23 Following an accidental acute exposure, three research workers experienced only mild irritant
24 symptoms consisting of cough and chest tightness, both of which lasted only a couple of
25 hours and left no abnormalities on the chest x-ray (Ross, 1985).
26 More severe pulmonary effects were reported in two other incidents of accidental
27 exposure to titanium tetrachloride. One worker who was splashed with hot titanium
28 tetrachloride suffered marked congestion of the mucous membranes of the pharynx, vocal
29 cords, and trachea (Ross, 1985). This exposure had long-term effects that included stenosis
30 of the larynx, trachea, and upper bronchi. In another accident, a worker who was sprayed
31 with titanium tetrachloride developed cough and dyspnea 20 min after exposure (Park et al.,
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1 1984). His symptoms progressed to severe upper airway distress that required intubation and
2 ventilation. Additional symptoms included hypoxia and diffuse pulmonary infiltrates,
3 suggestive of adult respiratory distress syndrome. Although he gradually improved,
4 fiberoptic bronchoscopy five weeks later revealed erythema of the entire bronchial tree and
5 the presence of 35-40 fleshy polypoid lesions. According to the authors, the presence of the
6 polyps was a sign of an exaggerated but normal reparative process of the tracheobronchial
7 injury. This delayed complication has been seen in thermal respiratory injuries, suggesting
8 that the severe adverse respiratory effects seen in this case are in part due to the exothermic
9 nature of the titanium tetrachloride hydrolysis reaction. His lungs appeared normal one year
10 after the injury, although mild stenosis remained.
11 Two retrospective studies (Garabrant et al., 1987; Mosley et al., 1980) of the
12 occupational exposure of 209 workers employed at a metals reduction facility indicate that
13 inhalation of titanium tetrachloride causes respiratory irritation (cough, phlegm production,
14 chronic bronchitis, and wheezing with dyspnea) and pulmonary impairment (pleural
15 thickening and reduced pulmonary function). Further analysis of the workers, based on job
16 and duration of employment, confirmed large decreases in forced vital capacity (FVC) in
17 workers employed in titanium tetrachloride reduction for at least 10 years (Garabrant et al.,
18 1987). A regression analysis of the data (adjusted for age, height, and smoking) revealed
19 that the rate of FVC loss was 24 mL per year for the titanium tetrachloride workers.
20 Garabrant et al. (1987) suggested that chronic exposure to titanium tetrachloride may result
21 in restrictive pulmonary changes and that there is no clear association between pleural
22 thickening and reduced ventilatory capacity. However, both studies were limited because of
23 the lack of information on the duration, route, and exposure levels, the concomitant exposure
24 to a mixture of chemicals, and the use of a control group consisting of maintenance workers
25 exposed to multiple chemicals.
26 A few epidemiological studies have examined cancer mortality in workers employed in
27 industries using titanium tetrachloride. No association between titanium tetrachloride and
28 lung cancer mortality was found in 969 male workers occupationally exposed to < 500 to >
29 3,000 pig/m3 titanium tetrachloride for up to five years or more (Fayerweather et al., 1992).
30
April 1995 11-385 DRAFT-DO NOT QUOTE OR CITE
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1 Laboratory Animal Data. Findings in laboratory animals support the observations
2 made in humans. Rats exposed by inhalation to titanium tetrachloride (370,000, 1,290,000,
3 1,900,000, or 2,900,000 /*g Ti/m3) for 10 min had wet noses, nasal discharge, swollen
4 eyelids, and dyspnea (Karlsson et al. 1986). The signs disappeared within three days
5 following exposure, and lung histopathology conducted 7 days post exposure showed minor
6 lesions. Rats chronically exposed to titanium tetrachloride (60 to 6,000 /xg Ti/m3 6 h/day, 5
7 days/week for 2 years) had concentration-related increased incidence of irregular respiration
8 and abnormal lung noises, tracheitis, and rhinitis (Du Pont, 1986; Lee et al., 1986a). Gross
9 pathology and histopathology revealed compound-related changes in the lungs and thoracic
10 lymph nodes and increased relative and absolute lung weights in treated rats. Foci laden
11 with yellow material (a titanium tetrachloride hydrolysis product) were found on the lung
12 pleural surface and on the slightly enlarged tracheobronchial lymph nodes in the mid- and
13 high-dose rats.
14 Although squamous cell carcinoma and keratinizing squamous cell carcinoma were
15 observed in rats chronically exposed to titanium tetrachloride, it is difficult to estimate their
16 relevance to lung tumors in humans (Du Pont, 1984; 1986; Lee et al., 1986a). Following a
17 two-year exposure to 100 to 10,000 /ig/m3 hydrolyzed titanium tetrachloride vapors, two
18 types of lung squamous carcinoma were found: well-differentiated squamous cell carcinoma
19 and a keratinized, cystic squamous cell carcinoma. The carcinomas occurred in the alveoli
20 with squamous metaplasia and next to the alveolar ducts with aggregated dust-laden
21 macrophages, and were probably a result of chronic tissue irritation from dust-laden
22 macrophages and cellular debris. According to the authors, these lung carcinomas are a
23 unique type of experimentally induced tumors that are not usually seen in humans or other
24 animals. Their etiology is also different from human squamous cell carcinoma. Therefore,
25 it is difficult to estimate the relevance of these keratinizing carcinomas to humans.
26
27 Titanium Hydride/Titan Dust
28 Human Data. No toxicity data were located.
29
30 Laboratory Animal Data. Other forms of titanium have also been studied to determine
31 their respiratory effects. Rats and rabbits were exposed by inhalation to titan dust (48%
April 1995 11-386 DRAFT-DO NOT QUOTE OR CITE
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1 titanium) and titanium hydride for periods of up to 1 year with a 1 year observation period.
2 Titan dust, at concentrations up to 476,000 /-tg/m3 (228,000 /*g Ti/m3), resulted in dust
3 deposition in the alveoli and lymph nodes of the rabbits, as well as thickening of the alveolar
4 wall, hyperplasia of the connective tissue, some fibrosis, and dust particles in the alveolar
5 macrophages and phagocytes. Inhalation of titanium hydride (concentration 507,000 fig
6 Ti/m3) by rabbits for up to 286 days resulted in histopathologic changes in the lung similar to
7 those seen with titan dust (Shirawaka, 1985).
8 No studies were located regarding reproductive or developmental effects in laboratory
9 animals of inhalation exposure to titanium compounds.
10
11 11.6.19.4 Factors Affecting Susceptibility
12 Because the respiratory system is the major target of inhaled titanium (Chen and
13 Fayerweather 1988; Daum et al. 1977; Elo et al. 1972; Fayerweather et al. 1992; Garabrant
14 et al. 1987; NIOSH 1980), individuals with respiratory impairments or the developing
15 respiratory tract of children may be at increased risk. Studies in humans and laboratory
16 animals have shown that titanium compounds are not absorbed systemically or metabolized;
17 therefore, it is unlikely that there are other susceptible populations at increased risk from the
18 inhalation of titanium compounds.
19
20 11.6.20 Vanadium
21 11.6.20.1 Chemical and Physical Properties
22 Elemental vanadium is a light grey or white lustrous metal that may be found in a
23 powder, crystal, or soft ductile solid form. Vanadium belongs to group V of the periodic
24 system of elements. It has six oxidation states, -1, 0, +2, +3, +4, and +5, of which +3,
25 +4, and +5 are the most common (Agency for Toxic Substances and Disease Registry,
26 1992; Rosenbaum, 1983). The element forms both anionic and cationic salts and is typically
27 bound to oxygen. In the presence of oxygen, air, oxygenated blood, or oxidizing agents,
28 vanadium compounds are found in the +4 oxidation state (World Health Organization,
29 1987). Divalent and trivalent vanadium compounds are oxidized in the presence of air
30 (Rosenbaum, 1983). Vanadium forms organometallic compounds, although they are
April 1995 H_387 DRAFT-DO NOT QUOTE OR CITE
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1 generally unstable. Elemental vanadium is insoluble in water but vanadium pentoxide (V2O5)
2 is slightly soluble at 25 °C and vanadyl sulfate (VOSO4 • 5H2O) is highly soluble.
3
4 11.6.20.2 Pharmacokinetics
5 Most inhalation exposure to vanadium occurs in workers engaged in its industrial
6 production and use. The most common vanadium compounds encountered occupationally are
7 vanadium pentoxide (V2O5), elemental vanadium (V), vanadyl sulfate pentahydrate
8 (VOSO4-5H2O), and bismuth orthovanadate (BiVO4). The pattern of absorption,
9 distribution, metabolism, and excretion differs slightly for each vanadium species, depending
10 on particle size and solubility. In general, vanadium compounds are primarily absorbed in
11 the lung and transported by the blood throughout the body (kidney, liver, testicles, spleen,
12 heart, teeth, breast milk). Retention occurs mainly in bone. Most inhaled vanadium is
13 excreted in the urine, but some is found in the feces.
14
15 Absorption and Distribution
16 The respiratory tract is the most significant entry site for vanadium compounds. The
17 extent to which various compounds are absorbed in the respiratory tract is not clear, but is
18 estimated to be about 25% for the soluble compounds. As with all particles, deposition and
19 rate of subsequent absorption are expected to depend on particle size and solubility
20 (Lagerkvist et al., 1986), as well as on alveolar and mucociliary clearance. Vanadium
21 accumulates in the lungs of the general population with increasing age, reaching
22 approximately 6.5 /zg/g (wet weight) in persons over age 65 (Tipton and Shafer, 1966).
23 Accumulation was not observed in other tissues. Increased urinary vanadium levels in
24 workers inhaling < 1 ppm vanadium (Glyseth et al., 1979; Kiviluoto et al., 1981b; Lewis,
25 1959; Orris et al., 1983) and increased serum vanadium levels in workers inhaling vanadium
26 pentoxide dusts (Kiviluoto et al., 1981b) have also been reported.
27 Data showing elevated vanadium levels in the tissues of rabbits exposed by inhalation to
28 vanadium pentoxide dust provides indirect evidence that vanadium is absorbed by this route
29 (Sjoberg 1950); no data on rate or extent of absorption were available. More data are
30 available from intratracheal administration studies, which show that the absorption rate of
31 vanadium from the respiratory tract depends on the solubility and chemical nature of the
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1 vanadium species deposited. In rats administered VOC12 (a water-soluble vanadium
2 compound) by intratracheal injection, 60% remained in the lungs after 15 min, and 33.5%
3 remained after nine weeks. Absorption of vanadium in rats receiving radiolabeled vanadyl
4 chloride intratracheally is rapid and complete (Conklin et al., 1982), with the greatest
5 absorption of 48V occurring 5 min after administration (Roshchin et al., 1980). Most of the
6 vanadium, 80 and 85% of the tetravalent (V4+) and pentavalent (V5+) forms, respectively,
7 cleared the lungs within 3 h of intratracheal exposure (Edel and Sabbioni, 1988). Greater
8 than 50% of vanadyl oxychloride was cleared after 24 h from the lungs of male rats (Oberg
9 et al., 1978), and 90% was cleared after 3 days from the lungs of female rats (Conklin et al.,
10 1982). Rhoads and Sanders (1985) reported 50% clearance in 18 min and 100% clearance
11 within several days.
12 Absorbed vanadium is transported mainly in the plasma, bound to transferrin.
13 Vanadium is widely distributed in body tissues; principal organs of vanadium retention are
14 kidney, liver, testicles, spleen, heart, bones, teeth, and breast milk (Byrne and Kosta, 1978).
15 A major fraction of vanadium from cellular vanadium is found in nuclei (Sabbioni and
16 Marafante, 1978).
17 No information was found regarding the distribution of inhaled vanadium in humans
18 following acute exposure. Vanadium has been detected in the lungs and intestines at autopsy
19 in humans with no known occupational exposure (Schroeder et al., 1963); lung vanadium
20 levels were attributed to environmental exposure. Serum vanadium levels in occupationally
21 exposed workers were highest within 24 h of exposure, and rapidly declined after exposure
22 ceased (Gylseth et al., 1979; Kiviluoto et al., 1981b).
23 No information was found regarding the distribution of vanadium in laboratory animals
24 following short- or long-term inhalation exposure. Vanadium administered intratracheally to
25 rats is rapidly distributed. Within 15 min after acute intratracheal exposure to 360 pig/kg
26 vanadium oxychloride, radiolabeled vanadium was detected in varying concentrations in all
27 rat organs except the brain, with the highest concentrations in the lungs, followed by the
28 heart and kidney. Maximum levels were obtained between 4 and 24 h (Oberg et al., 1978).
29 Vanadium has a two-phase lung clearance after a single intratracheal exposure in
30 laboratory animals. In the first phase, a large percentage of the absorbed dose is rapidly
31 distributed (within 24 h post-exposure) to most organs and blood. The second phase is a
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1 slower clearance. Vanadium is transported mainly in the plasma; most is found initially in
2 the blood, with only trace levels detected two days after exposure (Roshchin et al., 1980).
3 The pentavalent and tetravalent forms appear to have similar distribution patterns; 3 h after
4 exposure, 15 to 17% of the absorbed dose was found in the lung, 2.8% in the liver, and 2%
5 in the kidney (Edel and Sabbioni, 1988).
6 Vanadium appears to be retained in the bones. Skeletal levels of vanadium peaked 1 to
7 3 days post-exposure (Conklin et al., 1982; Rhoads and Sanders, 1985; Roshchin et al.,
8 1980) and have been detected as long as 63 days after exposure (Oberg et al., 1978). Orally
9 administered vanadyl sulphate pentahydrate has been found to cross the placenta (Paternain et
10 al., 1990).
11
12 Metabolism
13 Vanadium, in its elemental form, is not metabolized. In the body, vanadium
14 interconverts between two oxidation states, tetravalent vanadyl (V+4) and pentavalent
15 vanadate (V+5). In plasma, vanadium exists in either a bound or unbound form (Bruech et
16 al., 1984). Vanadyl (Patterson et al., 1986) or vanadate (Harris and Carrano, 1984)
17 reversibly binds to human serum transferrin at two metal-binding sites on the protein, and is
18 then taken up by erythrocytes. The interconversion of oxidation states and the reversible
19 binding to transferrin protein may affect the biphasic clearance of vanadium that occurs in
20 the blood. With intravenous administration of vanadate or vanadyl, there is a short lag time
21 for vanadate binding to transferrin, but at 30 h, the association is identical for the two
22 vanadium forms (Harris et al., 1984). The vanadium-transferrin binding most likely occurs
23 with vanadyl since this complex is more stable (Harris et al., 1984). In rats, the transferrin-
24 bound vanadium is cleared from the blood at a slower rate than unbound vanadium,
25 supporting the biphasic clearance pattern (Sabbioni and Marafante, 1978).
26 Vanadyl is taken up by erythrocytes more slowly than is vanadate. Five minutes after
27 intravenous administration of radiolabeled vanadate or vanadyl in dogs, 30% of the vanadate
28 and 12% of the vanadyl is found in erythrocytes (Harris et al., 1984). Five hours after
29 administration, blood clearance of vanadyl and vanadate is essentially the same, although
30 initially vanadyl leaves the blood more rapidly than does vanadate (Harris et al., 1984).
31 Vanadate is considered more toxic than vanadyl because vanadate reacts with multiple
April 1995 11-390 DRAFT-DO NOT QUOTE OR CITE
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1 enzymes and is a potent inhibitor of plasma membrane Na+K+-ATPase (Harris et al., 1984;
2 Patterson et al., 1986). Metabolism of the compound does not appear to be affected by the
3 route of exposure (Edel and Sabbioni, 1988).
4
5 Excretion
6 Epidemiological and laboratory animal studies suggest that inhaled vanadium is
7 eliminated primarily in the urine. Male and female workers occupationally exposed to 100 to
8 190 jig/m3 vanadium had significantly higher urinary levels (20.6 /ig/L) than did non-
9 occupationally exposed controls (2.7 /xg/L) (Orris et al., 1983). Although several
10 occupational studies indicate significantly higher urinary vanadium levels in workers (Orris et
11 al., 1983; Glyseth et al., 1979; Lewis, 1959; Zenz et al., 1962), the correlation between
12 ambient levels and urinary levels is difficult to assess because most studies did not monitor
13 other excretion routes (Kiviluoto et al., 1981b). Very low vanadium levels have been found
14 in human breast milk (Byrne and Kosta 1978).
15 Although no laboratory animal studies were located assessing excretion after inhalation
16 exposure, oral studies support the findings of the occupational data. Vanadium administered
17 intratracheally to rats was excreted predominantly in the urine (Oberg et al., 1978) at levels
18 twice that found in the feces (Rhoads and Sanders, 1985). Three days post-exposure to
19 radiolabeled vanadium pentoxide, 40% of the recovered dose was cleared in the urine, 30%
20 remained in the skeleton, and 2 to 7% was found in the lungs, liver, kidneys, or blood
21 (Conklinetal., 1982).
22
23 11.6.20.3 Health Effects
24 Human Data
25 Acute and chronic inhalation studies in humans are generally limited to occupational
26 case studies and epidemiology studies in workers engaged in the industrial production and use
27 of vanadium. Based on these studies, the respiratory tract is the primary target of vanadium
28 inhalation. Most of the reported exposures are to vanadium pentoxide dusts. Neurological
29 symptoms have been reported following acute exposure at high vanadium concentrations.
30 Gastrointestinal effects (nausea, vomiting), which may have occurred from swallowing
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1 vanadium via mucociliary clearance, eye irritation, and conjunctivitis have also been
2 reported. Human toxicity data are summarized in Table 11-51.
3 Acute and chronic respiratory effects were most commonly seen following exposure to
4 vanadium pentoxide dusts. Mild respiratory distress (cough, wheezing, chest pain, runny
5 nose, or sore throat) was observed in workers exposed to vanadium pentoxide dusts or
6 vanadium in fuel oil smoke for as few as 5 h (Levy et al., 1984; Musk and Tees, 1982;
7 Thomas and Stiebris, 1956; Zenz et al., 1962) or as long as 6 years (Lewis, 1959; Orris et
8 al., 1983; Sjoberg, 1956; Vintinner et al., 1955; Wyers, 1946). Most clinical signs reflect
9 the irritative effects of vanadium on the respiratory tract; only at concentrations
10 > 1,000 jiig vanadium/m3 were more serious effects on the lower respiratory tract observed
11 (bronchitis, pneumonitis). Rhinitis, pharyngitis, bronchitis, chronic productive cough,
12 wheezing, shortness of breath, and fatigue were reported by workers following chronic
13 inhalation of vanadium pentoxide dusts (Sjoberg, 1956; Vintinner et al., 1955; Wyers, 1946).
14 Two volunteers exposed to 60 /xg vanadium/m3 as vanadium pentoxide reported a delay of 7
15 to 24 h in the onset of mucus formation and coughing (Zenz and Berg, 1967).
16 Vanadium induced asthma in vanadium pentoxide refinery workers without previous
17 history of asthma, with symptoms continuing for 8 weeks following cessation of exposure
18 (Musk and Tees, 1982). Increased neutrophils in the nasal mucosa were reported in
19 chronically exposed workers (Kiviluoto, 1980; Kiviluoto et al., 1979, 1981c).
20 Few studies were found that reported effects of vanadium compounds on organ systems
21 other than the respiratory tract. However, nervous symptoms have been observed following
22 chronic exposure (Sjoberg, 1950). Workers chronically exposed to vanadium dusts
23 complained of nausea, vomiting (which may have resulted from ingesting dusts), slight to
24 moderate eye irritation (Levy et al., 1984; Lewis, 1959; Sjoberg, 1950; Thomas and Stiebris,
25 1956; Vintinner et al., 1955), and conjunctivitis (Zenz et al., 1962). Chronic occupational
26 exposure to vanadium dusts was also associated with some electrocardiographic changes
27 (Sjoberg, 1950). Vanadium dusts had no effect on hematology following acute exposure
28 (Zenz and Berg, 1967) or chronic exposure (Kiviluoto et al., 1981a; Sjoberg, 1950;
29 Vintinner et al., 1955). Blood pressure and gross neurologic signs were not affected
30 following chronic exposure to vanadium pentoxide dusts at levels up to 58,800 /zg
31 vanadium/m3 (Vintinner et al., 1955), although other authors reported anemia or leukopenia
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O
o
1
o
I
o
90
O
Exposure
Concentration
ppm
Acute
N/A
N/A
N/A
N/A
/tg V/m3
Studies
>500
NS
50-5,300
60
100
600
Exposure Chemical Particle size and
protocol form distribution
1 d (occup) V2O5 UK
dust,
fumes
1 d (occup) V2O5 dust NS
7 d (occup) V2O5 NS
fumes
8 h V2O5 98% < 5 /mi in
dust diameter
Species, Strain,
(Number) Sex
Human
(18) M
Human
(4)M
Human
(100) M
Human
(2-5) NS
Assays performed: Effect(s)
Subjective symptoms, chest x-ray, spirometry
(FVC, FEV, MEFR), UA V concentration;
Mucosal irritation, conjunctivitis, cough,
wheezing, bronchospasms. Chest x-rays, UA V
concentration, pulmonary function normal. V
found in urine.
Note: Symptoms developed on Day 1 of exposure,
and continued even when exposure was reduced.
Case studies - history, prick skin test, chest x-ray,
pulmonary function (FEV, FVC), total serum IgE:
Wheezing, airflow obstruction, green tongue,
asthma.
Questionnaire, CS, PF, chest x-ray, UA V
concentration: Bronchitis, productive cough, sore
throat, dyspnea on exertion, chest pain, wheezing.
Median latency of symptoms = 7 days. Exposure
concentration not correlated with effects. Normal
chest x-ray and blood work.
CS, spirometry, blood counts, V hi blood:
Bronchial irritation (cough, mucous formation)
post-exposure at 60 /tg/m3. Cough at 100, 600
/ig/m3 lasted about 1 wk. No change in
pulmonary function, blood counts, or hair or nail
cystine levels.
Reference
Zenz et al.
(1962)
Musk and Tees
(1982)
Levy et al.
(1984)
Zenz and Berg
(1967)
Chronic Studies
N/A
0
100-300
2 yr (occup) V2O5 93-100% of
dust particle < 5 /im;
est 2-100% of
part, mass < 5
Human
(24) M
Physical exam, history, electrocardiogram, UA V
concentration, hematocrit, serum cholesterol:
Productive cough, runny nose, sore throat,
wheezing, green tongue.
Lewis (1959)
M
-------
Exposure
Concentration Exposure
ppm
N/A
N/A
N/A
N/A
/ig V/m3 protocol
0 6 yr (occup)
130
est <6,500 1-2 yr (occup)
0-7 (control) < 1- > 10 yrs
10-2, 120 (occup)
(inactive ore
area) 20-
58,800
(active ore
area)
0 Syr
200-500 (occup)
Chemical
form
V205
dust
Mixture
of V205
(4.8-7.5%
of dust);
V203
(17%)
FeV204
Vanadium
ore (form
NS, but
included
V205)
V2O5 dust
Particle size and Species, Strain,
distribution (Number) Sex
NS Human
(39) M, F
22% of dust < Human (36) M
8 urn; 17% 8-12
urn; 17%
12-18 fim; 44% >
18 jtm
Inactive ore: 50% Human (37-39)
< 1 .5 urn diameter; NS
80% <2.5 /mi;
100% <5 /an;
Active ores: 75%
<1.5 fj.m diameter;
80% <2.5 urn;
100% <5 /xm
NS Human
(63) NS
Assays performed: Effect(s)
Questionnaire, physical exam, PF chest x-rays:
Skin rash, green tongue, wheezing, nose bleeds.
Normal pulmonary functions. X-ray s-pleural
thickening consistent with concurrent asbestos
exposure.
Physical exam, bronchoscopy, ECG,
hematology, urinalysis, serum bilirubin:
Rhinitis, nasal discharge, irritated throat,
bronchopneumonia, "asthmatic" bronchitis some
changes on ECG, one case of tremor,
neurasthenia, weakness. No effect on liver,
kidney, blood.
Med neuro exam, chest x-ray, spirometry:
exposed workers had subjective respiratory
complaints (cough, chest pain, and dyspnea) and
eye and nose irritation. Incidences higher in
active ore group than inactive ore group. No
significant differences in vital capacity, tremor,
coordination.
Micro- and macroscopic examination of upper
respiratory tract: No gross respiratory change,
inc neutrophils/plasma cells in nasal mucosa.
Reference
Orris et al.
(1983)
Sjoberg (1950)
Vintinner et al.
(1995)
Kiviluoto
(1980);
Kiviluoto et al.
(1979, 1981)
Abbreviations:
BAL = bronchioalveolar lavage; CS = clinical signs; d = days; ECG = electrocardiogram; EM = electron microscopy; est = estimated; F = female; GI =
gastrointestinal; h = hours; inc = increased; M = male; FEV = forced expiratory volume; FVC = forced vital capacity; mos = month; N/A = not applicable;
NS = not specified; occup = occupational; PF = pulmonary function; UA = urinalysis; V = vanadium; V2O5 = vanadium pentoxide; wk = week; yr = years.
-------
1 (Roschin, 1964; Watanabe et al., 1966). Based on serum biochemistry and urinalysis, there
2 was no indication of kidney or liver toxicity in workers chronically exposed to 200 to
3 58,800 fig vanadium/m3 vanadium dusts (Kiviluoto et al., 1981a,b; Sjoberg, 1950; Vintinner
4 et al., 1955). Vanadium green discoloration of the tongue resulting from direct deposition of
5 vanadium is often reported (Orris et al., 1983; Lewis, 1959; Musk and Tees, 1982).
6 No studies were located regarding developmental effects, reproductive effects, or
7 cancer in humans after inhalation or oral exposure to vanadium.
8
9 Laboratory Animal Data
10 Acute and chronic laboratory animal studies support the respiratory tract as the main
11 target of inhaled vanadium compounds. The animal data indicate that vanadium toxicity
12 increases with increasing compound valency, and that vanadium is toxic both as a cation and
13 as an anion (Venugopal and Luckey, 1978). The toxicity data for laboratory animals are
14 summarized in Table 11-52.
15 The mechanism of vanadium's effect on the respiratory system is similar to that of
16 other metals. In vitro tests show that vanadium damages alveolar macrophages (Castranova
17 et al., 1984; Sheridan et al., 1978; Waters et al., 1974; Wei and Misra, 1982) by affecting
18 the integrity of the alveolar membrane, thus impairing the cells' phagocytotic ability,
19 viability, and resistance to bacterial infection. Cytotoxicity, tested on rabbit alveolar
20 macrophages in vitro, was directly related to solubility in the order V2O5 > V2O3 > VO2.
21 Dissolved vanadium pentoxide (6 ^ig/ml) also reduces phagocytosis (Waters, 1977).
22 Respiratory effects in laboratory animals following acute inhalation of vanadium
23 compounds include increased pulmonary resistance and significantly increased
24 polymorphonuclear leukocytes in bronchioalveolar lavage fluid. These effects were observed
25 in monkeys 24 h following a 6-h inhalation exposure to 2,800 /xg/m3 vanadium/m3 as
26 vanadium pentoxide (Knecht et al., 1985). In addition, increased lung weight and alveolar
27 proteinosis were observed in rats after inhaling bismuth orthovanadate 6 h daily for
28 two weeks (Lee and Gillies, 1986). Rabbits exposed to high concentrations of vanadium
29 pentoxide dust for 1 to 3 days exhibited dyspnea and mucosal discharge from the nose and
30 eyes (Sjoberg, 1950). In a follow-up experiment, rabbits had difficulty breathing following a
31 daily 1-h exposure for 8 mo (Sjoberg, 1950).
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> TABLE 11-52. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
3 VANADIUM COMPOUNDS
\o Exposure
HH
AJ
H
6
0
2
o
H
O
d
s
w
o
w
H
W
Rat, UK CS, BW, HP of major organs: Nasal
(UK) discharge (sometimes containing blood),
difficulty breathing, dec BW; hemorrhages in
lung, heart, liver, kidney, brain. Fatty
degeneration in liver and kidney; edema,
bronchitis, focal interstitial pneumonia in
lungs. Effects mainly in lungs at low
concentration. Mild signs (not specified) of
toxicity at 2,800. "Absolute lethal
concentration" of 19,600. At high levels,
dysentery, paralysis of hind limbs, and
respiratory failure.
Note: Concentration at which effects seen
and form of V unclear from the available
literature
Roshchin
(1967a)
-------
TABLE 11-52 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
VANADIUM COMPOUNDS
U)
Exposure
Concentration Exposure
ppm /*g V/m3 protocol
NA 44,800- UK
392,000
NA 435,000 UK
Chemical Particle size and
form distribution
V2O5 dust UK "large
("grinding particles"
aerosol")
Ammonium UK
vanadate
presumably
as grinding
aerosol
(dust)
Species, Strain,
(Number) Sex Assays performed: Effect(s)
Rat, UK CS, BW, HP of major organs: Nasal discharge
(UK) (sometimes containing blood), difficulty breathing,
dec BW; hemorrhages in lung, heart, liver,
kidney, brain. Fatty degeneration in liver and
kidney; edema, bronchitis, focal interstitial
pneumonia in lungs. Effects mainly in lungs at
low concentration. At high levels, dysentery,
paralysis of hind limbs, and respiratory failure.
