c/EPA
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA/600/8-90/057A
July 1990
Workshop Review Draft
Research and Development
Health Assessment
Document for
Diesel Emissions
Workshop
Review
Draft
(Do Not
Cite or Quote)
Appendices: A Thru D
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.
-------
EPA/600/8-90/057A
July 1990
Workshop Review Draft
Health Assessment Document for
Diesel Emissions
Appendices: A Thru D
This document is an internal draft for review purposes
only and does not constitute Agency policy. Mention of
trade names or commercial products does not constitute
endorsement or recommendation for use.
U.S. Environmental Protection Agency
Office of Reasearch and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, NC 27711
-------
NOTICE
This document is an internal draft for review purposes
only and does not constitute Agency policy. Mention of
trade names or commercial products does not constitute
endorsement or recommendation for use.
11
-------
TABLE OF CONTENTS
LIST OF TABLES ix
LIST OF FIGURES xii
1. SUMMARY 1-1
1.1. INTRODUCTION 1-1
1.1 COMPOSITION OF DIESEL EXHAUST 1-4
1.11. Introduction 1-4
1.2.2. Overview of Pollutants and Pollution Formation 1-4
1.13. Emission Factors and Inventories 1-5
1.2.4. Emission Controls-Now and Projected 1-5
1.2.5 Conclusions 1-5
1.3. CONCENTRATIONS OF DIESEL-DERIVED POLLUTANTS IN
AIR, THEIR TRANSPORT AND TRANSFORMATIONS 1-6
1.3.1. Fundamental Nature of Diesel Pollutants in Air 1-6
1.3.2. Dispersion of Primary Emissions in Air 1-6
1.3.3. Atmospheric Transformations 1-6
1.3.4. Mutagenicity of Ambient Air Particles 1-6
1.4. NONCANCER HEALTH EFFECTS OF DIESEL EXHAUST .... 1-7
1.4.1. Toxic Effects of Diesel Exhaust on Humans 1-7
1.4.2. Toxic Effects of Diesel Exhaust on Animals 1-8
1.4.3. Interactive Effects of Diesel Exhaust
Components 1-10
1.4.4. Comparison of the Effects of Gasoline and
Diesel Exhaust Ml
1.5. MUTAGENICITY OF DIESEL ENGINE EMISSIONS 1-12
1.6. METABOLISM AND MECHANISM OF ACTION OF DIESEL
EMISSIONS INDUCED CARaNOGENICITY 1-12
1.7. CARCINOGENICITY OF DIESEL ENGINE EMISSIONS IN
LABORATORY ANIMALS 1-13
1.8. PHARMACOKINETIC CONSIDERATIONS IN THE PULMONARY
CARCINOGENICITY OF DIESEL ENGINE EMISSIONS 1-15
111
-------
TABLE OF CONTENTS (CONT)
1.9. EPIDEMIOLOGY OF DIESEL EMISSIONS
CARCINOGENICITY 1-16
1.10. QUANTITATIVE ESTIMATE OF UNIT RISK 1-20
1.12. REFERENCES 1-21
2. DIESEL EMISSIONS 2-1
2.1. INTRODUCTION 2-1
2.1.1. Diesel Engine - What it is and How it is Used 2-1
2.2. OVERVIEW OF POLLUTANTS AND POLLUTANT
FORMATION 2-1
111. Gas Phase Emissions 2-1
2.2.2. Carbon Formation and Emission 2-1
2.2.3. Gas-to-Particle Conversions 2-1
114. Mutagens 2-2
2.3. EMISSION FACTORS AND INVENTORIES 2-2
13.1. Existing Data 2-2
13.1 Models 2-2
14. EMISSION CONTROLS: NOW AND EXPECTED 2-2
14.1. Engine Modifications 2-2
14.1 Add-On Devices: Descriptions and Performance 2-2
14.3. Alternative Fuels: Performance 2-2
15. CONCLUSIONS 2-2
16. REFERENCES 2-2
3. DIESEL DERIVED POLLUTANTS: ATMOSPHERIC CONCENTRATIONS,
TRANSPORT, AND TRANSFORMATIONS 3-1
1.0. INTRODUCTION 3-2
10. PRIMARY DIESEL EMISSIONS 3-4
11. Gaseous Emissions 3-4
11.1. Inorganic Gases 3-4
11.2. Organic Gases 3-6
rv
-------
TABLE OF CONTENTS (CONT.)
11 Paniculate Emissions 3-9
2.2.1. Diesel Paniculate Matter 3-9
12.1 Paniculate Phase Matter 3-14
113. Paniculate Phase Organic Compounds 3-14
13. Factors Influencing Emissions of PAH and Nitro-PAH 3-25
2.4 Gaseous/Paniculate Phase Emission Partitioning 3-28
3.0. ATMOSPHERIC TRANSFORMATIONS OF PRIMARY DIESEL
EMISSIONS 3-32
3.1. The Fate of Primary Diesel Emissions and the Long Range
Transport 3-32
3.2. Chemical Transformations 3-35
3.11. Gas-phase Reactions 3-35
3.11 Paniculate-Phase Reactions 3-51
3.3. Physical Removal Processes 3-59
3.3.1. Dry Deposition 3-59
3.3.1 Wet Deposition 3-61
4.0. ATMOSPHERIC CONCENTRATIONS OF PRIMARY DIESEL
EMISSIONS AND THEIR TRANSFORMATION PRODUCTS .. 3-65
4.1. Volatile Organic Compounds (VOC) Attributable to Traffic 3-66
4.1 Potycyclic Aromatic Hydrocarbons 3-68
4.3. Nitroarene Concentrations in Ambient Air 3-72
4.4. The Need for Atmospheric Tracers of Diesel Emissions .... 3-78
5.0. MUTAGENICTTY OF RESPIRABLE AMBIENT PARTICLES .. 3-84
5.1. Bioassay Directed Chemical Analysis 3-85
5.1 Contribution of Nitroarenes to Ambient Air 3-88
6.0. SUMMARY 3-93
7.0. REFERENCES 3-95
-------
TABLE OF CONTENTS (CONT.)
4. NONCANCER HEALTH EFFECTS OF DIESEL EXHAUST 4-1
4.1. HEALTH EFFECTS OF WHOLE EXHAUST 4-1
4.1.1. Human Data 4-1
4.1.2. Animal Studies 4-8
4.2. COMPARISON OF HEALTH EFFECTS OF FILTERED AND
UNFELTERED EXHAUST 4-44
4.3. INTERACTIVE EFFECTS OF DIESEL EXHAUST
COMPONENTS 4-47
4.4. COMPARISON OF THE EFFECTS OF DIESEL EXHAUST AND
GASOLINE EXHAUST 4-50
4.5. SUMMARY AND DISCUSSION 4-53
4.5.1. Toxic Effects of Diesel Exhaust on Humans 4-53
4.5.2. Toxic Effects of Diesel Exhaust on Animals 4-54
4.5.3. Interactive Effects 4-62
4.5.4. Comparisons with Gasoline Exhausts 4-63
4.6. REFERENCES 7 4-65
5. MUTAGENIOTY 5-1
5.1. GENE MUTATIONS 5-1
5.2 CHROMOSOME EFFECTS 5-3
5.3 OTHER GENOTOXIC EFFECTS 5-5
5.4 SUMMARY 5-5
5.5 REFERENCES 5-6
6. METABOLISM AND MECHANISM OF ACTION IN DIESEL EMISSION-
INDUCED CARCINOGENESIS 6-1
6.1 METABOLISM CONSIDERATIONS 6-1
6.1.1. Metabolism and Disposition of B[a]P 6-2
6.1.2. Metabolism and Disposition of 1-Nitropyrene 6-7
VI
-------
TABLE OF CONTENTS (CONT.)
6.1 CARCINOGENIC MECHANISM OF PAH COMPONENTS OF
DIESEL EXHAUST 6-9
6.2.1. Carcinogenic Mechanism of B[a]P 6-11
6.2.2. Carcinogenic Mechanism of Nitropyrenes 6-14
6.3. CARCINOGENICITY OF ALDEHYDES 6-17
6.3.1. Metabolism and Carcinogenicity of Formaldehyde 6-17
6.3.1 Metabolism and Carcinogenicity of Acrolein 6-18
6.4. POTENTIAL INVOLVEMENT OF PULMONARY LEUKOCYTES
IN THE DEVELOPMENT OF LUNG TUMORS 6-19
6.5. SUMMARY OF METABOLISM AND MECHANISM OF ACTION
OF CARCINOGENIC COMPONENTS OF DIESEL EXHAUST . 6-23
6.6. REFERENCES 6-26
7. CARONOGENICITY OF DIESEL EMISSIONS IN LABORATORY
ANIMALS 7-1
7.1. INTRODUCTION r. 7-1
7.1 CARONOGENICITY STUDIES IN LABORATORY ANIMALS .. 7-2
7.11. Long-term Inhalation Studies 7-2
7.11 Short-term Inhalation and Intratracheal
Instillation Studies 7-38
7.13. Dermal Application, Subcutaneous Injection,
and Intraperitoneal Injection Studies 7-44
7.14. Summary of Animal Carcinogenicity Studies 7-50
7.3. REFERENCES 7-55
8. PHARMACOKINETIC CONSIDERATIONS IN THE PULMONARY
CARdNOGENICTTY OF DIESEL ENGINE EMISSIONS 8-1
8.1. INTRODUCTION 8-1
8.1 REGIONAL LUNG DEPOSITION OF INHALED
PARTICLES BY HUMANS AND ANIMALS 8-1
8.3. TRACHEOBRONCHIAL CLEARANCE OF
PARTICULATE MATTER 8-2
vu
-------
TABLE OF CONTENTS (CONT.)
8.4. CLEARANCE FROM DEEP LUNG REGIONS 8-3
8.4.1. Species Variability in Pulmonary Clearance
Processes 8-10
8.4.2. Role of Alveolar Macrophages in the Clearance
of Paniculate Matter 8-12
8.4.3. Summary: Pulmonary Clearance of Diesel Exhaust
Participate Matter 8-37
8.5. DESORPTION OF CONSTITUENTS FROM DIESEL EXHAUST
PARTICLES 8-38
8.5.1. Unavailability of Agents Adsorbed to Diesel
Exhaust Particles 8-38
8.5.2. Extraction of Carcinogens from Particles by
Alveolar Macrophages and Other Cell Types 8-42
8.5.3. Unavailability of Adsorbed Compounds as a
Function of Particle Clearance Rates and
Extraction Rates of Adsorbed Compounds 8-48
8.5.4. Summary: Unavailability of Particle-Adsorbed
Agents 8-50
8.6. INHIBITION OF RESPIRATION BY HIGH CONCENTRATIONS
OF NOXIOUS AGENTS 8-51
8.7. CONSIDERATIONS FOR DOSIMETOY MODELING 8-52
8.8. SUMMARY 8-53
8.9 REFERENCES 8-55
9. EPIDEMIOLOGY STUDIES 9-1
9.1. EPEDEMIOLOGIC STUDIES OF THE CARCINOGENICITY OF
EXPOSURE TO DIESEL EMISSIONS 9-1
9.2 COHORT STUDIES 9-2
9.11. Waller (1981): Trends in lung cancer in London
Relation to expsoure to diesel fumes 9-2
9.2.2. Howe et al. (1983): Cancer mortality (1965-1977)
in relation to diesel fume and coal exposure in
a cohort of retired railroad workers 9-4
9.2.3. Rushton et al. (1983): Epidemiological survey
of maintenance workers in the London transport
executive bus garages and Chiswick works 9-6
vm
-------
TABLE OF CONTENTS (CONT.)
9.2.4. Wong et al. (1985): Mortality among members of a
heavy construction operators union with potential
exposure to diesel exhaust emissions 9-7
9.2.5. Edling et al. (1987): Mortality among personnel
exposed to diesel exhaust 9-12
9.2.6. Boffetta and Stellamn (1988): Diesel exhaust
exposure and mortality among males in the American
Cancer Society prospective study 9-14
9.2.7. Garschick et aL (1988): A retrospective cohort
study of lung cancer and diesel exhaust exposure
in railroad workers 9-16
9.3 CASE CONTROL STUDIES OF LUNG CANCER 9-20
9.3.1. Williams et al. (1977): Associations of cancer
site with occuaption and industry from the third
national cancer survey interview 9-20
9.3.2. Hall and Wynder (1984): A case-control study of
diesel exhaust exposure and lung cancer 9-21
9.3.3. Damber and Larsson (1987): Occupation and male
lung cancer: A case control study in northern
Sweden 9-23
9.3.4. Lerchen et al. (1987): Lung cancer and occupation
in New Mexico 9-25
9.3.5. Garschick et al. (1987): A case-contol study of
lung cancer and diesel exhaust exposure in railroad
workers 9-27
9.3.6. Benhamou et aL (1988); Occupational risk factors
of lung cancer in a French case-control study 9-30
9.3.7. Hayes et al. (1988): Lung cancer in motor exhaust-related
(MER) occupations 9-32
9.4 CASE-CONTROL STUDIES OF BLADDER CANCER 9-34
9.4.1. Howe et aL (1980): Tobacco use, occupation,
coffee, various nutrients, and bladder cancer 9-34
9.4.2. Wynder et al. (1985): A case-control study of
diesel exhaust exposure and bladder cancer 9-37
9.4.3. Hoar and Hoover (1985): Truck driving and
bladder cancer mortality in rural New England 9-38
-------
TABLE OF CONTENTS (CONT.)
9.4.4. Iscovich et al. (1987): Tobacco smoking,
occupational exposure and bladder cancer in
Argentina 9-40
9.4.5. Steenland and Burnett (1987): A case-control
study of bladder cancer using city directories
as a source of occupational data 9-43
9.5 SUMMARY 9-45
9.6 REFERENCES 9-51
10. UNIT RISK ESTIMATES 10-1
10.1. INTRODUCTION 10-1
10.2. REVIEW OF PREVIOUS RISK ESTIMATES 10-4
10.3. RISK CALCULATIONS BASED IN ANIMAL BIOASSAY
DATA 10-10
10.3.1. Data Available for Risk Calculations 10-10
10.3.2. Calculations of Unit Risk 10-10
10.4. DISCUSSION 10-20
10.5 WEIGHT OF EVIDENCE 10-23
10.6. SUMMARY 10-27
10.7 REFERENCES 10-29
APPENDIX A: Emission Standards, Exhaust Components, Emissions Models ... A-l
APPENDIX B: Animal Carcinogenicity Summary Table B-l
APPENDIX C: Models for Calculating Lung Burdens C-l
APPENDIX D: Extrapolation Dosimetry Model D-l
-------
LET OF TABLES
TABLE 2-1 Levels of Emissions from Current Diesel and
Gasoline Engines (FTP cycle only) 3-5
TABLE 2-2 Emission Rates of Volatile Organic Compounds (VOC)
from Diesel and Gasoline Engines 3-7
TABLE 2-3 Paniculate Matter Emission Rates and Their
Distribution Between Total Carbon (TC) and Organic
Carbon (OQ for Heavy- and Light-Duty Diesel and
Gasoline Engines 3-13
TABLE 2-4 Summary of Composition and Emission Rates (rag/km) of
Airborne Paniculate Matter from On-Road Vehicles,
Tuscarora Mountain Tunnel 1977 Experiment 3-15
TABLE 2-5 Gasses of Organic Compounds Identified in Particulate-
Phase Combustion Emissions 3-17
TABLE 2-6 Polycyclic Aromatic Hydrocarbons Identified and
Quantified in Extracts of Diesel Particles 3-19
TABLE 2-7 Emission Rates of Particle-Bounded PAH from Heavy-
and Light-Duty Diesel and Gasoline Engines 3-21
TABLE 2-8 Concentrations of Nitro-PAH Identified in a
LDD Paniculate Extract 3-24
TABLE 2-9 Factors Affecting Rate of Emission of Polycyclic
Aromatic Hydrocarbons in /ig/mile from Diesel
Engine Exhaust and Mutagenicity 3-27
TABLE 2-10 Vapor Pressures at 25'C for a Series of PAH 3-29
TABLE 3-1 Calculated Atmospheric Lifetimes for Gas-Phase
Reactions of Selected Compounds Present in Automotive
Emissions with Atmospherically Important Reactive
Species 3-37
XI
-------
LIST OF TABLES (CONT.)
TABLE 3-2
TABLE 3-3
TABLE 3-4
TABLE 3-5
TABLE 4-1
TABLE 4-2
TABLE 4-3
TABLE 4-4
TABLE 5-1
TABLE 4-1
TABLE 4-2
TABLE 4-3
TABLE 4-4
TABLE 4-5
Summary of the Nitroarenes Produced from the Gas-Phase
OH Radical-Initiated and N2O5 Reactions and
Electrophilic Nitration of PAH 3-52
Average Atmospheric Lifetimes of Particles Due to
Dry Deposition 3-60
Examples of Dry Deposition Velocities 3-61
Mean Particle, Gas, and Overall Scavenging Ratios
for Neutral Organic Compounds 3-64
Concentrations of Individual Hydrocarbons and
Aldehydes Measured in Raleigh, NC 3-67
Particle- and Vapor-Phase PAH Concentrations for
Baltimore Harbor Tunnel Samples 3-69
Average Ambient Concentrations of PAH Measured in
Glendora, CA 3-71
The Maximum Concentrations of Nitrofluoranthene (NF)
and Nitropyrene (NP) Isomers Observed at Three South
Coast Basin Sampling Sites 3-73
Contribution of Nitrofluoranthene (NF) Isomers to the
Direct Mutagenicity of Ambient Paniculate Extracts 3-91
Composition of the exposure atmospheres in the
EPA studies 4-11
Composition of the exposure atmospheres in the
EPA studies
Composition of exposure atmospheres in the
Lovelace studies
4-13
4-15
Composition of exposure atmospheres in the
Ishinishi study 4-17
Composition of the atmosphere in the Lewis study 4-19
XII
-------
LIST OF TABLES (CONT.)
TABLE 4-6 Composition of the exposure atmosphere in the
Heinrich 1982 study 4-22
TABLE 4-7 Composition of the exposure atmosphere in the
Heinrich 1986 study 4-22
TABLE 4-8 Composition of exposure atmospheres in the
Mauderty et ah, 1987a study 4-28
TABLE 4-9 Composition of atmosphere in Campbell et al. study 4-34
TABLE 4-10 Emission rates for diesel and gasoline engines 4-51
TABLE 4-11 Exposure atmosphere for EPA chronic toxicity study 4-53
TABLE 4-12 Short-term toxicity of diesel exhaust to laboratory
animals 4-56
TABLE 7-1 Gas-phase components of control and diesel exhaust
exposure atmospheres 7-3
TABLE 7-2 Tumor and Lung paniculate matter (soot) burden in male
and female F344 rats exposed to diesel exhaust for
24 mo 7-5
TABLE 7-3 Gas-phase components of control (clean air) and Diesel
exhaust atmospheres 7-6
TABLE 7-4 Gas-phase components of control and diesel exhaust
atmospheres 7-8
TABLE 7-5 Tumor incidence in female F344 rats, NMRI mice, and
male and female Syrian golden hamsters following
long-term (120 70 140 weeks) inhalation exposure to
total diesel exhaust (4 mg particles/m3), filtered
exhaust, or clean air 7-10
TABLE 7-6 Gas-phase components of diesel exposure atmospheres 7-12
TABLE 7-8 Tumor incidence in male and female F344 rats following
long-term (30 mo) inhalation exposure to diesel
exhaust 7-14
xui
-------
LIST OF TABLES (CONT.)
TABLE 7-9 Tumor incidence in ICR and C57B6 mice following
long-term (24 mo) inhalation exposure to diesel
exhaust and in rats exposed to diesel exhaust with
or without DIPN treatment 7-18
TABLE 7-10 Pulmonary lesion incidence in female Wistar rats
following long-term (24 to 30 mo) inhalation exposure
to unfiltered diesel exhaust 7-20
TABLE 7-11 Tumor incidence in male and female F344 rats and
Syrian golden hamsters following long-term inhalation
exposure to filtered or unfiltered diesel exhaust
with or without DEN pretreatment 7-23
TABLE 7-12 Analysis of fresh air control (FA), diesel exhaust
(DE), coal dust (CD), and coal dust plus diesel exhaust
(DECD) atmospheres 7-26
TABLE 7-13 Concentration of gas-phase components and particles
in exposure chambers 7-29
TABLE 7-14 Lung tumor incidence in strain A mice exposed for 8
weeks to raw or irradiated exhaust at a particle
concentration of 6 mg/m3 7-31
TABLE 7-15 Lung tumor incidence in strain A mice exposed to diesel
exhaust at a particle concentration of 6 mg/m3 until
9 mo of age 7-32
TABLE 7-16 Effects of inhalation exposure to diesel exhaust on
lung tumor incidence in male and female SENCAR mice 7-34
TABLE 7-17 Lung tumor incidence in strain A mice exposed to a
particle concentration of 12 mg/m3 7-35
TABLE 7-18 Tumor incidence in male and female F344 rats
chronically exposed to whole exhaust from LD and HD
engines 7-37
TABLE 7-19 Tumor incidence and survival time of rats treated
with fractions from diesel exhaust condensate
(35 rats/groups) 7-39
XIV
-------
LIST OF TABLES (CONT.)