Note: Concentration at which effects seen and
form of V unclear from the available literature
Note: Described as one-fifth as toxic as the fume
Rat, UK CS, BW, HP of major organs: Nasal discharge
(UK) (sometimes containing blood), difficulty breathing,
dec BW; hemorrhages in lung, heart, liver,
kidney, brain. Fatty degeneration in liver and
kidney; edema, bronchitis, focal interstitial
pneumonia in lungs. Effects mainly in lungs at
low concentration.
Note: Concentration at which effects seen and
form of V unclear from the available literature.
Reference
Roshchin (1967a)
Roshchin (1967a)
Chronic Studies
NA 0 1 h/d
11,000- 8 mo
22,000
V2O5 30% by wt <5
/*m; 33 % by wt
<10/im; 67% by
wt > 10 jtim
Rabbit, NS CS, HP or major organs: Dyspnea, eye irritation
(12) NS at 800 jig/m3. Nasal discharge, laryngeal
irritation, bronchitis, emphysema. No fibrosis.
No significant kidney, GI, heart, or bone marrow
pathology. Some fatty degeneration of the liver,
which the authors attributed to infectious hepatitis.
Sjoberg (1950)
-------
TABLE 11-52 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
VANADIUM COMPOUNDS
H-t
(5J
i— '
i— '
i
VO
oo
M
^^
»>
»-j
6
o
2;
o
H
O
O
d
w
i
Q
H
W
Exposure
Concentration
ppm /ig V/m3
Chronic Studies
NA 0
1.2
15
NA 1,700
2,800
NA 5,600-
17,000
Abbreviations:
Exposure
protocol
"continuous"
70 d
2 h/every other
day
3 mo
2 h/every other
day
4 mo
BAL = bronchioalveolar lavage; BW =
mos = month; N/A
Chemical Particle size and Species, Strain,
form distribution (Number) Sex Assays performed: Effect(s)
V2O5 UK Rats, UK BW, motor chronaxy of extensor and flexor
fume (UK) muscles of tibia, serum biochemistry: No
effect on BW. Decreased motor chronaxie (a
measure of excitability) at 30 d and 7.6; no
effect at 1.2. Decreased blood cholinesterase,
serum protein at 15.
V2O5 UK Rat, UK CS, HP or major organs: Capillary
fume (UK) congestion, perivascular edema, hemorrhages
in lungs. Also focal edema and desquantitative
bronchitis in some cases, lymphocyte
infiltration of interstitial spaces, constriction of
small bronchi.
Note: Concentration at which effects seen
unclear from available literature.
V2O5 UK Rats, UK CS, HP or major organs: Capillary
dust (UK) congestion, perivascular edema, hemorrhages
in lungs. Also focal edema and desquantitative
bronchitis in some cases, lymphocyte
infiltration of interstitial spaces, constriction of
small bronchi.
Note: Concentration at which effects seen
unclear from available literature.
Reference
Pazynich (1966)
Roshchin (1967a)
Roshchin (1967a)
body weight; d = day; F = female; GI = gastrointestinal; h = hour; HP = histopathology; inc = increased; M = male;
= not applicable; NS = not specified; occup = occupational; PF = pulmonary function; UA = urinalysis; V = vanadium;
pentoxide; wk = week; WT = weight;
yr = years.
V2O5 = vanadium
-------
1 The effects of acute exposure to 5,600-39,200 /tg vanadium/m3 as vanadium pentoxide
2 fume or 44,800-392,000 /ig vanadium/m3 as vanadium pentoxide dust were investigated by
3 Roshchin (1967a); the exposure duration was not described in the available literature. For
4 vanadium pentoxide fume, "mild toxicity" occurred at 5,600 /-ig vanadium/m3, and deaths
5 were observed at the high level. The vanadium pentoxide dust was described as one-fifth as
6 toxic as the fume. Effects at the lower levels were mostly observed in the lungs. These
7 included irritation of respiratory mucosa, peri vascular and focal edema, bronchitis, and
8 interstitial pneumonia. Small hemorrhages were also observed in internal organs, along with
9 fatty degeneration of the liver and kidneys. In a subchronic experiment, rats were exposed
10 to vanadium pentoxide fume (1,700-2,800 /ig vanadium/m3) or vanadium pentoxide dust
11 (5,600-17,000 fig vanadium/m3) for 2 hours every other day for 3-4 months (Roshchin
12 1967a). Histopathological effects were limited to the lungs and were similar to those
13 observed following acute exposure. The study author concluded that vanadium inhalation
14 resulted in irritation of the respiratory mucosa, hemorrhagic inflammation, a spastic effect on
15 smooth muscle of the bronchi, and vascular changes in internal organs (at higher levels).
16 Similar effects were observed with the trivalent vanadium compounds vanadium trioxide and
17 vanadium trichloride, although vanadium trichloride caused more severe histological changes
18 in internal organs (Roshchin 1967b); further details were not available. This study also
19 reported disturbances of the central nervous system (impaired conditioned reflexes and
20 neuromuscular excitability) and electroencephalographic changes after inhalation exposure to
21 vanadium oxides or salts.
22 Rats exposed to vanadium pentoxide condensation aerosol (15 /ig vanadium/m3)
23 continuously for 70 days developed marked lung congestion, focal lung hemorrhages, and
24 extensive bronchitis (Pazynich 1966). Hemorrhage of the liver, kidneys, and heart, and
25 impaired neuromuscular excitability were also observed. There was no effect at 1.2 /ig
26 vanadium/m3. Rabbits exposed to vanadium pentoxide dusts exhibited fatty degeneration of
27 the liver (8-mo exposure), fatty degeneration of the kidney (acute or chronic exposure), and
28 conjunctivitis (acute or chronic exposure) (Sjoberg, 1950). No pathological changes in the
29 brain were observed in rabbits exposed to vanadium pentoxide for 8 mo (Sjoberg, 1950).
30 No studies were located regarding developmental effects, reproductive effects, or
31 cancer in laboratory animals following inhalation exposure to vanadium. Oral exposure to
April 1995 11-399 DRAFT-DO NOT QUOTE OR CITE
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1 sodium metavanadate resulted in no or slight developmental effects (Paternain et al., 1987;
2 Kowalska, 1988; Domingo et al., 1986). Oral studies using vanadium reported no significant
3 effects on fertility, reproduction, or parturition in rats (Domingo et al., 1986) or were
4 inadequate for evaluating carcinogenicity (Schroeder and Balassa, 1967; Schroeder and
5 Mitchener, 1975; Schroeder et al., 1970).
6
7 11.6.20.4 Factors Affecting Susceptibility
8 No data were located that identified subpopulations with heightened susceptibility to
9 vanadium. However, since the respiratory system is the main target of vanadium toxicity,
10 individuals with respiratory diseases would be expected to be more susceptible. The
11 developing respiratory tract of children may also increase susceptibility. There are also
12 indications that exposure to high levels may result in sensitization to lower levels (Zenz et al.
13 1962).
14 Data on systemic effects of vanadium are too limited to determine whether other
15 systems are also targets of vanadium toxicity. However, effects have been reported on the
16 liver, kidney, heart, and nervous system. If these are targets of vanadium, people with
17 impaired function may be more susceptible to vanadium toxicity.
18
19 11.6.21 Zinc
20 11.6.21.1 Chemical and Physical Properties
21 Zinc is a metallic element and belongs to Group 2B of the periodic system of elements.
22 Zinc forms all of its compounds with a valence of +2. The compounds formed by zinc are
23 all quite stable, and tend to be covalently bonded. However, compounds formed with highly
24 electropositive elements such as chlorine tend to be ionic (Lloyd, 1984). The most important
25 property of zinc is its high reduction potential toward other chemicals. Thus, oxidizing
26 elements such as oxygen, sulfur, and halides react with zinc at room temperature if moisture
27 is present, and at high temperatures in the absence of moisture. (Lloyd and Showak, 1984).
28 In nature, zinc usually occurs as the sulfide, but the oxide, carbonate and silicate may also be
29 mined (Lloyd, 1984). Evidence suggests that when zinc sulfide is exposed to the
30 atmosphere, it is oxidized to a more water-soluble form, zinc sulfate. Zinc exists as the +2
31 form in aqueous solution and exhibits amphoteric properties; it dissolves in acids to form
April 1995 11-400 DRAFT-DO NOT QUOTE OR CITE
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1 hydrated Zn+2 cations and in strong bases to form zincate anions (probably Zn[OH]4"2). At
2 the pH found in most natural waters, the formation of anionic zinc is not likely (Agency for
3 Toxic Substances and Disease Registry, 1994). Zinc metal is insoluble in water, whereas
4 zinc oxide (ZnO) and zinc sulfide (ZnS) are slightly soluble, zinc chloride (ZnCl2) is
5 moderatley soluble, and zinc sulfate (ZnSO4) is highly soluble.
6
7 11.6.21.2 Pharmacokinetics
8 There is limited information on the toxicokinetic properties of zinc following inhalation
9 exposure. Increased zinc levels in the blood and urine of humans and in the tissue of
10 laboratory animals after inhalation exposure to zinc indicate that zinc is absorbed by this
11 route. Once absorbed, zinc is widely distributed throughout the body. Zinc content is
12 highest in muscle, bone, gastrointestinal tract, kidney, brain, skin, lung, heart, and pancreas.
13 In plasma, two-thirds of the zinc is bound to albumin which represents the metabolically
14 active pool of zinc. This pool of plasma zinc is frequently referred to as loosely bound zinc
15 because albumin has the ability to give up bound zinc to tissues. Zinc is excreted in both
16 urine and feces.
17
18 Humans
19 The absorption of inhaled zinc depends on the particle size and solubility. Data are
20 limited to elevated levels of zinc found in the blood and urine of workers exposed to zinc
21 oxide fumes (Hamdi, 1969). Occupational studies provide indirect evidence that zinc may
22 distribute to tissues to produce systemic effects (Langham Brown, 1988; Drinker et al.,
23 1927a; Malo et al., 1990; McCord et al., 1926; Rohrs, 1957; Sturgis et al., 1972).
24 Zinc is one of the most abundant trace metals in humans. It is found normally in all
25 tissues and tissue fluids and is a cofactor in over 200 enzyme systems. Together, muscle and
26 bone contain approximately 90% of the total amount of zinc in the body ( = 60% and 30%,
27 respectively) (Wastney et al., 1986). Organs containing sizable concentrations of zinc are
28 the liver, gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas (Drinker and
29 Drinker, 1928; He et al., 1991).
30 Zinc is transported in the blood plasma, erythrocytes, leukocytes, and platelets, but is
31 chiefly localized within erythrocytes (of which 87% is in carbonic anhydrase, the major
April 1995 11-401 DRAFT-DO NOT QUOTE OR CITE
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1 binding site) (Ohno et al., 1985). Zinc deficiency has been demonstrated to decrease the
2 ability of erythrocytes to resist hemolysis in vitro. This finding suggests that zinc stabilizes
3 the erythrocyte membrane.
4 In plasma, two-thirds of the zinc is bound to albumin; the remainder is bound primarily
5 to a2-macroglobulin (Wastney et al., 1986). Plasma provides a metabolically active transport
6 compartment for zinc (Cousins, 1985), and zinc is most often complexed to organic ligands
7 (existing in loosely or firmly bound fractions) rather than free in solution as metallic ion
8 (Gordon et al., 1981). Zinc is found in diffusible or nondiffusible forms in the blood. In
9 the diffusible form, approximately two-thirds of plasma zinc is freely exchangeable and
10 loosely bound to albumin (Cousins, 1985); the zinc-albumin complex has an association
11 constant of about 106 (National Research Council, 1979). The diffusible form of zinc also
12 includes zinc bound to amino acids (primarily histidine and cysteine). The zinc-albumin
13 complex is in equilibrium with the zinc-amino acid complex (Henkin, 1974). The zinc-amino
14 acid complex can be transported passively across tissue membranes to bind to proteins. An
15 important binding protein in the kidney and liver is metallothionein, although other tissue-
16 binding proteins may be present.
17 In the nondiffusible form, a small amount of circulating zinc is tightly bound to
18 a2-macroglobulin in the plasma (Cousins, 1985). Zinc is incorporated into and dissociated
19 from a2-macroglobulin only in the liver (Henkin, 1974). This zinc-protein complex has an
20 association constant of > 1010 (Henkin, 1974; National Research Council, 1979). The zinc
21 bound to a2-macroglobulin is not freely exchangeable with other zinc ligands (i.e., zinc-
22 albumin and zinc-amino acid complexes) in serum.
23 The transfer of zinc across perfused placentas is slow; only =3% of maternal zinc
24 reached the fetal compartment in 2 hours (Beer et al., 1992). The in vitro transfer of zinc
25 between mother and fetus is bidirectional, with binding in the placenta (Beer et al., 1992).
26 Newborns may also be exposed to zinc from their mothers by milk transfer of zinc during
27 lactation (Rossowska and Nakamoto, 1992).
28 Information was limited regarding zinc excretion following inhalation exposure in
29 humans. Workers exposed to zinc oxide fumes had elevated levels of zinc in the urine
30 (Hamdi, 1969) indicating that this is a route of excretion.
31
April 1995 11-402 DRAFT-DO NOT QUOTE OR CITE
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1 Laboratory Animals
2 The rates or percentages of absorption of inhaled zinc in laboratory animals are not
3 available; however, studies provide data on zinc retention in the lungs. Zinc retention values
4 were 19.8%, 11.5%, and 4.7% in the lungs of guinea pigs, rats, and rabbits, respectively,
5 after inhalation exposure (nose-only) to 3,500 to 9,100 /^g zinc/m3 as zinc oxide aerosol for 2
6 to 3 h (Gordon et al., 1992). The retention of zinc in lungs was concentration-related in
7 male Wistar rats administered a single intratracheal instillation of 70 to 3,700 /-tg zinc/m3 as
8 zinc oxide (Hirano et al., 1989). A half-life of 14 h was calculated for this experiment.
9 The absorption of zinc oxide fumes led to increased levels of zinc measured in the
10 liver, kidney, and pancreas of cats exposed to zinc oxide fumes for durations ranging from
11 15 min to 3.25 h (Drinker and Drinker, 1928). The usefulness of the study is limited
12 because reporting was inadequate and particle size of the zinc oxide aerosol was not
13 determined. Some inhaled particles of zinc oxide are subject to ciliary clearance and
14 swallowing. Thus, a portion of the inhaled zinc may ultimately be absorbed from the
15 gastrointestinal tract. The presence of other trace metals (e.g., mercury, cadmium, copper)
16 may also diminish zinc transport. Zinc levels in the lungs of cats peaked immediately after
17 acute exposure to 12,000 to 61,000 ^ig zinc/kg/day as zinc oxide for approximately 3 h and
18 remained high for 2 days postexposure, then dropped significantly thereafter (Drinker and
19 Drinker, 1928). Levels in pancreas, liver, and kidneys increased slowly. No data were
20 located regarding the excretion pattern or rate of zinc in animals.
21
22 11.6.21.3 Health Effects
23 The majority of data available on zinc toxicity are human occupational and acute
24 laboratory animal studies. No chronic laboratory animal bioassays with zinc or its
25 compounds have been performed. Two epidemiological studies have reported no increased
26 incidence of cancers associated with occupational exposure to zinc (Logue et al., 1982;
27 Neuberger and Hollowell, 1982); however, some of the workers were also concurrently
28 exposed to copper.
29
30
April 1995 11-403 DRAFT-DO NOT QUOTE OR CITE
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1 Human Data
2 The major target organ of zinc toxicity appears to be the respiratory system as
3 demonstrated in experimental and occupational studies with acute exposure to zinc oxide
4 fumes or dust. Human toxicity data are summarized in Table 11-53. Heating zinc beyond
5 its boiling point in an oxidizing atmosphere produces ultrafme zinc oxide particles (0.2 to 1.0
6 )«m). Upon inhalation, these small particles (< 1 jim) reach the alveoli and cause
7 inflammation and tissue damage in the lung periphery (Langham Brown, 1988; Drinker et
8 al., 1927b; Vogelmeier et al., 1987).
9 There is a large amount of information on metal fume fever, an acute disease induced
10 by intense inhalation of metal oxides, especially zinc, that temporarily impairs pulmonary
11 function but does not progress to chronic lung disease; however, quantitative data are limited
12 (Langham Brown, 1988; Drinker et al., 1927b; Malo et al., 1990). Symptoms generally
13 appear within a few hours after acute exposure, usually with dryness of the throat and
14 coughing (Drinker and Drinker, 1927b). The most prominent respiratory effects of metal
15 fume fever are substernal chest pain, cough, and dyspnea (Rohrs, 1957). The impairment of
16 pulmonary function is characterized by reduced lung volumes and a decreased diffusing
17 capacity of carbon monoxide (Malo et al., 1990; Vogelmeier et al., 1987). The respiratory
18 effects have been shown to be accompanied by an increase in bronchiolar leukocytes
19 (Vogelmeier et al., 1987). The respiratory symptoms generally disappear in the exposed
20 individual within 1 to 4 days (Langham Brown, 1988; Drinker et al., 1927b; Sturgis et al.,
21 1927). A fever appearing 3 to 10 h after exposure to zinc oxide fumes and lasting
22 approximately 24 to 48 h is characteristic of metal fume fever caused by zinc (Mueller and
23 Seger, 1985).
24 The exact pathogenesis of metal fume fever from zinc exposures is not known. It is
25 believed to be an immune response to the inhaled zinc oxide (Mueller and Seger, 1985). It
26 has been suggested that the zinc oxide causes inflammation of the respiratory tract and the
27 release of histamine or histamine-like substances. In response, an allergic reaction may
28 occur upon subsequent exposure to the allergen. In response to the allergen-antibody
29 complex, an anti-antibody is formed. The anti-antibody dominates with continued exposure
30 to the zinc oxide, thereby producing tolerance. When the exposure is interrupted and
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TABLE 11-53. HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ZINC AND COMPOUNDS
3.
s
\*s
$
0
O
2*
s
O
el
1
Exposure
Concentration
ppm /—t
a
-------
TABLE 11-53 (cont'd). HUMAN EXPOSURE CONDITIONS AND EFFECTS FOR ZINC AND COMPOUNDS
vo
Ul
&
o
o
2
o
H
O
Exposure
Concentration
ppm
NA
NA
NA
/xg Zn/m3
3.6
8,000-
12,000
320,000-
580,000
53,000-
610,000
Exposure
protocol
2h
1-3 h
(occup)
3-5 h/d
2d
(occup &
experim)
Chemical Particle size and
form distribution
ZnSO4 • MMAD =
(NH4)2SO4 1.1 /urn
aerosol a. = 2.6
ZnO fumes* NS
ZnO NS
fumes*
Species, Strain,
(Number) Sex
Human
(21) NS
Human
NS
Human
(1)M
Assays performed: Effect(s)
Pulmonary function tests, symptoms:
Minimal substernal irritation and throat
irritation during exposure.
Symptoms: Nausea, chills, shortness of
breath and chest pains at 320,000-
580,000 fig/m3.
Note: Inadequate information on exposure
conditions.
Subjective symptoms and clinical tests: Mild
pain when breathing deeply and inc WBC
count at 430,000 jtg/m3.
Reference
Linn et al.
(1981)
Hammond
(1944)
Drinker et al.
(1927a)
Abbreviations:
CO = carbon monoxide; d = days; dec = decreased; hr = hours; inc = increased; LDH = lactate dehydrogenase; MMAD = mass median aerodynamic
diameter; NS = not specified; ag = geometric standard deviation of distribution; ZnSO4 (NH4)2SO4 = zinc ammonium sulfate (ambient metallic sulfate aerosol);
wk = week; wt = weight; ZnO = zinc oxide; ZnCl = zinc chloride.
Fumes refer to ultrafine zinc oxide particles originate from heating zinc beyond its boiling point in an oxidizing atmosphere.
**ZnCl produced from ZnO and hexachloroethane smoke.
n
HH
H
W
-------
1 re-exposure occurs, the response of the initial antibody dominates, producing an allergic
2 reaction and symptoms of metal fume fever (McCord, 1960).
3 Acute experimental exposures to low concentrations of zinc oxide (45,000 ^ig zinc/m3
4 for 20 min) and occupational exposures to similar concentrations (8,000 to 12,000 j*g
5 zinc/m3 for 1 to 3 h and 34 /*g zinc/m3 for 6 to 8 h) have not produced symptoms of metal
6 fume fever (Drinker et al., 1927b; Hammond, 1944; Marquart et al., 1989).
7 Exposure of subjects to 3,900 /*g zinc/m3 as zinc oxide resulted in sore throat and chest
8 tightness but no impairment of pulmonary function (Gordon et al., 1992). Nasal passage
9 irritation, cough, substernal chest pain, persistent rales of the lung base, and a decreased
10 vital capacity were observed in two volunteers =3 to 49 h following a 10 to 12 min
11 exposure to high levels of zinc oxide (Sturgis et al., 1927). Shortness of breath and chest
12 pains were also observed in individuals exposed to high acute concentrations of zinc oxide
13 fumes (Drinker et al., 1927a; Hammond, 1944). Minimal changes in forced expiratory flow
14 were observed 1 h after a 15 to 30-min exposure to 77,000 ^g zinc/m3 as zinc oxide (Blanc
15 et al., 1991). It is speculated that workers develop a tolerance to zinc following long-term
16 exposure to zinc oxide (Gordon et al., 1992), which may explain the lack of observation of
17 similar findings in chronic studies.
18 Zinc chloride, a corrosive inorganic salt, is more damaging than zinc oxide to the
19 mucous membranes of the nasopharynx and respiratory tract upon contact. Zinc chloride is a
20 primary ingredient in smoke bombs used by the military for screening purposes, crowd
21 dispersal, and occasionally in military and civilian fire-fighting exercises. Reports of serious
22 respiratory injury have been reported to result from accidental inhalation of smoke from
23 these bombs. These reports are of limited use in assessing the toxicity of zinc chloride
24 because exposure to other compounds, usually hexachloroethane, zinc oxide, and calcium
25 silicides, also occur. Furthermore, the specific concentrations inhaled are usually unknown.
26 Despite these limitations, several case studies have described similar respiratory effects in
27 humans following acute inhalation exposures. These effects include dyspnea, cough,
28 pleuritic chest pain, bilateral diffuse infiltrations, pneumothorax, and acute pneumonitis from
29 respiratory tract irritation (Johnson and Stonehill, 1961; Matarese and Matthews, 1966;
30 Schenker et al., 1981). In other studies, more severe effects have occurred, including
31 ulcerative and edematous changes in mucous membranes, fibrosis, subpleural hemorrhage,
April 1995 11-407 DRAFT-DO NOT QUOTE OR CITE
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1 advanced pulmonary fibrosis, and fatal respiratory distress syndrome (Evans, 1945; Hjortso
2 et al., 1988; Homma et al., 1992).
3 Zinc ammonium sulfate is a compound emitted during combustion of fossil fuels and is,
4 therefore, found in the ambient air. Humans acutely exposed to a concentration of 3.6 /zg
5 zinc/m3 as zinc ammonium sulfate for 2 hours exhibited minimal or no short-term respiratory
6 effects (Linn et al., 1981). However, no information was available about the health effects
7 associated with chronic exposures.
8 Hematological and immunological effects have also been associated with exposure to
9 zinc oxide. One of the hallmarks of metal fume fever is leukocytosis persisting for
10 approximately 12 hours after fever dissipates (Mueller and Seger, 1985). Such effects have
11 been observed in a number of case reports of occupational and experimental exposure of
12 humans to zinc oxide fumes (Langham Brown, 1988; Drinker et al., 1927a; Malo et al.,
13 1990; Rohrs, 1957; Sturgis et al., 1927). Increased leukocyte counts were observed
14 following acute experimental exposures to zinc oxide (Drinker et al., 1927a; Sturgis et al.
15 1927). These studies are limited because there was an inadequate number of subjects tested,
16 a lack of controls, and impurities in the zinc oxide.
17 Immunological effects following occupational exposure were reported in a group of 14
18 welders acutely exposed to 77,000 to 153,000 />ig zinc/m3 as zinc oxide. Significant
19 correlations were observed between the concentration of airborne zinc and the proportion of
20 activated T cells, T helper cells, T inducer cells, T suppressor cells, and activated killer T
21 cells (Blanc et al., 1991). In addition, significant increases in levels of polymorphonuclear
22 leukocytes, macrophages, and all types of lymphocytes were observed in the bronchoalveolar
23 lavage (BAL) fluid. Increased levels of lymphocytes, with a predominance of CDS cells, in
24 the BAL fluid were reported in a case study of a smelter exposed to unspecified levels of
25 zinc fumes (Ameille et al., 1992). Hives and angioedema developed in a man exposed to
26 zinc fumes at a zinc smelting plant (Farrell, 1987). The author suggested that the patient had
27 an immediate or delayed imimmoglobulin E (IgE) response (or both) after a low dose of zinc
28 fumes. Metal fume fever also resulted when the exposure was increased. The signs and
29 symptoms of toxicity were repeated in a challenge test.
30 There is no indication that zinc produces any reproductive or developmental effects in
31 humans following inhalation and oral exposures.
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1 Laboratory Animal Data
2 As with human exposure, the respiratory system is the primary site of injury following
3 inhalation exposure. The toxicity data for laboratory animals are summarized in
4 Table 11-54. Acute administration of zinc oxide to rats and rabbits resulted in the
5 pulmonary changes including congestion, various degrees of peribronchial leukocytic
6 infiltration, and exudate composed almost entirely of polymorphonuclear leukocytes in
7 bronchi (Drinker and Drinker, 1928). Cats similarly exposed exhibited more severe effects
8 including bronchopneumonia, leukocyte infiltration into alveoli, and grayish areas with
9 congestion, as well as labored breathing and evidence of upper respiratory tract obstruction.
10 Pulmonary function tests have been performed in Guinea pigs; results have been mixed.
11 A progressive decrease in lung compliance but no change in air flow resistance was observed
12 in guinea pigs following a 1-h exposure to low concentration of zinc oxide (730 pig zinc/m3)
13 (Amdur et al., 1982). These observations reflect a response in the lung periphery where
14 submicrometer aerosols are likely to deposit (Amdur et al., 1982). In contrast to the results
15 of Amdur et al. (1982), no effects on ventilation, lung mechanics (respiratory frequency,
16 tidal volume, pulmonary resistance, and pulmonary compliance), diffusing capacity of carbon
17 monoxide, or most lung volume parameters were observed by Lam et al. (1982) following
18 the exposure of guinea pigs to higher concentration of zinc oxide (6,300 /ig zinc/m3) for 3 h.
19 However, functional residual capacity was significantly decreased. The discrepancy between
20 the results may be attributable to the use of anesthetized animals by Lam et al. (1982). Lam
21 et al. (1985) observed functional changes (increased flow resistance, vital capacity, decreased
22 lung compliance, and decreased diffusing capacity) in guinea pigs exposed to 3,700 to 5,600
23 fj.g zinc/m3 as zinc oxide for 5 to 6 days (Lam et al., 1985; 1988); however, no effects were
24 observed in guinea pigs exposed to 2,200 pg zinc/m3. These effects have been seen in the
25 guinea pig at exposure levels lower than in humans, probably due to structural differences in
26 the lungs. The bronchi and peripheral airways of guinea pigs have a thicker smooth muscle
27 layer and only a small surface area covered by alveolar sacs compared to the bronchi and
28 peripheral airways of other laboratory animals and humans. This makes the guinea pig more
29 susceptible than other laboratory animals to functional impairment of the peripheral airways
30 (Lam etal., 1982).
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I
t— 1
VO
S
H- »
1— '
0
O
i
H
O
2
^-^
0
H
O
O
a
O
0
3
TABLE 11-54. LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ZINC
AND COMPOUNDS
Exposure
Concentration Exposure
ppm /ig Zn/m3 protocol
Acute Studies
NA 0 3 h/d
2,200 1 d
5,400
NA 0 2 h/d
4,600 1 d
NA 0 3 h/d
2,200 1 d
4,500
NA 0 3 h/d
1,800 1-3 d
4,700
9,700
NA 0 3 h/d
2,200 5 d
5,600
Chemical Particle size and
form distribution
ZnO MMAD =
(nose-only) 0.17 /mi
ffg = 1.8
ZnO MMAD =
(nose-only) 0.17 /mi
ag = 1.8
ZnO MMAD =
(nose-only) 0.1 7 /mi
°g = L8
ZnO Area diam =
(nose-only) 0.05 /im
(estimated)
(7=2
ZnO Area diam =
(nose-only) 0.05 /mi
(estimated)
-------
a.
TABLE 11-54 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR ZINC
AND COMPOUNDS
Exposure
Concentration
ppm
Zn/m3
Exposure
protocol
Chemical
form
Particle size and
distribution
Species, Strain,
(Number) Sex
Assays performed: Effect(s)
Reference
NA
0
3,700
4,300
3h/d
6d
ZnO Area diam = 0.05 Guinea pig,
(nose-only) /im (estimated) Hartley
a, = 2 (18-38) M
Pulmonary function tests (3,700 /xg/m3 only): Lam et al.