TABLE 7-20 Pulmonary adenoma response of strain A/J mice exposed
to diesel exhaust (1500 /ig/m3 particles)) for
three mo .......................................... 7-42
TABLE 7-21 Tumor incidence in female Wistar rats treated with
diphenylnitrosamine (DNP) and exposed to clean air
(CA), filtered diesel exhaust (FDE), or whole diesel
exhaust (DE) ....................................... 7-43
TABLE 7-22 Tumorigenic effects of dermal application of acetone
extracts of diesel exhaust .............................. 7-47
TABLE 7-23 Dermal, tumorigenic and carcinogenic effects of various
emission extracts .................................... 7-51
TABLE 10-1 Paniculate lung burden and lung tumors in rats
following a 2-year exposure to titanium dioxide (TiOj)
and diesel exhaust .................................... 10-2
TABLE 10-2 Estimated lifetime risk of cancer from inhalation of
diesel paniculate matter ........................ 10-9
TABLE 10-3 Incidence of lung tumors in Fisher 344 rats (males and
females combined) exposed to diesel exhaust in air .......... 10-11
TABLE 10-4 Incidence of lung tumors in Fisher 344 rats (males and
females combined) exposed to heavy duty engine
exhaust .......................................... 10-12
TABLE 10-5 Incidence of lung tumors in Fisher 344 rats (males
and females combined) exposed to diesel exhaust in air
(Brightwell et al., 1986) .............................. 10-13
TABLE 10-6 Combined dose-response data from four studies
conducted on Fisher 344 rats .......................... 10-14
xv
-------
LIST OF FIGURES
FIGURE 2-1 Typical Size Distribution of Diesel Exhaust Particles 3-11
FIGURE 2-2 Example of Human Respiratory System Aerosol Particle
Deposition Curve 3-12
FIGURE 2-3 Vapor/Particle Phase PAH Distribution in Samples
Collected in Baltimore Harbor Tunnel 3-31
FIGURE 3-1 Diesel-Derived Pollutants: Emission-to-Deposition
Atmospheric Cycle 3-33
FIGURE 4-1 Mass Chromatograms of the Molecular Ion of the
Nitrofluoranthenes (NF) and Nitropyrenes (NP) Formed
from the Gas-phase Reaction of Fluoranthene and Pyrene
with the OH Radicals and Present in Ambient Paniculate
Sample Collected at Torrance, CA 3-75
FIGURE 4-2 Mass Chromatograms of the Molecular Ion of the
Nitrofluoranthenes (NF) and Nitropyrenes (NP) Present
in Ambient Paniculate Samples Collected in Torrance,
CA and Claremont, CA -. 3-77
FIGURE 5-1 Protocol for Bioassay-Directed Chemical Analysis 3-86
FIGURE 5-2 Distribution of Direct-Acting Mutagenicity (TA98,
-S9) Between Moderately Polar and Polar Fractions of
Extracts of Paniculate Matter in Ambient Air, Wood
Smoke, and in the Exhaust from Heavy-Duty and Light-Duty
Motor Vehicles 3-89
FIGURE 6-1 Metabolic pathway for B[a]P and formation of ultimate
carcinogenic intermediate 6-3
FIGURE 6-2 Possible metabolic pathways for in. vivo
biotransformation of 1-NP to 6-hydroxy-N-
acetyH-aminopyrine 6-10
FIGURE 6-3 Proposed pathway for cellular activation of
1-nitropyrene (1-NP) 6-16
XVI
-------
FIGURE 6-4 Electron micrograph of an aggregate of particle-filled
AM in an alveolus on day 106 following the deposition
of 6.8x10* microspheres 6-24
FIGURE 8-1 Clearance of insoluble particles deposited in
tracheobronchial and pulmonary regions 8-4
FIGURE 8-2 Short-term thoracic clearance of inhaled particles as
determined by model prediction and experimental
measurement 8-5
FIGURE 8-3 Lung retention kinetics of 2.13 mm diam. polystyrene
microspheres after instillation into rat lungs 8-14
FIGURE 8-4 Estimated number of AM with an indicated particle load
of microspheres over a 174 d period following the
instillation of 1.6xl07 microspheres 8-16
FIGURE 8-5 Relationship between the slope (exponents) of later
phase AM disappearance relative to the particle loads
in the AM 8-17
FIGURE 8-6 Relationship of the rates (exponents) of early
component disappearance of AM relative to particle
loads in the AM 8-18
FIGURE 8-7 Proportions of AM with a given load of particles that
disappeared from the total AM population by the early
disappearance components as of a theoretical day 0
postinstillation time and as of day 7 after the particles
were administered 8-19
FIGURE 8-8 Percentage distribution of the retained lung burden
in the various particle-AM categories over the course
of lung clearance of the 1.6xl07 microsphere initial
burden 8-21
FIGURE 8-9 Estimated numbers of AM with a given particle burden
over the course of clearance of 2.0x10*
microspheres 8-23
xvu
-------
FIGURE 8-10 Percentage distributions of retained lung burdens in
the various particle-AM categories during the clearance
of the 2.0x10* initial lung burden of
microspheres 8-24
FIGURE 8-11 Estimated numbers of AM in the indicated particle-
containing categories following the deposition of
6.8x10* microspheres into the rat's lung 8-25
FIGURE 8-12 Electron micrograph of an aggregate of particle
filled AM in an alveolus on day 106 following the
deposition of 6.8x10* microspheres 8-26
FIGURE 8-13 Percentages of the retained lung burden contained in
the various particle-AM categories following the
deposition of 6.8x10* microspheres 8-27
FIGURE 8-14 Micrograph of cells lavaged from a lung 86 d after
the deposition of 6.8x10* microspheres 8-29
FIGURE 10-1 Lung burden (organic material, mg) in rats, under exposure scenario
(7 h/d5 d/week) in Mauderly et al. (1987) 10-15
FIGURE 10-2 Cumulative lung burden (particles, mg) in rats, under exposure
scenario (7 h/d,5d/week) in Mauderly et al. (1987) 10-17
FIGURE 10-3 Lung burden (organics, mg) in human adults over years after
exposure 10-18
FIGURE 10-4 Effect of increasing the mitotic rate of initiated cells on
the tumor incidence rate over age when other parameters are held
constant 10-22
xvui
-------
Principal authors of this document are:
Dr. Chao Chen
Carcinogen Assessment Statistics and Epidemiology Branch
U.S. Environmental Protection Agency
Washington, D.C.
Dr. Aparna Koppikar
Carcinogen Assessment Statistics and Epidemiology Branch
U.S. Environmental Protection Agency
Washington, D.C.
Dr. Bruce E. Lehnert
Pulmonary Biology-Toxicology Section
Los Alamos National Laboratory
Los Alamos, NM
Dr. Kumar Menon
Albert Einstein Medical Center
Philadelphia, PA
Dr. Gunther Oberdoerster
Department of Biophysics
University of Rochester
Rochester, NY
Dr. Dennis Opresko
Health and Safety Research Division
Biomedical and Environmental Information Analysis
Oak Ridge National Laboratory
Oak Ridge, TN
Dr. William Pepelko
Carcinogen Assessment Toxicology Branch
U.S. Environmental Protection Agency
Washington, D.C.
Dr. Larry Valcovic
Genetic Toxicology Assessment Branch
U.S. Environmental Protection Agency
Washington, D.C.
XIX
-------
Dr. Ronald K. Wolff
Lilly Research Laboratories
Greenfield Laboratories
Greenfield, IN
Dr. Robert A. Young
Health and Safety Research Division
Biomedical and Environmental Information Analysis
Oak Ridge National Laboratory
Oak Ridge, TN
Dr. C. P. Yu
Department of Mechanical and Aerospace Engineering
Sate University of New York
Buffalo, NY
Project Managers:
Mr. William Ewald
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC
Dr. William Pepelko
Carcinogen Assessment Toxicology Branch
U.S. Environmental Protection Agency
Washington, D.C.
-------
APPENDIX A
-------
TABLE A-l. NEW VEfflCLE STANDARDS SUMMARY
CARS1
The following itcndarda. up to 1975. apply only to gaaoline-fualed light-duty vehicle*. Staadaxd* tor 1975 and liter apply
to both gaaoitne-futlad and diesel light-duty vehicles.
3*
Prior to
contra is
1968-69
'.370
1971
1972
1973-74
1973-76
1977*
1978-79
1980
1981
I982io.ii
l9Mio.u
198411.12
1983-8613
1987 & later13
IZST
PKm-^LUKt
7 -Mode
7 -Mode
CTS-73
7 -Mode
20-100 CIO
101-140
Over 140
7 -Mode
7 -Mode
CVS-72
CTS-72
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
CTS-73
HYTtftQ*
CARBONS
830 ppa
11 tpa
8.8 spa
410 ppa
330 ppa
273 ppa
2.2 spa
2.2 spa
3.4 spa
3.4 spa
1.3 gpa
1.3 gpa
1.3 spa
0.41 gpa
0.41 gpa
0.41 gpa
(0.37)
0.41 gpa
(0.37)
0.41 gpa
(0.37)
0.41 gpa
0.41 gpa
CAHBCTf ^X I PRS OF
MOHODCICE HllHJUiH
3.4Z 1000 ppa
80 gpa 4 gpa
87.0 gpa 3.0 gpa
2.3Z
2.0Z
1.3Z
23 spa
23 spa
39 gpa
39 spa 3.0 gpa
13 spa5 3.1 gpa
13 spa 2.0 gpa
13 spa 2.0 gpa
7.0 gpa 2.0 gpa
3.4 gpa7 1.0 gpa''9
3.4 gpa7 1.0 gpa8'8
(7.$) (l.O)8
3.4 gpa 1.0 gpa8'8
(7.8) (l.O)8
3.4 gpa 1.0 gpa8
(7.8) (l.O)8
3.4 gpa 1.0 gpa
3.4 gpa 1.0 gpa
DIZSTL EVATOAim
PARTICUUTE HYDHOCARBOITS3
.
-
-
-
2 g/test
2 g/taat
2 g/test
2.0 g/teat
6.0 g/teat
6.0 g/test
2.0 g/test
0.60 spa 2.0 s/taat
(2.6)
0.60 spa 2.0 g/test
(2.8)
0.60 gpa 2.0 g/test
(2.6)
0.60 gpa 2.0 g/test
0.20 Spa1* 2.0 g/tsst
A-l
-------
AfTEHDXX A (continued)
LIGHT-DUTY u^Hlf'liT5
1. Standards do not apply to vahiclee wita anginas leaa than 30 CIO from 1998 through 1974. Diaaal
particulata standard* apply only to diesels.
2. ^Different t*at procedures have been used siBca the early years at emission control which vary in
stringency. Tha appaaranca that tha atandarda were relaxed from 1971 to 1972 Is incorraet. The 1972
standards are actually oora strlntant bacauaa of tha greater stringency of tha 1972 procadura.
3. Evaporative euaaions dataxminad by carbon trap Bathed through 1977. SHED procadura beginning in 1978.
Applies only to gasoline-fueled vehiclea.
*. Evaporative hydrocarbon standard doaa not apply to off-road utility vahiclaa for 1971.
'. Carbon Bonoxide stanaard for vehicles sold in tha Stata of California is 9.0 gpm.
5. Cars sold in spaeifisd high altituda countias raquirad to aaab standarda at high altltuda.
7. Carbon oonoxida standard can ba Maivad 7.0 gpa far 1981-82 by tha CPA Adninistrator.
8. Oxidas of nitrogan standard can ba waivad to 1.5 gpa for inammtiv* taebnology or diaaal.
9. Ozidaa of nitrogan standard can ba vaivad to 2.0 gpa for Acaarican Motors Corporation.
10. Standarda in paxanthaaaa apply to vahiclaa sold in specified high altituda counties. Vehicles eligible
for a carbon nonoxlde weive for 7.0 gpa at law altituda are eligible for a waiver to 11 gpn at high
altituda.
11. Exemptions free) tha high-altitude standarda are provided for qualifying iow-perfozaance vehicles.
12. Thaaa save nuaarical standarda apply to vehicles sold in high-altitude areas. Standarda in parenthesis
spply to heavy paaaaagar can sold in high-altitude araaa for tha 1984 nodal year only.
13. Thaae aana oaaarieal atandarda apply to vehicles sold in high-altitude araaa. Exemptions froa tha high-
altitude standarda are provided for cpiali£ying low-performance vehielaa.
14. EaiMions averaging nay fa* used to meat this standard.
Additional Jteaaizementa
No crankcasa emiaaiona are permitted (sppliea to gaaoliae-fueled only).
Emiasion control component maintenance is restricted to specified interval*.
gpa - grama par mile
CZO - cubic inch displace
CV8-72 - constant volume sample cold start teat
CVS-73 - constant volume aampla teat which includee cold and hot starts
7-ooda - #137 second driving cycle test
ppa - pasts par million
A-2
-------
TABLE A.2. NEW VEHICLE STANDARDS SUMMARY -
LIGHT DUTY TRUCKS1
Th. following standard*, up to 1978. apply only to guoiina-fualad light-duty truck*. Standard* for 1976 and later apply
io both gaaolina-fual.d and diaial light-duty truck*.
345
Prior to
control*
1968-69
1370
1371
:972
1973-74
1973-775
1978
1979-806
1981
1982-83 7
1984-667
1987 7
1988 & l«t.r7 (A)
(B)
TBT
^
7 -Mod*
7 -Mod.
CVS-75
7 -Mod*
30-100 CI3
101-140
Ov»r 140
7 -Mod.
7 -Mod.
CVS-72
CVS-72
CVS-73
CVS-75
CVS-75
CVS-75
CVS-75
CVS-73
CVS-73
CVS-75
CVS-75
HYDRO-
C AMOKS
SSO pp.
11 gp»
6.3 gp.
410 pp.
330 pp.
275 pp.
2.2 ipo
2.2 gpa
3 4 BM»
J . ^ •>!••
3.4 gp.
2.0 gp.
2.0 gp.
1-7 gp.
1.7 gp.
1 7 *«M
I./ gP.
(2.0)
0.80 gpa
(1.0)
0.80 gp.
(1.0)
0.80 gpa
(1.0)
0.80
(1.0)
CAUQR
HOBOXIPE
3.4Z
80 gp.
76.0 gp.
2.3Z
2.0Z
1.3Z
23 gpa
23 gpa
39 gp.
39 gpa
20 gp.
20 gp»
18 gp.
18 gpa
1> gPM
(28)
10 gp.
(14)
10 8PM
(14)
10 gP»
(14)
10 gp.
(14)
QQCXDE3 OF
HlTKLXjiH
1000 pp.
4 ItB
••"••
3.6 gp.
.
.
•
3.0 gp*
3.1 gpn
3.1 gp.
2.3 gpa
2.3 gp.
2.3 gpa
(2.3)
2.3 gpa
(2.3)
2.3 gp.
(2.3)
1.2 gp.
(1.2)
1.7 «P»9
(1.7)
DBSZL EVAPORATE
PAMieuiATE HYDEOCAMC
-
-
*
"
_ L
6 g/taat
2 c/taat
2 g/taat
2 g/t.at
6.0 g/taat
6.0 g/taat
2.0 g/t.at
0.60 gpm 2.0 g/t.at
(2.6)
0.60 gp. 2.0 g/taat
(2.6)
0.26 gpm8 2.0 g/taat
(2.6)
0.26 gpn8 2.0 g/taat
(0.26) (2.6)
0.26 gpa8 2.0 g/taat
(0.26) (2.6)
A-3
-------
APPENDIX A (continued)
L.I33I-DUTT TRUCKS
1. Standard* do not apply to vehicle* with anginss !••• than 20 CIO Cram 1968 through 1974. Diesel
paniculate standard* apply only to diaeeia.
2. 2iffarent teat procedures have been ui«d tine* the early year* of emission control which vary in
stringency. The appearance that the atandard* were relaxed from 1971 to 1972 in incorrect. The 1972
standards are actually more stringent because of the greater stringency of the 1972 procedure.
3. Evaporative eeuaaiona determined by carbon trap method through 1977, SHED proeedure beginning in 1970.
Applies only to gaaoliaa-fueled vehicles.
<•. Evaporative standard does not apply to off-road utility vehicles for 1971.
5. Trucks sold in specified high altitude countlea required to smet standarda at high «i»-«t»^. (1377
5. Effective in 1979, light-duty truck claaaificatlon wee extended from 0-6000 pounos GVW to 0-8300 pounds
5VWR.
Standards in perenthesis apply to veiucies sold in specified high altitude counties. Izsoptions from
the high altitude etandarda are provided for up to 301 of the high-altitude prooact line lot 1982-84;
tzemptions for qualifying lev-performance trucks are provided for 1983 and later.
3. -missions averaging may be used to meet this standard provided that trucks produced for sale in
California or deelgaated high-altitude areas may be averaged only within each of these arias.
». Standards o£ 1.2 gpm apply to LDIs up to and InflwUnf. 3,730 pound* loaded vehicle weight; 1.7 gpa
standard applies to LOT* equal and over 3.731 Ib* loaded vehicle weight. Eoiasions averaging may be
used to meet this standard provided that trucks produced tor sale in California or deaignated high-
altitude areas mar be averaged only within each of those areas. Dteael and gasoline-fueled engine
families stay not be averaged together.
Additional Rtoutrtments
No crankeaae soaaaiona are permitted from gaaoline-fueled trucka: applies to high-altitude trucks beginning
in 1982. dissel-powered trucka beginning in 1984.
A 00 standard of 0.30X at idle is established for 1984 end later model years: effective at high altitude
starting with the 1988 model year.
Full useful life ia established for 1983 and later model yean, defined ae 11 years/120.000 mile*. For 1984,
a number of useful life option* are available; prior to 1984, useful life i* 3 yean/30.000 miles.
emission control component maintenance is restricted to specified interval*.
gpm - grams per mile
CIO - cubic inch displacement
CVS-72 - constant volume aample cold start teat
CV3-7S - constant volume sample test which Includes cold and hot start*
7-oodo - #137 second driving cycle teat
ppm - part* per million
CrVMt - gross vehicle weight rating
A-4
-------
TABLE A3. NEW VEHICLE STANDARDS SUMMARY - DIESEL HEAVY-DUTY ENGINES
„
„,
m,in*
CAMOH
1970-73
197*-78
:379-»
««
1994 « i.t.r
1.3 ,/bhp-hr
1.3 ,/bhp-hr
0.3 ,/bhp-hr
*0 »/bph-hr
23 ./bh|r.te
23 g/bhp-hr
23,/bhp-hr
23
13.3 ,/bhp-hr
13.3 ,/bhp-hr
1.3 ,/bhp-hr 13.3
1.3 ,/bhp-hr 13.S
1.3 ./bhp-hr 13.S
OQODES OF
IR0BOCARBONS
& OXIDES OF DIZSEL
16 ,/bhp-hr
10 ,/bhp-hr
, JW .
5, /bhp-hr
10 ,/bhp-hr
< ,_,_
3 ,/bhp-hr
10.7 ,/bbp-hr
9.0 ,/bhp-hr
10.7 ,/bbp-hr
6.0. /bhp-hr
1.3 ,/bhp-hr 13.3 ,/bhp.te 3 Q ,,,^^3
0.60. /bhp-hr
ACCZL tOZ
LU3 20Z
ACCEL 2QZ
MB iiz
PEAK :sz
20Z
ACCEL 20Z
LOS 13Z
PEAK 30Z
ACCEL 20Z
UE 13Z
PEAK 20Z
ACCEL 201
UKJ isz
PEAK SOZ
20Z
UB 13Z
PEAK 30Z
0.10 ,/bhp-hr* LOB isz
PEAK SOZ
0.10 ,/bhp-hr5 ACCEL 20Z
LW isz
PEAK 30Z
A-5
-------
APPENDIX A (continued)
DIESEL HEAVY OUR ENGIKES
1. Tsst procedure for 1970-1983 standards is ths 13-ooda steady-state teat procedure, list procedure fox
1984 is either steady-state or the EPA transient teat procedure. For 1983 and liter, the EPA transient
test procedure is used.
2. At the manufacturers' option, either the 1983 standards and test procedures nay be used (option A), or
standards of 1.3 BC. 15.3 CO. and 10.7 HQx en the transient test procedure (option B). Also, standards
at 0.3 IE. 13.3 CO and 9.0 HOz are optional standards for 1984 diesals tested on the 13-oode test
procedure.
3. Emissions averaging »«y be used to meet this standard, but these emissions nay not be averaged with HD
gasoiiae engine emissions. Averaging is restricted to within useful life subclasses (see below). Also.
averaging is restricted rtgionaily •- the two regions are California and the other »9 states.
Tor urean ous engines, tr.i standard is 0.10 g/bhp-hr -- partlculate averaging is not allowed with this
standard, but •missions from these engines may be used in NQx averaging.
5. Emissions averaging aay be used to aeet this standard. However averaging is restricted to within useful
life subclasses (see below). Also, averaging is restricted regionally—the two regions are California
and the other *9 states. Emissions tram engines used in urban bueee stay not be included in the
averaging program.
Additional ReemiremeBts
No crankcase Missions are permitted starting in 1984. This does not apply to turboeharged engines or
engines whose intake air is inducted solely by pumps, blowers, or superchargers.
Full useful life is.established for 1983 and later defined as:
Light heavy-duty (normally under 19.300 Ibs GVWJO — • yrs/110.000 Biles
Medium heavy-duty (normally 19.300-33,000 Ibs GVHR) — S yrs/183.000 miles
He*vy heavy-duty (normally over 33.000 Uas GVHR) — 8 yn/290.000 Biles
For 1984 (option £ only), a number of useful life options are available: for 1984 (option A) and prior years.
useful life is 5 yew/30,000 miles.
Emission control component maintenance is restricted to specified intervala.
g/bhp-hr - grams per brake horsepower - hoax
ppm - parts per million
13-mode test procedure - dlesel engine dyn••muter teat with 13 steady-state test points
transient test procedure - tngine dynamometer procedure with starts, stops, and speed/load changes
A-6
-------
MODIFIED EPA NAAQS EXPOSURE MODEL (NEM) FOR CO
The following description of the modified NAAQS Exposure Model (NEM) for
CO is based on information given by Carey (1987) and Ingalls (1985).