Impaired lung function (dec compliance and (1985)
lung volume, inc pulmonary resistance, dec CO
diffusing capacity).
Respiratory epithelial permeability,
morphologic examination of respiratory tract,
and DNA synthesis in epithelial cells of
bronchi and terminal bronchioles (4,300 /xg/m3
only): Inc lung weight; inflammation, and
increased interstitial thickening, fibroblasts, and
interstitial infiltrates.
£
K-
>
H -
6
o
H
0
o
H
W
NA 0
6,300
NA 730
Subchronic Studies
NA 0
1,300
12,800
121,700
3h
1 h
1 h/d
5d/wk
20 wk
(Brno
postexp.)
ZnO Area diam = 0.05
/im (estimated)
ffg = 2
ZnO Mean geom. size
(head-only) = 0.0056-1 /tin
ZnCl** MMAD = 2 /im
( 1.92-2. 04 /im)
Zn content of
impact material
was 20% (w)
Guinea pig,
Hartley
(10-16) M
Guinea pig,
Hartley
(7)M
Rat, Porton-
Wistar
(50) F
Pulmonary function tests (anesthetized
animals): Dec functional residual capacity.
Pulmonary mechanics (e.g., intrapleural
pressure, tidal volume, compliance): Dec
pulmonary compliance, followed by inc during
2-h postexposure.
Body and organ wt, clinical signs,
histopathology: Inc macrophages in lungs at
121,700 /ig/m3.
Lam et
(1982)
Amdur
(1982)
al.
et al.
Marrs et al.
(1988)
s
-------
1
5
Ul
TABLE 11-54 (cont'd). LABORATORY ANIMAL EXPOSURE CONDITIONS AND EFFECTS FOR
AND COMPOUNDS
Exposure
Concentration
ppm /ig Zn/m3
NA 0
1,300
12,800
121,700
Exposure
protocol
1 h/d
5d/wk
20 wk
(13 mo
postexp.)
Chemical Particle size and
form distribution
ZnCl" MMAD = 2 /un
(1.92-2.04 urn)
Zn content of
impact material
was 20% (w)
Species, Strain,
(Number) Sex,
Mouse, Porton
(98-100)F
Assays performed: Effect(s)
Body and organ wt, clinical signs,
histopathology: inc incidence of fatty change
in liver at 12,800 /ig/m3 (not clear cone-
related), macrophage infiltration in lungs (0/78,
2/74, 2/76, 5/50) and alveogenic carcinoma
(6/78, 7/74, 8/76, 15/50) at 121,700 jtg/m3.
ZINC
Reference
Marrs et al.
(1988)
NA
0
1,300
12,800
119,300
Ih/d
5d/wk
<20 wk
(13 mo
postexp.)
ZnCl MMAD = 2 ^m
(1. 92-2.04 pan)
Zn content of
impact material
was 20% (w)
Guinea pig,
Dunkin-Hartley
(49-50) F
Body and organ wt, clinical signs,
histopathology: No effects in survivors.
Emphysema, alveolitis, congestion, minimal
fibrosis in respiratory system of high-
concentration animals that died during
exposure.
Marrs et al.
(1988)
Abbreviations:
CO = carbon monoxide; d = days; dec = decreased; h = hours; inc = increased; LDH = lactate dehydrogenase; MMAD = mass median aerodynamic diameter;
NS = not specified;
-------
1 The BAL fluid of rats or guinea pigs exposed acutely to zinc contained increased levels
2 of lactate dehydrogenase and protein, suggesting effects on cell viability or membrane
3 permeability (Gordon et al., 1992), and elevated angiotensin converting enzyme and
4 neutrophils (Conner et al., 1988). Increased levels of 0-glucuronidase, suggesting a change
5 in macrophage function, was also evident in BAL fluid (Gordon et al., 1992). In rabbits
6 treated with similar acute exposure conditions, no effects were observed.
7 Morphological changes in the lungs were observed in Guinea pigs exposed to
8 =4,000 /xg zinc/m3 as zinc oxide for an acute duration (Conner et al., 1988; Lam et al.,
9 1985). Effects included increased lung weight, inflammation involving the proximal portion
10 of alveolar ducts and adjacent alveoli, interstitial thickening, inflammation, and increased
11 pulmonary macrophages and neutrophils in adjacent air spaces. In Guinea pigs with evidence
12 of an inflammatory reaction involving the peripheral airways, DNA synthesis increased in
13 bronchiolar cells.
14 In longer duration studies, focal alveolitis, consolidation, emphysema, infiltration with
15 macrophages, and fibrosis were observed in Guinea pigs that died following exposure to high
16 concentrations of zinc chloride smoke for 3 weeks (Marrs et al., 1988). In rats and mice,
17 increased macrophages in the lungs occurred 13 months after a 20-week inhalation exposure
18 to similar levels of zinc chloride smoke (Marrs et al., 1988). The smoke also contained zinc
19 oxide, hexachloroethane, and other compounds.
20 An increased incidence of alveologenic carcinoma was reported in female mice 13
21 weeks after intermittent exposure to 121,700 /*g zinc/m3 as zinc chloride for 20 weeks
22 (Marrs et al., 1988). Guinea pigs and rats were also tested with similar dose levels, but no
23 significant carcinogenic response was observed. A number of factors limits the usefulness of
24 this study, including the presence of several compounds in the smoke that may have
25 carcinogenic potential, the use of only female animals, and the short duration of the exposure
26 period.
27 In mice, significant increases in the incidence of fatty liver were observed with
28 exposure to zinc chloride smoke for 20 weeks; however, the incidence did not increase with
29 concentration (Marrs et al., 1988). The smoke contained other compounds in addition to
30 zinc chloride. No adverse effects were observed in rats and guinea pigs at similar
31 concentrations of zinc chloride smoke.
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1 No adverse effects were seen in the mammary glands, ovaries, fallopian tubes, or uteri
2 of rats, mice, and guinea pigs following inhalation of zinc chloride smoke for 20 weeks
3 (Marrs et al., 1988). Although no inhalation developmental studies were available, oral
4 studies report increased fetal resorptions, reduced fetal weights, and reduced growth in
5 offspring following high level exposure to zinc in the diet prior to and/or during gestation
6 (Agency for Toxic Substances and Disease Registry, 1994).
7
8 11.6.21.4 Factors Affecting Susceptibility
9 No specific data regarding human subpopulations that are unusually susceptible
10 to the toxic effects of zinc were located. Because the respiratory tract is the major target
11 organ of zinc, individuals with respiratory difficulties or the developing respiratory of
12 children may be more susceptible to the toxic effects of zinc (Gordon et al. 1992; Hammond
13 1944). Data from laboratory animal studies indicate that certain human subpopulations may
14 be more susceptible to excess zinc because of zinc's depleting effect on copper (Underwood
15 1977). People who are malnourished or have a marginal copper status may be more
16 susceptible to the effects of excessive zinc than people who are adequately nourished
17 (Underwood 1977).
18 Hepatic zinc levels are elevated in patients with hemochromatosis, a genetic disease
19 associated with increased iron absorption from the intestine (Adams et al. 1991). The
20 chronic iron loading that occurs could result in hepatic metallothionein induction leading to
21 the accumulation of zinc because metallothionein has a greater affinity for zinc than iron.
22 These individuals may, therefore, have a greater likelihood of developing toxicity with zinc
23 exposure levels that do not normally result in any symptoms in the general population.
24
25
26 11.7 SILICA
27 This section on silica particle toxicity as well as the section on asbestos fibers is
28 designed to give an overview of current concepts regarding the pulmonary toxicity of these
29 environmental pollutants as they relate to different species, different polymorphs (crystalline
30 vs. amorphous), and biological mechanisms of action. No attempt has been made to review
31 all of the relevant toxicity data, which is voluminous. Silica is well established as a
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1 fibrogenic pollutant which also causes lung tumors following chronic exposures in
2 experimental animals. An review of the literature on the non-cancer effects of silica can be
3 found elsewhere (U.S. Environmental Protection Agency, 1995).
4 The pulmonary response to occupational concentrations of inhaled silica has long been
5 considered to be a major occupational hazard, causing disability and deaths among workers
6 in a variety of industries. Some of the processes and work environments which are
7 frequently associated with silica exposure include mining, sandblasting using abrasive
8 materials, quarrying and tunneling, stonecutting, glass and pottery manufacturing, metal
9 casting, boiler scaling, and vitreous enameling (Ziskind et al., 1976).
10
11 11.7.1 Physical and Chemical Properties
12 Silica particle emissions in the environment can arise from natural, industrial, and
13 farming activities. There is only limited data on ambient air concentrations of either
14 crystalline or amorphous silica particles, due in part, to the limits in accurately quantifying
15 crystalline silica and to the inability, under existing measurement methods, of separating the
16 identity of crystalline silica from other paniculate matter. Davis et al. (1984) used X ray
17 fluorescence and mass calibration methods of X ray diffraction to determine the inhalable
18 composition and concentration of quartz in ambient aerosols collected on dichotomous filters
19 at 25 U.S. metropolitan areas. They reported the average weight percent of quartz in the
20 coarse and fine particle mass to be 4.9 (+ 2.3) and 0.4 (± 0.7), respectively. Combining the
21 weight percent data for the coarse fraction and 7 year average annual arithmetic mean PM10
22 information available for 17 of the 25 areas, annual average and high U.S. ambient
23 metropolitan quartz levels of 3 and 8 j^g/m3, respectively, have been estimated (U.S.
24 Environmental Protection Agency, 1995). The actual fraction of quartz in the PM coarse
25 samples may be slightly lower than that which was estimated by Davis et al. (1984) in the
26 coarse fraction, however, due to the large number of sources and widespread emissions,
27 there is some potential for some silica particles to be in the fine mode (U.S. Environmental
28 Protection Agency, 1995).
29 Silica is one of the most common substances to which workers are exposed. There are
30 two physical forms of silica (i.e., crystalline and amorphous), with at least four polymorphs
31 or forms of crystalline silica. These include quartz, cristobalite, tridymite, and tripoli.
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1 Although identical chemically, they differ from quartz in their crystal parameters. The basic
2 structural units of the silica minerals are silicon tetrahedra, arranged in such a manner so that
3 each oxygen atom is common to two tetrahedra. However, there are considerable differences
4 in the arrangements of the silicon tetrahedra among the various crystalline forms of silica
5 (Coyle, 1982). Naturally occurring rocks that contain amorphous forms of silica include
6 diatomite or diatomaceous earth, a hydrated form such as opal, and an unhydrated form, flint
7 (Stokinger, 1981). Silica is also a component of many naturally occurring silicate minerals
8 in which various cations and anions are substituted into a crystalline silica matrix. Examples
9 of such silicates are kaolin, talc, vermiculite, micas, bentonite, feldspar, and Fuller's earth
10 (Silicosis and Silicate Disease Committee, 1988). Commonly encountered synthetic
11 amorphous silicas, according to their method of preparation, are SiO2 gel (silica G),
12 precipitated SiO2 (silica P), and fumed SiO2 (silica F). The most outstanding characteristics
13 of synthetic amorphous silicas are their particle size and high specific surface area, which
14 determine their numerous applications (Stokinger, 1981).
15
16 11.7.2 Health Effects
17 The causal relationship between inhalation of occupational levels of dust containing
18 crystalline silica and pulmonary inflammation and the consequent development of silica-
19 induced pulmonary fibrosis (i.e., silicosis) is well established (Spencer, 1977; Morgan et al.,
20 1980; Bowden and Adamson, 1984). During the acute phase of exposure, a pulmonary
21 inflammatory response develops and may progress to alveolar proteinosis and a
22 granulomatous-type pattern of disease in rats and other rodent species. A pattern of nodular
23 fibrosis occurs in chronically exposed laboratory animals and humans (Ziskind et al., 1976;
24 Spencer, 1977; Morgan et al., 1980; Bowden and Adamson, 1984). Although there is
25 experimental and some human evidence that quartz can also cause lung cancer, a clear
26 correlation between pulmonary fibrosis and neoplasia has been suggested but has not been
27 definitively established. Acute high occupational exposures can elicit a rapid onset of lung
28 inflammation, lead to serious, if not fatal, lung dysfunction.
29 The pulmonary morphological effects of inhaled crystalline silica are well established,
30 however, there is a paucity of information on the respiratory tract effects of inhaled
31 amorphous forms of silica. The limited information available suggests that the respiratory
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1 tract effects following exposures to amorphous silicates may be reversible in the absence of
2 continuing exposures (Groth et ah, 1981; Schepers, 1981; Gosicki et ah, 1978; Pratt, 1983).
3 Thus, current evidence infers that amorphous silica is not as severe a hazard as the various
4 polymorphs of crystalline silica.
5 Parameters which have been commonly used to assess the respiratory effects of silica
6 exposure in experimental animals include lung weight, development of pulmonary flbrosis, or
7 biomarkers for fibrosis, such as collagen content, cytotoxicity, respiratory inflammation,
8 biochemical indices of homogenized lung samples or BAL samples, and immunologic
9 responses. Few studies have provided exposure-response data from which definitive effect
10 levels could be derived, thus necessitating comparisons among studies in which experimental
11 conditions may vary considerably. A review of the published laboratory animal toxicology
12 studies is available (U.S. Environmental Protection Agency, 1995).
13
14 11.7.2.1 Differences Between Chemical Forms of Silica
15 A few studies have been carried out to compare the effects of inhaled crystalline and
16 amorphous silica particles. Pratt (1983) exposed guinea pigs to atmospheric suspensions of
17 either crystalline silica in the form of cristobalite, to amorphous diatomaceous earth, or to
18 amorphous volcanic glass for 21 to 24 mo. The index of lung effects was substantially
19 higher for the cristobalite-exposed animals when compared to guinea pigs exposed to the
20 other two polymorphs of amorphous silica particles (Pratt, 1983). Hemenway et ah (1986)
21 exposed rats for 8 days to aerosols of one of three silicon dioxide species, a-cristobalite, a-
22 quartz, and amorphous silica particles. The greatest measure of lung injury was produced
23 with cristobalite, which caused substantial inflammation and flbrosis. Exposures to a-quartz
24 produced intermediate effects, while amorphous silica produced only minimal pulmonary
25 effects. The authors concluded that amorphous silica particles were less toxic than the two
26 different species of crystalline silica polymorphs. In support of the results of Hemenway
27 et ah, Warheit and coworkers (1991a) carried out a number of short-term inhalation studies
28 using cristabolite, quartz, Ludox colloidal silica, a form of precipitated amorphous silica, and
29 amorphous silica particles in the form of Zeofree 80. Rats were exposed to silica aerosols
30 for periods ranging from 3 days to 4 weeks and evaluated by bronchoalveolar lavage and
31 cellular proliferation indices at several postexposure tune periods. Brief exposures to
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1 2 different forms of crystalline silica particles at 100,000 jig/m3 produced persistent
2 pulmonary inflammatory responses, characterized by PMN recruitment and consistent
3 elevated biomarkers of cytotoxicity in BAL fluids. Progressive histopathologic lesions
4 previously were observed within 1 mo after a 3-day exposure (Warheit et al., 1991a). In
5 contrast, a 3-day exposure to amorphous silica, Zeofree 80 particles produced a transient
6 pulmonary inflammatory response, and 2 or 4-week exposures to Ludox elicited pulmonary
7 inflammation at 50 or 150 mg/m3 but not at 10 mg/m3. Most biochemical parameters
8 returned to control values following a 3-mo recovery period. These results demonstrated that
9 the crystalline forms of silica dust were much more potent in producing pulmonary toxicity
10 in comparison to amorphous or colloidal forms of silica, which generally produced transient
11 pulmonary effects (Warheit et al., 1991a, 1991b, 1995).
12
13 11.7.2.2 Species Differences
14 It seems clear that the fibrogenic effects of crystalline silica exposure may vary
15 depending on the species used in experimental studies. Rats appear to be more sensitive to
16 the development of silica-induced lung injury when compared to other mice and hamsters.
17 For example, Uber and McReynolds (1982) reported that hamsters were more resistant to the
18 effects of silica when compared to other rodent species. In addition, Warheit et al., (1994)
19 reported that inhalation exposure to silica in complement-normal and complement-deficient
20 mice produced an acute pulmonary inflammatory response which was mild and transient,
21 compared to the pulmonary effects observed in rats wherein silica produced a sustained and
22 progressive pulmonary inflammatory response. In support of these results, mice
23 intratracheally injected with silica particles had a milder fibrogenic response when compared
24 with rats (Hatch et al., 1984). It seems clear, however, that the silica-induced response in
25 mice depends upon the strain, as there appear to be low and high responding strains of mice
26 to silica (Callis et al., 1985; Hubbard, 1989).
27 Differences are not only apparent across and within rodent species, but also between
28 rodents and humans. Unlike the nodules observed in human X rays, silicosis is manifested in
29 rat X rays as a diffuse "haziness," described as a ground-glass appearance with some
30 peripheral striation (Drew and Kutzman, 1984). In a chronic study by Muhle et al. (1989),
31 the principal nonneoplastic finding in the silica-exposed rats, extensive subpleural and
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1 peribronchiolar fibrosis, was described as being unlike the nodular fibrosis seen in human
2 silicosis. Such interspecies differences and the fact that most of the available laboratory
3 animal studies only examined one dose level may limit the use of laboratory animal data for
4 extrapolation of the silicosis risk observed in higher exposure conditions of human
5 occupational studies. Fortunately, recent documentation of several well conducted human
6 studies obviates the need to rely exclusively on extrapolation from laboratory animal data.
7 Table 11-55 summarizes the four epidemiologic studies reviewed. A more complete
8 review of these and other relevant human studies is available elsewhere (U.S. Environmental
9 Protection Agency, 1995). Because of the size of the cohorts, the use of similar longitudinal
10 retrospective study designs, and the use of a similar, high quality statistical approach to the
11 representation of silicosis risk from silica exposure, the studies of white South African gold
12 miners and Canadian hardrock miners are considered the most reliable basis for an
13 assessment of silicosis risk at low exposure levels. A 70-year continuous exposure to the
14 average and high estimates of ambient U.S. quartz levels (3 and 8 /*g/m3) would result in
15 approximate occupational equivalent cumulative silica exposures of 0.6 and 1.6 /*g silica/m3
16 x years, respectively (U.S. Environmental Protection Agency, 1995). Both the South
17 African and Canadian studies predict a silicosis risk of 0% for a cumulative silica exposure
18 of 0.6 mg/m3 x years.
19 The estimates of cumulative risk from these two studies quickly diverge at higher
20 cumulative exposures. At 1.6 mg/m3 x years, the South African study predicts a 2% and
21 the Canadian study predicts a 0.4% cumulative silicosis risk. Even greater divergence
22 occurs at higher exposure levels. An indication that the South African results may be more
23 representative of the true shape of the dose-response curve is given by the results of other
24 studies in the United States and Hong Kong. Muir et al. (1989b) suggest that the data from
25 studies of Vermont granite miners (Theriault et al., 1974) suggest that "...the true probability
26 of developing category 1 [on the ILO, 1972 scale] pneumoconiosis after 46 years of exposure
27 to 0.05 mg/m3 of respirable silica [a 2.3 mg/m3 X years cumulative exposure] might be
28 about 30%." Ng and Chan (1994) reported that 24% of the X rays of Hong Kong granite
29 workers that received an average cumulative silica exposure of 1.9 mg/m3 x years contained
30 rounded opacities indicative of silicosis. These estimates of risk are well above the < 1 %
31 cumulative risk of silicosis predicted by Muir et al. (1989b) for a cumulative exposure of
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TABLE 11-55. SUMMARY OF OCCUPATIONAL STUDIES OF SILICOSIS RISK
D
O
2
O
H
O
d
o
a
§
o
HH
H
W
Study Type Study Population
Health Effect
% Silica
(Quartz)
3 fig Q/M3
Risk (%)a
8 Mg Q/M3
Risk (%)a
Reference
LRC 2235 South African miners; started after
1938 & worked > 10 yrs; followed to
1991
LRC 2109 Canadian miners; started 1940-1959;
followed to 1982 or end of exposure
XRC 338 Hong Kong granite workers; 132 past
workers (1967-1985) and 206 current
workers (1985); only most recent X rays
examined
CC U.S. (North Carolina) dust trade workers
diagnosed with silicosis 1935-1980
313 cases of Silicosis 30%
(ILO > 1/1)
32 cases of silicosis
(ILO > 1/1)
36 radiographical
abnormalities, rounded
opacities (ILO > 1/1)
216 cases of silicosis; 1-50%
672 controls
2%
6-8.4%
27%
0%
6%
0.4%
10%
Hnizdo & Sluis-Cremer
(1993)
Muir et al. (1989a,b);
Verma et al. (1989)
Ng and Chan (1994)
Rice et al. (1986)
CC - Case-Control L - Longitudinal RC - Retrospective Cohort X - Cross-Sectional Q - Quartz
aTo obtain risk estimates for continuous lifetime exposures of 3 and 8 /*g Q/m3 from occupational studies, these ambient levels were converted to equivalent
cumulative occupational exposure levels of 0.6 and 1.6 mg/m3 x years (U.S. Environmental Protection Agency, 1995).
bA dose-response curve was not reported. The no measureable effect level of 80-100 /tg/m3 reported by Rice et al. (1986) represents number of cases in the group
exposed to this amount did not significantly differ relative to number of cases observed in the reference group. However, risk among the reference group was
notO.
2
Source: Adopted from Rice et al. (1993).
-------
1 2 mg/m3 X years, but are consistent with the 10% risk and the shape of the dose-response
2 curve reported by Hnizdo and Sluis-Cremer (1993) for South African gold miners (U.S.
3 Environmental Protection Agency, 1995). Also, a recently completed Italian study of male
4 workers employed in the ceramics industry (Cavariani et al., 1995) reports a 48% cumulative
5 risk of silicosis (95% confidence interval 41.5 to 54.9) after 30 years of employment (past
6 exposure levels not given, but estimated to be 3 to 5 times higher then the current 0.1 mg/m3
7 standard). The authors reported that their risk estimates were higher than those predicted by
8 Muir et al. (1989b), but "...consistent with the findings among South African gold miners."
9 Rice et al. (1993) have suggested that the differences in the South African and
10 Canadian studies at higher cumulative exposures are likely the combined result of several
11 factors, including differences in the definition of radiographic silicosis used in the two
12 studies, possible errors in exposure estimates, possible underestimation of the quartz content
13 of the dust in the Canadian study, inhalation of aluminum dust as a protective measure by
14 Canadian miners, reader variability, and the use of cumulative exposures to estimate risk.
15 These and other issues, such as the importance of tracking worker health beyond
16 employment, the quality of radiographs and the importance of surface properties, particle
17 size, distribution, and percentage of silica in the respirable dust fraction are discussed
18 elsewhere (U.S. Environmental Protection Agency, 1995).
19
20 11.7.3 Recent Concepts in the Mechanisms of Silica-related Lung Disease
21 Exposures to crystalline silica are associated with the development of chronic
22 inflammation and pulmonary fibrosis (i.e., silicosis) in humans (Ziskind et al., 1976;
23 Spencer, 1977; Sargent and Morgan, 1980) and in experimental animals (Allison et al.,
24 1966; Ziskind et al., 1976; Burns et al., 1980; Morgan et al., 1980; Lugano et al., 1982;
25 Donaldson et al., 1988). The pathogenetic mechanisms of silica-induced lung injury have not
26 been fully elucidated, however, it is generally considered that both alveolar and interstitial
27 macrophages play important roles in the development of this disease (Bowden, 1987). In this
28 regard, the fibrogenic stimulus of crystalline silica particles has been attributed, in part, to
29 the rupture of macrophage plasma and lysosomal membranes followed by the subsequent
30 synthesis and secretion of fibroblast proliferating factors (Allison et al., 1966; Reiser and
31 Last, 1986; Bowden, 1987; Brown et al., 1988). However, the continuous recruitment of
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1 flbroblasts, PMNs, lymphocytes, and plasma cells to alveolar and interstitial sites, as well as
2 the multifocal distribution of lesions, suggests that the development of silica-related
3 pulmonary lesions is a complex process. The Type 1 epithelial injury and consequent
4 hypertrophic and hyperplastic responses of Type 2 epithelial cells is probably an important
5 component of the fibrogenic process. Alternatively, the sequestration of silica-containing
6 lipid-filled, foamy AMs within alveoli is an example of an effect that may be independent of
7 the fibrogenic process (Warheit and Gavett, 1993).
8 The role of growth factor regulation of pulmonary cells in the development of
9 particle-related pulmonary fibrosis has been described in numerous reviews (Crouch, 1990;
10 Goldstein and Fine, 1986; King et al., 1989, Kovacs, 1991; Reiser and Last, 1986; Rom
11 et al., 1991). Briefly, it is generally considered that competence factors and progression
12 factors play important roles in facilitating the movement of cells through the cell cycle.
13 Competence factors, such as platelet-derived growth factor (PDGF) and fibronectin, prime
14 cells to respond to additional factors such as progression factors (e.g. interleukin-(IL)-!, and
15 insulin-like growth factor (IGF), which initiate DNA synthesis and mitosis. Pulmonary
16 macrophages synthesize and secrete numerous growth factors for fibroblasts, including
17 PDGF, transforming growth f'actor-0 (TGF-/3), IL-1, tumor necrosis factor-a (TNF-a), IL-6,
18 fibroblast growth factor (FGF) (Kovacs, 1991). Proliferation of interstitial flbroblasts and
19 consequent synthesis and secretion of collagen is thought to play a significant role in the
20 fibrogenic process (Warheit and Gavett, 1993).
21 Inhalation of high concentrations of crystalline silica particles in rats is known to
22 cause a sustained pulmonary inflammatory response. It appears that the development of
23 pulmonary inflammation and the corresponding release of inflammatory mediators are
24 necessary, but not always sufficient for the development of fibrosis (Crouch, 1990). This
25 conclusion is based upon the observation that the temporal onset of inflammatory cells in the
26 lung always precedes the development of pulmonary fibrosis.
27 The role of PMNs, which form a major component of the acute inflammatory
28 response to silica, in the development of silica-related lung injury has not been established.
29 A short-term inhalation bioassay (Warheit et al., 199la) was used to assess the contribution
30 of PMNs to lung injury induced by the inhalation of silica particles (Gavett et al., 1992). In
31 this study male CD rats were depleted of PMNs by intraperitoneal administration of
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1 anti-PMN serum immediately prior to the first and third days of a 3-day exposure to silica
2 (100,000 /ig/m3). There were no significant differences in biomarkers of lung injury
3 between normal and PMN-depleted, silica-exposed groups, measured in BAL fluids
4 immediately or 1 day following the 3-day exposure. These results were in contrast with the
5 data reported by Henderson and coworkers (1991) who studied the effects of PMN depletion
6 on silica-induced lung injury in female Fischer rats. These investigators found that depletion
7 of blood leukocytes one day prior to instillation of quartz particles caused a reduction in BAL
8 fluid markers of permeability and cytotoxicity. In this study, administration of anti-PMN
9 serum reduced numbers of AMs to one-third of their normal numbers. This reduction of
10 AM numbers was not however observed in the study of Gavett et al. (1992), and this may
11 indicate that AM release of cytotoxic proteases contributes significantly to lung injury
12 following exposure to crystalline silica particles.
13
14
15 11.8 ASBESTOS
16 This section on asbestos fibers is designed to give an overview of current concepts
17 regarding the pulmonary toxicity of this environmental pollutant and underlying mechanisms
18 of action. No attempt has been made to review all of the relevant toxicity data, which is
19 voluminous. Asbestos is well established as a fibrogenic pollutant and causes tumors
20 following chronic exposures in experimental animals. Reviews on the effects of asbestos can
21 be found elsewhere (U.S. Environmental Protection Agency, 1986; Mossman and Gee, 1989)
22 (Rom, Travis and Brody, 1991; Health Effects Institute - Asbestos Research, 1991).
23
24 11.8.1 General Characteristics
25 Asbestos fibers are ubiquitous atmospheric pollutants in the environment which have
26 been present in airborne concentrations for centuries. Evidence for the widespread nature of
27 asbestos can be found by the confirmation of fiber deposition recovered from Antarctic ice
28 samples (Kohyania, 1989). According to NIOSH and WHO counting rules, only fibers
29 greater than 5 /xm in length qualify for measurement. Using these criteria, mean fiber
30 concentrations of 0.0005 fibers/cc of air (f/cc) have been measured in rural areas. In urban
31 areas, total fiber concentrations of 0.002 f/cc greater than 5 /mi in length have been
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1 reported (Health Effects Institute - Asbestos Research, 1991). Fiber concentrations in
2 suburban areas are roughly an order of magnitude lower than in urban areas. As might be
3 expected, industrial sites or sites in close proximity to asbestos sources have higher fiber
4 counts than normal urban areas (Corn, 1994). The vast majority of asbestos fibers in
5 outdoor air are less than 5 jum in length (Health Effects Institute - Asbestos Research, 1991).
6 To summarize, the presence of asbestos fibers in the air is universal and all humans have a
7 significant numbers of fibers in their respiratory system.
8
9 11.8.1.1 Types of Asbestos
10 Asbestos fibers are usually identified as a family of crystalline hydrated silicates that
11 have a diameter of < 3.5 /xm and an aspect ratio of more than 3:1 (ratio of length to
12 diameter) which confers them with a fibrous geometry. The term asbestos does not refer to
13 a common mineralogical designation, but to a commercial one, as the six different asbestos
14 minerals are physically distinct types of minerals. There are two major groups of asbestos
15 materials, 1) the serpentine group, which contains curly chrysotile fibers, accounting for
16 95% of the world's production of asbestos; and the amphibole group which is generally
17 needlelike in shape and contains the five other types of asbestos fibers, namely crocidolite,
18 amosite, anthophyllite, tremolite, and actinolite (Mossman and Gee, 1989).
19 Long-term exposure to asbestos fibers in humans and experimental animals clearly
20 has been associated with the development of pulmonary disease (Selikoff and Lee, 1978).
21 Pleural mesothelioma, bronchogenic carcinoma, and asbestosis are likely to occur far more
22 frequently in asbestos workers when compared to the normal population. Asbestosis is a
23 restrictive lung disease manifested by diffuse and progressive interstitial fibrosis (Selikoff and
24 Lee, 1978). Several reviews have emphasized that the pathogenetic mechanisms of this
25 disease have not been well elucidated (Becklake, 1982; Craighead et al., 1982; Rom et al.,
26 1991). Similar to the effects of silica, alveolar and interstitial macrophages are postulated to
27 play a central role between the initial inflammatory process and the subsequent synthesis and
28 deposition of connective tissue, which is a characteristic feature of the fibrogenic response
29 (Warheit and Hesterberg, 1994).
30
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1 11.8.2 Biophysical Factors and their Roles in the Development of Fiber
2 Toxicity
3 The underlying mechanisms through which fibers cause lung disease have unique
4 biophysical elements which are related to the development of fiber-induced lung disease.
5 Two important factors, namely dimension and durability, will be briefly discussed here
6 because they are additional key factors which separate the biological effects of fibers from
7 those of simple low solubility particles. In addition, they play a significant role in the
8 toxicity of asbestos fibers.
9 Fiber dimension plays an important role in influencing the pathogenesis of asbestos-
10 related lung disease (Stanton et al, 1981). In support of this concept, Davis and coworkers
11 (1986) exposed rats by inhalation for one year to aerosols of specially prepared "short" (< 5
12 ptm in length) amosite asbestos fibers or a preparation of long (> 20 /mi) amosite fibers.
13 Both preparations were derived from the same source. The respirable dust mass
14 concentration was identical for each sample preparation, (10,000 /*g/m3); however the long
15 fiber amosite preparation contained 2060 fibers/cc > 5 /mi in length, while the short fiber
16 amosite preparation contained only 70 fibers/cc > 5 /mi in length. Thus, the short fiber
17 amosite sample contained greater numbers of fibers compared to the long fiber sample.
18 After a one year exposure, no histopathological effects were reported in rats exposed to the
19 short fiber amosite preparation, while one-third of the rats exposed to the long fiber amosite
20 preparation developed lung tumors. Moreover, virtually all of the rats exposed to the long
21 fibers developed diffuse interstitial lung fibrosis, while no fibrosis was observed in animals
22 treated with the short fiber amosite preparation (Davis et al., 1986). Similar effects were
23 observed when Davis and Jones (1988) compared the pathogenicity of long and short
24 chrysotile asbestos fibers in rats. One year inhalation studies were undertaken with rats
25 exposed to a specially prepared short-fiber sample of Canadian chrysotile asbestos. This was
26 compared, at equal gravimetric concentrations (10 mg/m3) to fibers generated from the same
27 chrysotile batch, but size-selected to contain the highest possible numbers of long fibers.
28 The short-fiber chrysotile sample contained 1170 fibers/cc > 5 /mi in length while the
29 longer-fiber sample contained 5510 fibers/cc > 5 /tm in length. Rats exposed to the long-
30 fiber chrysotile sample developed substantially more pulmonary fibrosis than animals treated
31 with the short fiber chrysotile and three tunes the number of pulmonary tumors (Davis and
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1 Jones, 1988). Based on the results of these studies and other reports, its seems likely that
2 fiber dimension and in particular, fiber length, plays an important role in the development
3 of lung pathological responses.
4 Fiber durability or biopersistence refers to the retention of inhaled or instilled fibers
5 in the lung over time with regard to number, dimension, surface chemistry, chemical
6 composition, surface area, or other characteristics (Warheit, 1994). The biological activity
7 of fibers can be affected by any alterations in these parameters. Elimination of inhaled fibers
8 from the lung occurs by bulk clearance, generally involving AM uptake and transport to the
9 mucociliary escalator, translocation of fibers to other sites (e.g., lymph nodes) or by
10 dissolution and/or fiber breakage.
11 Studies have been performed to evaluate the biopersistence/durability of various
12 asbestos fiber types. Two short-term inhalation studies were utilized by Roggli and
13 colleagues to investigate fiber clearance of either inhaled chrysotile or crocidolite asbestos
14 fibers in rats (Roggli et al., 1987; Roggli and Brody, 1984). Asbestos fibers were recovered
15 from digested lung tissue and assessed for dimensional changes at several postexposure time
16 points. After a short exposure to crocidolite asbestos fibers, there was a progressive increase
17 in mean fiber lengths with time, but no change in the mean diameters of fibers recovered
18 from the lung, indicating that the shorter fibers were cleared while the longer fibers were
19 retained (Roggli et al., 1987). In the rats exposed to chrysotile asbestos fibers, there was a
20 similar progressive enhancement of mean fiber lengths with increasing time, but also a
21 reduction in mean fiber diameter, suggesting longitudinal splitting of fibers (Roggli and
22 Brody, 1984). It was concluded that the long chrysotile and crocidolite fibers were
23 selectively retained in the lungs of exposed rats, but only the chrysotile asbestos fibers
24 underwent longitudinal splitting. These results have been corroborated in studies by
25 Bellmann and colleagues who instilled chrysotile and crocidolite fibers into the lungs of rats
26 and evaluated fiber clearance parameters over a 2-year post-instillation period. These
27 investigators reported that lung clearance of short crocidolite fibers was slow and the number
28 of crocidolite fiber longer than 5 /xm were not decreased over time suggesting that these
29 fibers were not cleared from the lung. In contrast, the number of retained chrysotile fibers
30 longer than 5 /^m was continuously increased over a 2-year period, again principally due to
31 longitudinal splitting of the fibers (Bellmann et al., 1987). In summary, the results of these
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1 studies indicate that asbestos fibers which are long and biopersistent such as amosite,
2 crocidolite, and to a lesser extent, chrysotile asbestos have a greater tendency to produce
3 pulmonary pathological effects relative to shorter fibers or fibers of low durability.
4
5 11.8.2.1 Studies on the Mechanisms of Asbestos-Induced Lung Injury
6 Laboratory animal models of asbestos-related pulmonary fibrosis (i.e., asbestosis)
7 have been developed in rats (Pinkerton et al., 1984; Wagner et al., 1974), mice (Bozelka et
8 al., 1983) guinea pigs (Holt et al., 1966) and sheep (Begin et al., 1981, 1983) exposed
9 chronically to fibers. The experimental models are important for evaluating the anatomic
10 patterns of disease. A major shortcoming of the chronic exposure models, however, is the
11 difficulty in identifying the early pathogenetic events. One example of this problem stems
12 from the fact that the connecting link between initial fiber deposition patterns and the
13 subsequent cellular events that lead to asbestos-related lung injury have not been addressed.
14 Similarly, the role of the macrophage in the early development of asbestos-induced lung
15 injury has not been elucidated. In an effort to address these questions, a rat model of
16 asbestos-induced lung disease was developed wherein animals were exposed for 1 h to an
17 aerosol of chrysotile asbestos fibers and the early physiologic as well as pathological
18 cellular events were evaluated at 48 h and 1 mo postexposure (Warheit et al., 1984; Chang
19 etal, 1988).
20 Following a 1-h inhalation exposure to chrysotile asbestos, fibers were observed to
21 have deposited selectively on alveolar duct bifurcations (Brody et al., 1981; Brody and Roe,
22 1983) and were cleared from epithelial surfaces by macrophage-mediated clearance or fiber
23 translocation. The translocated fibers migrated from airspace, through Type 1 epithelial
24 cells, into pulmonary interstitial sites, where they were phagocytized primarily by fibroblasts
25 or interstitial macrophages (Brody et al., 1981, Brody and Hill, 1982). The interactions of
26 these fibers with fibroblasts induced the formation of intracellular microcalcifications, a form
27 of nonspecific cellular injury (Brody and Hill, 1982). On the alveolar side, AMs rapidly
28 were recruited to sites of fiber deposition and phagocytized chrysotile fibers (Warheit et al.,
29 1984). The mechanisms for AM recruitment to alveolar duct bifurcations is associated with
30 complement activation by the inhaled fibers and consequent generation of chemotactic factors
31 (Warheit et al., 1985). Histologic examination of exposed lung tissue indicated that proximal
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1 alveolar duct bifurcations were prominent in asbestos-exposed animals sacrificed 48 h after
2 exposure (Warheit et al, 1984). Using ultrastructural morphometric methods, Chang et al.
3 (1988) demonstrated that the influx of recruited alveolar and interstitial macrophages formed
4 a component of an early lesion, which was characterized by enhanced volumes of the
5 epithelial and interstitial compartments of the alveolar duct bifurcation. Additionally, the
6 numbers of alveolar and interstitial macrophages, as well as Type 1 and Type 2 epithelial
7 cells were significantly increased over sham exposed controls. One month postexposure, the
8 numbers of alveolar macrophages on bifurcation surfaces were no longer elevated over the
9 normal level but the volume of the interstitium was still significantly increased by 67% over
10 sham controls. This was due to an increase in the volume of noncellular interstitial matrix,
11 along with an accumulation of interstitial cells, including macrophages, myofibroblasts,
12 fibroblasts, and smooth muscle cells (Chang et al., 1988). The authors concluded that acute
13 structural alteration measured at 2 days after a 1-h exposure were followed by a progressive
14 response, as evidenced by elevated numbers of interstitial cells and localized interstitial
15 fibrosis measured at 1 mo postexposure (Chang et al., 1988).
16 The measurement of an early asbestos-induced lesion at 48 h and 1 mo after a 1-h
17 exposure and identification of the target cell types have been useful for studying the
18 mechanisms underlying the acute pathologic response to asbestos exposure in rats. The
19 finding of changes in the cellular and noncellular interstitial compartments which precede the
20 consequent development of fibrosis implicates the involvement of fibroblasts in proliferating
21 and synthesizing matrix components such as collagen, elastin, and glycosaminoglycans. The
22 rate of collagen buildup is likely to be a function of both the number of fibroblasts (i.e.,
23 fibroblast proliferation) as well as the rate of collagen synthesis by individual cells, balanced
24 by the degradation of collagen by protease-secreting cells. It seems likely that fibroblast
25 proliferation and connective tissue formation are complex processes and may be
26 independently regulated (Goldstein and Fine, 1986; King et al., 1989). Moreover, although
27 fibroblasts are usually considered to be cells which respond passively to the products of
28 effector cells, it seems clear that these cell types play a more active role in facilitating the
29 development of fibrosis (Rom et al., 1991). Notwithstanding our lack of knowledge
30 regarding the complexity of cellular responses in the interstitial microenvironment, it is still
31 attractive to postulate that asbestos-exposed alveolar or interstitial macrophages synthesize
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1 and secrete mitogenic factors that stimulate interstitial cells to increase in number and
2 generate enhanced amounts of connective tissue proteins (Warheit and Hesterberg, 1994).
3
4 11.8.2.2 Fiber-Induced Inflammation
5 Similar to the responses associated with silica exposure, inhalation of asbestos fibers
6 is likely to cause a respiratory tract inflammatory response. Among the many responses that
7 can occur, reactive oxygen species are released by activated macrophages and neutrophils
8 causing tissue damage and may be linked to inflammation, fibrosis, and possibly genotoxic
9 effects. The production of reactive oxygen species by cells may result in their own death.
10 In this regard, in vitro exposure of macrophages to crocidolite asbestos fibers resulted in cell
11 death as well as a release of oxygen metabolites (Goodglick and Kane, 1990). This toxicity
12 was scavenged by administration of superoxide dismutase, catalase, or deferoxamine. The
13 role of oxidants in the development of asbestos-induced inflammation and pulmonary fibrosis
14 has also been evaluated by administering a chronic regimen of antioxidants to asbestos-
15 exposed rats (Mossman et al., 1990). The results of these studies demonstrated that the
16 antioxidants mitigated the inflammatory effects of asbestos exposure, and this finding
17 suggests that oxygen radicals (probably derived from inflammatory cells or AMs) may play a
18 role in asbestos-induced lung injury. In previous studies, it had been reported that asbestos
19 fibers induced the production of oxygen radicals by AMs in vitro as well as in cell-free
20 reaction mixtures (Hansen and Mossman, 1987; Weitzman and Graceffa, 1984).
21
22 11.8.2.3 Growth Factors
23 Growth factors have been implicated in mediating the progression of fiber-induced
24 pulmonary fibrosis. Many of the studies linking growth factors and the development of
25 fibrosis have been investigated in association with asbestos exposure. Chrysotile asbestos
26 fibers were shown to stimulate lavaged AMs to produce a platelet-derived growth factor
27 (PDGF) homolog that is mitogenic for rat lung fibroblasts in vitro (Kumar et al., 1988).
28 PDGF along with fibronectin is one of the classical competence factors for fibroblasts
29 (Goldstein and Fine, 1986). In addition, PDGF derived from AMs was shown to be
30 chemotactic for fibroblasts in vitro (Osornio-Vargas et al., 1990).
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1 Cells recovered by pulmonary lavage from asbestos-exposed rats are also capable of
2 releasing progression factors for fibroblasts. Asbestos-exposed macrophages secreted a
3 fibroblast growth factor (FGF), also referred to as macrophage-derived growth factor
4 (MDGF), over a period of 24 weeks following exposure (Lemaire et al., 1986). This
5 secretion of MDGF coincided with the development of histopathological changes in the lungs
6 of exposed animals. However, other studies have failed to demonstrate a correlation
7 between in vitro fibroblast proliferation and pathological responses in vivo. In one study,
8 AMs exposed to both long and short crocidolite asbestos fibers in vivo were evaluated for
9 fibroblast proliferation factors in vitro (Adamson and Bowden, 1990). It was surprising to
10 find, that no fibroblast activity could be measured in the culture supernatant of cells lavaged
11 from rats instilled with long fibers, despite significant pathological effects in the lungs of
12 instilled animals (Adamson and Bowden, 1990). In contrast, short fibers produced no
13 significant pathological effects, but significant fibroblast proliferation activity was measured
14 in cell culture supernatants from rats exposed to these fibers. This finding does not correlate
15 with the results of previous inhalation studies (described earlier in this section) which have
16 shown that long asbestos fibers are significantly more pathogenic than short fibers (Davis et
17 al., 1986).
18 The development of interstitial fibrosis depends upon production of connective tissue
19 proteins as well as increased mesenchymal cell proliferation. TGF-0 which is secreted by
20 AMs and induces fibroblast proliferation, also has been shown to increase elastin production
21 by neonatal rat lung fibroblasts (McGowan and McNamer, 1990). In this regard, it will be
22 important to more fully ascertain the functions of the different forms of TGF-/3 and TGF-/3
23 receptors on fibroblasts, in order to better understand the fibrogenic process (Kalter and
24 Brody, 1991; Segarini, 1991).
25
26
27 11.9 TOXICOLOGY OF OTHER PARTICIPATE MATTER
28 11.9.1 Introduction
29 This section reviews the toxicology of other PM within the framework described in
30 the introduction to the chapter. The particle classes chosen for inclusion here are those
31 which may actually occur in ambient air or may be surrogates for these. For example, some
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1 of the particles discussed are considered to be models of "nuisance" or "inert" dusts (i.e.,
2 those having low intrinsic toxicity) and, as such, are likely to be representative of similar
3 ambient PM. In many instances, there are only a few studies examining the response on
4 specific biological endpoints following inhalation exposure. In these cases, and where
5 available, intratracheal instillation studies (injection of a bolus of material into the lungs)
6 have been used to compare the toxicity of different particle types. While instillation may
7 produce more severe pulmonary damage than would inhalation (largely due to differences in
8 delivered doses and dose rates), the relative toxicities of different particles seem to be similar
9 when given by either method (Driscoll et al., 1991). Thus, intracheal instillation studies can
10 be used for comparative potency purposes, but it is not possible to quantitatively extrapolate
11 the resulting exposure-response data to inhalation exposure-responses. In a number of cases,
12 particles with low intrinsic toxicity have been used in instillation studies to delineate
13 nonspecific particle effects from effects of known toxicants. Some of these studies are
14 discussed herein, as they are often the only database for such materials.
15
16 11.9.2 Mortality
17 Table 11-56 shows results of mortality assays using particles > 1 /mi in diameter; all
18 of these involved repeated or chronic exposures to high concentrations of various PM, some
19 of which are considered to be of low toxicity. Essentially no treatment-related mortality was
20 observed in any of these studies.
21 Recent interest has been focused on the inherent toxicity of a smaller size class of
22 particles, namely the ultrafine particles which are discussed in section 11.5. While the mass
23 concentration of ultrafine particles in ambient air may be low, their number concentration
24 may be quite high, as discussed previously in terms of acidic sulfate aerosols.
25
26 11.9.3 Pulmonary Mechanical Function
27 Assessments of pulmonary mechanical function have generally been carried out with
28 particles having some inherent toxicity, but there have been some studies examining effects
29 due to other, low intrinsic toxicity particles for comparison.
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TABLE 11-56. EFFECTS OF PM
/tm) ON MORTALITY
3:
H- *
v§
tO
O
Tl
H
i
O
o
o
H
O
cj
O
0
O
H- 1
H
M
Particle
Raw shale oil
TiO2
Toner
Coal dust
Petroleum coke
(micronized)
Petroleum coke
(micronized)
Volcanic ash
Ti02
Fly ash (coal)
California road
dust
"Effect indicates
Species, Gender, Particle Characteristics
n. • 4 T^-imnr i-n H if n /"* J l'
Body Weight Technique (itg/m3) Size (jtm);
-------
1 Wright et al. (1988) instilled rats (Sprague-Dawley; F; 200g) with 10,000 ptg iron
2 oxide (0.1 /xm GMD, ag = 1.7) or silica (quartz) (1.3 pirn, ag = 2.5). At 1 mo after
3 exposure, they noted no changes in various indices of pulmonary mechanics (total lung
4 capacity [TLC]; functional residual capacity [FRC]; nitrogen [N2] washout; FEV1; or peak
5 expiratory flow [PEF]) in animals exposed to iron oxide, but silica exposure resulted in
6 changes in the N2 washout curve and decreased compliance. Begin et al. (1985) instilled into
7 sheep (Male; 25 to 45 kg BW) 100,000 ^g latex beads (0.1 /*m) or asbestos fibers. The
8 latex produced no change in pulmonary function (TLC, residual volume [RV]; vital capacity
9 [VC]; expiratory reserve volume [ERV]; pulmonary compliance [Cpulm]; pulmonary
10 resistance [Rpulm]; FRC), while the asbestos produced a reduction in compliance,
11 abnormalities in the N2 washout curve, and changes in forced expiratory flow measurements.
12 There are a few studies of pulmonary function responses following inhalation
13 exposures to PM. Wehner et al. (1983) exposed rats (F-344; M/F, 3mo) to 5,000 or
14 50,000 /jg/m3 volcanic ash (Mt. St. Helens) for 6 h/day, 5 days/week for up to 24 mo
15 (Table 11-57). By 12 mo of exposure, no changes in lung volume were noted. By 8 mo of
16 exposure, there was an increase in respiratory frequency in animals exposed at the higher
17 concentration, but no change at the lower concentration.
18 Heinrich et al. (1989) exposed rats for 6 h/day, 5 days/week up to 24 mo to titanium
19 dioxide (TiO2) at 5,000 ^ig/m3 and silica at 1,000 /*g/m3. Exposure to silica produced a
20 reduction in quasistatic lung compliance, tidal volume, (VT), inspiratory capacity (1C), VC,
21 RV, and TLC. Diffusion capacity for carbon monoxide (DLco) was also reduced, and the
22 N2 washout curve was altered; these changes indicate a functionally restrictive lung, a
23 finding often noted in humans occupationally exposed to silicates. None of these variables
24 were altered by exposure to TiO2.
25 Acidic sulfates have been associated with alterations in bronchial responsiveness, but
26 there are few studies with other particles which examined this response. Fedan et al. (1985)
27 exposed rats (F344, whole body) for 7 h/day, 5 days/week for 2 years to coal dust (size
28 described as respirable, but not specifically stated) at 2,000 ^g/m3, and examined the
29 pharmacological response of isolated tracheal preparations to various agonists. The coal dust
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£
^§ Particle
Volcanic ash
Fly ash (coal)
(Illinois # 6)
Fly ash (coal)
(Montana
lignite)
TABLE 11-57. EFFECTS OF INHALED PM ON PULMONARY MECHANICAL FUNCTION
Species, Gender,
Strain, Age, or Body
Weight
Rat, Sprague-Dawley,
40 days
Guinea pig, Hartley,
250-320 g
Guinea pig, Hartley,
250-320 g
Exposure Mass Concentration
Technique («!/m3)
Whole body 9,400
Nose-only 5,800
Nose-only 5,800
Particle Characteristics
Size (>tm); ag Exposure Duration Observed Effect1
0.65 (MMAD); 1.78 2 h/days, 5 days No changes (F, VT,
V V )
insp> exp'
0.21 (MMAD); 4.14 1 or 2 h 2 h: 1TLC, VC,
OLm up to 96 h PE
1 h: no effect
0.21 (MMAD); 4.14 1 or 2 h 2 h: tTLC, VC; no
change in DL^,
Reference
Raub et al. (1985)
Chen et al. (1990)
Chenetal. (1990)
Volcanic ash Rat, M/F, F-344, 3 mo Whole body
Volcanic ash
Coal dust
Guinea pig, Hartley,
300-425 g
Rat, Wistar, 200-300 g
Conventional and germ
free
Head
Whole body
5,000, 50,000
9,400
10,000
Respirable
6 h/day, 5 days/week,
24 mo
0.65 (MMAD); 1.78 2h
geometric mean <5 /wn 8 h/day, 120 days
t f for 50,000 ftg/m3 Wehner et al. (1983)
by 8 mo; no change
for 5,000 ng/m3
No change in Raw, Wiester et al. (1985)
Cdyn. f. V|. VE
* FEV!, V^ (10%) Moorman et al. (1977)
(Germfree); only
I Vmax(10%)conv.
OJ
TiO2
Rat, F, F-344, 8 weeks Whole body
5,000
6 h/day, 5 days/week,
24 mo
No changes (C, VT, Heinnch et al. (1989)
1C, VC, RV, TLC,
DL^, N2 washout)
O
o
z
o
H
O
c
s
w
Key to abbreviations:
f: breathing frequency
VT: tidal volume
Vinsp: inspiratory flow
Vexp: expiratory flow
TLC: total lung capacity
VC: vital capacity
DL,,,,: carbon monoxide diffusing capacity
PE: post exposure
1C: inspiratory capacity
RV: residual volume
R,w: airway resistance
Cdyn: dynamic compliance
V[ = max inspiratory flow
VE = expiratory minute volume
FEV[ Q = forced expiratory volume (1 sec)
vmax (10%) = maximal flow at 10% FVC
FVC = forced vital capacity
n
HH
H
W
-------
1 exposure increased the maximal contractile response of the tracheal smooth muscle to
2 acetylcholine (a bronchoconstrictor), compared to air exposed control tissue, but did not alter
3 the slope of the acetylcholine concentration-response curve nor sensitivity (i.e., EC50).
4 No change in response to isoproterenol (a bronchodilator) was noted. Wiester et al. (1985)
5 exposed guinea pigs for 2 h to 9,400 /xg/m3 of Mt. St. Helens volcanic ash (0.65 jum).
6 No changes in pulmonary mechanics measured during exposure (airway resistance, dynamic
7 compliance, breathing frequency, maximum inspiratory flow or expiratory minute volume)
8 were noted. However, following exposure, airway hyporesponsiveness to histamine
9 challenge was observed.
10 It should be noted that, as with acidic sulfates, changes in pulmonary function may
11 not be the most sensitive marker of response to other PM. For example, inflammatory
12 changes in sheep following the instillation of latex particles (100,000 /*g in 100 ml fluid)
13 were not associated with any changes in lung volumes, resistance, or compliance (Begin
14 etal.,1985).
15
16 11.9.4 Pulmonary Morphology and Biochemistry
17 The vast majority of the information concerning morphologic alterations from inhaled
18 particles involve diesel exhaust, and this is discussed in this chapter and reviewed in another
19 document (U.S. Environmental Protection Agency, 1994). In addition, and as previously
20 mentioned with acidic sulfate particles, markers in lung BAL have been used to assess
21 damage following PM exposure.
22 The ability of ambient particles to affect lung morphology was strongly suggested by
23 Bohm et al. (1989). They exposed rats (Wistar, F, 2.5 mo) for 6 mo to the ambient air of
24 two cities in Brazil, namely Sao Paulo and Cubatao. Although characterization of air
25 pollution levels was vague, pollution in the former appeared to be dominated by automobile
26 exhaust gases, while that in the latter by industrially derived particulate matter. Rats exposed
27 in Cubatao showed various responses, such as mucus hypersecretion and epithelial
28 hyperplasia, in both the upper and lower bronchial tree, while those exposed in Sao Paulo
29 showed effects generally limited to the upper bronchial tree. Particle concentrations (PM10)
30 were as high as 164 /ig/m3 in Cubatao. Thus, high PM levels were suggested to be
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1 responsible for the observed effects, although the contribution of other components of the
2 pollutant mix could not be discounted.
3 Some intratracheal instillation studies have compared morphological effects resulting
4 from exposure to different particles. Wright et al. (1988) instilled 10,000 jug iron oxide
5 (Fe2O3; 0.1 /mi GMD, ag = 1.7) or 10,000 jig quartz (1.3 laa GMD, ag = 2.5) into rats,
6 and examined the lungs 30 days following each exposure. The iron oxide did not produce
7 any histological or morphometric changes, while the quartz exposure resulted in aggregations
8 of PMNs and AMs around small airways, alveolar proteinosis, increased alveolar distances,
9 airspace enlargement, and increased thickness of respiratory bronchiolar walls.
10 Another example of an instillation study which may be used to compare effects from
11 different types of particles is that of Sanders et al. (1982), who instilled rats (F-344, female,
12 young adult) with 40,000 /ig of either soil (sandy loam, 1.6 /im CMD), volcanic ash (Mt. St.
13 Helens, 0.5 to 1.5 /mi CMD), or crystalline quartz (1.5 /mi CMD). Mononuclear cell
14 infiltration was noted with both the soil and ash particles in regions of high particle
15 aggregation. There was also some Type 2 epithelial cell hyperplasia 7 to 37 days following
16 ash or soil instillation. However, the ash produced a fibrotic response to a greater extent
17 than did the soil, with indications from the former of a simple pneumoconiosis and moderate
18 lipoproteinosis. Some foci of particle-laden macrophages were noted in the mediastinal
19 lymph nodes of soil exposed animals, but the ash-exposed animals showed reactive lymphoid
20 hyperplasia. Quartz resulted in production of granulomas, deposition of collagen,
21 widespread lipoproproteinosis, and fibrosis in regional lymph nodes.
22 The comparative fibrogenic potential of a number of particle types was examined by
23 Schreider et al. (1985). Rats (M, SD, 300g) were exposed by intratracheal instillation to
24 5,000, 15,000, or 45,000 /ig of Montmorillonite clay (0.84 /mi CMD), quartz (1.1 /mi), Mt.
25 St. Helens volcanic ash (1.2 /mi), stack-collected coal fly ash (1.5 /un) or hopper-collected
26 fly ash (1.9 /im), or to 5 or 15 mg of a coal-oil ash mixture (3.9 /im). Lung histology was
27 assessed at 90 days post instillation. Neutrophils were noted in alveoli only with quartz (all
28 concentrations), stack ash (at high concentration), and volcanic ash (low and mid
29 concentrations). Some fibrosis was produced by all of the particles, although there were
30 qualitative and quantitative differences among the different exposure groups. The order of
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1 fibrosis potential, from greatest to least, was as follows: quartz > clay > volcanic ash >
2 hopper coal ash > stack coal ash > oil-coal ash mixture.