The original NEM was based on an activity model that simulated a set of
age/occupation population groups called cohorts. In the model these cohorts
are referred to a specific location type (neighborhood/microenvironment) for
each hour of the day. Each of the several specific location types in the
urban area are then assigned a particular ambient pollutant concentration
based on fixed site monitoring data. The model computes the hourly exposure
for each cohort and then sums up these values over the desired average time to
arrive at average population exposures and exposure distributions. Monitoring
data for a full year arc input into the model to allov for the computation of
annual averages.
The NEM methodology vas modified to allov for the estimation of exposures
from mobile source pollutants and to allov for the inclusion of data for
short-term exposures to high concentrations such as might occur in on-road
vehicles. The NEM for CO vas used because outdoor CO vas considered to result
almost exclusively from mobile sources and exposure to other non-reactive
mobile source pollutants could also be modeled using this relationship.
The CO monitoring data vere used to provide CO concentrations for each
neighborhood and most of the microenvironments. For each location, CO emis-
sion factors (in grams/minute) vere chosen to best represent vehicle condi-
tions in that area. The emission factor is a fleet average emission factor,
thus veighting emissions from both LDO and HDD vehicles. The model ratios the
CO concentrations and appropriate emissions factors for each location so each
A-7
-------
location contains a factor expressed as ug/mVgrams/minute. Emissions factors
in grams/minute for the pollutant of interest for each location are input to
the model. The model multiplies the input emission factor (grams/minute) by
the second factor (ug/3/grams/minute) to obtain concentrations in each loca-
tion for the pollutant of interest.
The modified NEH model does not account for photochemical reactions
occurring in the atmosphere. The model also assumes that the pollutant of
interest has emission formation and dispersion characeristics similar to that
for CO.
The model accounts for indoor exposure to mobile source-generated pollu-
tants. A scaling factor of 0.85 was applied to the CO monitoring data for a
given location. The scaling factor vas based on comparisons of indoor and
outdoor CO levels for homes vith no indoor CO sources.
In the modiified NEH procedure indocr CO exposures were set at zero, and
three specific mobile source microenvironments vere added (street canyons,
tunnels, and parking garages). In addition, an extrapolation procedure vas
developed to estimate nationvide exposures.
Inputs into the model included population data for urban and rural areas,
emission factors, and ambient pollutant concentrations specifying the 24 con-
centration intervals or bins for vhich the cumulative person-hours of exposure
vere to be calculated. The output lists the total annual person-hours of
exposure found in each of the specified concentration intervals. Population
data vere derived from U.S. Department of Commerce information. The emissions
data included FTP emission factors (constant volume test procedure using both
cold and hot starts, resulting in an average speed of 19.7 mph) for veekday
urban residential and suburban vehicle use. For veekday urban commercial and
industrial vehicle use and for street canyons, an emission factor for an
A-8
-------
average speed of 10 mph, expressed in grams/minute, was included. For the
tunnel microenvironment and rural areas, a 35 mph steady-state emission factor
vas used. For LDD vehicles an idle emission factor vas also included. Week-
end emission factors vere based on a fraction of the weekday values. These
emission factors vere chosen to best represent the vehicle operating condi-
tions for each neighborhood or microenvironment.
The emission factors for each model year for each vehicle type vere com-
bined into a single, weighted calendar year emission factor for each vehicle
type. Each model year's emission factor vas multiplied by that model year's
fraction of the calender year VMT (vehicle miles driven) and the diesel sales
fraction for that model year and then summed across 20 model years to derive
the annual weighted emission factor for each vehicle type. These factors vere
then used to derive a composite emission factor for the entire fleet.
The model is highly dependent on the assumptions used to deriva the emis-
sion factors, particularly those for the non-FTF situations. The modified
model also does not take into account projected changes in VMT. Since the
model vas based on 1981 monitoring data, projected VMT values vere compared to
1981 VMT values, and exposures predicted by the model vere adjusted accor-
dingly.
The mean exposure levels predicted by the model, adjusted to take into
account projected increases in VMT, are shovn belov:
Urban Rural Nationwide
1986
1995 (high sales)
1995 (lov sales)
2.63 ug/m3
1.27 ug/m3
1.69 ug/m3
2.38 ug/m3
1.06 ug/m3
1.27 ug/m3
2.56 ug/m3
1.22 ug/m3
1.58 ug/m3
A-9
-------
Rural exposure are smilar to urban exposures due to the greater fraction
of some HDD vehicle classes in rural areas. Hovever, according to Carey
(1987), the values calculated for rural areas should be considered only rough
estimates.
REFERENCES
Carey, P. M. (1987) Air toxic emissions from motor vehicles. Ann Arbor,
MI: Office of Mobile Sources, U.S. Environmental Protection Agency.
EPA Report no. EPA-AA-TSS-PA-86-5.
Ingalls. M. N. (1985) Improved mobile source exposure estimation. Ann Arbor,
HI: Office of Mobile Sources, U.S. Environmental Protection Agency.
EPA Report no. EPA-460/3-85-002.
A-10
-------
TABLE A-4. ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
Aceanthrone
Acenaphthenol
Acenaphchylene
Acephenan throne
Acetaldehyde
Acetylaminofluorene
Acetylene
1-Acetylnapthalene
Acrolein
Anthanthrene
Anthracene
Anthracene carboxaldehyde
9-Anthracene carboxaldehyde
Anthracene dicarboxylic
acid anhydride
Anthracenedione
Anthracene quinone
9,10-Anthracene quinone
Anthracenone
Anthranthene
Anthroic acid
Anthrone
9-Anthrone
Anthroquinone
Benz(j)aceanthrylene
Benz(e)acephenanthrylene
Benzacridine
Benzaldehyde
Benz(a)anthracene
Benzanthracene dicarbox-
aldehyde
Benz(a)anthracene-7-12-
dione
7H-Benz(de)anthracene-7-one
Benzenamine
Benzene
Benzene, l-(l,l-dimethyl-
ethyl)4-raethyl)
1,4-Benzenediol
Benzene, ethenylmethyl-
1,2-Benzene dicarboxylic
acid, dibutyl ester
1,2-Benzene dicarboxylic
acid, dimethyl ester
Benzene, dimethyl-
Benzene, ethyl-
Benzene, methyl-
Benzene, (1-methylethenyl)-
Benzene, (1-methylethyl)-
Benzene, l,l'-oxybis-
Benz(j)fluoranthene
Benzo(a)anthracene
carboxaldehyde
Benzo(a)anthracenequinone
7,12-Benzo(a)anthracene
quinone
Benzoanthrone
7-Benzo(de)anthrone
Benzo(dh)anthrone
Benzo(b)chrysene
Benzo(c)cinnoline
Benzo(gni)fluoranthene
Benzo(k)fluoranthene
Benzo(j)fluoranthrene
Benzo(k)fluoranthrene
Benzofluorene
Benzo(c)fluorene
Benzo(a)fluorenone
H-Benzo(a)fluorenone
Benzofuran
Benzo(e)perylene
Benzo(gni)perylene
Benzophenanthracene-
carboxaldehyde
Benzo(c)phenan threne
1-Benzopyran-A(AH)-one
2H-l-Benzopyran-2-one
Benzo(a)pyrene
Benzo(e)pyrene
Benz o(e)pyrene-A,5-d ihydrod io1
Benzo(e)pyrene-9,10-epoxide
1,6-Benzo(a)pyrenequinone
3,6-Benzo(a)pyrenequinone
6H-Benzo(cd)pyrenone
Benzo(ed)pyrenone
Bicyclo(2.2.1)heptan-2-one
1,7,7-trimethyl
Binaphthalene
Binaphthyl
1,1-Biphenyl
Biphenylcarboxaldehyde
1,1'-Biphenyl-4-carbox-
aldehyde
Biphenyldicarbonitrile
Biphenylene
1,1'-Biphenyl, 2-methoxy-
A-ll
-------
ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
[l,l'-Biphenyl)-2-ol
[l,l'-Biphenyl]-4-ol
1,3-Butadiene
Butanal
2-Butanone
1-Butene
2-Butene
Butyl-2-methylpropyl-
phthalate
Butylnaphthalene
n-Butyraldehyde
o-Chlorophenol
Chrysene carboxaidehyde
Chrysene quinone
Coronene
Croconaldehyde
Cyclodexanol
2,5-Cyclohexadiene, 1,4-dione
Cyclohexane
Cyclohexane, methy1-
Cyclohexanol
Cycloh-xanone
Cyclohexanone, raethyl-
Cyclohexene
2-Cyclohexen-l-one,
3,5,5-trimethyl
Cyclopentacoronene
Cyclopentano(c,d)-pyrene
Cyclopen tano(c, d)pyrene-3,4-
cis-diol
Cyclopentano(c,d)pyrene-3,4-
oxide
Cyclopentano(c,d)-pyrene-
3,4-trans-diol
4H-Cyclopenta(def)phenanthren-
4-one
Cyclopen taphenan thren-5-one
Cyclopen tapyrene
Cyclopenta(cd)pyrene
Cyclopentenodibenzopyrene
Cyclopenteno(cfd)pyrene
Cyclopenteno(c,d)pyrene
anhydride
Decalin
Decane
Diazomethane
Dibenr(a,c)anthracene
Di benz(a,j)anthracene
Dibenz(a,h)anthracene
dicarboxaidehyde
Dibenz(c,g)carbazole
Dibenzo(def,mno)chrysene
Dibenzo(b,ej(l,4j-dioxin
1,2,3,4-Di benzofluoranthene
Dibenzofluorene
Dibenzo(a,g)fluorene
Dibenzofuran
1,2,3-Dibenzopyrene
Dibenzo(a,i)pyrene
1,2,9,10-Dibenzotetracene
Dibenzothiophene
2,6-Di-tert-butyl-4-methyl-
phenol
1,2-Dihydroacenaphthylene
9,10-Dihydrobenzo(e)pyrene
4,5-Dihydrodihydroxy
benzopyrene
Dihydrodihydroxy-
fluoranthene
Dihydrodihydroxypyrene
5,6-Dihydrodiolbenzo(a)-
anthracene
1,6-Dihydrodiolbenzo(a)-
pyrene
4,5-Dihydrodiolbenzo(a)-
pyrene
2,3-Dihydroinden-l-one
1,2-Dihydro t rime thy1-
naphtnalene
Dihydroxyanthracene
9,10-Dihydroxyanthracene
Dihydroxydimethyl-
anthracene
Dihydroxyfluorene
Dihydroxymethoxybenzene
Dihydroxymethylanthracene
Dihydroxymethylfluorene
Dihydroxymethyl
phenanthrene
Dime thyIan thracene
9,10-DimethyIanthracene
Dime thyIan thracene
carboxaidehyde
DimethyIanthrone
Dimethylbenz(a)anthracene
Dimethylbenzonaphthothiophene
A-12
-------
ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
Dimethylcyclopentacene-
naphthylene
Dimethyldecalin
1,9-Dimethylfluorene
Dimethylfluorenequinone
Dimethylfluorenone
DimethyIhydroxyanthracene
Dimethylhydroxyfluorene
Dime thyIhydroxyphenan threne
Dimethylindan
DimethyInaphthalene-
carboxaldehyde
Dimethylnaphthalene dicar-
boxylic acid anhydride
Dimethylnaphthothiophene
Dimethylperhydrophen-
anthrene
Dimethylphenanthrene
Dimethylphenanthrene
carboxaldehyde
Dimethyl phenanthrone
Dimethyltetrahydro-
naphthalene
Dimethyltetralin
2,7-Dinitrofluorene
l,5-Dinitro-2-methyl-9,10-
anthraquinone
1,5-Dini tronaphthalene
Dinitropyrene
1,4-Dioxane
Di phenylacenaph thylene
Diphenylacetylene
DiphenyIbenzene
n-Docosane
Dodecylcylohexane
n-Eicosane
Ethene
Ethylfluorene
1-Ethyl naphthalene
p-Ethylphenol
Ethyl tridecane
1,l'-U,2-Ethynediyl)-
bisbenzene
Fluoranthene carbox-
aldehyde
Fluoranthenequinone
Fluorantheno-2,3-dihydrodiol
Fluoranthone
Fluoranthrene
9-Fluoren-a-one
9H-Fluorene
2-Fluorene carboxaldehyde
9-Fluorene carboxaldehyde
Fluorenequinone
1,4-Fluorenequinone
9H-Fluoren-9-one
9H-Fluoren-9-one,2,4,7-
trinitro-
Formaldehyde
Formic acid
Formic acid, ethyl ester
2-Furancarboxaldehyde
2-Furanmethanol
Furan, tetrahydro-
n-Heneicosane
n-Heptadecane
1-Heptadecene
Heptane
n-Hexadecane
Hexaldehyde
Hexane
Hexanol
2-Hexanone
Hexone
Hydrocyanic acid
Hydroxyanthracene
Hydroxyanthroic acid
2-Hydroxybenzaldehyde
5-Hydroxybenzo(a)anthracene
6-Hydroxybenzo(a)pyrene
7-Hydroxybenzo(a)pyrene
Hydroxychrysene
Hydroxycoronene
Hydroxyfluorene
9-Hydroxyfluorene
Hydroxyfluorenone
Hydroxynaphthalene dicar-
boxy lie acid anhydride
Hydroxynaphthalic acid
Hydroxynaphthoic acid
Hydroxynit ro fluorene
1-Hydroxyphenanthrene
Hydroxyphenanthrene
Hydroxyphenanthroic acid
Hydroxyphthalic acid
Hydroxypyrene
A-13
-------
ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
Hydroxytrimethylanthracene
Hydroxytrimethylphen-
anthrene
Hydroxyxanthene
3-Hydroxyxanthen-9-one
Hydroxyxan throne
1-Indanone
Indeno(1,2,3-cd)fluoran thene
Isoamylfluorene
1,3-Isobenzofurandione
Isobutryaldehyde
Isobutylene
Isopentene
2-Isopropylnaphthalene
o-Isopropylphenol
He thoxybenazldehyde
Methoxybiphenyl
2-Methoxy,l,l'biphenyl
Hethoxyfluorene
He thoxyphenan t h rene
He thoxyxan thenone
Hethylacetylene
Me thyIan thracene
2-Me thyIan thracene
9-Metnylanthracene
Hethylanthracene
carboxaldehyde
2-Methyl-9-anthracene
carboxaldehyde
Hethyl-9-10-anthracenedione
Hethylanthracenequinone
Methyl-9-10-anthracenequinone
2-Methyl-9-10-anthracene-
quinone
Hethyl anthroic acid
Methylanthrone
Methyl-9-anthrone
4-Hethylbenzaldehyde
Methylbenz(a)anthracene
Me thyIbenzanthrone
Methylbenzoate
7-Methylbenzofuran
Methylbenzoic acid
Me thyIbenzo(a)pyrene
Methylbenzo(e)pyrene
10-Methylbenzopyrene
3-Methylbutanal
2-Hethylbutane
Methylcarbazole
Hethyl caronene
3-Hethylcholanthrene
Methylchrysene
Methylcyclohexanone
Methyl-AH-cyclopenta(def)-
phenan thren-4-one
Methyldecane
Methyldibenzothiophene
Methyldihydrofluoranthene
Methyldihydropyrene
Me thyIfluoranthenequinone
1-Methylfluorene
9-Methylfluorene
Hethylfluorenequinone
Methylfluorenone
2-Methylfluorenone
Hethyl-9-fluorenone
MethyIhydroxyanthracene
5-Methylhydroxybenzo-
phenanthrene
Methylhydroxyfluorene
Methylhydroxyphenanthrene
Methylindan
Methylnaphthaldehyde
6-Me thy1-2-naph thaldehyde
Me thyInaphthalene
Me thyInaph thalene
carboxaldehyde
HethyInaphthalene dicar-
boxy lie acid anhydride
MethyInaphthalic acid
Hethylnaphthoic acid
Hethylnitroanthracene
Hethylnitropyrene
Hethylpentadecane
Methylperylene
1-Methylphenanthrene
2-Methylphenanthrene
3-Hethylphenanthrene
4-MethyIphenanthrene
9-Methylphenanthrene
Methylphenanthrene
carboxaldehyde
Hethylphenanthrenequinone
Me thy1-9-10-phenanthrene-
quinone
Hethylphenanthroic acid
A-14
-------
ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
Hethylphenanthrone
4-He thylphenyIbenzo(c)-
cinnoline
Hethylphenylcinnoline
Methylphthalic acid
1-Methylpyrene
Methylpyrenequinone
Hethylquinoline
Methyltetralin
Hethyltriphenylene
Methylundecane
Honomethylaniline
Naphthalene
Naphthalene acetaldehyde
1-Naphthalene carboxaldehyde
2-Naphthalene carboxaldehyde
1-Naphthalene carboxylie acid
2-Naphthalene carboxylic acid
Naphthalene dicarboxaldehyde
1,8-Naphthalene dicarboxylie
acid
Naphthalene dicarboxylie
acid anhydride
IH-Naphthalenequinone
2-Naphthalenol
Naphtho(1234tde£)chrysene
Naphtho-2,3(b)furan-4,9-
dione
Naphthopyrandi one
Naphtho(l,8-cd)pyran-l,3-
dione
1H,3H-Naphtho-l,8-cd-pyran-
1,3-dione
l-Naphtho(cd)pyrone
C4-Naphthothi ophene
9-Ni troanthracene
6-Nitrobenzo(a)pyrene
Nitrochrysene
Nitroethane
2-Nitrofluorene
3-Nitro-9-fluorenone
Nitromethane
Nitronaphthalic acid
Ni trophenanthrene
Nitropyrene
1-Nitropyrene
Nitropyrone
N-Ni trosomorpholine
n-Nonadecane
n-Octadecane
Octahydrophenanthrene
Octane
Oxiranemethanol
Oxirane, (phenoxymethyl)-
Oxi rane, [(propenyloxy)-
methyl]
n-Pentadecane
n-Pentane
2-Pentanone
Pentaphene
1-Pentene
3-Penten-2-one, 4-methyl-
Perhydrophenanthrene
Perinaphthindenone
Peroxyacetyl nitrate
Peroxypropronyl nitrate
Perylene
Phenanthrene
Phenanthrene carbox-
aldehyde
2-Phenanthrene carbox-
aldehyde
Phenanthrene-9-carbox-
aldehyde
Phenanthrene dicarboxylic
acid anhydride
Phenanthrenequinone
9,10-Phenanthrenequinone
Phenanthroic acid
Phenanthrone
Phenanthroquinone
Phenol
Phenol, 2-methyl-
Phenol, 3-methyl-
Phenol, 4-nethyl-
Phenol, 2-nethyl-
4,6-dinitro-
Phenylbenzopyranone
Phenylethyl ketone
l-Phenyl-2,4-hexadiyn-l-one
1-Phenylnaphthalene
2-Phenylnaphthalene
Phenylpyrocatechol
Phenylpyrrolopyridine
Phthalic acid
Propanal
A-15
-------
ORGANIC COMPOUNDS FOUND IN DIESEL EXHAUST
Propane 9H-Thioxanthen-9-one
Propanone Thioxanthen-9-one
2-Propenoic acid, 9-Thioxanthone
ethyl ester Trihydroxyanthraquinone
2-Propenoic acid, Trihydroxyfluorene
methyl ester Trimethylanthracene
2-Propenoic acid, 2-methyl- Trimethylfluorene
methyl ester Trinethylfluorenone
Pyrene Trimethylindan
Pyrene carboxaldehyde Trimethylnaphthalene
1-Pyrene carboxaldehyde Trimethylnaphthalene
Pyrene quinone carboxaldehyde
3,10-Pyrene quinone Trimethylnaphthothiophene
Pyreno-3,4-dicarboxylic 2,2,4-Trimethylpenta-l,3-
anhydride dioldiisobutyrate (bkg)
Pyrenone Trimethylphenanthrene
Pyridine 2,3,5-Trimethylphenol
Pyrone Trimethyltetralin
Riphenylene Trinaphthenebenzene
Styrene Triphenylene carboxaldehyde
n-Tetradecane Triphenylene quinone
1-Tetradecene 9H-Xanthen-9-one
1,2,3,4-Te t rahyd ronaph thalene 9-Xanthone
Tetrahydrophenanthrene 2,6-Xylenol
Tetraoethylnaphthalene 3,5-Xylenol
Thioxanthenone
SOURCE: Adapted from Opresko et al., 1984.
References
Opresko, D. M.; Holleman, J. V.; Ross, R. H.; Carroll, J. V. (1984) Problem
definition study on emission by-product hazards from diesel engines for
confined space army workplaces. Oak Ridge, TN: Oak Ridge National Lab-
oratory, ORNL Report no. 6017.
A-16
-------
EPA MOBILE SOURCE EMISSIONS MODEL (MOBIL3)
The Mobile Source Emission Model (MOBILES) is an integrated set of FOR-
TRAN routines which are used in the analysis of the impact of highway mobile
sources on air quality (USEPA 1984). MOBILES is an updated modification of
the earlier MOBILE1 and MOBILE2. A basic description of the model is given in
the User's Guide to MOBILE2 (USEPA, 1981), and the following information is
taken from that report.
The MOBILES program calculates emission factors for the following
categories of vehicles:
Light duty gasoline-powered vehicles (LDGV).
Light duty gasoline-powered trucks, GW < 6001 Ib (LDGT1).
Light duty gasoline-powered trucks, GW 6000-8500 Ib (LDGT2).
Light duty gasoline-powered trucks, GW <8,501 Ib (LDGT3).