3 Begin et al. (1985) instilled 100,000 /ig of 0.1 fim latex beads or asbestos fibers into
4 the lungs of sheep (25 to 45 kg), and examined lavage at 1 to 60 days post instillation. The
5 latex produced only transient alveolitis and transient increases in the number of AMs and
6 PMNs in lavage beginning at day 1, while the asbestos-exposed animals had a persistent
7 inflammatory response and more severe damage. Callis et al. (1985) instilled silica or latex
8 particles (0.9 /mi) into the lungs of mice. While the latter produced some increase in protein
9 and cell number in lavage, the response to the former was much greater. Finally,
10 Lindenschmidt et al. (1990) instilled rats with either of two inert dusts, (A12O3; 5.3 /*m) and
11 TiO2 (2.2 urn) at 1,000 or 5,000 /ig/100g body weight and examined the lungs up to 63 days
12 post instillation. Both particle types produced similar increases in N-acetylglucosamine and
13 total recovered cells in lavage, while a minimal Type 2 cell hyperplasia noted with A12O3
14 was even less severe with TiO2. However, when results were compared with those for
15 instilled silica, any responses seen with the inert particles decreased towards control level
16 during the 2-mo study period, while changes with silica progressed. This highlights the
17 difference between the inert and fibrogenic materials. Thus, the instillation studies suggest
18 that there may be some nonspecific particle effect, but clearly the chemical characteristics of
19 the particle affects the ultimate biological response. In any case, levels of particles with low
20 intrinsic toxicity are not associated with major nonspecific effects.
21 The effects of inhaled PM on pulmonary morphology are outlined in Table 11-58.
22 Most of the studies used fly ash and volcanic ash; TiO2 has also been used to assess effects
23 of a "nuisance" (low intrinsic toxicity) type of particle. However, with the exception of the
24 study of road dust by Kleinman et al. (1995), exposure concentrations ranged from very
25 high to extremely high and likely caused overload with long-term exposures. Responses,
26 when they did occur, were quite similar for the various particles, characterized by focal
27 aggregates of particle-laden macrophages with evidence of an inflammatory response; the
28 intensity of both effects was related to exposure duration and concentration. On the other
29 hand, the Kleinman et al. (1995) study at relatively low particle concentrations showed a
30 more diffuse pattern of morphological change and no inflammatory loci.
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TABLE 11-58. EFFECTS OF PM ON RESPIRATORY TRACT MORPHOLOGY
oo
o
o
o
ej
§
i
n
Particle
Coal dust
( micro nized
bituminous)
Petroleum coke
(micronized
raw)
Fly ash (coal)
Volcanic ash
(Mt. St. Helens)
Species, Gender,
Strain, Age, or Exposure Mass Concentration
Body Weight Technique Oig/m3)
Rat, M, Whole body 6,600, 14,900
Wistar, 18 weeks
Rat, M/F, Whole body 10,000, 30,000
Sprague-Dawley ;
cynomologus
monkey
(mature)
Rat, M/F, Whole body 36,000
F-344, 10-13 mo
Rat, M/F, Whole body 5,000, 50,000
F-344, 3 mo
Particle Characteristics
Size (>tm);
-------
I
1— k
1— 1
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O
I
6
o
25
3
o
1
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W
Particle
TiO2
Fly ash (coal)
TiO2
Volcanic ash
California road
dust
TiO2
Fly ash (fluidized
bed coal
combustion)
Fly ash (coal)
Fly ash
(fluidized bed
coal combustion)
TABLE
Species, Gender,
Strain, Age, or
Body Weight
Rat, F,
F-344, 8 weeks
Mmice, M,
C57BL/6,
12 weeks
Guinea pig, F,
Dunkin-Hartley,
300-350 g
Rat,
Sprague-Dawley,
40 days
Rat, F-344
Rat, M/F,
CD
Rat, M/F, F-344,
12-16 weeks
Hamster, golden,
8 weeks
Rat, M/F,
F-344, 12 weeks
11-58 (cont'd). EFFECTS OF PM ON RESPIRATORY TRACT MORPHOLOGY
Exposure
Technique
Whole body
Nose-only
Whole body
Whole body
Nose Only
Whole body
Whole body
Whole body
Whole body
Particle Characteristics
(/ig/m3) Size (jan);
-------
if
^g Particle
^" Fly ash
(pulverized coal
combustion)
Carbon black
Carbon black
Fly ash (coal)
TABLE 11-58 (cont'd). EFFECTS OF PM ON
Species, Gender,
Strain, Age, or Exposure Mass Concentration
Body Weight Technique (Mg/m3)
Rat, M/F, Whole body 37,000
F-344, 12 weeks
Rat, M, Whole body 10,000
F-344,
14-15 weeks
Rat, F, Wistar 6,000
6 weeks
Rat, M, Whole body 270,000
Wistar, 160-175 g
Particle Characteristics
Size (/un); ag
2.7 (MMAD); 2.1
2.0/0.12
(MMAD)
(bimodal distr.
with 70% in
smaller mode) 2.5/2.3
n/s
47% <3.75 urn
PULMONARY MORPHOLOGY
Exposure Duration
7 h/day, 5 days/week,
4 weeks
7 h/day, 5 days/ week,
12 weeks
18 h/day, 5 days/week,
10 mo
6 h/day, 15 days
Observed Effect
Moderate enlargement of lung
associated lymph nodes due to
hyperplasia and cell accumulation
(persistent up to 48 weeks PE);
small granulomas in lungs.
Mild hyperplasia of Type 2 cells;
particle laden macrophages in distal
terminal bronchioles and proximal
alveolar ducts.
Moderate to severe hyperplasia in
bronchio-alveolar region; some
inflammation; alveolar
lipoproteinosis
Mild infiltration of mononuclear
cells and mild pneumonitis 45 days
Reference
Bice et al. (1987)
Wolff et al. (1990)
Nolle et al. (1994)
Chauhanetal. (1987)
0
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o
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g
Q
H
W
Shale dust (raw or Monkey,
spent) cynomolgus, M/F,
2-4.5 kg
rat, M/F, F344,
90-95 g
Key to abbreviations:
NS: Not specified
PE: Post-exposure
Whole body
10,000, 30,000
3.9-4.5; 6 h/day, 5 days/week,
(1.8-2.2) 2 years
PE; numerous particle-laden
macrophages outside alveoli up to
105 days PE; ^ lung weight by
30 days PE.
Concentration-related accumulation MacFarland et al.
of macrophages; subacute (1982)
bronchiolotis and alveolitis
Concentration-related proliferative
bronchiolitis and alveolitis, chronic
inflammtion with spent shale; no
lymph node inflammation;
accumulation of macrophages
-------
1 There is some evidence for interspecies differences in response to comparable
2 exposure atmospheres (Klonne et al., 1987). In the study of Shami et al. (1984), increased
3 proliferation of large and small airway epithelial cells occurred in the absence of overt
4 histopathology following exposure to fly ash. The authors suggested that this may indicate
5 some potential for the interaction of fly ash with carcinogens.
6 Table 11-59 outlines studies in which lavage fluid was analyzed following inhalation
7 exposure to PM. As with morphology, most exposure concentrations were very high, but
8 effects, when they occurred, indicated inflammation.
9 As mentioned earlier, eicosanoids are potent mediators of various biological functions,
10 and alterations in arachidonic acid metabolism, which may be involved in lung pathology,
11 can be assessed in lavage fluid. Exposure to coal dust (25,000 pig/m3) produced decreases in
12 prostaglandin £2, and increases in thromboxane A2 and leukotriene B4, perhaps suggesting
13 smooth muscle constriction, vasoconstriction and increased chemotactic activity of
14 macrophages (Kuhn et al., 1990).
15 Table 11-60 outlines studies examining lung biochemistry following particle
16 inhalation, mostly to fly ash. In some cases, effects on the xenobiotic metabolizing system
17 of the lungs were examined. For example, van Bree et al. (1990) exposed rats to coal fly
18 ash (10,000, 30,000, 100,000 /ttg/m3) and examined cytosolic antioxidant enzymes and the
19 microsomal P-450 linked mixed function oxidase system involved in lung metabolic defense
20 against reactive oxygen species and xenobiotic compounds. They noted both exposure-
21 related increases and decreases in different components of this system, which they ascribed to
22 differential effects of organic and trace metal components of the ash. Srivastava et al. (1985)
23 also found that the effects of fly ash were likely due to chemicals adsorbed onto, or that were
24 part of, the fly ash particle, rather than to some nonspecific particle effect. This was
25 because the activity of the lung mixed function oxidase system was induced in rats by
26 instillation of coal fly ash (< 0.5 /mi), but not by instillation of glass beads.
27 There is some evidence that fly ash exposure can initiate cell division and DNA
28 synthesis in the lungs (Hackett, 1983; Shami et al., 1984), but exposure levels were very
29 high (> 30,000
April 1995 H_441 DRAFT-DO NOT QUOTE OR CITE
-------
1
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TABLE 11-59. EFFECTS OF PM ON
Particle
Carbon black
Volcanic ash
TiO2
TiO2
Coal dust
California
road dust
TiO2
Fe203
Carbon black
Carbonyl
iron
Carbon
black
Species, Gender,
Strain, Age, or
Body Weight
Mouse, F,
Swiss, 20-23 days
Mouse, F,
CD-I, 4-8 weeks
Rat, M, F-344
180-200 g
Rat, HAN
Rat, HAN
Rat, F-344
Rat, M/F, F-344,
8 weeks
Rat, M,
Long-Evans,
225-250 g
Rat, M,
F-344,
14-15 weeks
Rat, M
Crl:CDBR,
8 weeks
Mouse, F,
Swiss
20-23 g
Exposure Mass Concentration •
Technique (/ig/m3)
Nose-only 10,000
Whole body 9,400
Whole body 50,000
Whole body 50,000
Whole body 10,000, 50,000
Nose-only 300, 900
Whole body 5,000
Nose-only 18,000-24,000
Whole body 10,000
Nose-only 100,000
Nose-only 10,000
Particle Characteristics
Size (urn); ag
2.45 (MMAD); 2.54
0.65 (MMAD); 1.8
1 (MMAD); 2.6
4 (MMAD); 2.2
1.1 (MMAD); 1.6
1.45-1. 7 (MMAD);
2.9-3
2.0/0.12
(MMAD)
(bimodal distr.
with 70% in
smaller mode); 2.5/2.3
3.6 (MMAD); 1.7
2.4 (MMD); 2.75
MARKERS IN LAVAGE FLUID
Exposure Duration
4 h/day, 4 days
2h
6 h/day, 5 days
8 h/day, 5 days/week
(up to 15 weeks)
8 h/day, 5 days/week
(up to 15 weeks)
4 h/day, 4 days/week,
8 weeks
6 h/day, 5 days/week,
24 mo
2h
7 h/day, 5 days/week,
12 weeks
6 h; 6 h/day, 3 days
4h
Observed Effect
No change in total cell no. or
differential counts; no change in albumin
levels.
Increase in PMN.
No change in: AMs, PMNs, lymphocytes;
LDH; protein; to 63 days PE.
Slight increase in PMN at 15 weeks.
Increased PMN (persistent).
t Albumin at 900 jtg/m3; no change in
total cells or differential counts
No change in total cell no. in lavage but
t AMs and 1 PMNs some time points; no
change in LDH, protein, 6-glucuronidase
in lavage.
No change total cell no. or
differential counts.
t PMN in lavage; t acid
proteinase in lavage.
No change in total cell no,
protein, or LDH.
No change in total cell no. or
differential count at 20 h PE.
Reference
Jakab (1992, 1993)
Grose et al. (1985)
Driscoll et al.
(1991)
Brown et al. (1992)
Brown et al. (1992)
Kleinman et al.
(1995)
Muhle et al. (1991)
Lehnert and
Morrow (1985)
Wolff etal. (1990)
Warheit et al.
(1991)
Jakab and
Hemenway (1993)
-------
TABLE 11-59 (cont'd). EFFECTS OF PM ON MARKERS IN LAVAGE FLUID
Particle
TiO2
Coal dust
Ti02
Species, Gender,
Strain, Age, or Exposure N
Body Weight Technique
Guinea pig, M/F, Whole body
400g
Rat, F, F-344, Whole body
180 g
Guinea pig, M/F, Whole body
400 g
Particle Characteristics
(/ig/m3) Size (jun); ag Exposure Duration
24,000 85% < 2 nm 8 h/day, 5 days/week,
3 weeks
25,000 4-5 16 h/day, 7 days/week,
2 weeks
24,000 most between 0.5-2 (GMD) 8 h/day, 5 days/week,
3 week
Observed Effect
No change in LDH, AP,
AG, Cathepsin D at 4-24 h
PE.
t TxA2, LTB4, protein; i
PGEj at 1 day PE; TxA2,
and LTB4 change persistent
for 2 weeks.
No change PMN; t no.
AM, eosinophils by
16 weeks PE.
Reference
Sjostrand and Rylander
(1984)
Kuhn et al. (1990)
Fogelmark et al. (1983)
Key to abbreviations:
LDH: lactate dehydrogenase
AP: acid phosphatase
AG: N-acetyl-fi-d-glucosaminidase
TxA2: thromboxane A2
LTB4: LeukotrineB4
PGEj: Prostaglandin Ej
AM: alveolar macrophage
PE: post-exposure
PMN: polymorphonuclear leukocyte
t: increase
^ : decrease
-------
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t Cytosolic GSM?,, protein at 30,000
100,000; t G6PDH at 100,000; 1 lung
microsomal protein, i microsomal BROl
at 30,000/100,000; no change microsom!
P-450 content; induction of EROD activ
at all cone, (all in lung tissue).
jj
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t Labeling of Type 2 cells; t incorpora
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persistent up to 4 days PE.
j=
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t Labeling index of large airway basal c
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by 4 weeks, resolved by 2 weeks PE.
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t P-450 content; t activity of aryl
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synthetase; inhibition of hemeoxygenase.
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April 1995
11-444 DRAFT-DO NOT QUOTE OR CITE
-------
1 11.9.5 Pulmonary Defenses
2 11.9.5.1 Clearance Function
3 Mucodliary Transport
4 Grose et al. (1985) exposed (whole-body) rats (Sprague-Dawley CD, M, 60 to
5 70 days) to volcanic ash from Mt. St. Helens (0.65 /mi, ag = 1.8) at 9,400 /Ag/m3 for 2 h.
6 At 24 h post exposure, a depression in ciliary beat frequency in excised tracheas was noted.
7 Whether this would contribute to any change in mucociliary transport function in the intact
8 animal is unknown.
9
10 Pulmonary Region Clearance and Alveolar Macrophage Function
11 A number of studies have examined particle retention following exposure to high
12 concentrations of inhaled particles, some of which have low intrinsic toxicity. Such
13 exposures resulted in a phenomenon known as overload, in which the effectiveness of lung
14 clearance mechanisms is significantly reduced. This response, which is nonspecific to a wide
15 range of particles, is discussed in detail in Chapter 10.
16 While there are no studies of effects of exposure to nonacidic sulfate particles on
17 alveolar region clearance, there have been several studies examining AM function following
18 inhalation exposures (Table 11-61) or with in vitro exposure. High exposure concentrations
19 of various particles can depress the phagocytic activity of AMs following inhalation.
20 To examine the effects of different fly ashes, Garrett et al. (1981b) incubated rabbit
21 AMs with < 1,000 /xg of either conventional coal combustion fly ash or fluidized bed
22 combustion fly ash at > 3 and < 3 jum, for 20 h. While all exposures caused reductions in
23 cell viability and cell ATP levels, conventional coal fly ash <3/xm produced the greatest
24 effect. These results suggest toxicity somewhat dependent on size, as observed previously
25 with other endpoints.
26 To examine for a nonspecific particle effect on phagocytosis, Finch et al. (1987)
27 exposed bovine AMs in vitro to TiO2 (1.57 /xm MMD, og=2.3) or to glass beads (2.1 /mi,
28 ag=1.8), the former at 2.3 or 5 /ig/ml, and the latter at 5 or 8.4 pig/ml. Neither exposure
29 altered phagocytic activity, but TiO2 did produce some decrease in cell viability.
April 1995 H_445 DRAFT-DO NOT QUOTE OR CITE
-------
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TABLE 11-61. EFFECTS OF PM ON ALVEOLAR MACROPHAGE FUNCTION
Particle
Carbon black
Volcanic ash
TiO2
Fly ash
(coal)
Ti02
Coal dust
California
road dust
Iron oxide
(Fe203)
Carbonyl
iron
Carbon black
TiO2
Species, Gender,
Weight Technique (pg'm3)
Mouse, F, Nose-only 10,000
Swiss, 20-23 g
Mouse, F, Whole body 9,400
CD-I, 4-8 weeks
Rat, M, F-344 Whole body 50,000
1 80-200 g
Mouse, F, Whole body 535
BALB/C; C57BL; (fine particle
6-8 weeks fraction
< 2.1 fan)
Rat, HAN Whole body 50,000
Rat, HAN Whole body 10,000, 50,000
Rat, F-344 Nose-only 300, 900
Rat, M, Nose-only 18,000-24,000
Long-Evans,
225-250 g
Rat, M, Nose-only 100,000
Crl:CDBR,
8 weeks
Mouse, F, Nose only 10,000
Swiss, 20-23 g
Guinea pig , M/F Whole body 24,000
400g
Particle Characteristics
Size (pin); og Exposure Duration Observed Effect1
2.45 (MMAD); 2.54 4 h/day, 4 days No change in Fc-mediated AM
phagocytic activity up to
40 days PE.
0.65 (MMAD); 1.8 2 h No change in viability of
recovered cells; no effect on
AM phagocytosis at 0 or 24 h
PE.
1 (MMAD); 2.6 6 h/day, 5 days No change hi spontaneous/
stimulated release of IL-1 by
AMs up to 63 days PE.
32 % < 2.1 /an 148 days 1 AM phagocytic activity by
(by wt) 21 days of exposure.
8 h/day, 5 days/week No change in chemotactic
activity of AM.
8 h/day, 5 days/week Decreased AM chemotactic
activity.
4 (MMAD) 4 h/day, 4 days/week, 1 Production of superoxide at
8 weeks high concentration; no change
in Fc receptor mediated
phagocytic activity.
1 .45-1 .7 (MMAD); 2.9-3 2 h No change in AM adherence;
t phagocytic activity of AM
(Fc-mediated) up to 20 days
PE.
3.6 (MMAD); 1.7 6 h; 6 h/day, 3 days No change in AM chemotactic
activity; cell viability ; slight t
AM phagocytic activity for
single exp.
2.4 (MMD); 2.75 4 h No change in Fc-receptor
mediated AM phagocytic
activity.
Most between 8 h/d, 5 days/week, No change in AM phagocytic
0.5-2 (GMD) 3 weeks activity.
Reference
Jakab (1992, 1993);
Jakab and Hemenway
(1993)
Grose et al. (1985)
Driscoll et al. (1991)
Zarkower et al. (1982)
Brown et al. (1992)
Brown et al. (1992)
Kleinman et al. (1995)
Lehnert and Morrow
(1985)
Warheit et al. (1991)
Jakab and Hemenway
(1993)
Fogelmark et al. (1983)
-------
1 Macrophages may contact particles via chemotactic-directed movement. Constituents
2 of lung fluid having high chemotactic activity are components of complement, and particles
3 which activate complement tend to show greater chemoattractant activity for macrophage
4 accumulation at sites of particle deposition (Warheit et al., 1988). For example, in an in
5 vitro study, iron-coated asbestos and carbonyl iron particles activated chemotactic activity in
6 rat serum and concentrated rat lavage proteins, while volcanic ash did not. When the rats
7 were exposed by inhalation to 10,000 to 20,000 ^g/m3 of these particles, only the volcanic
8 ash failed to produce an increased number of macrophages on the first alveolar duct
9 bifurcations, the primary deposition site for these particles and fibers. Complement proteins
10 on alveolar surfaces are likely to be derived primarily from normal transudation of serum
11 components from the pulmonary vasculature (Warheit et al., 1986). The generation of
12 chemotactic factors at particle deposition sites may facilitate clearance for some particle
13 types, but not for others, such as silica (Warheit et al., 1988, 1991).
14 In a somewhat related study, Hill et al. (1982) examined the interaction with
15 complement of coal combustion fly ash particles (2 to 3 /mi MM AD) from different sites,
16 using serum from dogs. In addition to releasing peptides that are chemotactic for
17 macrophages and other inflammatory cells, fly ash also induced release of lysosomal
18 enzymes and increased vascular permeability, all processes involved in inflammation. While
19 the authors noted that some fly ash samples activated complement, while others did not, they
20 were not able to determine which component on or in the ash was responsible for this action.
21 A possibility was suggested to be some metals, such as Mn, which are potent activators of
22 the complement cascade (Lew et al., 1975).
23 Thoren (1992) examined the metabolic activity of AMs by measuring heat exchange
24 rates after exposing cell monolayers to TiO2 or manganese dioxide (MnO2) at 0.6 — 4 x 106
25 particles/ml. The former affected metabolism only at the highest concentration used, while
26 the latter caused changes at lower concentrations as well.
27 The response of AMs to PM is influenced by both physical and chemical
28 characteristics of the particles with which they come into contact. Shanbhag et al. (1994)
29 exposed a macrophage cell line (P388D1) to particles of two different composition (TiO2 or
30 latex) at comparable sizes, 0.15 and 0.45 /xm for the former, and 0.11 and 0.49 for the
31 latter. They also used pure titanium at 1.76 /mi for comparison to latex at 1.61 /mi.
April 1995 11-447 DRAFT-DO NOT QUOTE OR CITE
-------
1 Titanium dioxide decreased cellular proliferation, depending upon both size and
2 concentration. Similar sizes and concentrations of latex produced lesser responses.
3 In addition, cells incubated with latex released factors, into the medium, which produced
4 fibroblast proliferation to a greater extent than did cells incubated with TiO2 of a similar size
5 and concentration.
6
7 11.9.5.2 Resistance to Infectious Disease
8 Susceptibility of mice to challenge with several infectious agents has been used to
9 assess effects of various inhaled particles on microbial defense of the lungs (Table 11-62).
10 The study of Jakab (1993) is of particular interest because the infectious agents used were
11 selected based upon differences in the antimicrobial defense mechanism most effective in
12 eliminating each organism. Thus, Staphylococcus aureus defense depends primarily upon the
13 integrity of AMs, while that for Proteus mirabilis involves both AMs and PMNs. Listeria
14 monocytogenes defenses involve specific acquired immunity, namely the integrity of the
15 lymphokine-mediated components of the cell- mediated immune response (e.g., AMs and
16 lymphocytes). A number of host defenses play a role in defense against influenza, including
17 specific cytotoxic lymphocytes. However, repeated exposure to 10,000 /ig/m3 carbon black
18 did not alter any of these antimicrobial defense systems.
19 Particles of low intrinsic toxicity may impair mechanisms involved in the clearance of
20 bacteria, perhaps increasing their persistence and resulting in increased infectivity. To
21 examine this possibility, a study was aimed at determining whether animals (guinea pigs) in
22 which phagocytic activity was impaired by exposure to a high concentration (23,000 /ig/m3)
23 of an "inert" dust (TiO2) were more susceptible to bacterial infection, in this case due to
24 Legionella pneumophila (Baskerville et al., 1988). While those AMs having heavy burdens
25 of Ti02 particles did not phagocytize the bacteria, there was no increase in infectivity in
26 particle-exposed compared to air-exposed control animals; this was suggested to be due to the
27 recruitment of monocytes into the lungs of the TiO2-exposed animals, and these cells were
28 able to phagocytize the bacteria.
29 The studies presented in Table 11-62 indicate that particles inhaled even at high
30 concentrations did not reduce resistance to microbial infections. However, some changes
31 were noted in an instillation study. Hatch et al. (1985) examined various particles
April 1995 11-448 DRAFT-DO NOT QUOTE OR CITE
-------
3.
so
TABLE 11-62. EFFECTS OF PM ON MICROBIAL INFECTIVITY
Particle
Species, Gender, Particle Characteristics
Strain, Age, or Exposure Mass Concentration
Body Weight Technique (pg/m3) Size pan); ag Exposure Duration
Observed Effect
Reference
Carbon black
Mouse, F,
Swiss, 20-23 g
Nose-only
4,700-6,100 2.45 (MMAD); 2.54 4 h/day, 4 days
No effect on susceptibility to infection
from 5. aureus administered 1 day PE;
no effect on intrapulmonary killing of
bacteria by AM.
Jakab (1992)
Carbon black
Mouse, F, Swiss,
20-23 g
Nose-only
10,000
2.4 (MMAD); 2.75 4 h/day, 4 days
No change in no. of S. aureus or P.
mirabilis recovered in lung after bacterial
challenge or on intrapulmonary killing of
bacteria administered 1 d PE; no effect
on proliferation of L. monocytogenes;
no effect on proliferation or elimination
of influenza A virus; no change in
albumin level in lavage 4 h after bacterial
challenge; no change in PMN in lavage
4 h after challenge.
Jakab (1993)
TiO2
Coal dust
Volcanic ash
TiO2
Guinea pig, F,
Dunkin-Hartley
300-350 g
Mouse, F, Swiss
CD-I, 20-24 g
Mouse, F, CD-I,
4-8 weeks
Mouse,
Harlan-Olac, 8
weeks
Whole body 23,000 95%<1.98/*m 20 h/day, 14 days
(MMAD)
Whole body 2,000 80% < 10 /im; 50% 7 h/day, 5 days/week,
<5 fim 6 mo
Whole body 9,400 0.65 (MMAD); 1.8 2h
Whole body 2,000, 20,000 95% < 1 .98 f«n (UDS) 20 h/day, 2 or 4 weeks
No change in susceptibility to Legionella
pneumophila administered 1-6 days PE
but AM with heavy particle burden did
not ingest bacteria.
No change in susceptibility to influenza
virus administered after 1, 3 and 6 mo
exposure; decrease in interferon level in
lung at 3 mo; no change in inflammatory
response to virus.
No change in susceptibility to bacteria
(Streptococcus) or virus administered 0 or
24 h PE; no change in lymphocyte
response to mitogens.
1 Clearance of P. haemolytica
administered after exposure in proportion
to exposure duration at 20,000 /ig/m3
only.
Baskerville et al.
(1988)
Hahon et al.
(1985)
Grose et al.
(1985)
Gilmour et al.
(1989a)
-------
u
TABLE 11-62 (cont'd). EFFECTS OF PM ON MICROBIAL INFECTIVITY
O
O
O
d
o
H
W
Particle
TiO2
TiO2
Species, Gender,
Strain, Age, or Body
Weight
Mouse, Harlan-Olac,
8 weeks
Mouse, Harlan-
Olac, 8 weeks
Exposure Mass Concentratio
Technique (/tg/m3)
Whole body
Whole body
20,000
20,000
Particle Characteristics
Size (nm); ag
95% < 1.98pm (UDS)
95% < 1.98pm
(UDS)
Exposure
20 h/day,
Duration
10 days
20 h/day, 7 days
Observed Effect
i Clearance of P. haemolytica,
persistent up to 10 days PE.
i Response to bacterial antigens of
mediastinal lymph node
lymphocytes from mice inoculated
with P. haemolytica after exposure.
Reference
Gilmour et al.
(1989a)
Gilmour et al.
(1989b)
Key to abbreviations:
I: decrease
PE: post-exposure
O
I— I
H
W
-------
1 administered by intratracheal instillation for their ability to alter infectivity in mice
2 subsequently exposed to a bacterium (Streptococcus sp). The specific particle types and their
3 sizes (VMD) were as follows: conventional coal combustion fly ash from various sources
4 (0.5 jim); various samples of fluidized bed combustion coal fly ash (0.4 to 1.3 /*m); various
5 samples of oil combustion fly ash (0.8-1.3/mi); volcanic ash (1.4 and 2.3^m); latex (0.5 and
6 5 /xm); and urban air particles (0.4 /xm) from Dusseldorf, Germany, Washington, DC, and
7 St. Louis, MO. The instillation dose was 100 /*g particles/mouse. An increase in infectivity
8 was found with all oil fly ash samples, some of the combustion and fluidized bed coal fly ash
9 samples, ambient air particles from Dusseldorf and Washington, latex, and also from carbon
10 and ferric oxide particles of unstated size. Exposure to volcanic ash, St. Louis ambient
11 particles, and other coal fly ash samples did not have an effect. It was postulated that the
12 activity of the fly ash reflected either the speculated presence of metals or the ability of the
13 ash to alter the pH of airway fluid. In a corollary to the above study, rabbit AMs were
14 incubated for 20 h with the various particles and cell viability assessed. Viability was
15 reduced by all oil fly ash samples, coal fly ash, ambient particles from all three sites,
16 volcanic ash and latex. These results did not totally correlate with the response following
17 in vivo exposures.
18 To examine effects of particles on nonimmunological antiviral defense, Hahon et al.
19 (1983) exposed monolayers of mammalian cells (rhesus monkey kidney cell line) to coal
20 combustion fly ash (2.5 /xm) at 500 to 5,000 /ig/10 ml medium and assessed effects on
21 interferon. Induction of interferon due to infection with influenza and parainfluenza virus
22 was reduced when the cells were pretreated with the fly ash. This was suggested to be due
23 to either the matrix itself, or to some surface component which was not extractable with
24 either polar or nonpolar solvents.