Heavy duty gasoline-powered vehicles (HDGV).
Light duty diesel-powered vehicles (LDDV).
Light duty diesel-powered trucks (LDDT).
Heavy duty diesel-powered vehicles (HDDV).
Motocycles (MC).
All vehicles combined.
The MOBILES program computes emission factors for hydrocarbons (HC), car-
bon monoxide (CO), and oxides of nitrogen (NO ). Three major geographic
J\
regions are considered: (1) low altitude, non-California regions; (2) low
altitude California regions; and (3) high altitude, non-California regions.
The program calculates emission estimates for January 1 of any calender year
based on data for the twenty most recent model years. The basic exhaust eais-
sion data for the model is derived from tests conducted on vehicles operated
under standardized conditions. The basic test conditions for LDD and HOD
vehicles are given in Table 0-1.
A-17
-------
TABLE A-5. STANDARDIZED TEST CONDITIONS
Engine off period, cold start
Engine off period, hot start
Average trip length
Average trip speed
Average % idle
Average X VMTa cold start
Average % VMT stabilized
Average % VMT hot start
LDDV & LDDT
12-36 hr
10 man
7.5 mi
19.6 mph
18*
20. 6Z
52. 1*
27. 3*
HDDV
12+ hr
20 min
6.4 mi
19.2 mph
37*
U.3Z
OX
86. 7*
Source: USEPA, 1981
a Vehicle miles traveled.
The MOBILE program estimates emissions for each calender year by weighting the
emission factors for the twenty most recent model years based on the distribu-
tion of the total vehicle miles traveled (VMT) for those model years. The
program uses calculation procedures and emission factors presented in the 1977
EPA Compilation of Air Pollution Emission Factors and subsequent revisions
(USEPA, 1977). Emissions from light duty diesel vehicles during a calendar
year (n) and for a pollution (p) are approximated from the equation:
n
enp ' iu^u cipn °in
where:
e * Composite emission factor in grams per vehicle mile for
p calendar year (n) and pollutant (p).
c. a The FTP emission rate for pollutant (p) in grams/mile for
p the i-th model year at calendar year (n).
m. a The fraction of total light-duty diesel vehicle miles
driven by the i-th model year vehicles.
A-18
-------
Emissions from heavy duty diesel vehicles during a calendar year (n) and for a
pollutant (p) are approximated from the equation:
n
enps = - °ipn
where :
e » Composite emission factor in grams per vehicle mile for
p calendar year (n), pollutant (p), and average speed (s).
c. = The emission rate (g/mi) for pollutant (p) for the i-th
•ipn
model year vehicles in calendar year (n) over a trans-
ient urban driving schedule vith an average speed of
approximately 18 mi/hr (29 km/hr).
v. = The speed correction factor for i-th model year heavy
lp duty diesel vehicles for pollutant (p) at average
speed (s).
Values for c. are derived from testing of the various types of vehicles vith
FTP procedures or on-the-road sampling. Travel weighting factors take into
account both January 1 registration and fleet annual mileage accumulation dis-
tributions for the given vehicle type. The program computes and applies
correction factors for speed, ambient temperature, and vehicle operating mode
for scenarios that differ from the basic standardized conditions.
MOBILE3 differs from MOBILE2 (USEPA, 1984) in tvo basic vays. Data on
the basic emission rates for certain vehicle types and model years has been
updated and revised. The MOBILE2 program had a built-in adjustment for tam-
pering by misfueling. In MOBILES the calculation of the basic emission rates
is for untampered vehicles and the effects of tampering (e.g., misfueling,
catalyst removal, etc.) are included as offsets which can be estimated from
the percentage of vehicles being tampered at a given time and the effects of
such tampering. MOBILES also has the capability to take into account the
effects of anti-tampering programs.
A-19
-------
References
U.S. Environmental Protection Agency (1977) Compiliation of air pollutant
emissions factors. Third edition (including supplements 1-7). Research
Triangle Park, NC: Offfice of Air Quality Planning and Standards.
U.S. Environmental Protection Agency (1981) User's guide to MOBILE2
(Mobile Source Emission Model). Ann Arbor, MI: Office of Mobile
Source Air Pollution Control. EPA rept. no. 450/3-81-006.
U.S. Environmental Protection Agency (1984) User's guide to MOBILES
(Mobile Source Emission Model). Ann Arbor, MI: Office of Mobile
Source Air Pollution Control. EPA rept. no. 460/3-84-002.
A-20
-------
APPENDIX B
-------
TABLE B-l. SUMMARY OF DIESEL EXHAUST, WHOLE
ANIMAL CARCINOGEN1CITY STUDIES
Model system
Study Species Strain Sex Number
Mauderly Kai F 344/Crl M and F 365
it al.,
IVH7 366
367
364
1 Icinrich 1 lamsler Syrian M and F 96
1 1 al., Golden
90
96
96
%
96
Treatment
None
None
None
None
None
None
N< >ne
45 Dig UEN/kg,
s.c. acute*
45 Dig DEN/kg,
s c. aculcb
45 Dig DEN/kf.
s.c. acute*
Exposure protocol
Concentration
mg/m1 Duration
("lean air Sham -exposed
0.35 7 h/d.
5 dAveek to
30 mo
35 7 h/d.
5 dAveek to
30 mo
70 7 h/d,
5 dAveek to
30 in<>
Clean air Sham-exposed
40 19 h/d.
5 dAveck,
lifetime
1 illcu-d* Sham-exposed
Clean air Sham-exposed
lifetime
4.0 19 h/d,
5 dAveck,
lifetime
Filtered* 19 h/d.
5 dAveck.
lifetime
Lung toot
burden
(mg/lung)
0
0.6
(24 mo)
11.5
(24 mo)
20.8
(24 mo)
NA
NA
NA
NA
NA
NA
Results
Histology
0.9% Pulmonary
tumor formation
1 .3% pulmonary
tumor incidence
3.6% Pulmonary
tumor incidence
12.0% Pulmonary
tumor incidence
No tumor formation
No tumor formation
No tumor formation
10% Respiratory
tract tumors
Not lignificantly
different from
control
Not significantly
different from
control
-------
TABLE B-l. (continued)
T
Model System
.Study Species Strain Sex Number Treatment
llcinrich Hamster Syrian M and F 96 0 25 mg B|a|P, Ilr.
i tat., golden 20 weeks'1
96 0.2S mg U|a|P. Ilr.,
20 weeks'1
96 0.2S mg B|»|P, ilr,
20 weeks'1
96 None
llcinrich Mouse NMUI F 96 None
< l al.,
96 None
64 01 mgB(a|P,
iir.b/week,
1 0 weeks
64 I) 1 mg B(a|P,
hrb/week,
1 0 weeks
64 II 1 mg B(a|P,
iir.b/week.
10 weeks
Exposure preload
Concentration
mg/m1 Duration
Clean air Sham-exposed
lifetime
Filtered* IV h/d.
Sd/wcek.
lifetime
40 IV h/d.
J d/weck.
lifetime
Clean air Sham-expuaed
lifetime
Filtered* IV h/d.
5 d/weck,
lilclime
40 IV h/d.
5 d/week.
lifetime
Clean air Sham -exposed
lifetime
Filtered* 19 h/d.
5 d/weck.
lilclime
4.0 IV h/d.
5 d/week.
lifetime
Results
Lung soot
burden
(mg/lung) 1 listology
NA 2% Respiratory tract
tumors
NA Not significantly
different from
control
NA Not significantly
different from
control
NA 2.4% Pulmonary
adenocarcinoma
NA 19% Pulmonary
adenocarcinoma
(I8/93)1
NA 17% Pulmonary
adenocarcinoma
(IJ/76)1
NA Specific data not
presented
NA Specific data not
presented
NA Specific data not
presented
-------
TABLE B-l. (continued)
Model System Exposure protocol
Conccnlnilion
Study Specie* Strain Sex Number Treatment rag/hi1
i kinrich Mouse NMRI F 64 O.OS mg B(a|P, ilr.%eek, Clean air
1 al., 20 weeks
64 DOS mg B[a|P, ilr.'/week. Filtered*
20 weeks
64 0 05 mg B|a)P, ilr.»/Week, 40
20 weeks
03
1
Ul 64 0 05 mg DllahA Clean Air
itr^/week, 10 week*
64 iH>5mgDBahA 1 illcicd'
iir.%eek, 10 week*
64 ii 05 mg DBahA 40
iir.Vwcek. 10 weeks
96 0 005 DBahA/kg, Clean air
s c.d, acute
96 0 005 DBahA/kg, Filtered*
s c.*, acute
Duration
Sham-exposed
lifetime
19 h/d,
5 d/week.
liletime
19 h/d,
5 d/week.
lilelime
Slmni expoced
lifetime
19 h/d,
5 d/week,
lilelime
19 h/d,
5 d/week,
lifetime
Sham-exposed
6 mo
19 h/d,
5 d/week,
6 mo
Results
Lung soot
burden
(mg/lung) Histology
NA 71% Lung tumor
formation
NA 41% Lung tumor
formation
NA Not significantly
different from
control
NA No significant effects
•
NA No significant effects
NA No significant effects
NA 46% tumor formation
NA No change relative to
control
-------
TABLE B-l. (conlinueiJ)
Model System
Study Specie* Strain Sex Number
ilcinrich Mouse NMKI F 96
I al.,
I986a
96
(neonaics)
96
(neonales)
96
(neonales)
96
96
luinrich Ral SPI- Wislar F
c: al..
96
48
48
Exposure protocol
Concentration
Treatment mg/m1
0.01 mg DBahAAg i.e.*, 40
acute
0 Ol/mg DBahA, i.e.*" Clean air
acute
0 Ol/mg DBahA, i.e.* Fillercr*
acute
0 Ol/mg DBahA, I.e.*" 40
acute
None Clean air
None Filtered*
None Clean air
250 mg DPN/kg, Clean air
s c.Aveekd 25 week*
250 mg DPN/kg, Fillered*
s c /week4 25 week*
Duration
19 h/d.
S dAveck,
6 mo
Sham -exposed
lifetime
19 h/d,
5 dAvcek.
6 mo
IV h/d,
5 dAveck,
6 mo
Mum exposed
lifetime
IV h/d,
5 dAveck,
lilelime
IV h/d,
5 dAveck,
lilelime
Shu in -exposed
lifetime
IV h/d.
5 d/wcek.
lilelime
Results
Lung soot
burden
(nag/lung) Histology
NA No change relative to
control
NA 81% tumor incidence
NA Not provided
NA 63% Tumor
incidence
NA No tumor formation
NA No Tumor formation
NA 9.5% Squamous cell
lung tumor (9/95)'
NA 2.2% Squam|K>us cell
carcinoma; 2.2%
malignant tumors
NA 4.4% Squamous cell
carcinoma
-------
TABLE B-l. (continued)
Model System Exposure protocol
Concentration
Sludy Specie* Strain Sex Number Treatment mg/m1 Duration
Ikinrich Rat SPF Wislar F 48 250 mg DPN/kg. sc./Wk4 40 19 h/d.
tl al., 25 weeks 5 d/week,
1986 lifetime
48 500 mg DPN/kg. s.c./wkd Clean air I1' h/d,
25 weeks 5 d/wcek,
lilclime
48 500 mg DPN/kg. t.cjvk* 1 illcicJ" 19 h/J.
25 weeks 5 d/wcek.
lilclime
w
vJi 48 500 mg DPN/kg. i.cVwk* 40 19 h/d,
25 weeks 5 d/week,
lilclime
i imshi Hal F344/JCL M and F 64 M; 59 1 None 0 1 Icavy-duty engine
1 1 al.. sham-exposed
1 'M 30 mo
l>4 M; 5V 1 None 046 1 Mi/day
6dAveek
.10 mo
d4 M; 59 1 None 096 1 Mi/day
6dAvcek
30 mo
«>4 M; .VJ 1 None 1.84 K.h/day
6d/wcek
30 mo
64 M; 59 1 None 3 72 I6h/day
6dA*cek
30 mo
Results
Lung soot
burden
(mg/lung) Histology
NA 46.8% Squamous cell
carcinoma
NA 16.7% Squamous cell
carcinoma; 8.3%
malignant lumors
NA 14.6% Squamous cell
carcinoma; IZ5%
malignant lumors
31.3% Squaraous
NA carcinoma; 16.7%
malignant lumors
NA 08% Incidence of
lung tumors
NA 0.8% Incidence of
lung lumors
NA No lung lumors
observed
NA 3.3% Incidence of
lung lumors
NA 6.5% Incidence of
lung tumors
-------
'FABLE B-l. (continued)
Model System
Study Species Strain Sex Number Treatment
iHhinishi Hal F-344/JCI. M and F 64 M; 59 1 None
rl al.,
1986
64 M; 59 1 None
64 M; 59 1 None
64 M; 59 1 None
64 M; 59 1 None
1 .ai cl al . Hal F-344/SI'F 1- 24 None
I'»H6
24 None
24 None
Exposure protocol
Conoenlraliiin
mg/m1 Duration
0 Light duty engine
sham-exposed
30 mo
0.11 16 h/d
6dArcek
34) mo
041 Id h/d
6dAveek
341 mo
1.08 16 h/d
6d/wcck
I 34) mo
2.32 Id h/d
6dAveck
Clean air Sham-exposed
24 mo
49 8 h/d
7d/Week
24 mo
Filtered* 8 h/d
TdAvcek
24 mo
Results
Lung soot
burden
(mg/lung) Histology
NA 3.3% Incidence of
lung tumors
NA 2.4% Incidence of
lung tumors
NA 0.8% Incidence of
lung tumors
NA 4.1% Incidence of
lung tumors
NA 2.4% Incidence of
lung tumors
NA 0% Tumor incidence
NA 26.3% Malignant
lung tumors (42.1%
total tumors')
NA 0% Tumor incidence
-------
TABLE B-l. (continued)
Model System
Study Specie* Strain Sex Number
l.ikcmolo Rat F-344/JCL F 110
.1 al..
1986
Panioning
among groups
not pnivided
Fan ion ing
among groups
not provided
Panioning
among groups
not provided
Mouse O57HI/6N M and F 225
225
Mouse
ICR M and F 205
205
Exposure protocol
Concentration
Treatment mg/mj
None Clean air
None 24
1 g DIPN/kg. 2 4
i.pVweck,
3 weeks'
1 g DIPN/kg. ' Clean air
i p. /Week.
3 weeks'
None Clean air
None 24
None Clean air
None 24
Duration
Sham-exposed
24 mo
4 h/d
4dAveek
24 mo
4 h/d
4dAKeek
24 mo
Sham -ex posed
24 mo
Sham-expticed
24 mo
4 h/d
4 dAveek
24 mo
Sham-exposed
24 mo
4 h/d
4dAvcek
24 mo
Results
Lung soot
burden
(mg/lung) Histology
NA No tumors delected
NA No tumors detected
NA 39% (7/18)'
Incidence of
carcinoma (18 to 24
mo)
NA 19% (4/21)'
Incidence of lung
carcinoma (18-24
mo)
NA No adenocarcinomas
observed
NA Lung adeno-
carcinoma (2/33M;
11/38 Fat I9lo
28 mo)c
NA Lung adcno-
carcinoma (2/33M;
11/38 Fat I9lo
28 mo)c
NA Lung adeno-
carcinoma (2/33M;
11/38 Fat I9lo
28 mo)c
-------
TABLE B-l. (conlinued)
DO
Model System
>iudy Species Strain Sex Number
lohrel Hat Wisiar F 96
.1, 1986
96
96
l.iighlwell Kal 1344 M and F 144
(l al.,
l"86
144
144
144
llamsler Syrian M and F 104
golden
104
KM
Exposure protocol
Conccnimiion
Treatment mg/rn1 Duration
None Clean ,iir Sham exposed
None Filtered' IH h/d
SdAveck
24 lo 30 mo
None 39 18 h/d
5 d/week,
24 to 30 mo
None Clean air Shnin-ex|Nncd
24 mo
None lf> h/d
07 5 dAwxk,
24 mo
None l<> h/d
22 5 il/Week,
24 mo
None lo h/d
66 5 uTweck,
24 mo
None Clean air Sham-exposed
24 mo
4.5 mg DEN/kg, Clean air Sham-exposed
s.c., acute' 24 mo
None 0.7 16 h/d
5 d/Week,
24 mo
Lung soot
burden
(mg/Iung)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Results
Histology
No neoplaslic tumors
Data nol presented
15.8% Neoplaslic
luraon (I5/96)C with
1 carcinoma
I.ung tumor
Incidence al
2%M; I%F
I.ung tumor
incidence at
1% M; 0% F
I.ung tumor
incidence at
4% M; 15 % F
I.ung tumor
incidence ol
23% M, 54% F
No tumors delected
Increase in trachea!
papillomas
No tumors delected
-------
TABLE B-l. (continued)
Model System Exposure protocol
Concentration
Mudy Species Strain Sex Number Treatment mg/hj3 Duration
Mrighlwell Hamster Syrian M and F 104 4.5 rag DEN/kg, 07 16 h/d
< I «l , Golden s.c., acute* 5 dAveek,
, ''86 24 mo
104 None 2.2 lo h/d
5 dAveek.
24 mo
104 4.5 mg DEN/kg. 22 16 h/d
* c., acute* 5 dAveek,
U 24 mo
1
vO
104 None 66 lo h/d
5 h/d
5 dAveck
lo 30 mo
Results
1 .ung soot
burden
(tug/lung) Histology
NA No tumors attributed
to diesel exhaust
exposure
No tumors attributed
NA lo diesel exhaust
exposure
NA No tumors attributed
lo diesel exhaust
exposure
No tumors attributed
NA lo diesel exhaust
exposure
NA No tumors attributed
lo diesel exhaust
exposure
NA 2.4% Carcinoma
incidence
NA 1.6% Carcinoma
incidence
NA 0% Carcinoma
incidence
-------
TABLE B-l. (continued)
—i
o
Model System Eipcxure protocol
Concentration
Study Species Strain Sex Number Treatment Dig/to1 Duration
lakakiel Rat F344 M inJ F 123 None I.I1 16 h/d
il., 1989 6 dAvetk
to .to mo
124 None 2 3r 16 h/J
6d/weck
to 30 mo
123 None 0 Sham-expoced
123 None 05* 16 h/J
6dA»eek
to 30 mo
125 None 1.0* 16 h/J
6 d/weck
to 30 mo
123 None 1.8* Id h/J
6 d/week
to 30 mo
124 None 3.7* 16 h/d
6d/Weck
to 30 mo
Lung tool
burden
(rag/lung)
NA
NA
NA
NA
NA
NA
NA
Results
Histology
4.1% Carcinoma
incidence
1.6% Carcinoma
incidence
0.8% Carcinoma
incidence
0.8% Carcinoma
incidence
0% Carcinoma
incidence
3.3% Carcinoma
incidence
6.5% Carcinoma
incidence
Tillered exhaust, no p.uliclcs.
N "oncurrenl treatment.
'Number of animals with tumors/numbers of animals examined.
Jrrcireatmenl.
'Malignant splenic lymphomas also reported. Abbreviations: s.c.. suhcuuneous; itr, inlracheal; DEN, dimethylnitimamine; DliahA, dibeiu|ah|anlhracene; DPN, dipcntylnilrosaniine;
|)|I'N, di isopropanol-niln»amiiie; n|.i|P, l>eiii<>|:i)pyrenc; NA, not available.
'i ighl-July engine emissions.
' Icavy-duly engine emission.
-------
APPENDIX C
-------
DRAFT — DO NOT QUOTE OR CITE
APPENDIX C. MODELS FOR CALCULATING LUNG BURDENS
C.I. INTRODUCTION
The lung burden of diesel exhaust particles (DEPs) during
exposure is determined by both the amount and site of particle
deposition in the lung and, subsequently, by rates of
translocation and clearance from th<=> r^pn^ition sites.
Mathematical models have often been used to complement
experimental studies in estimating the lung burdens of inhaled
particles in different species under different exposure
conditions. This section presents a mathematical model that
simulates the deposition and clearance of DEPs in the lungs of
rats and humans.
Diesel particles are aggregates formed from primary spheres of
15-30 mm in diameter. The aggregates are irregularly shaped and
range in size from a few molecular diameters to tens of microns.
The mass median aerodynamic diameter (MMAD) of the aggregates is
approximately 0.2 ^m. The primary sphere consists of a
carbonaceous core (soot) on which numerous kinds of organic
compounds are adsorbed. The organics normally account for 10% to
30% of the particle mass. However, the exact size distribution
of DEPs and the specific composition of the adsorbed organics
depend upon many factors, including engine design, fuels used,
engine operating conditions, and the thermodynamic process of
exhaust. The physical and chemical characteristics of DEPs have
been reviewed extensively by Amann and Siegla (1982) and
Schuetzle (1983).
Four mechamisms deposit diesel particles within the
respiratory tract during exposure: impaction, sedimentation,
interception, and diffusion. The contribution from each
mechanism to deposition, however, depends upon lung structure and !
size, the breathing condition of the subject, and particle size
C-l 03/27/90
-------
DRAFT ~ DO NOT QUOTE OR CITE
distribution. Under normal breathing conditions, diffusion is
found to be the most dominant mechanism. The other three
mechanisms play only a minor role.
Once DEPs are deposited in the respiratory tract, both the
carbonaceous cores and the adsorbed organics of the particles can
be removed from the deposition sites by two mechanisms:
(a) mechanical clearance, provided by mucociliary transport in
the ciliated conducting airways as well as macrophage
phagocytosis and migration in the nonciliated airways, and (b)
clearance by dissolution. Since the carbonaceous soot of DEPs is
insoluble, it is removed from the lung by mechanical clearance,
whereas the adsorbed organics are removed prinicpally by
dissolution.
C.2. COMPARTMENTAL LUNG MODEL
To simulate the transport and removal of DEPs from the lungs
mathematically, we use a compartmental model consisting of six
anatomical compartments: the nasopharyngeal or head (H),
tracheobronchial (T), alveolar (A), gastrointestinal tract (G),
lymph node (L), and blood (B)
compartments as shown in Figure C-l. In this figure, r^, r^1, and
are, respectively, the mass deposition rates of DEP material
components (i=l soot), 2 (slowly cleared organics), and 3 (fast
cleared organics) in the head, tracheobronchial, and alveolar
compartments; and A^' represents the transport rate of material
from compartment X to compartment Y.
Let the mass fraction of material component i of a diesel
particle be fi.
C-2 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Then
(02)
(C-3)
where r^' , ZT^ • and rx(a> are, respectively, the total mass
deposition rates of DEPs in the H, T, and A compartments,
determined from the equations:
ZH - C(TV) (RF) (DF) H (C-4)
T" C(TV) (RF) (DF) T (C-5)
TA - C(TV) (RF) (DF) A (C-6)
In equations C-4 to C-6, C is the mass concentration of DEPs
in the air, TV is the tidal volume, RF is the respiratory
frequency, and (DF)H, (DF)T, and (DF)A are, respectively, the
deposition fractions of DEPs in the H, T, and A compartments over
a breathing cycle. The values of (DF)H, (DF)T, and (DF)A vary
with the particle size distribution of DEPs, lung geometry, and
breathing conditions, as will be discussed later.
On the basis of the clearance characteristics, we assume that
a diesel particle is composed of three material components: (a)
carbonaceous soot, (b) adsorbed organics which are slowly
C-3 03/27/90
-------
H
B
(i)
^HB
(!)
. (i)
AAB
(i)
XLB
0 (
H AH(
f
0- . (
T AT(
1
"*2
f
A
i
r
I
i)
%
6
)
%
0
t
\
AAL
•»
Figure C-l. Coropartmental Lung Model of Particle Deposition and
Clearance
cleared, and (c) adsorbed organics that are quickly cleared. The
presence of two separate organic components in the particle model
is suggested by observations that the removal of the particle-
associated organics from the lung exhibited two distinct half-
times (Sun et al., 1984; Bond et al., 1986a). In a typical
diesel particle, the mass fraction of the total adsorbed organics
is about 20%, with half of this mass composed of slowly cleared
organics and the other half composed of quickly cleared organics.
The differential equations for m^, the mass of material
component i in compartment X, as a function of exposure time t
can be written as
C-4
03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Head (H)
dmm
•£- • **" - **W - *BX21 (C-7)
Tracheobronchial (T)
*mu)
-Je- • *P + «iX"' - «v - xtf^ («>
Alveolar (A)
^r • r "' - ^X" - ^'^^ - ^'^(i) (C-9)
GI Tract (G)
^ • XS'jn"' + X«X» (C-10)
Lymph Nodes (L)
dt
,(a) jfij-ti) cr m
!A - Aj-^ m, (^11)
C-5 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Blood (B)
Equation C-9 nay also be written as
where
is the total clearance rate of material component i from the
alveolar compartment.
The total mass of the particle-associated organics in
compartment X is the sum of m™ and roj3' , and the total mass of
DEPs in compartment X is equal to
The lung burdens of carbonaceous soot and organics are defined,
respectively, as
-------
DRAFT ~ DO NOT QUOTE OR CITE
.,(2)*(3) _(2) __ _(3) __ _{2) _(3)
"Lung " mT + %• * MA + mA
Because clearance of the particle-associated organics is much
faster than diesel soot, M^y(2) constitutes only a very small
fraction of total particle mass accumulated in the lung a short
time after exposure.
In the compartmental model described above, both compartments
B and G do not contain any excretion pathways. The results of
mg*} and m^ therefore, represent the accumulative amount of
particle mass transported into that compartment.
C.3. SOLUTIONS TO KINETIC EQUATIONS
The solutions to Equations C-7 to C-13 can be found when
Tui} , *TI} • and *xr are known. For exposures to DEPs of constant
concentrations under specified breathing conditions, r^', XT*} • and
are constant. The values of X^y are also constant, except
those of XJr and A^f' which are found from the experimental
data of rats to be a function of mA or m™ (Yu et al., 1988).
This is attributed to the overloading of DEPs in the lung.
To find solutions for Equations C-7 to C-13 , m^ is first
determined from Equation C-13, which is solved numerically by a
second order Runge-Kutta method. Once mjf} is found, the other
kinetic equations for both diesel soot and the particle-
associated organics are obtained readily since they are linear
differential equations. The solutions to these equations for
constant r#i} , r^ , and i^ are as follows:
C-7 03/27/90
-------
Head (H)
DRAFT — DO NOT QUOTE OR CITE
« \ «—, / 1 li) *\
- rw /Afl )exp(- AW c)
where A
Tracheobronchial (T)
» <^> ««-^ / 5 '•*' t-\ f e
raT - exp(-AT t) /
Jo
(C-19)
(to \ _„_ / 1 (i)
(ji)
*\ j*. ^ „ j /r« in\
t) at + mTO (C-20)
where
GI Tract (G)
fc
• I
Jo
Lymph Nodes (L)
f '
Jo
(C-21)
(C-23)
C-8
03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Blood (B)
i)_U> ^ i U)«.U)
F c
- J
(C-24)
"BO
In Equations C-18 to C-24, ^o* represents the value of m*1*
at t = o.
In the sections to follow, the methods of determining r^', TT*} • and
or (DF)H/ (DF)T, and (DF)A as well as the values of \(£ in the
compartmental lung model are presented.
C.4. DETERMIKATION OF DEPOSITION FRACTIONS
The mathematical models for determining the deposition
fractions of DEPs in various regions of the respiratory tract
have been developed by Yu and Xu (1986, 1987) and are adopted in
this report. Yu and Xu consider DEPs as a polydisperse aerosol
with a specified mass median aerodynamic diameter (MMAD) and
geometrical standard deviation ag. Each diesel particle is
represented by a cluster-shaped aggregate within a spherical
envelope of diameter de. The envelope diameter de is related to
the aerodynamic diameter of the particle by the relation
d C 1/2 r 1/2
±£ . 4ri/2(±£, (J.) (C-25)
"a C• ^o
where C is the bulk density of the particle in g/cm3, C0 = 1
g/cm3; 0 is the packing density, which is the ratio of the space
actually occupied by primary particles in the envelope to the
overall envelope volume; and Cx is the slip factor given by the
expression:
C-9 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
r 11-257 + 0.4 exp(- 0>5,5d*)3 (C-26)
dx A.
in which A « 8 x 10"6cm3 is the mean free path of air molecules at
standard conditions. In the diesel particle model of Yu and Xu
(1986), C has a value of 1.5 g/cm3 and a 0 value of 0.3 is chosen
based upon the best experimental estimates. As a result,
Equation C-25 gives de/da =1.35. In determining the deposition
fraction of DEPs, da is used for diffusion and interception
according to the particle model.
C.4.1. Determination of (DF)H
Particle deposition in the naso- or oro-pharyngeal region is
referred to as head or extrathoracic deposition. The amount of
particles that enters the lung depends upon the breathing mode.
Normally, more particles are collected via the nasal route than
the oral route because of the nasal hairs and the more complex
air passages of the nose. Since the residence time of diesel
particles in the head region during inhalation is very small
(about 0.1 second for human adults at normal breathing),
diffusional deposition is insignificant and the major deposition
mechanism is impaction. The following empirical formulas derived
by Yu et al. (1981) for human adults are adopted for deposition
prediction of DEPs:
C-10 03/27/90
-------
DRAFT ~ DO NOT QUOTE OR CITE
For mouth breathing:
(DF)Hi ia - 0, for dlz 3000
(C-27)
(DF)Hi in - -1.117 * 0.324 log(djp) , for d*0 > 3000
(C-29)
and for nose breathing:
~ -0.014 + 0.023
, for d2aQ s 337 (C-30)
(DF)
H>
- -0.959 * 0.397 log(d*C>) / for d^C > 337
(C-31)
(DF)Ht in - 0.003 * 0.033 log(dJ0) , for dlo $ 215
(C-32)
H. .x • -0.851 f 0.399 log(djp) , for d\Q > 215 (C-33)
where (DF)H is the mean deposition efficiency in the head, the
subscripts in and ex denote inspiration and expiration,
respectively, da is the particle aerodynamic diameter in fim, and
Q is the air flowrate in cm3/sec.
Formulas to calculate deposition of diesel particles in the
head region of children are derived from those for adults using
the theory of similarity, which assumes that the air passage in
the head region is geometrically similar for all ages and that
the deposition process is characterized by the Stokes number of
C-ll
03/27/90
-------
DRAFT ~ DO NOT QUOTE OR CITE
the particle. Thus, the set of empirical equations from C-27
through C-33 are transformed into the following form.
For mouth breathing:
(DF)H> ifl - 0, for d\Q <> 3000 (C-34)
(D&H in - -1-117 * 0.972 logK +
'2 a CC-35)
0.324 log d,0) , for d\Q > 3000 *• '
. 0. (C-36)
and for nose breathing:
H in " ~ 0-014 * 0.690 logk + 0.023
,
for dD & 337 (C"37)
H. in " -0.959 * 1.191 logK +
0.397 log(d*0) , for d\Q > 337 ^C"3 '
H. ex " 0-003 * 0.099 logK +
0.033 log(dfff) , for C&? S215 (C"39)
Hi €X - -0.851 * 1.197 logK*
0.399 log(d*0) » for d\Q > 215 l J
C-12 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
where K is the ratio of the linear dimension of the air passages
in the head region of adults to that of children, which is
assumed to be the same as the ratio of adult/child tracheal
diameters.
For rats, the following empirical equations are used for
deposition prediction of DEPs in the nose:
Mt 0X - 0 . 046 t-
0.009 log(da£>) , for d\Q * 13.33
_ ex - -0.522 +
0.514 log(dlQ) , fordlQy 13.33
C.4.2. Determination of (DF)T and (DF)A
The deposition model adopted for DEPs is the one previously
developed for monodisperse and (Yu, 1978) and polydisperse
spherical aerosols (Diu and Yu, 1983). In the model, the
branching airways are viewed as a chamber model shaped like a
trumpet (Figure C-2). The cross-sectional area of the chamber
varies with airway depth, x, measured from the beginning of the
trachea. At the last portion of the trumpet, additional cross-
sectional area is present to account for the alveolar volume per
unit length of the airways.
Inhaled diesel particles that escape capture in the head
during inspiration will enter the trachea and subsequently the
bronchial airways (compartment T) and alveolar spaces
(compartment A).
C-13 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE'
Summtd tivtotor Cross Stcuend AIM
Airway Lngtfts
Figure C-2. Trumpet model of lung airway,
C-14
03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE •
Assuming that the airways expand and contract uniformly during
breathing, the equation for the conservation of particles takes
the form:
(013)
where c is the mean particle concentration at a given x and time
t; A, and A2 are, respectively, the summed cross-sectional area
(or volume per unit length) of the airways and alveoli at rest; 77
is the particle uptake efficiency per unit length of the airway;
(3 is an expansion factor, given by:
P ' 1 * (C-44)
and Q is the air flow rate, varying with x and t according to the
relation
where Q0 is the air flow rate at x = 0. In Equations C-44 and C-
45, Vt is the volume of new air in the lungs and Vx and Vt are,
respectively, the accumulated airway volume from x = 0 to x, and
total airway volume at rest.
Equation C-43 can be solved using the method of
characteristics with appropriate initial and boundary conditions;
the amount of particles deposited between location x1 and x2 from
time t, to t2 can then be found from the expression
For diesel particles, rj is the sum of those due to the individual
deposition mechanisms described above, i.e.,
C-15 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
DF - I foar\dxdt (C-46)
n -tix + i)s + iip + iia (CAT)
where 17,, r?s, r?p, and D are, respectively, the deposition
efficiencies per unit length of the airway due to impaction,
sedimentation, interception, and diffusion. On the basis of the
particle model described above, we obtained the expressions for
H!/ ns, f?P/ and r?D in the following form:
r> tm ~~ n*».n _ c (2/3) _ 01/3 ./i _ £>2/3 ±. ein"l
T] - [ (C-50)
and
C-16 03/27/90
-------
DRAFT ~ DO NOT QUOTE OR CITE
Tip- -i[l-0.819exp(-14.63A) -
0.0976 exp(-89.22A) -
0.0325 exp(-228A) - 0.0509 exp(-125A2/3) ]
for Reynolds numbers of the flow smaller than 2000, and
T) • — A1'2 (1 - 0.444A1/2) (C-52)
for Reynolds numbers greater than or equal to 2000. SC-dju/ (18n/?)
is the particle Stokes number,
6 - L/(BR)e - 3\iUgL/(32uR)T - djR
and A - Z?L/(4J?2u) in which u is the air velocity in the airway; M
is the air viscosity; L and R are, respectively, the length and
radius of the airway; us - Cad«/(18n) is tne particle settling
velocity; and D = CekT(37TMde) is the diffusion coefficient with k
denoting the Boltzmann constant and T the absolute temperature.
In the deposition model, it is also assumed that 77, = rj = o for
expiration, while r70 and ns have the same expressions for both
inspiration and expiration.
During the pause, only diffusion and sedimentation are
present. The combined deposition efficiency in an airway, E, is
equal to:
E - 1 - (1 -Es) (1 - ED) . (C-53)
where E0 and Es are, respectively, the deposition efficiencies
due to the individual mechanisms of diffusion and sedimentation
over the pause period. The expressions for E0 and Es are given
by
C-17 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
3 3
E -7- ex*>(- ***D> (1 ' E -7
• ^"^ •••*
2 - 1
(C-54)
where TO = Dr/R2 in which r is the pause time and a,, a2, and a3
are the first three roots of the equation:
J0(a) -0. (C-55)
in which J0 is the Bessel function of the zeroth order, and:
Es - 1.1094T,. - 0.1604T2S, for 0 < tff s 1. (C-56)
and:
Es - 1 - 0.0069T51 -0.0859t~s2 - 0.0582t~s3, /T 5T»
for TS> 1, ^ '
where TS = usr/2R.
The values of (DF)T and (DF)A over a breathing cycle are
calculated by superimposing DF for inspiration, deposition
efficiency E during pause, and DF for expiration in the
tracheobronchial airways and alveolar space. It is assumed that
the breathing cycle consists of a constant flow inspiration, a
pause, and a constant flow expiration, each with a respective
duration fraction of 0.435, 0.05, and 0.515 of a breathing
period.
C-18 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
C.4.3. Lung Models
Lung architecture affects particle deposition in several ways:
the linear dimension of the airway is related to the distance the
particle travels before it contacts the airway surface; the air
flow velocity by which the particles are transported is
determined by the cross-section of the airway for a given
volumetric flowrate; and flow characteristics in the airways are
influenced by the airway diameter and branching patterns. Thus,
theoretical prediction of particle deposition depends, to a large
extent, on the lung model chosen.
C.4.3.1. Lung Model for Rats—Morphometric data on the lung
airways of rats were reported by Schum and Yeh (1980). Table C-l
shows the lung model data for Long Evans rats with a total lung
capacity of 13.784cm3. Application of this model to Fischer rats
is accomplished by assuming that the rat has the same lung
structure regardless of its strain and that the total lung
capacity is proportional to the body weight. In addition, it is
also assumed that the lung volume at rest is about 40% of the
total lung capacity and that any linear dimension of the lung is
proportional to the cubic root of the lung volume.
C.4.3.2. Lung Model for Human Adults--The lung model of mature
human adults used in the deposition calculation of DEPs is the
symmetric lung model developed by Weibel (1963). In Weibel's
model, the airways are assumed to be a dichotomous branching
system with 24 generations. Beginning with the 18th generation,
increasing numbers of alveoli are present on the wall of the
airways and the last three generations are completely
aleveolated. Thus, the alveolar region in this model consists of
all the airways in the last seven generations.
C-19 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Table A-2 presents the roorphometric data of the airways of
Weibel's model adjusted to a total lung
volume of 3,000 cm3.
C.4.3.3. Lung Model for Children—The lung model for children
in the diesel study was developed by Yu and Xu (1987) on the
basis of available morphometric measurements. The model assumes
a lung structure with dichotomous branching of airways, and it
matches Weibel's model for a subject when evaluated at the age of
25 years, the age at which the lung is considered to be mature.
The number and size of airways as functions of age t (years) are
determined by the following equations:
C.4.3.3.1. Number of airways and alveoli. The number of
airways N;(t) at generation i for age t is given by
tf4(O - 2', t or 0 z i *20 (C-58)
N2i(C) - 221,
iN22(C) - NT(t) -2", fox 22i < NT(t) i 222 (C-60)
N3(t) - 0,
C-20 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
TABLE C-1 LUNG MODEL FOR RATS AT TOTAL LUNG CAPACITY
Generation
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Iff
17
18
19
20
21
22
23
24
Number of
Airways
1
2
3
5
8
14
23
38
65
109
184
309
521
877
1,477
2.487
4,974
9.948
19.896
39.792
79.584
159.168
318.336
636.672
Length
(cm)
2.680
0.715
0.400
0.176
0.208
0.117
0.114
0.130
0.099
0.091
0.096
0.073
0.075
0.060 ~
0.055
0.035
0.029
0.025
0.022
0.020
0.019
0.018
0.017
0.017
Diameter
(cm)
0.340
0.290
0.263
0.203
0.163
0.134
0.123
0 112
0.095
0.087
0.078
0.070
0.058
0.049
0.036
0.020
0.017
0.016
0.015
0.014
0.014
0.014
0.014
0.014
Accumulative
Volume1 (Crrr i
0.243
0.338
0.403
0431
0466
0489
0.520
0.569
0615
0674
0758
0845
0.948
1.047
1 141
1.185
1.254
1.375
1.595
2.003
2.607
4.389
7.554
13.784
* Terminal bronchioles.
0 Including the attached alveolar volume
(number of alveoli = 3 x 107 alveolar diameter = 0.0086 cm).
C-21
03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
TABLE C-2. LUNG MODEL BY WEIBEL (1963) ADJUSTED TO 3.000 CM5 LUNG VOLUME
Generation
Number
0
2
2
3
4
s
6
7
8
9
10
11
12
13
14
15
161
17
18
19
20
21
22
23
Number of
Airways
i
2
4
8
16
32
64
128
256
512
1.024
2.048
4.096
8.192
16.384
32.768
65.536
131.072
262.144
524.283
1.048.576
2.097.152
4.194.304
8.388.608
Length
(cm)
10.260
4.070
1.624
0.650
1.086
0.915
0.769
0.650
0.547
0.462
0.393
0.333
0.282
0.231
0.197
0.171
0.141
0.121
0.100
0.085
0.071
0.060
0.050
0.043
Diameter
(cm)
1.539
1.043
0.710
0479
0.385
0.299
0.239
0.197
0.159
0.132
0.111
0.093
0.081
0.070
0.063
0.056
0.051
0.046
0.043
0.040
0.038
0.037
0.035
0.035
Accumulative
Volume1 (cnrf j
1906
25.63
2863
29.50
31.69
33.75
35.94
38.38
41 13
4438
48.25
53.00
59.13
66.25
77.13
90.69
109.25
139.31
190.60
288.16
512.94
925.04
1.694.16
3.000.00
* Terminal bronchioles.
6 Including the attached alveolar volume
(number of alveoli = 3 x if/. alveolar diameter = 0.0288 cm)
C-22
03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
tf2l(t) - 221,
Wj2(t) - 222, . for Nr(t) > 221 + 222,
N23(t) - Nf(t) -221 -222
where Nr(t) is the total number of airways in the last three
airway generations. The empirical equation for Nr which best
fits the available data is
Thus, Nr(t) increases from approximately 1.5 million at birth
to 15 million at 8 years of age and remains nearly constant
thereafter. Equations A-59 to A-61 also imply that in the last
w ,H / 2.036 xl07(l-0.926e-°-15t) , t*8
N*(C} ( 1.468 X107, t > 8
three generations, the airways in the subsequent generation begin
to appear only when those in the preceding generation
have completed development.