25 For some endpoints, there may be a particle size dependence of effect, with ultrafine
26 particles having greater inherent toxicity than larger particles. One study examined the effect
27 of two larger particles on infectivity. Grose et al. (1985) instilled (42 /xg/animal) mice
28 (CD-I, F, 4 to 8 weeks) with two sizes of volcanic ash from Mt. St. Helens, namely coarse
29 mode (12.1 /xm MM AD, ag=2.3) and fine mode (2.2 jim MM AD, ag = 1.9), followed by
30 challenge with bacteria (Streptococcus sp.) immediately or 24 h postexposure. No particle
31 size related difference was noted in susceptibility to bacterial infection, with both sizes
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1 producing a similar increase in infection following bacterial challenge at 24 h, but not
2 immediately, after pollutant exposure. However, inhalation exposure to 9,400 /xg/m3
3 volcanic ash (0.65 /mi) produced no change in infectivity (Table 11-62).
4
5 11.9.5.3 Immunologic Defense
6 The few studies on effects of inhaled particles on respiratory tract immune function
7 are shown in Table 11-63. Particles may affect some aspects of immune defense and not
8 others. For example, fly ash did not produce any change in the cellular immune response,
9 namely delayed hypersensitivity, but did depress the ability of macrophages to enhance T-cell
10 mitogenesis (Zarkower et al., 1982).
11
12 11.9.6 Systemic Effects
13 A few studies have examined systemic effects of inhaled particles. One assessed the
14 ability of particles to affect systemic immune responses (Eskew et al., 1982). Mice (F,
15 BALB/C) were continuously exposed for various times to coal combustion fly ash (32% by
16 wt <2.1 jiim), and the antigenic response of spleen cells to protein derivatives after
17 sensitization with BCG (delayed hypersensitivity reaction) was examined, as was the
18 mitogenic response of spleen cells to concanavalin A or lypopolysaccharide (LPS). Exposure
19 for 1 to 8 weeks to 1,150 ^ig/m3 reduced the mitogenic response of spleen cells after 3 weeks
20 of exposure, but not after 5 or 8 weeks and only for concanavalin A. Exposure for 5 mo to
21 2,220 /tg/m3 increased thymidine incorporation into spleen cells from BCG-sensitized mice.
22 Finally, exposure for 5 weeks to 871 jug/m3 reduced the number of antibody plaque forming
23 cells in the spleen and the hemagglutinin liter. These results suggest that fly ash has little
24 effect on the cellular immune response, but depresses the humoral response. The
25 implications of the increase in thymidine incorporation into the spleen of BCG-sensitized
26 mice was not clear, but may indicate an increase in resistance to infection.
27 In another study of systemic immunity, Mentnech et al. (1984) exposed rats (F344,
28 M, whole body) to 2,000 jug/m3 coal dust (40%
-------
TABLE 11-63. EFFECTS OF PM ON RESPIRATORY TRACT IMMUNE FUNCTION
2:
i— '
g
Ui
H*
^
t^>
Particle
Fly ash
(fluidized bed
coal
combustion)
Fly ash
(pulverized coal
combustion)
Fly ash (coal)
Key to abbreviati
Species, Gender,
Strain, Age, or
Body Weight
Rat, M/F, F-344,
12 weeks
Rat, M/F,
F-344, 12 weeks
Mouse, F BALB/C;
C57BL 6-8 weeks
ons:
Exposure Mass Concentration —
Technique (/tg/m3)
Whole body 36,000
Whole body 37,000
Whole body 760
(fine particle
fraction, <2.1 /tm)
2,200
(fine particle
fraction, <2.1 /an)
Particle Characteristics
Size (urn); ag Exposure Duration
3.6 (MMAD); 2.0 7 h/day, 5 days/week,
4 weeks
2.7 (MMAD); 2.1 7 h/day, 5 days/week,
4 weeks
32% < 2.1 fan 28 days (continuous)
(by wt)
160 days (continuous)
Observed Effect Reference
No effect on humoral immune Bice et al.
function. (1987)
t Antibody response at 48 weeks Bice et al.
PE. (1987)
^ Ability of AMs to stimulate Zarkower et al.
PHA-induced T-lymphocyte ( 1 982)
mitogenesis.
No change hi ability of animals
sensitized with BCG during
exposure to respond to purified
protein derivative challenge
(delayed hypersensitivity cellular
immune response).
H
6
o
2
s
AM: macrophage
PE: post-exposure
IL = interleukin
t: increase
I: decrease
I
o
n
-------
1 proliferative response of splenic T-lymphocytes to the mitogens concanavalin A and
2 phytohemagglutin was used to assess cellular immunity. No changes were found.
3
4
5 11.10 MECHANISMS OF TOXICOLOGICAL INTERACTIONS
6 Toxicological interactions with PM may be antagonistic, additive, or synergistic. The
7 presence and nature of any interaction seems to depend upon the concentration of pollutants
8 in the mixture, the exposure duration, and the endpoint being examined, and it is not possible
9 to predict a priori from the presence of certain pollutants whether there will be any
10 interaction.
11 Mechanisms responsible for the various forms of interaction are generally not known.
12 The greatest hazard in terms of potential health effects from pollutant interaction is the
13 possibility of synergism, especially if effects occur at all with mixtures which do not occur at
14 all when the individual constituents are inhaled. Various mechanisms may underly
15 synergism. One is physical, the result of adsorption or absorption of one material on a
16 particle and subsequent transport to more sensitive sites, or sites where this material would
17 not normally deposit in toxic amounts. This may explain the interaction found in studies of
18 mixtures of carbon black and formaldehyde, or carbon black and acrolein (Jakab, 1992,
19 1993), especially since formaldehye has been shown to be absorbed onto particles
20 (Rothenberg et al., 1989).
21 Somewhat related to this hypothesis is the possibility of reactions on particle surfaces,
22 forming some secondary products which may be more lexicologically active than the primary
23 material and which is then carried to some sensitive site. This may explain the results of the
24 Jakab and Hemenway (1993) study, wherein mice were exposed to carbon black either prior
25 to or after exposure to O3, and then to both materials simultaneously. Simultaneous
26 exposure produced evidence of interaction, while exposure to carbon black either before or
27 after O3 did not produce responses which were different from that due to exposure to
28 03 alone. The authors' suggested that this was due to a reaction of O3 on the surface of the
29 carbon black particles in the presence of adsorbed water, producing surface bound, highly
30 lexicologically active reactive oxygen species. Production of these species would not occur
31 when the exposures were sequential.
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1 Another mechanism may involve a pollutant-induced change in the local
2 microenvironment of the lung, enhancing the effects of the co-inhalant. Thus, the observed
3 synergism in rats between O3 and acidic sulfates was suggested to be due to a shift in the
4 local microenvironmental pH of the lung following deposition of acid, enhancing the effects
5 of O3 by producing a change in the reactivity or residence time of reactants, such as radicals,
6 involved in O3-induced tissue injury (Last et al., 1984). This hypothesis was examined in a
7 series of studies (Last et al., 1983, 1984, 1986; Last and Cross, 1978; Warren and Last,
8 1987; Warren et al., 1986) in which rats were exposed to various sulfur oxide aerosols
9 [H2SO4, (NH4)2SO4, Na2SO4] with and without oxidant gases (O3 or NO2), and various
10 biochemical endpoints examined. Acidic sulfate aerosols alone did not produce any response
11 at concentrations that caused a response in conjunction with O3 or NO2. Further evidence
12 that the synergism was due to H+ was the finding that neither Na2SO4 nor NaCl was
13 synergistic with O3 (Last et al., 1986). But if this was the only explanation for acid/O3
14 interaction, then the effects of ozone should be consistently enhanced by the presence of acid
15 in an exposure atmosphere regardless of endpoint examined. However, in the study of
16 Schlesinger et al. (1992b), in which rabbits were exposed for 3 h to combinations of 0.1,
17 0.3, and 0.6 ppm 03 with 50, 75, and 125 /*g/m3 H2SO4 (0.3 pm), antagonism was noted
18 when evaluating stimulated production of superoxide anion by AMs harvested by lavage
19 immediately after exposure to 0.1 or 0.3 ppm ozone in combination with 75 or 125 /-ig/m3
20 H2SO4, and also for AM phagocytic activity at all of the ozone/acid combinations; there was
21 no change in cell viability compared to air control.
22
23
24 11.11 TOXICOLOGY OF PM IN COMPROMISED HOST ANIMAL
25 MODELS
26 Epidemiological studies suggest there may be subsegments of the population that are
27 especially susceptible to effects from inhaled particles (see Chapter 12). One particular
28 group may be those having lungs compromised by respiratory disease. However, most
29 toxicology studies have used healthy adult animals, and there are very few data to allow
30 examination of the effects of different disease states upon the biological response to PM.
31 A number of studies have examined the effects of lung disease on deposition and/or clearance
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1 of inhaled aerosols, and these are discussed in Chapter 10. Alterations in deposition sites
2 and clearance rates/pathways due to concurrent disease may impact upon dose delivered from
3 inhaled particles and ultimate toxicity.
4 Some work has been performed with acidic sulfate aerosols using models of
5 compromised hosts. Rats and guinea pigs with elastase-induced emphysema were examined
6 to assess whether repeated exposures (6 h/day, 5 days/week, 20 days) to (NH4)2SO4
7 (1,000 /xg/m3, 0.4 j*m MMAD) or NH4NO3 (1,000 /*g/m3, 0.6 /*m MMAD) would alter
8 pulmonary function compared to saline-treated controls (Loscutoff et al., 1985). Similarly,
9 dogs having lungs impaired by exposure to NO2 were treated with H2SO4 (889 /-ig/m3,
10 21 h/day, 620 days) (Lewis et al., 1973). Results of both of these studies indicated that the
11 specific induced disease state did not enhance the effect of acidic sulfate aerosols in altering
12 pulmonary function; in some cases, there were actually fewer functional changes in the
13 diseased lungs than in the unimpaired animals. It is possible, however, that other types of
14 disease states could result in enhanced response to inhaled acidic aerosols; as mentioned,
15 asthma is a likely one, but there are no data to evaluate whether effects are enhanced in
16 animal models of human asthma.
17 Few studies have examined effects of other particles in health compromised host
18 models. Mauderly et al. (1990) exposed young rats having elastase-induced emphysema to
19 whole diesel exhaust (3,500 jug soot/m3) for 24 mo (7 h/day, 5 days/week). Various
20 endpoints were examined after exposure, including pulmonary function (e.g., respiratory
21 pattern, lung compliance, DLco), biochemical components of BAL (e.g., enzymes, protein,
22 collagen), and histopathology and morphometry. There was no evidence that the diseased
23 lungs were more susceptible to the diesel exhaust than were normal lungs. In fact, in some
24 cases, there seemed to be a reduced effect of the diesel exhaust in the emphysematous lungs.
25 But this could be due to a reduced lung burden in the diseased lungs, resulting from
26 differences in deposition and/or clearance compared to normal lungs.
27 Rats having elastase-induced emphysema were exposed to 9,400 /xg/m3 (0.65 jtm) Mt.
28 St. Helens volcanic ash for 2 h/day for 5 days (Raub et al., 1985; Table 11-78), with and
29 without 2,700 Mg/m3 SO2. Effects on pulmonary mechanics in these rats were similar to
30 those noted in normal animals exposed to the same atmosphere.
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1 Raabe et al. (1994) exposed rats with elastase-induced emphysema to two particle
2 atmospheres, a California-type aerosol and an London-type aerosol. The former consisted of
3 1.1 to 1.5 /im (MMAD; erg = 1.7 to 2.4) particles of graphitic carbon, natural clay,
4 NH4HSO4, (NH4)2SO4, NH4NO3, PbSO4, VOSO4, MnSO4, and NiSO4. The latter consisted
5 of 0.8 to 0.9 /im particles (ag = 1.7 to 1.8) of NH4HSO4, (NH4)2SO4, coal fly ash, and
6 lamp black carbon. While the elastase treated rats showed increased lung DNA and RNA,
7 exposure for 3 days (23 h/day) to the London aerosol produced a further increase not seen in
8 exposed normal rats. There were no changes in tracheobronchial clearance or lung
9 permeability compared to normals. A 30-day exposure to the California aerosol enhanced
10 small airway lesions in the elastase-treated animals, but did not alter lung hydroxyproline,
11 tracheobronchial clearance, or small airway fibrosis.
12 Thus, the available toxicological database is yet unable to provide a conclusion as to
13 any enhanced susceptibility to PM of "compromised" hosts with concurrent lung disease.
14 One potential inherent host factor affecting susceptibility to particles is age. In an
15 early study, Amdur et al. (1952) determined that the H2SO4 (1 jmi, MMD) concentration
16 needed to produce 50% mortality (LC50) for an 8-h exposure in guinea pigs was 18,000
17 /ig/m3 for 1-to 2-mo old animals, and 50,000 /*g/m3 for 18-mo old animals.
18
19
20 11.12 FACTORS INFLUENCING PM TOXICITY
21 The factors modulating biological responses to PM are not always clear. However,
22 the available toxicological database does allow for some speculation as to which factors may
23 influence biological responses to diverse types of PM. For example, the toxic potency of
24 inorganic particles may be related to certain physicochemical characteristics. While the bulk
25 chemical makeup of a particle would clearly influence its toxicity, responses may also be
26 driven by chemical species adsorbed onto the particle surface, even for those particles
27 considered to have low intrinsic toxicity. Furthermore, certain physical properties of
28 particles, such as size or surface area, and of aerosols, such as number concentration, may
29 be factors in determining reponses from PM. This section provides an overview of current
30 hypotheses concerning characteristics of particles which may relate to their toxicity.
31
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1 11.12.1 Particle Acidity
2 It should be clear from discussions in Section 11.2 that the deposition of acidic
3 particles in the respiratory tract can result in various biological effects. The bulk of the
4 toxicologic database on acidic PM involves sulfate particles, primarily H2SO4, but the
5 available evidence indicates that the observed responses to these are likely due to the H+,
6 rather than to the SO4=. Thus, effects observed for this pollutant likely apply to other
7 inorganic acidic particles having similar deposition patterns in the respiratory tract, although
8 the specific chemical composition of different acids may be a factor mediating the
9 quantitative response (Fine et al., 1987). In terms of H+, the irritant potency of an acid
10 aerosol may be related more to the total available H+ concentration (i.e., titratable acidity in
11 lung fluids following deposition) rather than to the free H+ concentration as measured by pH
12 (Fine et al., 1987). In any case, the response to acidic particles appears to be due to a direct
13 irritant action and/or the subsequent release of humoral mediators.
14 Acidic particles exert their action throughout the respiratory tract, with the response
15 and location of effect dependent upon particle size and mass concentration. They have been
16 shown to alter bronchial responsiveness, mucociliary transport, clearance from the pulmonary
17 region, regulation of internal cellular pH, production of cytokines and reactive oxygen
18 species, pulmonary mechanical function, and airway morphology.
19 Particles do not have to be pure acid droplets to elicit health effects. The acid may
20 be associated with another particle type. For example, in the study of Chen et al. (1990),
21 guinea pigs were exposed to two different fly ashes, one derived from a low sulfur coal and
22 one from a high sulfur coal (Table 11-52). Levels of acidic sulfates associated with the fly
23 ash were found to be proportional to the coal sulfur content, and greater effects on
24 pulmonary functional endpoints were noted for the high sulfur fly ash than for the low sulfur
25 fly ash.
26
27 11.12.2 Particle Surface Coatings
28 The presence of surface coatings may make certain particles more toxic than expected
29 based solely upon particle core composition. This was noted in studies of acid-coated metal
30 oxides (Section 11.4). Certain surface metals may be especially important in this regard, and
31 because trace metal species vary geographically, this may account to some extent for
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1 particles in different areas having different toxic potentials. Garrett et al. (198la) exposed
2 rabbit AMs in vitro to fly ash, with and without surface coatings of various metal oxides.
3 Reductions in cell viability and cellular ATP content were found only with the metal-coated
4 ash particles. To determine potencies of specific metals, Berg et al. (1993) examined
5 different fractions of fly ash, all of which were <4 fj.m in diameter, for their ability to
6 stimulate bovine AMs to secrete reactive oxygen species, namely superoxide anion and
7 hydrogen peroxide. They noted that production of these species was often associated with
8 the metal content of the fly ash particle, with the order of greatest association as follows:
9 iron> manganese > chromium > vanadium > arsenic. The positioning of iron as first in this
10 scheme is consistent with results of some other studies examining the biological effect of iron
11 present as a particle surface coating.
12 Ohio et al. (1992) and Ohio and Hatch (1993) examined surface components which
13 may be responsible for the biological effects of silica. Functional groups on the surface of
14 mineral oxides coordinate ferric ion, and such complexes can result in an increased capacity
15 to catalyze an electron exchange, producing hydroxyl radicals. This could then expose lung
16 tissues to oxidant stress, which can result in an increase in the products of lipid peroxidation
17 and induction of gene expression. They noted that an extracellular accumulation of
18 surfactant following silica exposure was associated with the concentration of ferric ion (Fe+3)
19 complexed to the surface of the particles, and that surfactant-enriched material was a target
20 for oxidants, the production of which was catalyzed by ferric ion. In addition, they noted
21 that the ability of silicates to catalyze the generation of reactive oxygen species, to trigger
22 respiratory bursts, and to elicit release of leukotriene B4 by AMs increased with increasing
23 surface-complexed ferric ion content.
24 A role of iron-induced oxidative stress in PM-related lung injury is further supported
25 by a study demonstrating that surface available iron and the oxidizing power of mineral
26 particles were both correlated with cytotoxicity, expression of cytokeratin-13, and formation
27 of cross-linked envelopes of rabbit tracheal epithelial cells (Guilianelli et al., 1993), and that
28 deferoxamine treatment blocked these effects. Thus, it is possible that reactive oxygen
29 species produced through chemical reactions involving iron could initiate lipid peroxidation
30 of the cell membrane, resulting in cell death and subsequent lung injury.
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1 Recently, surface complexed iron has been implicated in pulmonary injury due to a
2 variety of environmental particles (Costa et al., 1994a,b; Tepper et al., 1994). Three
3 particle types (Mt. St. Helen's volcanic ash, ambient particles of Dusseldorf, Germany, and
4 residual oil fly ash), which represented a range of inflammatory potential, were
5 intratracheally instilled into rats. Both the degree of acute inflammation (as measured by
6 assessing PMNs, eosinophils, LDH and protein in lavage) and nonspecific bronchial
7 responsiveness correlated with the iron (specifically Fe+3) loading of the particles.
8 An interesting observation was that surface iron was correlated with particle acidity, yet
9 when instillation of H2S04 at comparable pH was performed, the lavage analysis indicated
10 much less inflammation with the pure acid compared to the high surface iron particles.
11 In fact, neutralization of the fly ash instillate (which could occur if similar particles were
12 inhaled, due to endogeneous respiratory tract ammonia) actually enhanced particle toxicity,
13 while the pulmonary response diminished when iron was removed from the fly ash by acid
14 washing. These preliminary results generally support the notion that oxidant generation by
15 iron present on the surface of particles may increase lung injury; but clearly other factors are
16 likely to contribute to this response. For example, some metals can catalyze conversion of
17 S02 to acidic sulfate on some particles, increasing their acidity (Kleinman et al., 1984).
18
19 11.12.3 Particle Size
20 Studies which have examined PM-induced mortality seem to suggest some inherent
21 potential toxicity of ultrafine particles (Section 11.5), and other endpoints appear to show this
22 as well. This is especially important when considering particles which may have low
23 inherent toxicity at one size, yet greater potency at another. However, the mechanism which
24 underlies a size-related difference in toxicity is not known at this time.
25 To compare toxic potency of particles of different sizes, intratracheal instillation has
26 often been used. This technique allows the delivery of equivalent doses of different materials
27 and avoids differences in deposition which would occur if particles of different sizes were
28 inhaled. While this approach may highlight inherent similarities and differences in responses
29 to particles of various sizes, in reality, there would be greater deposition of singlet ultrafine
30 particles (in the size range used in the toxicology studies described) in the lungs, especially
31 within the alveolar region, than for the larger fine or coarse mode particles.
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1 The release of proinflammatory mediators may be involved in lung disease, and their
2 levels may be increased with exposure to ultrafine particles. For example, Driscoll and
3 Maurer (1991) compared effects of instilled fine (0.3 /urn) or ultrafine (0.02 /mi) TiO2, in rat
4 (F344) lungs. Concentrations were 10,000 ^g particles/kg BW. Lavage was performed up
5 to 28 days post-exposure, and pathology was assessed at this 28-day time point. While both
6 size modes produced an increase in the number of AMs and PMNs in lavage, the increase
7 was greater and more persistent with the ultrafine particles. The release of another
8 monokine, tumor necrosis factor (TNF), by AMs was stimulated with both sizes, but again
9 the response was greater and more persistent for the ultrafines. A similar response was
10 noted for fibronectin produced by AMs. Finally, fine particle exposure resulted in a
11 minimally increased prominence of particle-laden macrophages associated with alveolar
12 ducts, while ultrafine particle exposures produced somewhat of a greater prominence of
13 macrophages, some necrosis of macrophages and slight interstitial inflammation associated
14 with the alveolar duct region. In addition, increased collagen occurred only with ultrafine
15 particle exposure.
16 Oberdorster et al. (1992) instilled rats with 500 jig TiOj in either fine (0.25 pirn) or
17 ultrafine (0.02 pim) sizes, and performed lavage 24 h later. Various indicators of acute
18 inflammation were altered with the ultrafine particles; this included an increase in the number
19 of total cells recovered, a decrease in percentage of AMs and increase in percentage of
20 PMNs, and an increase in protein. On the other hand, instillation of the fine particles did
21 not cause statistically significant effects. Thus, the ultrafine particles had greater pulmonary
22 inflammatory potency than did the larger size particles of this material. The investigators
23 attributed enhanced toxicity to greater interaction of the ultrafine particles, with their large
24 surface area, with alveolar and interstitial macrophages, resulting in enhanced release of
25 inflammatory mediators. They suggested that ultrafine particles of materials of low in vivo
26 solubility appear to enter the interstitium more readily than do larger size particles of the
27 same material, which accounted for the increased contact with macrophages in this
28 compartment of the lung. In support of these results, Driscoll and Maurer (1991) noted that
29 the pulmonary retention of ultrafine TiO2 particles instilled into rat lungs was greater than for
30 the same mass of fine mode TiO2 particles.
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1 Not all ultrafine particles will enter the interstitium to the same extent, and this may
2 influence toxicity. For example, both TiO2 and carbon black elicit an inflammatory
3 response, yet much less of the latter appears to enter the interstitium after exposure
4 (Oberdorster et al., 1992). Since different particles may induce chemotactic factors to
5 different extents, it is possible that a lower generation with TiO2 results in less contact with
6 and phagocytosis by macrophages, a longer residence time at the area of initial deposition,
7 and a resultant greater translocation into the interstitium. Similarly, Brown et al. (1992;
8 Table 11-24) noted following inhalation exposure of rats to TiO2 or coal mine dust that the
9 former did not affect macrophage chemotaxis, while the latter reduced it; the coal dust also
10 produced a greater inflammatory response than did the TiO2. This is consistent with less
11 interaction of coal dust with AMs and greater movement into the interstitium.
12 The above studies appear to support the concept of some inherent toxicity of ultrafine
13 particles compared to larger ones. Both particle size and the resultant surface area of a unit
14 mass of particles likely influences toxic potential. Surface area is important because, as
15 noted above, adsorption of certain chemical species on particles may enhance their toxicity,
16 and this could be an even greater factor for ultrafine particles with their larger surface area
17 per unit mass.
18 Other studies have compared effects following exposures to larger than ultrafine
19 particle sizes, and the results ranged from none detectable to some particle size-related
20 differences. Raub et al. (1985) instilled into rats coarse mode (12.2 pirn) and fine mode (2.2
21 pm) volcanic ash at two dose levels, 50,000 or 300 /*g particles/animal. The coarse mode
22 produced a change in end expiratory volume, but no changes in other pulmonary function
23 endpoints (i.e., frequency, VT, peak inspiratory and expiratory flows, VC, RV, TLC).
24 When lungs were examined 6 mo after instillation, animals exposed to the low dose of either
25 size fraction showed no changes in lung weight or hydroxyproline content compared to
26 control, while those exposed to the high concentration of coarse mode ash showed increased
27 lung weight. In terms of histopathology, both size modes produced some focal alveolitis.
28 Thus, there were essentially no differences in responses between the two size modes,
29 especially at the low exposure dose. In a similar study, Grose et al. (1985) instilled mice
30 with 42 /ig/animal of volcanic ash in the same two size fractions as above, coarse and fine,
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1 24 h prior to challenge with bacteria (Streptococcus sp.). A small, but similar, increase in
2 susceptibility to infection was noted with both particle sizes.
3 Shanbhag et al. (1994) exposed a mouse macrophage cell line (P388D1) to particles of
4 two different composition (TiO2 or latex) at comparable sizes, 0.15 and 0.45 /*m for the
5 former, and 0.11 and 0.49 for the latter. They also used pure titanium at 1.76 pm for
6 comparison to latex at 1.61 /*m. In order to examine effects of particle surface area, the
7 cells were exposed to a constant surface area of particles, expressed in terms of mm2 per unit
8 number of cells. This was obtained based upon particle size and density and, therefore, the
9 weight percentage was greater for larger particles than for smaller ones for the same surface
10 area. Furthermore, because of particle density differences, the weight percentage for
11 similarly sized particles of different materials to obtain the same surface area also differed.
12 The authors noted that at a constant total particle surface area to cell ratio, the 0.15 and
13 0.45 /xm particles were less inflammatory than were the 1.76 /jm particles, in that the smaller
14 particles produced lower elicited levels of interleukin-1 and less cell proliferation. These
15 results indicate that the larger particles had greater toxicity than the smaller ones in this
16 experimental system. Thus, the exact relationship between particle size and toxicity is not
17 resolved, but may differ for different size modes.
18
19 11.12.4 Particle Number Concentration
20 The number concentration of particles within an aerosol will increase as the size of
21 the constituent particles decrease. Thus, for a given mass concentration of a material, there
22 would be greater particle numbers in an ultrafine aerosol than in a fine aerosol.
23 As previously discussed (Section 11.3.1), studies have shown various biological responses,
24 such as reductions in lung volumes and diffusion capacity, alterations in biochemical
25 markers, and changes in lung tissue morphology, in guinea pigs following exposure to
26 ultrafine ZnO having a surface layer of H2SO4. These responses were much greater than
27 were found following exposure to H2SO4 aerosols in pure droplet form yet having a similar
28 mass concentration.
29 A possible contribution to this differential response is that the number concentration
30 of particles in the exposure atmospheres were different, resulting in different numbers of
31 particles deposited at target sites. At an equal total sulfate mass concentration, H2SO4
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1 existed on many more particles when layered on the ZnO carrier particles than when
2 dissolved into aqueous droplets (i.e., pure acid aerosol); this was because the particle size
3 distribution of the former aerosol was smaller than that of the latter. Therefore, it is possible
4 that the greater the number of particles containing H2SO4, the greater will be the number of
5 cells affected after these particles deposit in the lungs, and the more severe will be the
6 overall biological response. While differences in particle size distributions between the
7 coated and pure acid particles may have influenced the results to some extent, a recent in
8 vitro study confirmed that the number of particles in the exposure atmosphere, not just total
9 mass concentration, is an important factor in biological responses following acidic sulfate
10 particle inhalation (Chen et al., 1995) when aerosols having the same size distribution were
11 compared.
12
13
14 11.14 SUMMARY
15 11.14.1 Summary of Acid Aerosols
16 The results of human studies indicate that healthy subjects do not experience
17 decrements in lung function following single exposures to H2SO4 at levels up to 2,000 /xg/m3
18 for 1 h, even with exercise and use of acidic gargles to minimize neutralization by oral
19 ammonia. Mild lower respiratory symptoms occur at exposure concentrations in the mg/m3
20 range, particularly with larger particle sizes. Acid aerosols alter mucociliary clearance in
21 healthy subjects, with effects dependent on exposure concentration and the region of the lung
22 being studied.
23 Asthmatic subjects appear to be more sensitive than healthy subjects to the effects of
24 acid aerosols on lung function, but the effective concentration differs widely among studies.
25 Adolescent asthmatics may be more sensitive than adults, and may experience small
26 decrements in lung function in response to H2SO4 at exposure levels only slightly above peak
27 ambient levels. Although the reasons for the inconsistency among studies remain largely
28 unclear, subject selection and acid neutralization by NH3 may be important factors. Even in
29 studies reporting an overall absence of effects on lung function, occasional asthmatic subjects
30 appear to demonstrate clinically important effects. Two studies from different laboratories
31 have suggested that responsiveness to acid aerosols may correlate with degree of baseline
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1 airway hyperresponsiveness. There is a need to identify determinants of responsiveness to
2 H2SO4 exposure in asthmatic subjects. In very limited studies, elderly and individuals with
3 chronic obstructive pulmonary disease do not appear to be particularly susceptible to the
4 effects of acid aerosols on lung function.
5 Two recent studies have examined the effects of exposure to both H2SO4 and ozone
6 on lung function in health and asthmatic subjects. Both studies found evidence that
7 100 /ig/m3 H2SO4 may potentiate the response to ozone, in contrast with previous studies.
8 Human studies of particles other than acid aerosols provide insufficient data to draw
9 conclusions regarding health effects. However, available data suggest that inhalation of inert
10 particles in the respirable range, including three studies of carbon particles, have little of no
11 effect on symptoms or lung function in healthy subjects at levels above peak ambient
12 concentrations.
13 The bulk of the toxicologic data base on PM involves sulfur oxide particles, primarily
14 H2SO4, and the available evidence indicates that the observed responses to these are likely
15 due to H+ rather than to SO4=.
16 Acidic sulfates exert their action throughout the respiratory tract, with the response
17 and location of effect dependent upon particle size and mass and number concentration.
18 At very high concentrations that are not environmentally realistic, mortality will occur
19 following acute exposure, due primarily to laryngeal or bronchoconstriction; larger particles
20 are more effective in this regard than are smaller ones. Extensive pulmonary damage,
21 including edema, hemorrhage, epithelial desquamation, and atelectasis can also cause
22 mortality, but even in the most sensitive animal species, concentrations causing mortality are
23 quite high.
24 Both acute and chronic exposure to H2SO4 at levels well below lethal ones will
25 produce functional changes in the respiratory tract. The pathological significance of some of
26 these are greater than for others. Acute exposure will alter pulmonary function, largely due
27 to bronchoconstrictive action. However, attempts to produce changes in airway resistance in
28 healthy animals at levels below 1,000 /ig/m3 have been largely unsuccessful, except when the
29 guinea pig has been used. The lowest effective level of H2SO4 producing
30 bronchoconstriction to date in the guinea pig is 100 /*g/m3 (1-h exposure). In general, the
31 smaller size droplets were more effective in altering pulmonary function, especially at low
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1 concentrations. Yet even in the guinea pig, there are inconsistencies in the type of response
2 exhibited towards acid aerosols. Chronic exposure to H2SO4 is also associated with
3 alterations in pulmonary function (e.g., changes in the distribution of ventilation and in
4 respiratory rate in monkeys). But, in these cases, the effective concentrations are
5 >500 fig/m3. Hyperresponsive airways have been induced with repeated exposures to
6 250 jug/m3 H2SO4 in rabbits, and have been suggested to occur following single exposures at
7 75 /ig/m3.
8 Severe morphologic alterations in the respiratory tract will occur at high acid levels.
9 At low levels and with chronic exposure, the main response seems to be hypertrophy and/or
10 hyperplasia of mucus secretory cells in the epithelium; these alterations may extend to the
11 small bronchi and bronchioles, where secretory cells are normally rare or absent.
12 The lungs have an array of defense mechanisms to detoxify and physically remove
13 inhaled material, and available evidence indicates that certain of these defenses may be
14 altered by exposure to H2SO4 levels < 1,000 /xg/m3. Defenses such as resistance to bacterial
15 infection may be altered even by acute exposure to concentrations of H2SO4 around
16 1,000 /ig/m3. However, the bronchial mucociliary clearance system is very sensitive to
17 inhaled acids; fairly low levels of H2SO4 produce alterations in mucociliary transport rates in
18 healthy animals. The lowest level shown to have such an effect, 100 pg/m3 with repeated
19 exposures, is well below that which results in other physiological changes in most
20 experimental animals. Furthermore, exposures to somewhat higher levels that also alter
21 clearance have been associated with various morphometric changes in the bronchial tree
22 indicative of mucus hypersecretion.
23 Limited data also suggest that exposure to acid aerosols may affect the functioning of
24 AMs. The lowest level examined in this regard to date is 500 /xg/rn3 H2SO4. Alveolar
25 region particle clearance is affected by repeated H2S04 exposures to as low as 250 pig/m3.
26 The assessment of the toxicology of acid aerosols requires some examination of
27 potential interactions with other air pollutants. Although such interactions may be
28 antagonistic, additive, or synergistic, the exact mechanism by which they occur is not well
29 defined, and evidence for them may depend upon the sequence of exposure as well as on the
30 endpoint examined. Low levels of H2SO4 (100 jug/m3) have been shown to react
31 synergistically with O3 in simultaneous exposures using biochemical endpoints. In this case,
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1 the H2SO4 enhanced the damage due to the O3. This is common in studies with O3, while
2 H2SO4 effects themselves may be more manifest with other, less potent, co-inhalants. The
3 most realistic exposures are to multicomponent atmospheres, but the results of these are often
4 difficult to assess due to chemical interactions of components and a resultant lack of precise
5 control over the composition of the exposure environment.
6
7 11.14.2 Summary of Complex Mixtures
8 11.14.2.1 Summary of Carcinogenicity of Atmospheric Particulate Matter
9 The 1982 Air Quality Criteria Document for Particulate Matter and Sulfur Dioxide
10 concluded from its review of studies on the genotoxicity and carcinogenicity of atmospheric
11 particles that "all the major types of airborne paniculate matter may contain adsorbed
12 compounds that are mutagenic and/or carcinogenic to animals and may contribute in some
13 degree to the human cancer associated with exposure to urban air pollution." Recent
14 research activity has added data that support this conclusion, but do not warrant that it be
15 changed significantly. Recent research activity has included:
16
17 (1) extensive in vitro mutagenicity testing and limited in vivo animal
18 tumorigenicity testing or organic-solvent extracts of ambient air paniculate
19 matter showing predominately positive responses;
20
21 (2) mutagenicity and tumorigenicity testing of condensates or organic-solvent
22 extracts of paniculate emissions from specific combustion sources (e.g., diesel
23 engines, gasoline engines and burning of cooking and heating fuels) showing
24 predominately positive responses;
25
26 (3) and fractionation studies showing that significant portions of the genotoxic or
27 carcinogenic activity of whole extracts of paniculate matter emitted from
28 specific combustion sources are accounted for by fractions containing complex
29 mixtures of neutral organic molecules including polycyclic aromatic
30 hydrocarbons.
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1 The direct relevance of the evidence for the mutagenicity and tumorigenicity of extracts of
2 paniculate matter in experimental systems to exposure scenarios experienced by humans is
3 uncertain at this time. Recent analytical epidemiological studies, that adjusted for tobacco
4 smoking and other major potential risk factors, have found a weak to non-existent association
5 between human lung cancer and indices of exposure to air pollution including paniculate
6 matter. Most investigators believe that the epidemiological evidence obtained thus far does
7 not substantiate causality, although the hypothesis remains credible.
8
9 11.14.2.2 Summary of Diesel Emissions
10 Noncancer effects of diesel emissions
11 Acute toxic effects caused by exposure to diesel exhaust are mainly attributable to the
12 gaseous components (i.e., mortality from carbon monoxide intoxication and lung injury from
13 respiratory irritants). When the exhaust is diluted to limit the concentrations of these gases,
14 acute effects are not seen.
15 A total of 10 different long-term (> 1 year) animal inhalation studies of diesel engine
16 emissions have been conducted. The focus of these studies has been on the respiratory tract
17 effects in the alveolar region. Effects in the upper respiratory tract and in other organs were
18 not found consistently in chronic animal exposures. Several of these studies are derived
19 from research programs on the toxicology of diesel emissions that consisted of large-scale
20 chronic exposures, which are represented by multiple published accounts of results from
21 various aspects of the overall research program. The respiratory system response has been
22 well characterized in terms of histopathology, biochemistry, cytology, pulmonary function,
23 and respiratory tract clearance. The pathogenic sequence following the inhalation of diesel
24 exhaust as determined histopathologically and biochemically begins with the phagocytosis of
25 diesel particles by AMs. These activated macrophages release chemotactic factors that attract
26 neutrophils and additional AMs. As the lung burden of diesel particles increases, there is an
27 aggregation of particle-laden AMs in alveoli adjacent to terminal bronchioles, increases in the
28 number of Type 2 cells lining particle-laden alveoli, and the presence of particles within
29 alveolar and peribronchial interstitial tissues and associated lymph nodes. The PMNs and
30 macrophages release mediators of inflammation and oxygen radicals and particle-laden
31 macrophages are functionally altered resulting in decreased viability and unpaired
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1 phagocytosis and clearance of particles. There is a substantial body of evidence for an
2 impairment of paniculate clearance from the bronchio-alveolar region of rats following
3 exposure to diesel exhaust. The latter series of events may result in the presence of
4 pulmonary inflammatory, fibrotic, or emphysematous lesions. The noncancer toxicity of
5 diesel emissions is considered to be due to the particle rather than the gas phase, since the
6 long-term effects seen with whole diesel are not found or are found to a much lesser extent
7 in animals exposed to similar dilutions of diesel exhaust filtered to remove most of the
8 particles. Chronic studies in rodents have demonstrated pulmonary effects at 200 to 700
9 Mg/m3 (expressed as equivalent continuous exposure to adjust for protocol differences). No-
10 effect level have been reported ranging from 60 to 260 /xg/m3.
11 Several epidemiologic studies have evaluated the effects of chronic exposure to
12 diesel exhaust on occupationally exposed workers. None of these studies are useful for a
13 quantitative evaluation of noncancer toxicity because of inadequate exposure
14 characterization, either because exposures were not well defined or because the possible
15 confounding effects of concurrent exposures could not be evaluated.
16
17 Carcinogenic effects of diesel emissions
18 The U.S. Environmental Protection Agency (1994) has developed a draft qualitative
19 and quantitative cancer assessment for diesel emissions. The summary to follow was drawn
20 from that document. This draft is currently undergoing external review by the public and
21 the Clean Air Scientific Advisory Committee. As a result of limited evidence from
22 epidemiological data, supported by adequate evidence for carcinogenicity of diesel engine
23 emissions in animal studies, as well as positive evidence for mutagenicity, it was concluded
24 that diesel engine emissions best fit into cancer weight-of-evidence Category Bl. Diesel
25 engine emissions are thus considered to be probable human carcinogens. This is in
26 agreement with a 2A classification by the International Agency for Research on Cancer.
27 Using a dosimetry model that accounted for animal-to-human differences in lung
28 deposition efficiency, lung particle clearance rates, lung surface area, ventilation, metabolic
29 rate, as well as elution rates of organic chemicals from the particle surface, equivalent
30 human doses were calculated on the basis of particle concentration per unit lung surface
31 area. Following dosimetric adjustment, risk estimates were derived using a linearized
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1 multistage model. A unit risk estimate of 3.4 x 10~5 (the upper 95% bound of the cancer
2 risk from lifetime exposure to 1 /ig/m3 diesel particulate matter) is recommended. This
3 estimate is based on the geometric mean of estimates derived from three separate animal
4 bioassays using Fischer 344 rats.
5 This unit risk estimate should not be used to evaluate the cancer risk of other types
6 of particulate matter present in the ambient air. These particles may have differing
7 solubilities, surface areas, presence of free radicals, or other properties which may greatly
8 affect cancer potency.
9
10 11.14.3 Summary of Metals
11 11.14.3.1 Aluminum
12 Although pharmacokinetic data following inhalation exposure are somewhat limited,
13 the existing data indicate that there are no major differences between the pharmacokinetics
14 of aluminum in humans and laboratory animals. Differences in deposition are anticipated
15 however.
16 Human occupational and epidemiological studies and animal studies support the
17 respiratory tract as the primary target of inhaled aluminum compounds. Common reported
18 symptoms include asthma, cough, and decreased pulmonary function (Abramson et al.,
19 1989; Chan-Yeung et al., 1983; Simonsson et al., 1985); fibrosis has also been reported
20 (Chen et al., 1978; De Vuyst et al., 1986; Gaffuri et al., 1985; McLaughlin et al., 1962;
21 Musk et al., 1980; Shaver and Riddel, 1947). However, the occupational studies report
22 concomitant exposure to known carcinogens and other respiratory irritants (PAHs, carbon
23 monoxide, sulfur dioxide, hydrogen fluoride), and many of the workers were chronic
24 smokers. Therefore, it is not clear whether effects reported in workers with occupational
25 inhalation of aluminum can be attributed to the metal itself since the studies were
26 confounded by co-exposure to other agents with known respiratory tract effects.
27 For these reasons, short- and long-term studies in laboratory animals may more
28 accurately reflect the effects of inhaling aluminum. These studies have generally found that
29 effects are limited to macrophage proliferation (Christie et al., 1963; Drew et al., 1974;
30 Steinhagen et al., 19781 Thomson et al., 1986), pulmonary alveolar macrophage damage,
31 and effects on Type II alveolar cells (Finelli and Que Hee, 1981). These studies support
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1 the findings from human studies that aluminum acts via an irritant, rather than an allergic,
2 mechanism (Abramson et al., 1989).
3
4 11.14.3.2 Antimony
5 Although kinetic data are limited, no major differences in the pharmacokinetics of
6 antimony in humans and laboratory animals are evident. There is limited information on
7 antimony toxicity, with human data primarily from chronic occupational exposures. Both
8 human and laboratory animal data do demonstrate that the respiratory system is the primary
9 target organ for antimony (trioxide) following inhalation exposure. However, the
10 differences in toxicity for different particle sizes or valence states of antimony have not
11 been well studied. In humans, respiratory effects (irritation, inflammation, pneumoconiosis,
12 pulmonary dysfunction) have been reported in workers chronically exposed to mg levels of
13 antimony dust (Cooper et al., 1968; Potkonjak and Pavlovich, 1983; Renes, 1953). Similar
14 effects have been reported in several laboratory animal species (Bio/dynamics Incorporated,
15 1990; Gross et al., 1952, 1955; Groth et al., 1986; Watt, 1980, 1983; Wong et al., 1979).
16 In addition, rats had increased number of alveolar macrophages following antimony
17 exposure (Bio/dynamics Incorporated, 1985, 1990).
18 Altered ECG records is a cardiovascular effect observed in both workers (Brieger et
19 al., 1954; Renes, 1953) and laboratory animals exposed to antimony trisulfide (Brieger et
20 al., 1954). Gastrointestinal symptoms have also been reported in exposed workers, but may
21 be due to mucociliary clearance from the lungs resulting in oral ingestion. Ocular and
22 dermal effects are probably due to direct contact with antimony particles.
23 A Russian study (Belyaeva, 1967) reported reproductive effects on female workers;
24 however, the study lacked quantitative exposure information. An animal study conducted
25 by the same author suggested reproductive effects with mg level antimony exposure. A
26 decreased number of offspring occurred in rats exposed to high concentrations of antimony
27 prior to conception and during gestation. In those animals that failed to conceive, effects
28 on the uterus and ovum-maturing process were observed.
29 Although increased tumor incidences have not been seen in workers exposed to
30 antimony oxides (Potkonjak and Pavlovich, 1983), lung tumors developed in rats exposed to
31 antimony trioxide or antimony trisulfide aerosols for a year (Groth et al., 1986). Therefore,
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1 antimony may possibly be carcinogenic in humans but there are insufficient data for a
2 definitive conclusion.
3
4 11.14.3.3 Arsenic
5 The toxicity data on inhalation exposures arsenic are limited in humans and
6 laboratory animals. Acute data are largely lacking for this route of exposure. In humans,
7 inhalation exposure data are primarily limited to long-term occupational exposure of smelter
8 workers, which have indicated that chronic exposure leads to lung cancer. In laboratory
9 animals, intratracheal administration of arsenic compounds in the lungs have not indicated
10 tumor development in rats and mice (Berteau et al., 1978; Ishinishi et al., 1977), but
11 insufficient exposure duration may have been used in these studies. However, respiratory
12 tract tumors occurred in hamsters exposed to intratracheal doses of arsenic when a charcoal
13 carbon carrier dust was used to increase arsenic retention in the lungs.
14 Chronic inhalation exposure has also been shown to cause skin changes
15 (hyperpigmentation, hyperkeratosis) (Perry et al., 1948) and peripheral nerve damage
16 (Feldman et al., 1979) in workers; however, the available inhalation studies in laboratory
17 animals have not evaluated these endpoints. The laboratory animal inhalation data are
18 limited and thus do not allow a thorough comparison of the toxicological and carcinogenic
19 potential of arsenic with the human data. Oral data may be considered; however, it does
20 not seem prudent to compare data from oral exposure to inhalation exposure since a portal-
21 of-entry effect occurs for inhaled arsenic trioxide. Species differences in dosimetry,
22 absorption, clearance, and elimination of arsenic (i.e., strong affinity to rat hemoglobin)
23 exist between rats and other animal species, including humans, which complicate
24 comparisons of quantitative toxicity (Mast et al., 1990; Vahter et al., 1982).
25
26 11.14.3.4 Barium
27 Both human and laboratory animal data are extremely limited, with no
28 epidemiological data available, and no standard inhalation toxicity studies in animals.
29 Occupational case studies are available for only the insoluble barium sulfate and barium
30 carbonate salts, with no difference between effects of these compounds being apparent
31 (Doig, 1976; Essing et al., 1976). The respiratory tract appears to be a target of these
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1 barium compounds, based on subjective symptoms, physical examinations, chest
2 radiography, spirometry and lung function tests; but, very few subjects were studied.
3 Histopathological changes in rats exposed to barium carbonate for 1 or 4 months support
4 the human data (Tarasenko et al., 1977). Guinea pigs exposed intratracheally exhibited
5 bronchoconstriction (Hicks et al., 1986); there are no data on corresponding effects in
6 humans, such as whether inhalation of barium compounds causes asthma or is
7 immunogenic.
8 Cardiovascular effects were also reported in both human and laboratory animal
9 studies, but the data are too limited by lack of controls and poor reporting to determine if
10 these observations were related to barium exposure. Gastrointestinal, neurological and renal
11 effects reported in one human by Shankle and Keane (1988) were not observed in the
12 available animal studies, but no high quality animal studies of sufficient sensitivity assessed
13 these endpoints. The general deficiencies in the Tarasenko et al. (1977) study preclude its
14 use for predicting reproductive, developmental, or systemic endpoints in humans.
15
16 11.14.3.5 Cadmium
17 The kidney is clearly the primary target of chronic inhalation exposure to cadmium
18 in the human; toxicity is dependent on cumulative exposure (Chia et al., 1989; Blinder
19 et al., 1985a,b; Falck et al., 1983; Kjellstrom et al., 1977; Mason et al., 1988; Smith et al.,
20 1980; Thun et al., 1989). Tubular proteinuria occurs after kidney levels of cadmium
21 accumulate to a certain level, estimated at 200 ug/g (Ellis et al., 1985; Roels et al., 1983).
22 An early 7 to 9 mo animal study found proteinuria in rabbits (Friberg, 1950), but this
23 finding has not been replicated in more recent 90-day studies (Glaser et al., 1986; Prigge,
24 1978a). Because the threshold for renal cadmium toxicity is determined by the cadmium
25 levels accumulated in the kidney, these differences are likely to be due to an insufficient
26 exposure duration, rather than metabolic or mechanistic differences between humans and
27 rodents.
28 The respiratory system is also a target of inhaled cadmium in humans and animals.
29 Intense irritation occurs following high-level exposure in humans (Beton et al., 1966), and
30 more mild effects on pulmonary function (dyspnea, decreased forced vital capacity) occur
31 following chronic low-level exposure (Chan et al., 1988; Davison et al., 1988; Smith et al.,
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1 1976). These effects and their mechanism have been investigated to a greater degree in
2 animals, although spirometry has not been conducted in animals. The observed effects
3 (increased lung weight, inhibition of macrophages and edema) (Boudreau et al., 1989;
4 Buckley and Bassett, 1987; Bus et al., 1978; Grose et al., 1987; Henderson et al., 1979;
5 Palmer et al., 1989) are consistent with the irritation observed in human studies. In humans
6 (Chan et al., 1988), symptoms reverse with cessation or lessening of exposure; animal
7 studies have reported no progression or slight reversal with continued exposure (Hart, 1986;
8 Hart et al., 1989a).
9 Developmental toxicity has been reported in animals (Baranski, 1985); but no
10 corresponding studies of developmental or reproductive toxicity have been conducted with
11 humans.
12 Rat studies show that several forms of cadmium (cadmium chloride, cadmium oxide
13 dust or fume, cadmium sulfide, or cadmium sulfate) can cause lung cancer (Oldiges et al.,
14 1989; Takenaka et al., 1983). There is some evidence that lung cancer has been observed
15 in humans following high occupational exposure (Blinder et al., 1985c; Sorahan, 1987;
16 Thun et al., 1985), although confounding exposures were present. Because animal cancer
17 studies only examined the lung, they did not address the suggestive evidence of cadmium-
18 related prostate cancer found in several occupational studies (Blinder et al., 1985c; Sorahan,
19 1987).
20
21 11.14.3.6 Chromium
22 Human and laboratory animal data are in agreement that the respiratory system is the
23 primary target of chromium compounds, and Cr(VI) is more toxic than Cr(III). This
24 difference in toxicity is attributed to the greater solubility of Cr(VI) compared to Cr(III).
25 Because acute data are limited to a single study showing that Cr(III) causes macrophage
26 accumulation in the lungs of hamsters, this discussion is limited to subchronic and chronic
27 studies. Human and animal data are in agreement regarding the specific nature of nasal
28 effects (irritation, perforation of nasal septum). Lung lesions (e.g., abscesses) have been
29 reported only in animals (Adachi, 1987; Adachi, et al. 1986; Steffee and Baetjer, 1965), but
30 studies in humans have not been conducted in a manner that would detect such lesions.
31 Similarly, several animal studies have reported evidence of inflammation, such as alveolar
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1 macrophage accumulation and increased lymphocytes in BAL fluid (Glaser et al., 1985;
2 1986; 1990; Johansson et al., 1980; 1986a,b; 1987; Steffee and Baetjer, 1965), but no
3 human BAL studies have been performed that would detect such changes. The reports of
4 altered pulmonary function characteristic of obstructive lung disease (Langard, 1980;
5 Lindberg and Hedenstierna, 1983) indicate that the lung is a target of chromium toxicity in
6 humans. Human and animal data are also in agreement that Cr(VI) compounds cause lung
7 cancer. In most human studies, the type of cancer was not identified. However, Langard
8 and Norseth (1975) reported bronchial carcinomas in pigment workers, and Langard and
9 Vigander (1983) reported epithelial cell carcinoma and adenocarcmoma in a followup of the
10 same cohort. In animal studies, lung cancers were adenomas and adenocarcinomas (Glaser
11 et al., 1986; Nettesheim et al., 1971). Due to the lack of human data, it is unlikely that
12 these differences reflect actual differences in target cells.
13 Human studies have also reported early signs of renal damage (increased urinary
14 levels of the proteins B-2-microglobulin, retinol binding protein, and renal tubular antigen)
15 with exposure to Cr(VI) compounds (Franchini and Mutti, 1988; Lindberg and Vesterberg,
16 1983b). Although such effects were not seen in animals, it is not clear if the analyses in
17 animals were sufficiently sensitive to detect a subtle effect. Only two animal studies
18 (Glaser et al., 1986; 1990) used histological examinations of the kidney, and small changes
19 may have been missed because chronic nephrosis was common in both experimental and
20 control groups. Also, urinalyses only measured total protein, so changes in individual
21 proteins may have been missed.
22
23 11.14.3.7 Cobalt
24 Human and laboratory animal studies agree that the respiratory tract is the major
25 target of the inhalation of cobalt compounds. In humans, two major types of effects are
26 observed, interstitial lung disease (fibrosis) and asthma. Cobalt-related asthma is related to
27 the induction of an immune response to inhaled cobalt (Roto, 1980; Shirakawa et al., 1988;
28 1989). The applicability of an laboratory animal model could not be evaluated because no
29 studies were located that assessed the immunogenic potential of cobalt inhalation in
30 animals. Several epidemiological and case studies of workers exposed to cobalt metal alone
31 or in combination with tungsten carbide have shown that interstitial lung disease is
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1 manifested as small opacities on radiographs, reduced lung function, and respiratory
2 symptoms, such as dyspnea (Gennart and Lauwerys, 1990; Mosconi et al., 1991; Roto,
3 1980; Sprince et al., 1984; 1988). Evidence of inflammation (accumulation of
4 macrophages, infiltration of macrophages into alveolar spaces) (Johannson and Camner,
5 1986; Bucher, 1991) and decreased lung function (Kerfoot et al., 1975) have been observed
6 in laboratory animals.
7 Effects on the upper respiratory tract (nose, trachea, and larynx) were observed in
8 the Bucher (1991) study, but were not reported in human studies. The cobalt sulfate used
9 in the Bucher (1991) study is more soluble than the cobalt dusts evaluated in human
10 studies, the differences in observed effects could also be due to differences in dosimetry in
11 the URT region between rodents and humans, to the greater sensitivity of URT evaluation
12 (e.g., histopathology) in laboratory animal studies, or the higher exposure levels used in the
13 animal study. Alternatively, it could be due to differences between humans and rats or
14 mice in species sensitivity.
15 Cardiomyopathy has been observed following occupational exposure to cobalt
16 (Barborik and Dusek 1972; Kennedy et al., 1981). Although the data are limited to case
17 studies, they are supported by oral evidence for cardiovascular effects of cobalt (Morin et
18 al., 1971) and a report of elevated cobalt levels in the hearts of exposed workers (Kennedy
19 et al., 1981). No effects on heart histology or on biochemical measures of cardiac damage
20 were found in the one study that assessed these effects (Bucher, 1991), but high background
21 levels in the controls may have obscured any effect. However, ECG findings consistent
22 with cardiomyopathy were observed in miniature swine (Kerfoot et al., 1975).
23 Effects on the thymus and testes were observed at near-fatal exposure levels in acute
24 and subchronic studies of rats and mice (Bucher, 1991). These effects have not been
25 observed in humans, but they were observed at levels higher than those to which humans
26 are exposed for more than brief periods. In addition, no studies were located that
27 specifically assessed these endpoints in people. Finally, such systemic effects may be more
28 likely to occur following exposure to soluble cobalt sulfate, as in the Bucher (1991) study,
29 than following exposure to cobalt or hard-metal dust.
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1 No standard neurotoxicity studies have been conducted with laboratory animals to
2 evaluate the suggestion of deficits following cobalt inhalation reported by Jordan et al.
3 (1990) and Meecham and Humphrey (1991).
4 Data on carcinogenic effects are limited to single studies in humans and laboratory
5 animals. Although increased lung cancer was observed in a study of workers in an
6 electrochemical plant, the small study size and concomitant exposure to other chemicals
7 mean that the effect cannot be strongly attributed to cobalt (Mur et al., 1987). No effect on
8 lung cancer was seen in hamsters exposed to cobalt oxide for 14 mo, but few study details
9 were available (Wehner and Craig, 1972). Thus, no conclusion can be reached regarding
10 the carcinogenic potential of inhaled cobalt compounds in humans or laboratory animals.
11
12 11.14.3.8 Copper
13 Although both human and laboratory animal data are limited, both data bases
14 support the respiratory system as a major target of inhaled copper and copper compounds,
15 including copper sulfate.and copper chloride. In humans, the data are limited primarily to
16 subjective reporting of respiratory symptoms following acute and chronic inhalation
17 exposures to copper fumes or dust. Suciu et al. (1981) supported the respiratory symptoms
18 with radiographic evidence of pulmonary involvement. The human data do not include
19 pulmonary function tests or histopathology of the respiratory tract. In laboratory animal
20 studies, supporting evidence exists for the involvement of the respiratory system after
21 copper inhalation exposure. Respiratory tract abnormalities in mice repeatedly exposed to
22 copper sulfate aerosols, and decreased tracheal cilia beating frequency in singly exposed
23 hamsters have been reported (Drummond et al., 1986). Respiratory effects, although minor,
24 have also been observed in rabbits (Johansson et al., 1983, 1984); these included a slight
25 increase in amount of lamellated cytoplasmic inclusions in alveolar macrophages, and a
26 slight increase in volume density of alveolar Type 2 cells. Although respiratory effects
27 were observed in both human and laboratory animal studies, direct comparisons are not
28 possible since different parameters were examined in the different species for which limited
29 data exist. Immunological effects have been investigated in only one animal study
30 (Drummond et al., 1986). In the one study addressing the issue, immunotoxic effects
31 observed included: decreased survival time after simultaneous S. zooepidemicus aerosol
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1 challenge, and decreased bactericidal activity after simultaneous K. pneumonia aerosol
2 exposure. No laboratory animal studies have addressed whether the gastrointestinal,
3 hepatic, neurological and reproductive effects observed in humans by Suciu et al. (1981) are
4 reproducibly attributable to copper inhalation. This study is also possibly tainted with
5 concomitant oral exposure to the copper dust.