The number of alveoli as a function of age can be represented
by the following equation according to the observed data:
N.(t) - 2.985 X 108(1 -0.919e-°'
-------
DRAFT ~ DO NOT QUOTE OR CITE
model; (c) the growth pattern of the bronchial airways; and (d)
variation in alveolar size with age. From these data, it is
found that the lung volume, LV(t) at age t, normalized to
Weibel's model at 4,800 cm3 for an adult (25 years old), follows
the equation
LV(t) - 0.959 x 105(1 - 0.998e-°-002t) (cm3). (C-64)
The growth patterns of the bronchial airways are determined by
the following equations
ZUt) - Div - ttAH(C) -#(25)], (C-65)
Lj(t) - Liv - pj[#(t) - #(25)], (C-66)
where D. (t) and Lf(t) are, respectively, the airway diameter and
length at generation i and age t, Diw and Ljw the corresponding
values for Weibel's model, a,, and p{ are coefficients given by
a,. - 3,26 x 10'2exp [-1.183 (i + 1)0-5] (C-67)
P; •= 1.05 x 10-6 exp [10.1 (
and H(t) is the body height, which varies with age t in the form
Hit) - 1.82 x 102(1 - p.725e-°-14t) (cm). (C-69)
For the growth patterns of the airways in the alveolar region,
it is assumed that
C-24 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
.±L - -p- - —i. - f (t) , for 17 s i * 23
£iwr Liw D,,,,
(C-70)
where D. is the diameter of an alveolus at age t, D_ = 0.0288 cm
0 AH
is the alveolar diameter for adults in accordance with Weibel's
model, and f(t) is a function determined from
f(t) -
16
(LV(t) -
2-0
23
J - 17
4
(C-71)
C.5. TRANSPORT RATES
The values of transport rates \r? for rats have been
determined from the experimental data of clearance for diesel
soot (Chan et al., 1981; Strom et al., 1987, 1988) and for the
particle associated organics (Sun et al., 1984; Bond et al.,
1986). These values are used in the present model of lung burden
calculation and are listed below:
j - 1.05 x lO-'expUO.lU+l)'0'2] ,
(C-68)
O25
03/27/90
-------
DRAFT ~ DO NOT QUOTE OR CITE
iff - 1.73 U - 1,2,3) (072)
iff - iff - iff - 0.00018 (073)
Aff - Iff -Xff -*ff -0.013 (074)
iff ' iff - iff - iff - 12.57 (075)
iff - 0.693 (2 - 1,2,3) (076)
- 0.00068 [1 - exp(-0.046/ni'")3 (O77)
1 J U) / • , ^ V
•"" A «B V •*• m £ I J I
4
i.ir - 0.012 exp(-0.11^'76) +
0.00068 exp{~0.046^'") (i - 1,2,3)
C-26 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
l£ - 0.00018 (OSO)
- 6
0.012 exp(-0.11;njf- 6) + 0.00086
* A - A - 0.012
0.00068 exp(-0.046;nalt6) * 0 . 016 .
lt62 ^ '
13) 1 (3) } (3) i (3) n ni->
~ " * ^- * *fl " 0-012
0.00068 exp(-0.046m]>62) + 15.71
where lj£ is the unit of day'1.
Experimental data on the deposition and clearance of DEPs in
humans are not available. To estimate the lung burden of DEPs
for human exposure, it is necessary to extrapolate the transport
rates A^' from rats to humans. For organics, we assume that
the transport rates are the same for rats and humans. This
assumption is based upon the observation of Schanker et al.
(1986) that the lung clearance of inhaled lipophilic compounds
appears to depend only on their lipid/water partition
coefficients and is independent of species. In contrast, the
transport rates of diesel soot in humans should be different from
that of rats, since the alveolar clearance rate, TA, of insoluble
particles at low lung burdens for human adults is approximately
seven times that of rats (Bailey et al., 1982).
No data are available on the change of the alveolar clearance
rate of insoluble particles due to excessive lung burdens among
C-27 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
different species. It is seen that for rats can be written
in the following form
A.^ - a exp(-Jhm/) * d • (C-84)
where a, b, c, and d are constants. The right-hand side of
Equation A-84 consists of two terms, representing, respectively,
macrophage-mediated mechanical clearance and clearance by
dissolution. The first term depends upon the lung burden,
whereas the second term does not. To extrapolate this
relationship to humans, we assumed that the dissolution clearance
term was independent of species and that the mechanical clearance
term for humans varied in the same proportion as in rats under
the same unit surface particulate dose. This assumption results
in the following expression for AJ1' in humans
Af} - £ exp(-b(mA/S) + d (C-85)
where P is the ratio of the alveolar clearance rate by mechanical
clearance in humans to that of rats in low lung burdens, and S is
the corresponding ratio of the pulmonary surface area between
humans and rats. Equation A-85 implies that rats and humans have
the same "local" biological response in the lung to inhaled DEPs,
an assumption that needs to be confirmed by future experiments.
From the data of Bailey et al. (1982) , we obtain a value of
^AO ~ 0.00169 day"1 for humans. This leads to P = 14.4.
Also, we find S-148 from the data of the anatomical lung model of
Yen and Schum (1980) for rats and Weibel's model for human
adults. For humans less than 26 years old, we assume the same
value for P, but S is computed from the data of the lung model
for young humans (Yu and Xu 1987) . The values of S as a function
of age are shown in Table C-3.
C-28 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
The equations for other transport rates that have a lung-
burden-dependent component are extrapolated from rats to humans
in a similar manner. The following lists the values of XJ£
(in day"1) for humans used in the present model calculation:
JL$ - 1,73 (i - 1,2,3) (C-86)
- 0.00018 (087)
(2) _ i (2) i (2) i (2) n
- A- *- ** U .
Xj[ - 0.0694 {0.012 exp [-0.11 01^/5)1/7S] *
0.00068 exp [-0.046 (^75)1-76]} (i-1,2,3)
- 0.00018
VAT
0.0694 {0.012 expt-O.llOfy/S)1-76]} + 0.00086
- 0.693 (i - 1,2,3) (C-90)
- 0.00068 {1 - 0.0694 exp [-0. 046 On./S) ^"l } (C-91)
- 2,3) (C-92)
Xff (094)
C-29 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
TABLE C-3 RATIO OF PULMONARY SURFACE AREAS BETWEEN HUMANS
AND RATS AS A FUNCTION OF HUMAN AGE
Aoe (Yean Surface Area
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4.99
17.3
27.6
36.7
44,7
51.9
58.5
64.6
70.4
76.0
81.4
86.6
91.6
96.4
101
106
110
115
119
123
128
132
136
140
144
148
C-30 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
1 (2) i (2) i (2) i (2)
* A AAL * '•AT * AAB
0.0694 {0.012 expt-O.llOnj/A)1-76] +
0.00068 exp[-0.046(mJ,/5)1-76]} + 0.016
.,(3) _ JO) ,(3) , (3)
AA - A;u, + AAT f A.JIB
0.0694 {0.012 expt-O.lK^/5)1-76] * (C-96)
0.00068 exp[-0.046(^/5)1-76} + 15.71
1(3) m i<3) 1<3) ,(3)
AA • AJU, * AAT * Aj^fl
0.0694 {0.012 exp[-0.119^/5)1'76] + (C-97)
0.00068 exp [-0.046 (m^/5)1-76} + 15.71
C-31 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
REFERENCES
Amann, C.A.; Siegla, D.C. (1982) Diesel particles — What
are they and why. Aerosol Sci. Tech. 1:73-101
Bailey, M.R.; Fry, F.A.; James, A.C. (1982) The long-term
clearance kinetics of insoluble particles from the human
lung. Ann. Occup. Hyg. 26:273-289.
Bond, J.A.; Sun, J.D.; Medinsky, M.A.; Jones, R.K.; Yeh, H.C.
(1986a ) Deposition, metabolism and excretion of 1-
[uC]nirropyrene and l-[uC]nitropyrene coated on diesel
exhaust particles as influenced by exposure concentration.
Toxicol. Appl. Pharmacol. 85:102-117.
Chan, T.L.; Lee, P.S.; Bering, W.E. (1981) Deposition and
clearance of inhaled diesel exhaust particles in the
respiratory tract of Fisher rats. J. Appl. Tox. 1:77-82.
Diu, C.K.; Yu, C.P. (1983) Respiratory tract deposition of
polydisperse aerosols in humans. Am. Ind. Hyg. Assoc. J.
44:62-65.
Schanker, L.S.; Mitchell, E.W.; Brown, R.A. (1986) Species
comparison of drug absorption from the lung after aerosol
inhalation or intratracheal injection. Drug Metab. Dispos.
14(1):79-88.
Scheutzle, D. (1983) Sampling of vehicle emissions for chemical
analysis and biological testing. Environ. Health Perspect.
47:65-80.
Schum, M.; Yeh, H.C. (1979[?]) Theoretical evaluation of aerosol
deposition in anatomical models of mammalian lung airways.
Bull. Math. Biol. 42:1-15.
Strom, K.A.; Chan, T.L.; Johnson, J.T. (1987) Pulmonary
retention of inhaled submicron particles in rats: diesel
exhaust exposures and lung retention model. Research
Publication GMR-5718, Warren, MI: General Motors Research
Laboratories.
Strom, K.A.; Chan, T.L.; Johnson, J.T. (1988) Inhaled particles
VI. Dodgson, J.; McCallum, R.I.; Bailey, M.R.; Fischer, D.R.,
eds. London: Pergamon Press, pp. 645-658.
Sun, J.D.; Woff, R.K.; Kanapilly, G.M.; McClellan, R.O. (1984)
Lung retention and metabolic fate of inhaled benzo(a)pyrene
associated with diesel exhaust particles. Toxicol. Appl.
Pharmacol. 73:48-59.
C-32 03/27/90
-------
DRAFT — DO NOT QUOTE OR CITE
Weibel, E.R. (1963) Morphometry of the human lung.
Berlin:Springer-Verlag.
Yeh, H.C.; Schum, M. (1980) Models of human lung airways and
their application to inhaled particle deposition. Bull. Math.
Biol. 42:461-480.
Yu, C.P. (1978) Exact analysis of aerosol deposition during
steady breathing. Powder Tech. 21:55-62.
Yu, C.P.; Diu, C.K.; Soong, T.T. (1981) Statistical analysis of
aerosol deposition in nose and mouth. Am. Ind. Hyg. Assoc. J.
42:726-733.
Yu, C.P.; Xu, G.B. (1986) Predictive models for deposition of
diesel exhaust particiates in human and rat lungs. Aerosol
Sci. Tech. 5:337-347.
Yu, C.P.; Xu, G.B. (1987) Predicted deposition of diesel
particles in young humans. J. Aerosol Sci. 18:419-429.
C-33 03/27/90
-------
APPENDIX D
-------
D. EXTRAPOLATION MODEL
5 D.I. INTRODUCTION
Calculations of unit risk estimates based on animal inhalation data were presented
in Chapter 10. Alternate methods of quantitation are presented in this appendix that use
animal and human data to construct dosimetiy models for assessing carcinogenic risk in
10 humans from exposure to diesel engine emissions.
Both chronic animal bioassays as well as human epidemiological data provide at least
some evidence for the carcinogenicity of diesel engine emissions. Use of human data for
estimating dose response has several advantages. Species extrapolation with its associated
uncertainties regarding differences in such parameters as delivered dose, and target organ
15 sensitivity is avoided. On the other hand, the animal biossays are carried out under
controlled conditions allowing for greater accuracy in estimating dose. Confounding factors,
especially those relating to life style, are also avoided. In the case of diesel engine emissions,
the animal studies also provide unequivocal evidence for carcinogenicity, whereas the human
evidence is less certain. Because data are available for both animals and humans and
20 because use of each has advantages and disadvantages, quantitative risk estimates will be
carried out for both. In the present chapter, dosimetry models for extrapolating risk from
rats to humans will be illustrated.
In the development of dosimetry models, a variety of factors must be considered.
The first of these is rate of respiratory gas exchange. Since respiration is seldom measured
25 in chronic animal bioassays, estimates are usually used. The concentration and properties
of the agent and the time of day of exposure are the primary factors inducing variability of
respiratory exchange rates in animal exposures. Hesseltine et al. (1985) showed, for
example, that exposure of rats at night when they are awake and active results in minute
volumes considerably greater than daytime values. Of the chronic diesel exposure studies,
30 only those by Brightwell (1986) included exposure during night-time hours. Although mice
have been shown to decrease respiration greatly during exposure to an irritant gas, rats show
May, 1990 D-l DRAFT - DO NOT QUOTE OR CITE
-------
much less inhibition, so this is not likely to be a large potential source of error in estimating
target organ dose (Chang et ah, 1983). Since humans are highly variable in this respect,
because of differences in activity levels, estimated respiratory values well above resting levels
are generally selected.
5 A second important dosimetric variable is particle deposition efficiency. Since
transport from the nasal region and conducting airways is more rapid than desorption of
organics from the diesel particles, this fraction probably contributes little to the effective
dose. Deposition in alveolar regions is of primary importance because particles not only
remain long enough to accumulate and possibly induce particle related effects, but also
10 because they remain long enough for the carcinogenic agents present on the surface of the
particles to desorb and become bioavailable.
Since desorption of the organics from diesel particles is expected to be fairly complete
in animals as well as humans, bioavailability is not expected to differ greatly either because
of species differences in clearance rates or impaired clearance from high exposure levels (see
15 Chapter 8 for pharmacokinetic information). However, clearance rates are important
because, as mentioned above, accumulation of the particles themselves may have effects
independent of the PAHs and other potentially harmful agents present on the surface of the
particle.
A complete model would also consider the gaseous components of the diesel
20 emissions. Some of the diesei toxicology studies have included groups of animals exposed
to exhaust filtered to remove the paniculate matter and have subsequently provided negative
results. The reverse experiment, exposure to paniculate matter alone, unfortunately has not
been carried out because of the technical difficulties of such an undertaking. Thus, while
the gaseous components alone do not appear to be carcinogenic, it is uncertain whether they
25 may exert some promotional, or even inhibitory, effect on tumor induction by the paniculate
fraction. Because of this uncertainty, there is no reasonable method for factoring effects of
gaseous components into the dosimetry model.
Finally, transport of particles to lung-associated lymph nodes and to lung surface area
will be adjusted for.
30
May, 1990 D-2 DRAFT ~ DO NOT QUOTE OR CITE
-------
D.2. BASIS FOR EXTRAPOLATION MODEL
Two different extrapolation models will be developed. In the first one it will be
assumed that the retention and accumulation of inhaled paniculate matter in the lungs plays
5 a significant role in the carcinogenic process and that the retardation of alveolar
macrophage-mediated clearance of particles has an influence on effects; i.e., the particle
mediated impairment of alveolar clearance, which was observed in rats will be extrapolated
to humans. The possibility that retention and accumulation of organic material desorbing
from particles is primarily responsible for the carcinogenic effects will also be considered.
10 In the second model, the delivered dose rate of the organic material together with the
particles and the duration of exposure (competing risks) as well as cell proliferation and
transition rates will be considered the most important parameters.
D.2.1. Principle of Extrapolation Based on Deposition and Retention
. 15 Modeling
The principles of this approach have been described by Oberdfirster (1989) and is
based on species specific lung dosimetry as depicted in Figure D-l. Using deposition and
retention data for inhaled diesel particles for the rat as described by Yu and Yoon
20 et al (1988) a retained dose per gram lung or per unit epithelial surface area of the lung
can be calculated for each of the exposure situations of the different rat studies. The
retention model by Yu et al. (1987) takes into account a retardation of particle clearance
from the alveolar region at high inhaled concentrations that is due to a particle overload
effect. Assuming that the long-term retained dose must be the same in rat and man to
25 induce effects, a deposited dose for the human lung can be calculated from the retained
dose - applying human specific retention half-times - to arrive at an inhaled dose and at an
Equivalent Human Exposure (EHE). This EHE is different from the rat exposure, but -
according to the assumption made about the retained dose, it results in the same effects in
humans as in rats.
30 The following steps are involved in this model: (1) The retained doses resulting from
chronic exposure of rats under the different exposure conditions of the reported rat studies
May, 1990 D-3 DRAFT - DO NOT QUOTE OR CITE
-------
O
I
§
Bat
I
Exposure
I
Inhaled Dose \ny(kg) '\
Deposited Dose [
Lung Dosimelry
Breathing
Minute Volume
Tidal Volume. Resp. Ftnlo
Resp. Pause
characteristic
Anatomy
Clearance
Retention
Regional Uptake
(Metabolism. T±.)
Retained (Accumulated) Dose
li'
-------
will be calculated and plotted against the observed respective lung tumor incidences, using
a logistic regression. (2) Respective EHEs for human exposures can then be calculated
according to Figure D-l. On the basis of the logistic model, the tumor risks for humans for
relevant low inhaled concentrations of diesel exhaust can then be estimated.
5
D.2.L1. Deposition and retention model for inhaled diesel exhaust
A mathematical model for deposition and clearance of diesel exhaust particles has
been developed by Yu and Yoon (1988). The retention model used by them is shown in
Figure D-2. Diesel exhaust particles, consisting of a carbon core (80 percent) and adsorbed
10 organics (Figure D-3), are cleared from the lung by mechanical processes (mucociliary
escalator and alveolar macrophage mediated) and by dissolution processes. Half of the
organic material is strongly bound to the core and half of it is weakly bound. The transport
rate A (% of particle component i from compartment x to compartment y that is due to
dissolution is assumed to be constant. However, transport rates for mechanical clearance
15 from the alveolar compartment vary with the paniculate lung burden when this lung burden
reaches a certain value, as has been observed in the animal studies with high inhaled
concentrations of diesel exhaust. This functional dependence of mechanical alveolar
clearance rates on paniculate lung burden was determined by the best fits of experimental
data and model predictions for rats. The extrapolation to humans from the results in rats
20 was accomplished under the assumption that the relative responses (impairment of clearance
due to particle load) of the transport rates of particles to the same paniculate dose per unit
alveolar epithelial area were independent of the species. However, human specific clearance
rates for normal, undisturbed particle clearance from the alveolar region were used as the
starting point
25 At low particle burdens the alveolar clearance rate was essentially the normal
clearance rate controlled by macrophage migration to the mucociliary escalator, whereas the
alveolar clearance rate at high paniculate burdens was principally determined by the
transport to the lymphatic system and eventually to the blood compartment once alveolar
macrophage-mediated clearance ceased completely (Yu and Yoon, 1988).
May, 1990 D-5 DRAFT - DO NOT QUOTE OR CTTE
-------
(i)
H
1 1
8
'Ve
x(i)
_ AAB
ALB
H
T
T
AHG .
^TC
tx(il
|AAT
)
%
rA
<>
G
A
1
r^
L
Figure D-2. Model of panicle retention in the lung.
May, 1990
DRAFT - DO NOT QUOTE OR CITE
-------
carbon core
2 organics strongly
bound to core
3 organics weakly
bound to core
Figure D-3. Model of diesei exhausi panicle.
May, 1990
D-7 DRAFT - DO NOT QUOTE OR CITE
-------
The transport rates used in the model by Yu and Yoon (1988) are listed in Table D-l.
The material components i are as follows:
1 = carbon core
2 = strongly bound organics
5 3 = weakly bound organics
The conclusions reached by Yu and Yoon (1988) based on their model are given below and
are depicted in Figures D-4 through D-7:
• When exposed to the same exposure concentration of diesel exhaust particles, the
reduction in the clearance of the carbon core in humans due to high paniculate
10 burden is smaller than the reduction in rats; children have a larger reduction than
adults.
• The organics and carbon core burdens in various compartments vary with age of
humans for the same exposure period.
15
• The carbon core burden per unit exposure concentration in the lung reaches a steady
state value after a long period of exposure. The steady state value increases with
increasing exposure concentration level.
20 By using the specific exposure data of the different rat inhalation studies for calculating
particle deposition and the estimated specific clearance rates given in Table D-l one can
calculate the accumulated lung burden both for the carbon core and for the organics. The
resulting lung burdens of the organics after exposure for 24 mo and the observed lung tumor
incidences in rats (observed at 30 mo) are shown in Figure D-8. Lung tumor incidence is
25 expressed here as the ratio of the lung tumors observed in the exposed animals (P) vs. those
found in the unexposed (control) animals [P(O)j. These data can be described by a logit
function with the following expression:
P = 100/[l+exp(3.88-ll/374 mj]. (1)
Since the experimental data of Mauderly et al. (1987) are most complete with regard to
30 different exposure concentrations and different time points of study termination their results
were also plotted separately (Figure D-9), which gave the following logistic expression (based
on exposure of 24 mo and tumor data at 30 mo):
P = 100/[l+exp(4.709-40.544 mj]. (2)
May, 1990 D-8 DRAFT - DO NOT QUOTE OR CITE
-------
TABLE D-l. TRANSPORT RATES USED IN RETENTION MODEL FOR
DIESEL EXHAUST PARTICLES
5 ——-————-----———-—--—--—--——-•—-—
The values of X (J/ in the unit of day'1 that we used in the model calculation for rats are listed
below:
10
X^ - 1.73, i - 1, 2, 3 (Chan et aL, 1981; ICRP, 1979)
15
o\ cy\ CT\ C2\
XWB " xra " *-LB " IAB " a023 (Sun et aL> 1984;
Bond et aL, 1986)
20
(31 (2} (3) (31
1\ / _ i \.JJ _ i \JJ _ i ^J/ _ 19 <7 /'Qiin ^t al IQftd*
Arrij s Tf) t P >dP 1*~J I ^>JU11 Cl ai., 17OH,
x-z> /u> Bond et aL, 1986)
25
x*j " 4\i2' '" *3 (ICRP'1979)
30
fi. - 0.693, i - 1, 2, 3 (Chan et aL, 1981)
The following values of X ^ were determined from the data on lung burden and lymph node
burden for rats (Strom et aL, 1987|.
40
" °-012 exP(-(U1 m"*) + 0-00068 exp(-0.04 mi62) i - 1, 2, 3
45
May, 1990 D-9 DRAFT ~ DO NOT QUOTE OR CITE
-------
20
TABLE D-l (Continued)
0.00068[1 - exp(-0.046 mi'62)]
A. = 0.00018
10
X/B " xra " *S *a00018
15
0.012 exp(-0.11 mi76) + 0.00086
25 A . x® + 0^88
A AT
15.71
30
35 where mAis is the paniculate burden (rag) for the alveolar compartment; as mA - 0, A.\2 « 0.0129.
For humans, - 0.00169 (Bailey et aL, 1982)
40 AU
May, 1990 D-10 DRAFT - DO NOT QUOTE OR CITE
-------
I
s
D
O
1
O
c:
§
§
l-*igmc !>••!. Variations ttf L-lciiiancc rules.
-------
1 il
J.U
I
o
o
1
o
o
A Wolf fetal. H985)
o llcmricliclal. (1986)
« Shoinelal. (1987b)
u
I ....
8
I.
1
2-168 JO \Z
I niifj Uurden per Gram of I UNO, mn/g
11
Figure D-5. Change of alveolar clearance rate with lung burden during chronic diesel
exhaust exposure.