6
7 11.14.3.9 Iron
8 There is limited information on iron toxicity, with human data primarily from
9 chronic occupational exposures. Both human and laboratory animal data, mostly qualitative
10 information, do demonstrate that the respiratory system is the primary target organ for iron
11 oxides following inhalation exposure. However, the differences in toxicity (if any) for
12 different particle sizes or valence states of iron have not been well studied. In humans,
13 respiratory effects (coughing, siderosis) have been reported in workers chronically exposed
14 to iron dust (Buckell et al., 1946; Charr, 1956; Friede and Rachow, 1961; Morgan, 1978;
15 Schuler et al., 1962; Sentz and Rakow, 1969; Teculescu and Albu, 1973). In laboratory
16 animals, hyperplasia and alveolar fibrosis have been reported after inhalation or
17 intratracheal administration of iron oxide (Creasia and Nettesheim, 1974; Port et al., 1973).
18 The lack of information on the histopathological changes in the lungs of exposed workers
19 precludes direct comparison with animal data.
20 The available human and laboratory animal studies are limited and do not provide
21 conclusive evidence regarding the respiratory carcinogenicity of iron oxide exposures (Boyd
22 et al., 1970; Campbell, 1940; Creasia and Nettesheim, 1974; Faulds, 1957).
23
24 11.14.3.10 Mercury
25 Both human and animal data demonstrate that the neurological system is the most
26 sensitive target organ for elemental mercury following inhalation exposure for acute or
27 chronic durations. Effects range from reversible neurological symptoms to psychomotor
28 and neurobehavioral changes and peripheral nerve dysfunction (Hallee, 1969; Jaffe et al.,
29 1983; Albers et al., 1988; Piikivi et al., 1984; Ellingson et al., 1993). In animals,
30 neurological and behavioral findings have been reported, but some studies have serious
31 limitations (Ashe et al., 1953). It is clear that mercury can produce significant neurological
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1 damage to humans; however, direct comparisons on the neurological dysfunction and
2 symptoms are not possible because histopathology of the brain has been only performed in
3 animal species.
4 Respiratory, gastrointestinal, and cardiovascular symptoms have also been reported
5 in case reports and occupational studies (Fagala and Wigg, 1992; Hallee, 1969; Jaffe et al.,
6 1983; Kanluen and Gottlieb, 1991); these effects appear with exposure to higher
7 concentrations of mercury. Animal data on elemental mercury exposure are limited.
8 Respiratory, cardiovascular, and liver effects have been reported, but information is
9 inadequate (Ashe et al., 1953). The kidney is a sensitive target organ of toxicity following
10 elemental mercury exposure in humans, due to the high accumulation of mercury in the
11 kidneys (Barregard et al., 1988; Cardenas et al., 1993; Ehrenberg et al., 1991; Stewart et al.,
12 1977). In animals, data on renal effects were limited to one study that reported proteinuria
13 in Brown-Norway rats exposed to mercuric chloride aerosol (Bernaudin et al., 1981).
14 Clearly, the database for inhalation mercury exposure is more extensive for humans than for
15 laboratory animals, and therefore, available data for comparison between species is
16 inadequate.
17 Inhalation exposure to elemental mercury does not appear to produce fertility effects
18 in exposed workers (Alcser et al., 1989; Cordier et al., 1991; Lauwerys et al., 1985;
19 Mishonova et al., 1980; Sikorski et al., 1987); however, exposure data are lacking for these
20 studies. A developmental study in rats suggest that inhalation of mercury vapors during
21 gestation may also lead to developmental effects in the offspring (Baranski and Szymczyk,
22 1973).
23
24 11.14.3.11 Manganese
25 As Roels et al. (1992) and other investigators have noted, a threshold for the
26 neurotoxic effects of manganese has not been reported in the epidemiological literature.
27 However, a LOAEL may be obtained from the study by Roels et al. (1992) by dividing the
28 geometric mean integrated respirable dust concentration (793 jug Mn/m3 x years) by the
29 average period of worker exposure (5.3 years) to eliminate time (in years) from the
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1 time-weighted average,1 thereby yielding a LOAEL of 150 /^g Mn/m3. The workplace-
2 based LOAEL of 150 ug Mn/m3 could be adjusted for nonoccupational lifetime exposure
3 by multiplying it by (1) the quotient of 10 m3/day divided by 20 m3/day (for worker versus
4 nonworker ventilation rates) and (2) the quotient of 5 days divided by 7 days (for work
5 week versus full week). The resulting adjusted LOAEL is 50 u£ Mn/m3.
6 The U.S. Environmental Protection Agency (IRIS, 1993) used the above approach in
f\
7 deriving an inhalation reference concentration (RfC) for manganese. More recently, the
8 U.S. Environmental Protection Agency (1994) considered various alternative approaches to
9 deriving a quasi NOAEL from the data of Roels et al. (1992), as part of its evaluation of
10 the manganese gasoline additive methylcyclopentadienyl manganese tribcarbonyl (MMT).
11 In particular, a benchmark dose (BMD) approach was used to estimate the concentration
12 that would produce a specified effect (e.g., a 10% increase in the prevalence of abnormal
13 scores on the eye-hand coordination test of Roels et al. [1992]). The BMD was calculated
14 by fitting a mathematical model to the data from Roels et al. (1992) and additional data
15 supplied by Roels (1993). A maximum likelihood estimate of the dose associated with a
16 10, 5, or 1% increase in response is denoted as the BMD10, BMD5, or BMDj, respectively.
17 The 95th percentile lower confidence limit on the BMD is denoted as the benchmark dose
18 level (BMDL), as in BMDL10, BMDL5, or BMDLP Of six mathematical models
19 considered, the U.S. EPA concluded that the quantal linear model was the most suitable
20 choice for the data available in this case. Focusing primarily on 10 and 5% effect levels,
21 the U.S. EPA calculated BMDL10 and BMDL5 values of 26 and 13 ng/m3, respectively,
22 after adjusting for the non-occupational exposure scenario.
23 Additional analyses by the U.S. EPA using a Bayesian statistical approach
24 essentially duplicated the results of the benchmark analyses. In essence, the Bayesian
25 approach yields a distribution of concentrations (rather than a point estimate) associated
26 with a specified effect. In addition, the Bayesian approach made it possible to estimate the
27 2The geometric mean concentration was used to represent the average exposure because the workers' exposure
28 measurements were log-normally distributed, and the arithmetic mean exposure period was used because it was the
29 only value reported by Roels et al. (1992).
30 3The reference concentration is defined as an estimate (with uncertainty spanning about an order of magnitude) of
31 a continuous inhalation exposure level for the human population (including sensitive subpopulations) that is likely
32 to be without appreciable risk of deleterious noncancer effects during a lifetime.
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1 concentrations associated with specified increases of errors on the eye-hand coordination
2 test of Roels et al. (1992) (e.g., 32 jwg/m3 for a 10% increase; 19 /zg/m3 for a 5% increase;
3 and 17 /ig/m3 for a 4% increase, which was the minimum difference achieving statistical
4 significance [all concentrations adjusted to nonoccupational exposure conditions]).
5 In evaluating the potential health risks associated with inhalation exposure to
6 manganese, various uncertainties must be taken into consideration. Virtually all of the
7 human health evidence is based on healthy, adult male workers. However, certain
8 populations, such as children, pregnant women, elderly persons, iron- or calcium-deficient
9 individuals, and individuals with liver impairment, may have an increased potential for
10 excessive manganese body burdens due to increased absorption or altered clearance
11 mechanisms. In addition, the potential reproductive toxicity of inhaled manganese has not
12 been adequately investigated in females or males. Limited available information concerning
13 the developmental toxicity of inhaled manganese suggests the possibility that prenatal
14 and/or postnatal exposure of laboratory rodents to MnO2 (via the air supplied to the
15 pregnant mother) may depress neurobehavioral activity. The concentrations and durations
16 of exposure sufficient to induce such effects are not known.
17 Another uncertainty is due to the lack of adequate human or laboratory animal
18 studies involving chronic exposures and effects. As noted above, it may be that longer
19 exposure and/or testing later in life would result in the detection of effects at lower
20 concentrations than is possible after shorter periods of exposure and/or in younger workers.
21 On the other hand, it is also evident from these studies that a much shorter period than a
22 full lifetime of occupational manganese exposure may be sufficient to induce manganese
23 neurotoxicity. Another uncertainty owes to the fact that different forms of metals may have
24 different toxic properties (due to different oxidation states, different solubilities, and
25 possibly other factors). Sufficient data are not available to judge the comparative toxicity
26 of different compounds of manganese.
27
28 11.14.3.12 Magnesium
29 Data on the inhalation toxicity of magnesium and its compounds in humans and
30 laboratory animals are very limited, but they do support the respiratory tract as a target.
31 Acute exposure of humans (Drinker et al., 1927) or laboratory animals (Drinker and
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1 Drinker, 1928) to magnesium oxide fume results in a reaction described as similar to zinc
2 oxide metal fume fever. Fever was observed in humans, and dyspnea and hypothermia in
3 animals. The reason for the opposite effects on body temperature is unclear. There are no
4 acute data on humans or laboratory animals exposed to magnesium carbonate.
5 There is suggestive evidence in humans and laboratory animals that chronic
6 exposure to magnesium carbonate or magnesium oxide dusts may produce pneumoconiosis;
7 the evidence is stronger for an association with magnesium oxide dust. Pneumoconiosis has
8 been reported in workers exposed to magnesium carbonate dust, but the effect may have
9 been due to concomitant exposure to silicon dioxide and/or asbestos (Tokmurzina and
10 Dzangosina, 1970; Zeleneva, 1970). However, a correlation with exposure to magnesium
11 oxide (roasted magnesite) has been observed (Zeleneva, 1970). It is unclear if fibrosis was
12 assessed in these studies. Irritation of the eyes and nose has also been reported in humans
13 exposed to magnesium oxide dust (Pleschitzer, 1936). In laboratory animals, fibrosis was
14 observed following chronic exposure to high levels of magnesium oxide or magnesium
15 carbonate dusts, although magnesium oxide was more fibrogenic (Katsnel'son et al., 1964;
16 Zeleneva, 1970). No more sensitive measures of inflammation appear to have been
17 assessed. No data were available on chronic inhalation exposure of humans or laboratory
18 animals to magnesium oxide fume.
19 Nonrespiratory effects of inhalation exposure to magnesium have not been reported,
20 but the degree to which such effects have been assessed is unclear. Indirect evidence
21 indicates that magnesium is absorbed following inhalation of magnesium oxide (Pleschitzer,
22 1936), and the solubility of magnesium carbonate in aqueous solutions would suggest that it
23 is also absorbed from the respiratory tract. Due to the large amounts of magnesium stored
24 in the body, one would expect that relatively large amounts of inhaled magnesium would
25 need to be absorbed before any systemic effects occur. However, toxic effects resulting
26 from hypermagnesemia have been reported following oral dosing with large amounts of
27 magnesium sulfate (Garrelts et al., 1989; Gren and Woolf, 1987; Ratzan et al., 1980).
28
29 11.14.3.13 Molybdenum
30 The respiratory tract appears to be the main target in humans and animals of
31 inhalation exposure to molybdenum compounds; however, inhalation exposure to
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1 molybdenum has also been associated with nonspecific effects in humans. These
2 nonspecific complaints from occupationally exposed workers in Russia include general
3 weakness and dizziness (Mogilevskaya, 1963). Studies on U.S. molybdenum workers have
4 failed to show specific complaints other than increased serum ceruloplasmin and serum uric
5 acid concentrations (Walravens et al., 1979). However, high employee turnover may have
6 resulted in the elimination of sensitive employees from the study population.
7 Data from inhalation experiments in animals indicate that molybdenum toxicity
8 varies with the molybdenum compound. Subchronic exposure to molybdenum trioxide or
9 ammonium molybdate resulted in greater toxicity than did exposure to molybdenum dioxide
10 or metallic molybdenum (Mogilevskaya, 1963). Similarly, subchronic exposure to
11 molybdenum trioxide dust was more toxic to guinea pigs than was exposure to comparable
12 levels of molybdenum disulfide dust; molybdenum trioxide fumes were less toxic than
13 molybdenum trioxide dust, but the exposure levels were also lower, so a direct comparison
14 is difficult (Fairhall et al., 1945). Data from acute exposure studies also suggest that
15 ammonium dimolybdate is more toxic than molybdenum trioxide or ammonium
16 dimolybdate, but differing exposure levels make comparisons difficult (Barltrop, 1991).
17 Animal studies did not address the complaints of weakness and dizziness reported in an
18 occupational study (Mogilevskaya, 1963).
19 Pharmacokinetic data are insufficient to provide meaningful data on comparative
20 toxicity. However, indirect data indicate that inhaled molybdenum compounds are
21 absorbed, so the possibility of systemic effects (most likely gout-like symptoms) is of
22 interest.
23
24 11.14.3.14 Nickel
25 Both human and laboratory animal data demonstrate that the respiratory tract is the
26 primary target organ for nickel compounds following inhalation exposure. In humans,
27 respiratory effects include asthma and altered pulmonary function (reduced vital capacity
28 and expiratory flows) (Dolovich et al., 1984; Kilbam et al., 1990; McConnell et al., 1973;
29 Novey et al., 1983). In laboratory animals, inflammatory response (morphological and
30 enzyme changes in alveolar macrophages, interstitial infiltrates) were observed in rabbits,
31 rats, and mice (Benson et al., 1987, 1988, 1989, 1990; Bergham et al., 1987, Dunnick
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1 et al., 1988, 1989; Horie et al., 1985; Jarstrand et al., 1978; Johansson and Camner, 1980,
2 1986; Murthy et al., 1983). These animal data do suggest an immunological response in
3 the lungs. Occupational studies have not evaluated these lung parameters in exposed
4 workers; therefore, it is not known whether nickel can produce similar immunological
5 changes in the respiratory tract of humans. Bencko et al. (1983, 1986) did report
6 immunological changes (altered serum levels of IgG, IgA, IgM, and IgE levels,
7 a2-macroglobulin) occurring in refinery workers exposed to nickel. In animals,
8 immunosuppression was also observed following acute exposure to nickel chloride aerosols
9 in rats (Graham et al., 1978) and for up to 6 mo with various nickel compounds in rats,
10 mice, and rabbits (Benson et al., 1987, 1988; Dunnick et al., 1988; Haley et al., 1990;
11 Spiegelberg et al., 1984). Although human and laboratory animal studies indicate
12 immunological effects associated with nickel, the studies measured different immunological
13 endpoints.
14 In humans, the potential of lung and nasal cancer (primarily squamous cell
15 carcinomas) was evident in occupational settings; nickel refinery workers are exposed to
16 both soluble and insoluble nickel compounds (Chovil et al., 1981; Doll et al., 1970).
17 Quantitative data on acute exposures in humans were not available. Animal data
18 demonstrated increased tumor incidences in the respiratory system following longer duration
19 exposures to insoluble nickel compound (nickel subsulfide); tumors included adenomas,
20 adenocarcinomas, squamous cell carcinomas, and fibrosarcomas (Ottolenghi et al., 1974).
21 An occupational study of exposed nickel refinery workers reported increased
22 incidence of abortions and structural malformations (Chashschin et al., 1994). Laboratory
23 animal studies also suggest reproductive effects (decreased fetal body weight, testicular
24 degeneration) associated with nickel exposure (Benson et al., 1987, 1988; Weischer et al.,
25 1980).
26
27 11.14.3.15 Potassium
28 The available data on the toxicity or pharmacokinetics of inhaled potassium
29 compounds are insufficient to assess the comparative toxicity in humans and laboratory
30 animals. Data on the response to inhaled potassium are limited to one abstract assessing
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1 the effects in atopic subjects (Dixon et al., 1989); some other data may be available from
2 the Russian literature, but cannot be assessed currently.
3 Other inhalation data are available from studies in which potassium was used as the
4 counterion for the study of the ion of interest; such studies are discussed in the sections on
5 bromine and chromium. Other studies on compounds such as potassium ferricyanide were
6 not discussed here because the potassium ion would not be expected to contribute
7 significantly to the compound's overall toxicity.
8 No data were located on the pharmacokinetics of potassium following the inhalation
9 of potassium compounds. Although many of these compounds are water-soluble and the
10 potassium could be distributed systemically, systemic toxicity would not be expected to
11 result, since large amounts would need to be absorbed in order to disturb potassium
12 homeostasis. The pharmacokinetics of potassium absorbed from the gastrointestinal tract
13 are well-characterized and do not differ qualitatively between humans and laboratory
14 animals.
15
16 11.14.3.16 Selenium
17 There is limited information on selenium toxicity, with human data primarily from
18 chronic occupational exposures. Both human and laboratory animal data demonstrate that
19 the respiratory system is the primary target organ for selenium following inhalation
20 exposure. In humans, respiratory effects (irritation, edema, bronchitis, pneumonia) have
21 been reported in workers chronically exposed to selenium (Buchan, 1974; Clinton, 1947;
22 Glover, 1970; Hamilton, 1949). Similar effects have been reported in several animal
23 species (Dudley and Miller, 1941; Hall et al., 1951). Gastrointestinal effects and irritation
24 of the skin and eyes have also been reported in humans following exposure to elemental
25 selenium, selenium dioxide, or hydrogen selenide (Clinton, 1947; Glover, 1970; Middleton,
26 1947; Pringle, 1942); however, these effects may be attributed to ingestion of or direct
27 contact with selenium particles. Laboratory animal data suggest that mild hepatic effects
28 may occur in humans with exposure to selenium. However, the effects of selenium on the
29 liver has not been investigated in exposed workers, although selenium has been detected in
30 human liver (Jereb et al., 1975).
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1 Reproductive and developmental endpoints have not been evaluated in humans or
2 laboratory animals following inhalation exposure to selenium. However, Archimbaud et al.
3 (1992) has demonstrated that selenium can readily cross the placenta to reach the fetus,
4 suggesting that developmental or reproductive effects may be possible. Occupational
5 studies have not reported any increased incidence of tumors in exposed workers.
6 No chronic carcinogenicity bioassays have been conducted in laboratory animals so that
7 comparative evaluation of this endpoint is precluded.
8
9 11.14.3.17 Tin
10 Inorganic Tin
11 Human (Cutter et al., 1949; Dundon and Hughes, 1950; Robertson and Whitaker,
12 1954; Robertson et al., 1961; Schuler et al., 1958) and animal (Pendergrass and Pryde,
13 1948; Robertson, 1960) studies agree that inorganic tin is relatively lexicologically inert,
14 and that effects are limited to mild respiratory effects, along with the formation of radio-
15 opaque nodules in the lungs. Fibrosis is not observed. No other target systems for
16 inhalation exposure to inorganic tin have been reported.
17
18 Organic Tin
19 Limited data indicate that the nervous, hepatic, renal, and respiratory systems are
20 targets of inhalation exposure to organotin compounds. Nervous system toxicity symptoms
21 are the most slowly reversible effects of organotin compounds in humans (Rey et al., 1984).
22 Neurotoxicity effects could not be confirmed in laboratory animals, since no standard
23 neurological testing has been conducted. Limited animal data, including histopathological
24 data, confirm that organotin compounds adversely affect the lungs, liver, and kidney
25 (Gohlke et al., 1969; Igarashi, 1959; Iwamoto, 1960). Organotin compounds may also
26 decrease reproductive success (Igarashi, 1959).
27
28 11.14.3.18 Titanium
29 Both human and laboratory animal data demonstrate that the respiratory system is
30 the primary target organ for titanium following inhalation exposure. Although few studies
31 have assessed titanium toxicity outside the respiratory tract, no histopathology of other
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1 organs was found in rats chronically exposed to titanium tetrachloride at up to 6,000 fj.g
2 Ti/m3 (Du Pont, 1986; Lee et al., 1986a). In addition, occupational studies in humans and
3 experimental data from animals indicate that titanium is not translocated in the body, as
4 titanium has not been found body organs other than the respiratory tract, even with chronic
5 exposure and with high concentrations. The toxic compounds most studied are titanium
6 dioxide and titanium tetrachloride. In humans and animals, exposure to titanium dioxide
7 has resulted in deposition of the titanium particles in the alveoli of the lungs. This results
8 in pneumoconiosis in humans (Daum et al., 1977) and signs of inflammation in animals
9 (Oberdorster et al., 1992). However, data do not suggest that titanium dioxide causes lung
10 cancer in humans (Chen and Fayerweather, 1988). In rats, very high levels (150,000 jug
11 Ti/m3) did result in lung cancers that are believed to be unique to rats and are not
12 suggestive of similar cancers in humans or other laboratory animals. These high exposure
13 levels also overwhelmed the clearance capacity of the lung.
14 Because titanium tetrachloride degrades to highly corrosive hydrochloric acid, it is a
15 much stronger irritant that titanium dioxide. This has been illustrated in studies of acute
16 and chronic occupational exposure. Symptoms in humans include stenosis of the upper
17 respiratory tract (Park et al., 1984) and decreased lung capacity (Garabrant et al., 1987);
18 deposits of titanium metal were also found in the lungs (Elo et al., 1972; Ophus et al.,
19 1979; Redline et al., 1986). In rats with acute exposure to titanium tetrachloride,
20 respiratory tract irritation was also seen, chronic exposure resulted in more severe
21 symptoms such as tracheitis and abnormal lung noises with accompanying histopathological
22 changes (Du Pont, 1986; Lee et al., 1986a). In humans, exposure to titanium tetrachloride
23 has not been associated with cancer. As with titanium dioxide, chronic exposure of rats to
24 titanium tetrachloride has led to squamous cell carcinoma and keratinizing squamous cell
25 carcinoma (Du Pont, 1986; Lee et al., 1986a). The relevance of these unique cancers to
26 humans is unknown, as these tumors are not usually seen in humans.
27
28 11.14.3.19 Vanadium
29 Human and laboratory animal data confirm the respiratory tract as the primary target
30 of inhaled vanadium compounds. Laboratory animal data suggest that vanadium
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1 compounds damage alveolar macrophages, and that toxicity is related to compound
2 solubility and valence.
3 Because of the difficulty in obtaining clinical signs of respiratory distress in
4 laboratory animals, most reported animal data consisted of histological findings (increased
5 leukocytes and lung weights, perivascular edema, alveolar proteinosis, and capillary
6 congestion) (Knecht et al., 1985; Lee and Gillies, 1986; Roscin, 1967; Paynich, 1966).
7 Human occupational case studies and epidemiological studies generally emphasize clinical
8 symptoms of respiratory distress, including wheezing, chest pain, bronchitis, rhinitis,
9 productive cough, and fatigue (Levy et al., 1984; Musk and Tees, 1982; Sjoberg 1956;
10 Thomas and Stiebris, 1956; Zenz et al., 1962). No human data were found describing
11 histopathology following oral or inhalation exposure.
12 There are insufficient data to definitively determine whether vanadium inhalation
13 causes extrarespiratory (systemic) effects. However, symptoms of the nervous and
14 cardiovascular systems have been observed following chronic occupation exposure
15 (Roschin, 1964 Sjoberg, 1950; Watanaze et al., 1966), and laboratory animal studies have
16 observed effects on the liver, kidneys, gonads, nervous, hematological and cardiovascular
17 systems (Pazynich, 1966; Roshchin, 1967a,b; Sjoberg, 1950).
18 There was a lack of information on developmental effects, reproductive effects, or
19 cancer in both humans and in animals following inhalation exposure. However, following
20 oral exposure to sodium metavanadate, no or very slight developmental effects were
21 reported in rats (Paternain et al., 1987; Kowalska, 1988; Domingo et al., 1986).
22
23 11.14.3.20 Zinc
24 No major differences in the pharmacokinetics of zinc in humans and laboratory
25 animals were evident. Both human and laboratory animal data demonstrate that the
26 respiratory system is the primary target organ for zinc following inhalation exposure; the
27 toxic compounds most studied are zinc chloride and zinc oxide. In humans, the
28 development of metal fume fever, characterized by respiratory symptoms and pulmonary
29 dysfunction, was observed in workers and experimental subjects during acute exposures to
30 zinc oxide (Gordon et al., 1992; Hammond, 1944). An immunological component is
31 believed to be responsible for these respiratory responses (Sturgis et al., 1927).
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1 Quantitative data on chronic exposures in humans are not available. In Guinea pigs, BAL
2 fluid and pulmonary function were assessed after zinc oxide exposures for less than a day
3 (Conner et al., 1988; Gordon et al., 1992). Inflammation with altered macrophage function
4 (as suggested by biochemical and morphological changes in the lungs) and impaired
5 pulmonary function (decreased compliance, total lung capacity, decreased carbon monoxide
6 diffusing capacity) were observed in guinea pigs. Rats also showed altered macrophage
7 function in the lungs (Gordon et al., 1992). At subchronic durations, histopathological
8 changes in the lungs (increased macrophages) were observed in rats, mice, and Guinea pigs
9 exposed to zinc chloride (Marrs et al. 1988). It is clear that zinc can produce inflammatory
10 response in both human and animal species, however, direct comparisons on the respiratory
11 etiology are not possible because pulmonary function tests and BAL fluid analyses for
12 humans examine different parameters than those for animals, and immunological
13 evaluations in BAL fluid were performed only on humans. Alveologenic carcinomas have
14 been observed in mice exposed to zinc chloride for 20 weeks (Marrs et al., 1988); however,
15 human studies have shown no evidence of increased tumor incidences at exposure levels
16 found in occupational settings (Logue et al., 1982; Neuberger and Hollowell, 1982).
17
18 11.14.4 Silica
19 Emissions of silica into the environment can arise from natural, industrial, and
20 farming activities. There are only limited data on ambient air concentrations of amorphous
21 or crystalline silica, principally because existing measurement methods are not well suited
22 for distinguishing silica from other particulate matter. Using available data on the quartz
23 fraction of coarse dust (Davis et al., 1984) and average annual arithmetic mean PM10
24 measurements for 17 U.S. metropolitan areas, annual average and high U.S. ambient quartz
25 levels of 3 and 8 /ig/m3, respectively, have been estimated (U.S. Environmental Protection
26 Agency, 1995). Davis et al. (1984) found that most of the quartz was in the fraction
27 between 2.5 to 15 /zm MMAD.
28 Silica can occur in two chemical forms, amorphous and crystalline. Crystalline
29 forms include quartz, which is the most prevalent; cristobalite; tridymite; and a few other
30 rare forms. Freshly fractured crystalline silica is more lexicologically reactive than aged
31 forms of crystalline silica or forms that may be coated with other chemical compounds.
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1 Amorphous silica is less well studied and may have similar toxic endpoints but is less
2 potent than crystalline silica. With sufficient exposure, crystalline silica is toxic to the
3 respiratory system. Acute high exposure in both humans and animals causes lung
4 inflammation and, if the exposure is high enough, rapid onset of a fibrotic lung disease
5 which can be fatal. Occupational studies show that chronic exposure to crystalline silica
6 causes inflammation of the lung which is followed by fibrosis and a human fibrotic disease
7 called silicosis which can lead to early mortality. Some occupational studies also show a
8 concurrent incidence of lung cancer. The role, if any, of silica-induced lung inflammation,
9 fibrosis, and silicosis in the development of lung cancer is hypothesized but not adequately
10 demonstrated. Crystalline silica interaction with DNA has been shown. Chronic exposure
11 animal studies in rats also show a similar pattern of lung inflammation, fibrosis, and lung
12 cancer. In 1987, the International Agency for Research on Cancer classified crystalline
13 silica as a "possible" human carcinogen owing to a sufficient level of evidence in animal
14 studies with inadequate evidence in human studies. While surveillance of the U.S.
15 population for fibrosis and silicosis is not standard practice, the health statistics of the U.S.
16 do not reveal a population increase of these crystalline silica diseases. However, there is an
17 increase in these diseases within segments of the occupational work force.
18 An assessment of the occupational risk of silicosis was made using recent studies
19 from South Africa (Hnizdo and Sluis-Cremer, 1993) and Canada (Muir et al, 1989b), both
20 of which examined medical histories of over 2000 miners. Both predicted zero risk for
21 cumulative silica exposures of 0.6 mg/m3-years (equivalent to a 20-year workplace exposure
22 to an average concentration of 30 jig/m3). At higher exposures, excess risk was observed in
23 these workers (e.g., 2% risk at 1.6 mg/m3 • years). These effective occupational exposures
24 are greater and the particle sizes smaller (Verma et al., 1994) than those likely to be
25 experienced by the public; however, the public would be expected to include susceptible
26 subpopulations. Information gaps still exist for both the exposure-response relationship
27 (especially in potentially susceptible subgroups) for levels of exposure within the general
28 population.
29
30
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1 11.4.5 Asbestos
2 The mechanisms underlying the development of asbestos-induced pulmonary fibrosis
3 in rats is complex. While the acute response to asbestos results in pulmonary inflammation
4 and cell proliferation, the pattern of fibrosis following chronic exposures becomes more
5 complex. It is likely that the retention of inhaled fibers and consequent accumulation of
6 interstitial fibers concomitant with prolonged inflammation will contribute to the
7 development of a diffuse and progressive pattern of pulmonary fibrosis. The pathogenesis
8 of asbestos-related lung tumors clearly is a complex process and requires further
9 investigation.
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1 REFERENCES
2
3 Abbey, D. E.; Mills, P. K.; Petersen, F. F.; Beeson, W. L. (1991) Long-term ambient concentrations of total
4 suspended participates and oxidants as related to incidence of chronic disease in California Seventh-Day
5 Adventists. Environ. Health Perspect. 94: 43-50.
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