-------
o
i
O
O
2
9
O
I
O
&
U
E
M
E
c
o
u
c
o
o
-o
u
00
c
I O ill p. / 111
\ .0
0
0.2
I
0.4
—I 1 —
O.G
(Thousands)
0.8
rxponurr Time (uerfc)
Figure D-6. Calculated Jung burdens of the carbon core per unit exposure concentration
in human adults exposed continuously to diesel exhaust of different concentration levels
of 5 d/week and 8 h d. The dashed lines indicate the corresponding burdens in the rats.
-------
8
I
O
I
O
to
e
«D
e
3
_*
3
9
•J
3
o
"x
h.
3
•3
0
0.2
0.4
0.6 0.8 1
(Thousonda)
Exposure Time (week) (7d. 12M)
Figure D-7. Calculated lung burdens of the carbon core per unit exposure concentration
in humans from birth to adulthood exposed for 12 h/d, 7 d/week to diesel exhaust of
different concentration levels.
-------
f - 100/M < c.ip(3.388 - 11.37* mA(ng)/E)l
<5
o
Cft
D
§
0
O
2!
2
M
O
g
a
i
o
p«
»
0
O
C
0
o
0
i.
0.
l_
o
E
l~
o»
c
•o
0
3
§
o
i*-
Organlcs
B
.
10 -
9 -
8 -
7 -
6 -
i •
*
*
'i
4 -
3 -
2 -
M
B *
K
^
.
1 T '. K K
K
o -$
f*1 K R
r i i i i i i i i i i
0 0.04 0.03 012 0.16 0.2 0.24
lung Burden/Lung Weight (mg/g)
Figure D-8. Correlation between normalized lung tumor prevalence and calculated lung
burden of organics from different rat studies. Asterisks represent logit fit of data,
function shown on top.
Key to individual studies: (see Ishinishi et al., 1986):
B = Brightwell; K = Ishinishi, M = Mauderly; S = StOber, Z = Iwai.
-------
P - 100/H I ixp(A./(!'» - '.0.544 mA(mr,)/r.) I
d
O\
d
}w
£
,
d
O
5«
^^
~j
0
c:
2
o
js
0
OL.
O
O
C
o
(L
0
1-
o>
c
a
TJ
V
N
O
§
O
1 3
14
13 -
12 -
11 -
10 -
9 -
8 -
7 -
6 -
5 -
4 -
3 -
2 -
.. |
l T
Organics ft
,
M
M
*
• i 1 1 i i
0 0.02 0.04 0.06
lung Burden/Lung Weight (mg/g)
Figure D-9. Correlation between normalized lung tumor prevalence and calculated lung
top.
-------
Figures D-10 and D-ll depict the same relationships for lung tumors vs. lung burden based
on the carbon core:
P = 100/[l+exp(3.37-0.0874
5 for data from all experimental rat studies, and
P - 100/[l+exp(4.2633-0.1504 mj](4)
for data from Mauderfy et al. (1987) only.
Different exposure scenarios for exposures of rats to diesel exhaust can be simulated
10 (e.g. 100 Mg/m3, 24 h/d, 7 d/week). These will eventually result in lung burdens (mA) of
accumulated particles or associated organics which can be predicted with the deposition and
retention models by applying the specific transfer rates for organics and the carbon core
listed in Table D-l. With Equations (1) through (4) one can then estimate a certain lung
tumor prevalence in the rat that correlates with the respective exposure concentrations. The
15 result of one example is shown in Figure D-12. For a given exposure concentration, the
predicted lung tumor prevalence is different depending on whether the prediction is based
on the accumulated organics or on the accumulated particles of the carbon core. This result
is difficult to interpret, showing that the organics have a lower impact than the particles at
high inhaled concentrations. Ideally, both curves should fall together, it is possible that the
20 divergence of the two curves reflects the importance of exposure duration. The exposure
duration is only partly considered in this model through the retention half-times for particles
and for organics. Since they differ, equilibrium lung burdens are reached much faster for
organics than for the carbon core. Thus, the equilibrium in the lung of the retained dose,
which is reached very quickly for organics, will not change during further continuous
25 exposure over 2 yr; yet it is very likely that this continuing exposure after equilibrium is
reached will have a major influence on tumor induction. For particles, inhaled at a
concentration above a few milligrams per cubic meter, retarded clearance will become an
increasingly important factor for their accumulated dose over an extended exposure period.
May, 1990 D-17 DRAFT - DO NOT QUOTE OR CTEE
-------
100/1
exp(1.37 - 0.0874 mA(mg)/r,)|
d
H*
00
d
5
3
i
8
25
3
O
a
o
a
o
o
fb
ru
0
O
C
o
9
i.
a
o
E
o>
c
3
O
N
75
§
o
z
1 .)
12
11
10
9 -
8 -
7 -
6 -
5 -
4 -
3 -
2 -
1 -
0 -
7
Carbon Core
B
*
*
*
S
ML
**
8 •
* 1
K
*
** * M
K
° T> 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I
0 -1 3 12 1G 20 24 28 32
lung Burden/Lunq Weight (mq/g)
Figure D-10. Correlation between normalized lung tumor prevalence and lung burden of
diesel exhaust particles from different rat studies. Asterisks represent logit fit of data,
equation shown on top. See Fig. 8 for key to individual studies.
-------
P • 100/11 4exp(«.2633 - 0.1504 «A(ing)/g)|
HH
\J
^.
VO
d
C
M
H
1
d
O
|
O
O
a
0
III
0
a?
* ^
• 8
0 °
c
I 7 -
i.
Q.
o 6 -
E
3
*"" «\ -
o»
c
3
4-
•o
0
N
c 3 "
5
o
2 2-
1 -
1
Carbon Core
ffl
'
M
*
0 - i i i i i i i i - - -| •• — |- i r • • -7 • i i
0 2 4 6 8 10 12 14 IE
1 unq But dcn/l ling tVri(|lil (niq/a)
^-^« ir-^ 4 4 ^~i • * • L * I* If t t fll • • f
Figure D-ll. Correlation between normalized lung tumor prevalence and lung burden of
diesel exhaust particles from study by Mauderly et al. (1987) Logit function shown on
top.
-------
d
O
O
I
O
I
0»
o
«
o
•
-------
The impact of diesel exhaust exposures on lung clearance in rats is examined first in
the following section. Next, based on the retention model by Yu and Yoon (1988) and the
extrapolation model outlined in Figure D-l, separate EHEs are estimated for a retardation
in alveolar particle clearance (overload related) on the one hand and for rumor incidences
5 on the other hand. This extrapolation model assumes that effects on clearance retardation
are correlated to the particle load (carbon core) in the lungs, whereas lung tumor incidences
are predicted separately as either a function of the load of particles or of the organics.
D.2,12. Extrapolation of lung tumor risk based on retention of diesel exhaust particles
10 and adsorbed organics
DJ2.L2.1. Influence of particle load on retention
The retardation of alveolar particle clearance found in the lungs is shown in Figure
15 D-5, which was discussed above. This figure shows the ratio of the actual alveolar particle
clearance, A A ^ over ^c normal, undisturbed alveolar particle clearance, Aj^ for different
lung burdens both per unit lung weight (lower x-axis) and per unit pulmonary surface area
(upper x-axis). Figures D-13 and D-14 show the extrapolated EHE's leading to alveolar
clearance retardation in humans based either on the particulate burden per lung weight or
20 per pulmonary surface area. Two cases were considered for each category: either
continuous exposure for 24 h/d and 7 d/week (environmental exposure) or for 8 h/d and 5
d/week (occupational exposure). The extrapolation predicts, that a continuous exposure to
a concentration of 1 mg diesel exhaust/m3 may result in a significant impairment of particle
clearance in humans (Figure D-14) whereas at more relevant concentrations of 100 jj/m3 and
25 below no such effect should be expected. Likewise, at occupational exposures to 100 to 350
/xg/m3, which were estimated in the study by Garshick et al. (1987), no significant effect can
be predicted either. If this is correct, observed carcinogenic responses in quoted
epidemiological studies may not have been influenced by increased particulate accumulation
caused by an impairment of particle clearance. Since
May, 1990 D-21 DRAFT - DO NOT QUOTE OR CITE
-------
d
I
o
o
1
§
1
0.9 ~
0.9 -
v.4 -
•M -
10
-2
(A) 24 hrs/day and 7 days/wk
(B) 8 hrs/day and 5 days/wk
i I I
io-i
Soot Concentration
•
\
(A)
\
\
(B) \
\
'.
',
\ A
\ \
1
\ \
\ \
• 1
\
\_____ \
1.0
10
Figure D-13. Predicted impairment of alveolar particle clearance in humans due to
accumulation of diesel exhaust particles in the alveolar region (per unit surface area) for
different inhaled concentrations and different exposure scenarios.
-------
I
o
o
1
*
v.1 -
10
-2
d 7 days/wk
d 5 days/wk
i 1 1 i
li>~' 1.
(B)\
\
\
\
\
\
(A) \
*
I
\
\
\
\
1 1 1 I
0 10
Snot Concentration tng/m^
Figure D-14. Predicted impairment of alveolar particle clearance in humans due to
accumulation of diesel exhaust particles in the alveolar region (per unit lung weight) for
different inhaled concentrations and different exposure scenarios.
-------
alveolar macrophages are the mediators of mechanical clearance of particles from the
alveolar compartment an effect on clearance might better be expressed based on paniculate
burden of alveolar macrophages. Therefore, assuming that the frequency distribution of AM
alveolar macrophages per pulmonary surface area is similar in rat and man (Crapo et aL,
5 1983), the predictions in Figure D-14, based on pulmonary surface area, might be better
justified than predictions based on lung weight (Figure D-13).
D2JL12. Extrapolation of lung tumor prevalence based on accumulated doses of carbon
10 cone and organic*
Assuming that the same accumulated doses of either the paniculate carbon core or
the adsorbed organics per unit lung (mass or epithelial surface area) of rat and man will
induce the same response, the data presented in Figures D-8 through D-ll, showing the
15 relationship between lung tumors and lung doses, and in Figures D-13 and D-14, showing
clearance rates vs. paniculate lung burden, were used to extrapolate EHEs for predicting
lung tumor frequency in man. Again, two exposure scenarios were simulated, one for
continuous 24 h/d and 7 d/week (environmental) and one for 8 h/d and 5 d/week
(occupational) exposure. Extrapolations were also based either on the experimental data
20 from all rat exposure studies or solely on the data by Mauderly et al. (1987). In addition,
in analogy to Figure D-12, predictions of lung tumors were made considering either the
accumulated particles (carbon core) alone or the organics alone. The results are shown in
Figures D-15 through D-18. Depending on the data base used, the results predict a
relatively low excess lung tumor incidence of 2J to 9 percent for continuous exposure for
25 20 yr at 1 mg/m3; for occupational exposure to the same concentration and for the same
duration, it is between 0.7 and 23 percent Extrapolated risks for more relevant
concentrations of 100 pg/m3 are 10"3 to 10"* (Table D-2).
Compared to results from epidemiological studies by Garshick et al. (1987) these
numbers are very low. However, as stated before, these model extrapolations based on
30 accumulated lung doses of either the paniculate carbon core or the adsorbed organics do
not take into consideration the influence of a continuing exposure after steady-state values
of lung doses of the soot particles and organics are reached. It is very likely that such
May, 1990 D-24 DRAFT - DO NOT QUOTE OR CITE
-------
D
fc
8
as
9
o
I
g
u
c
•
o
V
-------
3
O
o
so
o
c
0
0>
c
3
1.6
1.5
1.4
1.3 -
1.2 -
1.1 -
1 1
10-2
(A) 24 hrs/day and 7 days/wk
(B) 8 hrs/day and 5 days/wk
Soot Concentration mg/m3
Figure D-16. Predictions of lung tumors in humans for different exposure conditions
based on accumulation of the particulate carbon cord (CC) or of organics (O) per unit
surface area of the pulmonary region. Extrapolated from results of all rat studies.
<*>
>*»
o
-------
I
D
O
I
§
g
u
c
i.
o
o«
c
3
•Q
9
N
w
I
(A) 24 hrs/day and 7 days/wk
(B) 8 hrs/day and 5 daya/wk
10
Soot Concentration mg/m3
Figure D-17. Predictions of lung tumors in humans for different exposure conditions
based on accumulation of the particulate carbon core (CC) or of organics (O) per unit
lung weight. Extrapolated from result of study by Mauderty et al. (1987).
-------
g
1
o
o
o
c
o
•
c
3
N
O
2.6
2.5 -
2.4 -
2.3 -
2.2 -
2.1 -
2 -
1.9 -
1.8 -
1.7 -
1.6 -
1.5 -
1.4 -
1.3 -
1.2 -
1.1 -
1 -
(A) 24 hrs/day and 7 days/wk
(8) 0 hrs/day and 5 days/wk
10-2
o
I
o
Soot Concentration
Figure D-18. Predictions of lung tumors in humans for different exposure conditions
based on accumulation of the particulate carbon core (CC) or of organics (O) per unit
surface area of the pulmonary region. Extrapolated from result of study by Mauderly et
al. (1987).
-------
TABLE D-2
10
15
20
EXTRAPOLATED LUNG TUMOR RISK FROM EXPOSURE TO DIESEL
EXHAUST FOR CONTINUOUS (24 H/D, 7 D/WEEK) OR DISCONTINUOUS (8
H/D, 5 D/WEEK) CHRONIC EXPOSURE. BASES FOR EXTRAPOLATION ARE
AS INDICATED IN FIGURES 14-17.
Exposure concentration (mg/m3)
Bases of extrapolation
0.01
1.0024 1.0
10.0
25
30
35
Rat studies,
continuous exposure
(Mauderty et aL, 1987)
Lung weight
Pulmonary
surface area
Lung weight
Pulmonary
surface area
Organic 1.002 1.0024 1.024 1284
Carbon core 1.00023 1.0024 1.024 1.57
Organic 1.00024 1.0024 1.025 1.286
Carbon Core 1.00024 1.0024 1.03 1.58
Organics 1.0008 1.009 1.091 2.49
Carbon core 1.0004 1.004 1.043 122
Organics 1.0009 1.009 1.093 ZSO
Carbon core 1.0004 1.004 1.053 1236
40
45
50
Rat Studies
discontinued exposure
(Mauderly et aL, 1987)
Lung weight
Pulmonary
surface area
Lung weight
Pulmonary
surface area
Organics 1.00005 1.0005 1.0055 1.056
Carbon core 1.00006 1.0006 1.0056 1.061
Organics 1.00006 1.0005 51.006 1.056
Carbon core 1.00006 1.0006 1.0057 1.115
Organics 1.0002 1.002 1.02 122
Carbon core 1.0001 1.001 1.01 1.11
Orgnaics 1.0002 1.002 1.02 1234
Carbon core 1.0001 1.001 1.01 121
May, 1990
D-29 DRAFT - DO NOT QUOTE OR CITE
-------
continuing exposure is of decisive influence on lung tumor rates and that the dose rate at
which a carcinogenic compound is delivered to the target cell rather than the accumulated
dose determines the chances for transformation. An extrapolation model based on the
delivered dose rate to target cells and the exposure time and the proliferation and transition
5 rates of these cells will be discussed in the following section.
D22. Risk Extrapolation Based on Competing Risks and Proliferation
Rates of Target Cells
10 If the induction of lung rumors after diesel exposure is due to an increased
accumulation of particles (via direct mechanisms), one should expect that effective clearance
of these particles from the lung - i.e., no impairment of lung clearance mechanisms • would
prevent the induction of such tumors unless these tumors are caused additionally or solely
by the adsorbed PAH (organics, direct carcinogens). Indeed, retardation of particle
15 clearance with increased accumulation of soot particles and lung tumors have been observed
in rats during chronic exposures exceeding about 1 mg/m3, whereas low exposure
concentrations (035 mg/m3) did not impair clearance mechanisms and an increased tumor
incidence was not seen (Mauderty et aL, 1987).
There is some direct evidence for a particle effect. In studies with inhaled TjO2
20 particles of low cytotoxicity, tumors could be induced, but only at exposure concentrations
much greater than used in any of the chronic diesel studies (Lee et al., 1986). On the other
hand, ten consecutive doses of carbon black particles instilled intratracheally were found to
be as effective for induction of lung tumors as the same amount of instilled diesel exhaust
particles, indicating the possibility of a pure particle effect (Kawabata et al., 1986). This is
25 a remarkable result, but needs confirmation by inhalation studies to exclude a possible
influence of repeated mucosal wounding on tumor induction (Saffiotti et al., 1988).
If relatively inert particles can induce lung cancer, it is uncertain how this occurs.
One possibility is that activation, cellular injury, or death of particle-laden macrophages may
result in the release of a variety of mediators including reactive oxygen species, chemotactic
30 factors, lysosomal hydrolases, other proteinases, prostaglandins, plasminogen activators, and
May, 1990 D-30 DRAFT - DO NOT QUOTE OR CITE
-------
growth' activators that could cause, by unknown mechanisms, further lung injury, including
tumors. This condition is exasperated by the tendency of the macrophages to aggregate,
especially for large lung burdens, thus increasing the local concentration of the potentially
damaging factors.
5 Nevertheless, even if particles can be shown to induce lung tumors under certain
conditions, it is unlikely that this is the sole mechanism, or even the predominant one for
induction of lung tumors by diesel exhaust More likely, panicles could act as cofactors,
either by release of a variety of factors from the macrophage or by optimizing the dose or
dose rate of PAH to target cells by slow desorption from particles. Thus, both particles and
10 organics may be responsible for the observed tumorigenic effect of inhaled diesel exhaust,
with the organics acting directly and the particles acting indirectly as promoters, or as
vehicles for carcinogen delivery.
Desorption of PAH are relatively rapid compared to particle clearance and, therefore,
: bioavailability can be expected to be high and not greatly increased by impaired clearance.
15 Although more rapid than particle clearance, PAH desorption nevertheless occurs over a
period of days. This results in a slower delivery of PAH to the target organs than, for
example, administration of pure B[a]P, allowing for a greater fraction to be metabolized to
an active form. Partial activation of the PAH by the macrophages should also increase the
effectiveness of the delivered dose. Studies showing the formation of greater amounts of
20 metabolites after exposure to B[a]P alone and studies showing the greater inducibility of lung
tumors after B[a]P plus particles vs. B[a]P alone are consistent with these concepts.
This concept seems to be contradicted by inhalation studies in rats with 1000-fold-
higher concentrations for B[a]P than in the diesel exhaust studies, but with the same
concentration of particles (albeit of different kind, Le. tar particles vs. diesel particles) which
25 resulted in the same tumor incidence in both studies (Heinrich et aL, 1986). However, in
accordance with the concept of delivered dose rate, this result can be explained by the
kinetics of the adsorbed organics: slow release of adsorbed PAH from carbonaceous
particles on the one hand (diesel exhaust) and fast release of adsorbed PAH from tar
particles on the other hand (pitch pyrotysis studies).
May, 1990 D-31 DRAFT - DO NOT QUOTE OR CITE
-------
Thus, in this extrapolation model we will consider the dose rate of particles and
adsorbed organics delivered over an extended period of time. A scheme of this concept for
extrapolation from rat to man is shown in Figure D-19. The deposited dose rate (expressed
per unit epithelial surface area) of the inhaled particles is essentially equivalent to the
5 delivered dose rate of the organics to epithelial cells because a steady state between
desorbed and deposited amounts is reached after about 3 mo of exposure (see rate
constants, Table D-l). For estimating the deposited dose rates and inhaled dose rates, the
rat and man specific deposition and breathing parameters are applied (Yu and Yoon et aL,
1988).
10 As pointed out above, the duration of exposure plays an important role, too. For
example, a very high dose rate delivered over a short time may cause fewer tumorigcnic
effects than a lower dose rate delivered over a longer time, although the product of time
and exposure may be the same. Thus, the product of time and exposure may not be a good
exposure index for a carcinogenic compound. Duration of exposure and dose rate have to
15 be considered separately since tumor induction may not be adequately described in two
dimensions. This concept of competing risks has ben discussed extensively and is accepted
widely in radiation dosimetry (NCRP, 1980; Raabe, 1987), and it may also be applicable to
chemical carcinogens (Krewski et al., 1981). Results from the diesel study in rats exposed
for different time periods and at different concentrations by Mauderty et al. (1987) point in
20 the same direction. These results show that exposure to 7 mg/m3 for 30 mo yielded a more
than fourfold higher tumor response than exposure to 3.5 mg/m3 for 30 mo, i.e.,
corresponding to an increase in exposure index (times x exposure) by a factor of 2. It is
difficult to compare the results between the different exposure groups of this study at time
points prior to 30 mo because of the long latency period for tumor development («12 mo
25 in rats).
Therefore, in analogy to radiation effects, separate influences of the delivered dose
rate and of the exposure time on the risk of tumor development will be considered here for
the carcinogenic effects of diesel exhaust A schematic representation of this concept is
shown in Figure D-20. The dose rate to the epithelial cell in this figure could be converted
30 into an exposure concentration (EHE, mg soot/m3) according to Figure D-19.
May, 1990 D-32 DRAFT - DO NOT QUOTE OR CITE
-------
DOSE Ft A TE vs. EFFECT
Rat
I
Exposure
I
Inhaled Dose Rale [mg(dyi\
Deposited Dose Rate
Particles
Man
t
Exposure (EHE) \\\g(irP)1\
\
Inhaled Dose Rate
Deposited Dose Rate
a
o
§
O
Jtf
Organics
Dose Rate to Epithelial Cells
I
Effects
Figure D-19. Extrapolation of results from inhalation studies from rat to man based on
delivered dose rate to target cells.
-------
Figure D-20. Model of competing risks for lung tumor induction by inhalation of diesel
exhaust considering delivered dose rate to epithelial target cells and exposure time.
May, 1990
D-34 DRAFT - DO NOT QUOTE OR CITE
-------
In addition, the importance of the target cell proliferation rates and transition rates
should be considered. As described in their two stage model for human carcinogenesis by
Moolgavkar and Knudson (1981), the growth and differentiation rate of normal target cells
into normal cells and their transition rate into intermediate cells can be important
5 determinants for the transition into malignant cells (Figure D-21). Carcinogens or promoters
could affect these different rates to increase malignant transformation. For example, an
increase in the normal proliferation rate of target cells or, even more, of intermediate cells
(e.g., as a response to increased particle load?) will increase the probability of tumor
induction and will shift the dose rate-response curves of Figure D-20 towards the foreground,
10 Le. the exposure time is shortened until the effect occurs. In contrast, if the proliferation
rate of the intermediate cells is inhibited, then dose rate-response curves in Figure D-20
move towards the background, i.e., time to the same response increases.
Available data from the rat inhalation study by Mauderly et al. (1987) allow the
: construction of dose rate-response and time-response curves for the rat necessary for the
15 construction of Figure D-20. However, for the extrapolation of the results to humans based
on the two-stage model by Moolgavkar and Knudson (1981), knowledge of the basic cell
proliferation rates of the target cells (Type II cells,, their progenitor cells, bronchial epithelial
and stem cells) and of the generated intermediate cells as well as the transition rates for rats
and for humans, would be needed.
20 Lacking such data - only limited data for the rat indicating a normal cell turnover
time of alveolar epithelial cells of about 21 to 28 d could be found (Adamson, 1986; Sanders,
1989) - an alternative approach could be considered which is described in the following
paragraphs. However, this approach needs to validated before it is applied to extrapolation
from rat to man.
25 As pointed out by Moolgavkar and Knudson (1981), one or both of two possibilities
exist for a chronically administered carcinogenic agent to increase the incidence of cancer.
(1) The carcinogenic agent could increase the transition rates, MI and/or M» to new constant
levels; this would imply that the risk for exposed individuals relative to nonexposed
individuals remains constant with time when chronically exposed to a given dose. Only the
30 intensity of the dose determines this risk, not the duration of exposure. (2) The carcinogenic
May, 1990 D-35 DRAFT - DO NOT QUOTE OR CITE
-------
First Event
Second Event
Figure D-21. Two stage cancer model of Moolgavkar and Knudson (1980). S. = normal
stem cell; = intermediate cell; D = dead cell; M = malignant cell; M = rate at which
first event occurs; n2 - rate at which second event occurs; a, = rate of division of
intermediate cell; B2 = rate of differentiation and death of intermediate cell.
May, 1990
D-36 DRAFT - DO NOT QUOTE OR CITE
-------
agent increases the proliferation rate of intermediate cells by a constant amount without
effect on the transition rates; this implies that risk in exposed individuals increases with time,
relative to the unexposed. This is because the ratio of intermediate cells of
exposed/unexposed increases with time.
5 As will be shown later, diesel exhaust may act like an agent as described under (1)
in the rate, i.eM no increase in relative tumor risk with exposure time at a given inhaled
concentration. It is possible that proliferation rates of normal cells may also be affected by
diesel particles which however, has only little effect on tumor incidence unless large changes
in proliferation rates occur. Such large changes of normal cell proliferation that are due to
10 chronic irritation may occur particularly at high inhaled concentrations of diesel exhaust
Differences in age, specific lung tumor incidence between unexposed rats and man
may also be due to differences in the transition rates, MI and p2. Comparing these age-
specific tumor incidences for unexposed humans (Doll, 1971) and unexposed rats (Mauderly,
1987), an 18-fold higher tumor incidence at the end of life span was found in control rats
15 of the diesel study compared to humans (about 0.05 percent in humans vs. 0.9 percent in
rats). Table D-3 shows respective data for other time points of rat and human life span.
For rats, respective tumor incidence in unexposed animals were extrapolated from the
limited data available for control rats. The total lifespan, 1, is equivalent to 80 yr in humans
and to 30 mo in rats.
20
TABLE D-3
RATIO OF AGE SPECIFIC TUMOR INCIDENCE FOR UNEXPOSED INDIVIDUALS,
25 RAT/MAN, FOR DIFFERENT FRACTIONS OF LIFE SPAN
Fraction of lifespan O5 0.625 0.75 0.875 1.0
30 Ratio rat/man 1.95 320 4.90 933 18.23
35
However, whether and how these ratios can be used for deriving a factor for
extrapolating from rat to humans is not obvious and requires some further discussion. One
May, 1990 D-37 DRAFT - DO NOT QUOTE OR CITE
-------
could argue that if both age-specific incidence of lung tumors in unexposed individuals and
lung tumor incidence in exposed individuals are due to effects on the transition rates (see
above), then lung tumor incidence normalized for life span may have to be lowered by these
ratios when extrapolating from rat to man. This assumes that the transition rates /*,, and
5 /*2 are equally affected in rat and man leading to a corresponding increase of the age-specific
lung tumor incidence in both species after diesel exposure.
However, because of the long latency period for lung tumor development (rat »12
mo) relative to the exposure duration, it may not be possible to use ratios of age specific
lung tumor incidence between rat and man. Tentatively, we propose therefore not to
10 include the age-related factors but rather to express the results as relative tumor prevalence
(relative to base line tumor rate at a specific age), which may not require further application
of an extrapolation factor. However, an adjustment has to be made for differences in
numbers of exposed target cells between rat and man. If we assume that epithelial cells are
roughly of equal size in rat and man (Crapo et al., 1983), then a ratio of epithelial cell
15 numbers for man/rat can be derived from the size of the epithelial surface areas. Lung
models by Yeh and Schum (1980) and Sebum and Yeh (1979) can be used to calculate
surface areas for both species. Wojciak (1988) calculated these areas, taking into account
overlapping areas at bifurcations, and arrived at ratios for man/rat of 125 for alveolar surface
areas and 110 for tracheobronchial surface areas. If only the numbers of Type II cells, which
20 are probably one target cell type in rats are considered, then a factor of 450 would apply
(Crapo et al., 1983). Since the tumor sites may be different for rats and man - involving
bronchial, bronchiolar, and alveolar cells - we will use the factor of 125 derived above. This
will be too low if Type II cells are considered, but may be too high if bronchial cells are
involved. Information on tumor types from the epidemiological diesel studies is not
25 available; if significant differences exist between tumor types in exposed rat and man, this
model, as well as other models, needs further refinement
Assuming that the model is applicable, the extrapolation involves the following steps
(using results of the inhalation study by Maudcrly et al. (1987):
May, 1990 D-38 DRAFT - DO NOT QUOTE OR CITE
-------
1. Calculation of deposition rates of inhaled diesel exhaust per epithelial surface area
(tracheobronchial and alveolar) for the different groups of the rat study.
2. Calculation of EHEs from the respective dose rates according to Figure D-19.
5
3. Determination of dose rate - response (tumor prevalence) relationships as a function of
exposure time for the rat study (three-dimensional description).
4. Determination of EHE - tumor prevalence relationships for human diesel exhaust
10 exposure as a function of time adjusted for difference in cell numbers between rat and
man (i.e., multiplication of normalized tumor prevalence in the rat by 125).
Figure D-22 shows the result of step 3 above, the normalized tumor prevalence, P/P(0), as
a function of the epithelial surface dose rates r* and of exposure time / for the rat exposed
15 7 h/d, 5 d/week for 30 mo.
The respective functions for P derived from results of the rat study, separately for the
I,*
alveolar (A) and tracheobronchial (TB) regions, are as follows:
JA(M"A) = l/[l+exp (15.06-0.0115/-452.65rA)] (r = 0.980) , and (5)
20
l/[l+exp (15.06-0.0115MO.7r-n,)] (6)
(derived by fitting the tumor data of diesel exposed rats; compares well with the data point
for controls) where r is in days; r A and r'^ = surface dose rate of organics in alveolar and
25 tracheobronchial region in jig-cm'2*!"1,
PA and PTB = tumor prevalence in alveolar and bronchial region assuming:
12 percent of inhaled diesel soot is
organics, rat tidal volume = 1.55 cm3,
respiratory frequency = 97 min"1,
30 body weight = 250 g,
exposure for 24 th/d, 7 d/week,
particle size = 0.25 urn with GSD of 4.4.
May, 1990 D-39 DRAFT - DO NOT QUOTE OR CITE
-------
il
Figure D-22. Result of three dimensional model of normalized lung tumor prevalence in
rats considering delivered dose rate (or inhaled soot concentration) and exposure time
separately. Exposure is for 7 h/d, 5 d/week.
May, 1990
]>40 DRAFT - DO NOT QUOTE OR CTTE
-------
The respective equations for the exposure concentrations'c are:
exp (15.06-0.0115M).336c)] = P
5 where t is in days, is c in mg/m3. Table D-4 shows the resulting predictions for normalized
lung tumor prevalence as a function of time and exposure concentration in the rat This
table shows that the normalized lung tumor prevalence after diesel exposure in rats is
constant with time, which would indicate an effect of diesel exhaust on the transition
10
TABLE EM
EXTRAPOLATED LUNG TUMOR PREVALENCE FOR RATS CHRONICALLY
EXPOSED TO DIESEL EXHAUST AT DIFFERENT CONCENTRATIONS.
15
20
25
30
35 rates of cells in the cancer model by Moolgavkar and Knudson (1981). We have to keep
in mind, however, that only very limited data were available to express tumor incidence over
time in control rats as a function of time.
The extrapolated lung cancer incidence in humans according to step 4 is shown in Table D-
5. This assumes lifelong exposure at the exposure conditions of the rat study. Lung tumor
40 incidence is considerably higher than predicted from results of the epidemiological studies.
Exposure concentration, mg/m3
Time/years
05
1
2
3
0
1
1
1
1
aoi
1.003
1.003
1.003
1.003
0.1
1.034
1.034
1.034
1.031
05
1.18
1.18
1.18
1.17
1
1.4
1.4
1.4
136
5
5.4
5.4
5.4
5.0
10
29
29
29
28
May, 1990 D-41 DRAFT - DO NOT QUOTE OR CTTE
-------
TABLE D-5
EXTRAPOLATED NORMALIZED LUNG TUMOR PREVALENCE FOR HUMANS
CHRONICALLY EXPOSED TO DIESEL EXHAUST 7 H/D, 5 D/WEEK AT
5 DIFFERENT CONCENTRATIONS,
10
15
Exposure concentration
mg/Qi
Normalized lung tumor
prevalence, P/P(0)
0.01
1375
0.1
4375
0.5
77 ?S
1.0 5.0
46
626
20
25
30
35
D.23. Extrapolation Based on Competing Risks
Another possible approach uses the concept of competing risks and eliminates the
necessity of having to make assumptions on differences in target cell numbers and cell
proliferation rates between species. Briefly, this approach includes:
1. including separate time functions for diesel exposed and for exposed and for unexposed
individuals since the approach used in the present model gave unsatisfactory results for
high exposure rates at short exposure times (most obvious for exposure time / = 0), see
Fig. 22,
2. describing age-specific lung tumor rates for humans according to Doll (1971) to find the
constants for the respective equations (5) to (7) for humans at zero exposure, and
3. calculating the dose rates (r) of the delivered particles (organics) for humans by using
the deposition model of Yu et al. (1987) for insertion into new equations (5) to (7).
D3. SUMMARY
40 Two extrapolation models were discussed in this chapter. Each gave very different
results. In both models the final extrapolation steps for the prediction of lung tumors are
probably too simplistic and need consideration of additional aspects. However, lacking
results of mechanistic studies about the carcinogenicity of diesel exhaust, it is very difficult
May, 1990
D-42 DRAFT - DO NOT QUOTE OR CITE
-------
at this time to refine the models in a reasonable way. Although the extrapolation models
and the predicted lung tumor prevalences may be based on too many assumptions, they gave
two possible important hints. One is that accumulation of soot particles in the lung even
during chronic occupational diesel exhaust exposure (concentration 100 to 500 Mg/m3) will
5 not reach lung burdens that cause significant impairment of alveolar clearance (first model);
the other is that the normalized lung tumor prevalence in diesel exhaust-exposed rats may
not depend on exposure duration (second model), thus pointing to a specific mode of action
if a two-stage cancer model is considered.
The first model, based on accumulated doses of particles or organic material in the
10 lung, does not consider fully the influence of exposure time. This is true in particular for
the organic compounds since they have a relatively short retention half time that is assumed
to be the same in humans and rats. This model is probably not applicable for substances
with short turnover times in the lung, in which case the deposition rates of those substances
appear to be more appropriate dose parameters. It is probably for this reason that
15 extrapolated risks from the first model were much lower than those calculated from
epidemiological studies. Presently it is hoped that ongoing studies with pure carbon black
particles wfll hopefully shed light on the involvement of carbonaceous particles in lung tumor
induction.
In the second model, based on the interrelation of competing risks (three-dimensional
20 relationships) and on the two stage cancer model by Moolgavkar and Knudson (1981), the
final extrapolation steps become quite uncertain as to whether and how to adjust for
differences between rats and man in cell proliferation rates and transition rates of normal
and intermediate cells, for differences in target cells and in tumor sites, and for differences
in age-specific lung tumors. These factors could not adequately be considered because of
25 a lack of data, and the preliminary result based on an adjustment for differences in numbers
of target cells predicts a much higher lung tumor risk than epidemiology does. Successful
use of this model wfll require further discussion and filling of data gaps.
May, 1990 D-43 DRAFT - DO NOT QUOTE OR CITE
-------
Adamson, L Y. R. (1986) Cellular kinetics of the lung. In: Witschi, H. P.; Brain, J. D., eds. Handbook of
5 Experimental Pathology. VoL 75, New York: Springer-Verlag. pp. 289-317.
Bailey, M. R. et aL (1982) Ann. Occnp. Hyg. 26:273-289.
Bond, J. A; Son, J. D.; Mitchell, C R; Dutcher, J. S^ Wolff, R. 1C; Mcdellan, R. O. (1986) Biological
10 fate of inhaled organic compounds associated with paniculate matter. In: Lee, S. D.; Schneider, T.;
Grant, L. D.; Verker, P. J., eds. Aerosols, Lewis Publisher, pp. 570-591
BrightweU, J.; Fouillet, X; Cassono-Zoppi, A. -L; Bernstein, D.; Gatz, R^ DuchosaL F. (1986) Neoplastic
and functional changes in rodents after chronic inhalation of engine exhaust emissions. In: Ishinishi,
15 N.; Koizumi. A; Mcdellan, R. O.; StOber, W., eds. Carcinogenic and Mutagenic Fffeg»« of Diesel
Engine Exhaust Amsterdam: Elsevier. pp. 471-485.
Chan, T. L.; Lee, P. S.; Hering, W. E (1981) Deposition and clearance of inhaled diesel exhaust particles
in the respiratory tract of Fisher rats. J. AppL ToxicoL 1:77-81
20
Chang, J. F. C; Cross, E A.; Swenberg, J.A.; Barrow, C S. (1983) Nasal cavity depositioiUiistopathology,
and cell proliferation after single or repeated formaldehyde exposures in B6C3F, mice and F-344 rats.
ToxicoL AppL PharmacoL 68:161-176.
25 Crapo, J. D. et aL (1983) Morphometric characteristics of cells in the alveolar region of mammalian lungs.
Am. Rev. Respir. Dis. 128:542-546.
DolLR. (1971) The age distribution of cancer Implications for models of carcinogenesis. J.R.Soc.
Med. (Series A) 134:133-166.
30
Garshick, E4 Scbenker, M. B.; Munoz, A; et aL (1987) A case-control study of lung cancer and diesel
exhaust exposure in railroad workers. Am. Rev. Respir. Dis. 135:1242-1248.
Heinrich, U. et aL (1986) Comparison of chronic inhalation effects in rodents after long-term exposure to
35 either coal oven flue gas mixed with pyrolized pitch or diesel engine exhaust. In: Ishinishi, N.;
Koizumi, A; Mcdellan, R^ Stober, W., eds. Carcinogenic and Mutagenic Effects of Diesel Engine
Exhaust Amsterdam: Elsevier, pp. 441-457.
Hesseltine, G. R; Wolff, R. 1C; Hanson, R. L; Mcdellan, R. CX; Mauderly, J. L. (1985) Comparison
40 of lung burdens of inhaled panicles by rats exposed during day and night J. ToxicoL Environ. Health
16: 323-329.
International Commission on Radiological Protection (LARQ. (1989) Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans. VoL46. Engine Exhausts and Nitroarenes, Lyon, France,
45 14-21. June 1988 (in press).
International Agency for Research on Cancer (ICRP). (1979) Publication No. 30 Pan 1. Annals of ICRP,
2.
May, 1990 D-44 DRAFT - DO NOT QUOTE OR CTTE
-------
Ishinishi, N. et aL (1986) Rffecrs of diesei soot on unscheduled DNA synthesis of tracheal epithelium and
lung tumor formation. In: Ishinishi, N.; Koizumi, A4 Mcdellan, R4 Stober, W., eds. Carcinogenic
and Mutagenic Effects of Diesel Engine Exhaust. Amsterdam: Elsevier, pp. 213-222.
5 Kawabata, Y. et aL (1986) Effects of diesei soot on unscheduled DNA synthesis of tracheal epithelium
and lung tumor formation. In: Ishinishi, N.; Koizumi, A.; Mcdellan, R^ Stober, W., eds.
Carcinogenic and Mutagenic Effects of Diesel Engine Exhaust Amsterdam: Elsevier, pp. 213-221
Krewski, D. et aL (1981) A comparison of statistical methods for low dose extrapolation utilizing time to
10 tumor data. Fundam. AppL ToxicoL 3: 140-160.
Lee JCP. et aL (1986) Pulmonary response to impaired lung clearance in rats following excessive TIO, dust
deposition. Environ. Res. 41: 144-167.
15 Mauderty, J.L; Jones, R. 1C; Griffith, W. C; Henderson, R. E; Mcdellan, R. O. (1987) Diesel exhaust is
a pulmonary carcinogen in rats exposed chronically by inhalation. Fundam. AppL ToxicoL 9: 208-221.
Moolgavkar, S.H.; Knudson, A.G. (1981) Mutation and cancer A model for human carcinogens. J. NatL
Cancer Inst 66: 1037-1052.
20
National Committee on Radiation Protection and Measurements (NCRP) (1980) Influence of dose and its
distribution in time on dose-response relationships for low LET radiations. Report No. 64, NCRP
Publication, Washington D.C
25 OberdOrster, G. (1989) Deposition and retention modeling of inhaled cadmium in rat and human lung:
And example for extrapolation of effects and risk estimation. In: Crapo, J.; et aL, eds. Extrapolation
of Dosimetric Relationships for Inhaled Particles and Gases. New York: Academic Press, in press.
Raabe, O.G. (1987) Three dimensional models of competing risk and natural life span. Fundam. AppL
30 ToxicoL 8: 465-473.
Saffiotti, U. et aL (1988) Multifactorial hamster respiratory carcinogenesis: Oxide, benzo(a)pyrene and
Ar-methyl-Af-nitrosourea (MNU). Presented at: Biology, Toxicology and Carcinogenesis of
Respiratory Epithelium, Albuquerque, NM, Nov. 1988.
35
Sanders. C personal communication. (1989).
Sebum, M.; Yen, H.G (1979) Theoretical evaluation of aerosol deposition in anatomical models of
mammalian lung airways. BulL Math. BioL 42; 1-15.
40
Strom, K. (1987) Presentation at HEI-Diesel Symposium, Seabrooke Island, S.C Feb. 1987.
Sun, JJX; Wolff, R. 1C; Kanapilly, G. M^ Mcdellan, R. O. (1984) Lung retention and metabolic fate of
inhaled benzo(a)pyrene associated with diesei exhaust particles. ToxicoL AppL PbarmacoL 73: 48-59.
45
Wojtiak, JJ7. (1988) Theoretical and experimental analyses of aerosol deposition in the lung: implications
for human health effects. PfauD. Thesis, University of Rochester, Rochester, NY.
May, 1990 D-45 DRAFT - DO NOT QUOTE OR CITE
-------
Wolff, R. 1C; Henderson, R. E; Snipes, MA; Sun, J. D^ Bond, J.A.; Mitchell, C R; Manderiy, J. L;
Mcdellan, R. O.; (1986) Long retention of diesel soot and associated organic compounds. In:
Ishinishi, R; Koizumi, A; McQellan, R. (X; StOber, W., eds. Carcinogenic and Matagenic Effects of
Diesel Engine Exhaust Amsterdam: Elsevier, pp. 191-211.
5
Wolff, RJC; Bond, J. A.; Sun, J. D^ et aL (1989) Effects of adsorption of benzo(a)pyrene onto carbon
black particles on levels of DNA adducts of rats exposed by inhalation. ToxicoL AppL PharmacoL
97:289-299.
10 Yen, KG; Sebum, M. (1980) Models of human lung airways and their application to inhaled particle
deposition. Bull Math. BioL 42:461-480.
Yu, CP.: Yoon, KJ. (1988) Determination of lung doses of diesel exhaust paniculates. Presented at 5th
Annual Conference of Health Effects Institute, Colorado Springs, CO. April 1988.
15
Yu, CP. et aL 1987. A nonlinear model of alveolar clearance of insoluble particles from the lung,
ToxicoL, premier issue, 97-107.
May, 1990 EM6 DRAFT - DO NOT QUOTE OR OTE
------- |