United States
Environmental Protection
Agency
Office of Research and
Development
Washington, DC 20460
EPA/600/8-90/045J
December 1991
Air Quality Criteria for
Carbon Monoxide
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EPA600/8-90/045F
December 1991
Air Quality Criteria for
Carbon Monoxide
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Printed on Recycled Paper
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
11
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PREFACE
The U.S. Environmental Protection Agency (EPA) promulgates the National Ambient
Air Quality Standards (NAAQS) on the basis of scientific information contained in criteria
documents. In 1971, the first air quality criteria document for carbon monoxide (CO) was
issued by the National Air Pollution Control Administration, a predecessor of EPA. On the
basis of scientific information contained in that document, NAAQS were promulgated for CO
at levels of 9 ppm for an 8-h average and 35 ppm for a 1-h average. The last full-scale CO
criteria document revision was completed by EPA in 1979, and an Addendum was issued in
1984. This revised and enlarged criteria document assesses the current scientific basis for
reevaluation of the CO NAAQS in accordance with the provisions identified in Sections 108
and 109 of the Clean Air Act.
Key chapters in this document evaluate the latest scientific data on the health effects of
CO measured in laboratory animals and exposed human populations; supporting chapters
describe the nature, sources, distribution, measurement, and concentrations of CO in the
environment. These chapters were prepared and peer reviewed by experts from various state
and Federal government offices, academia, and private industry for use by EPA to support
decision making regarding potential risks to public health. Although the document is not
intended to be an exhaustive literature review, it is intended to cover all the pertinent
literature through early 1991.
The Environmental Criteria and Assessment Office of EPA's Office of Health and
Environmental Assessment acknowledges with appreciation the contributions provided by the
authors and reviewers and the diligence of its staff and contractors in the preparation of this
document at the request of the Office of Air Quality Planning and Standards.
James A. Raub
Thomas B. McMullen
111
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CONTENTS
LIST OF TABLES xv
LIST OF FIGURES .-. xxi
AUTHORS, CONTRIBUTORS, AND REVIEWERS xxvii
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE ............. xli
PROJECT TEAM FOR DEVELOPMENT OF AIR QUALITY CRITERIA
FOR CARBON MONOXIDE . . xliii
1. SUMMARY AND CONCLUSIONS 1-1
1.1 INTRODUCTION . . , 1-1
1.2 THE GLOBAL CYCLE OF CARBON MONOXIDE 1-2
1.3 SOURCES, EMISSIONS,, AND CONCENTRATIONS OF
CARBON MONOXIDE IN URBAN AREAS 1-2
1.4 POPULATION EXPOSURE TO CARBON MONOXIDE 1-4
1.5 PHARMACOKINETICS AND MECHANISMS OF ACTION
OF CARBON MONOXIDE 1-7
1.6 HEALTH EFFECTS OF EXPOSURE TO CARBON
MONOXIDE 1-10
1.6.1 Acute Pulmonary Effects 1-10
1.6.2 Cardiovascular Effects i-11
1.6.3 Cerebrovascular and Behavioral Effects 1-13
1.6.4 Developmental Toxicity 1-14
1.6.5 Other Systemic Effects of Carbon Monoxide 1-15
1.6.6 Adaptation 1-16
1.7 COMBINED EXPOSURE OF CARBON MONOXIDE WITH
OTHER POLLUTANTS, DRUGS, AND ENVIRONMENTAL
FACTORS . . 1-17
1.7.1 High Altitude Effects 1-17
1.7.2 Carbon Monoxide Interaction with Drugs ......... 1-17
1.7.3 Combined Exposure of Carbon Monoxide with Other
Air Pollutants and Environmental Factors , 1-18
1.7.4 Environmental Tobacco Smoke ............... 1-19
1.8 EVALUATION OF SUBPOPULATIONS POTENTIALLY
AT RISK TO CARBON MONOXIDE EXPOSURE 1-19
1.9 SUMMARY : . 1-20
REFERENCES . 1-22
2. INTRODUCTION 2-1
2.1 ORGANIZATION AND CONTENT OF THIS DOCUMENT .. 2-1
2.2 LEGISLATIVE HISTORY OF NAAQS 2-3
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CONTENTS (cont'd)
2.3 REGULATORY BACKGROUND FOR CARBON
MONOXIDE NAAQS 2-4
2.4 SCIENTIFIC BACKGROUND FOR THE CURRENT
CARBON MONOXIDE NAAQS . . 2-6
2.4.1 Mechanisms of Action . * , . . 2-6
2.4.2 Carbon Monoxide Exposure Levels 2-8
2.4.3 Health Effects of Low-Level Carbon Monoxide
Exposures 2-8
2.4.3.1 Cardiovascular Effects , ...... .-. ..... 2-8
2.4.3.2 Neurobehavioral Effects . 2-10
2.4.3.3 Other Health Effects 2-11
2.5 CRITICAL ISSUES IN REVIEW OF THE NAAQS FOR
CARBON MONOXIDE . 2-11
2.5.1 Exposure Assessment in the Population 2-11
2.5.2 Mechanisms of Action of Carbon Monoxide ....... 2-14
2.5.3 Health Effects from Exposure to Carbon Monoxide ... = 2-16
2.5.3.1 Effects on the Cardiovascular System .... 2-16
2.5.3.2 Neurobehavioral Effects 2-18
2.5.3.3 Perinatal Effects ................. 2-19
2.5.4 Population Groups at Greatest Risk for Ambient
Carbon Monoxide Exposure Effects ............ 2-20
2.6 CARBON MONOXIDE POISONING 2-20
REFERENCES 2r25
3. PROPERTIES AND PRINCIPLES OF FORMATION OF CARBON
MONOXIDE 3-1
3.1 INTRODUCTION 3-1
3.2 PHYSICAL PROPERTIES 3-2
3.3 GASEOUS CHEMICAL REACTIONS OF CARBON
MONOXIDE 3-2
3.4 PRINCIPLES OF FORMATION BY SOURCE CATEGORY .. ' 3-6
3.4.1 General Combustion Processes 3-8
3.4.2 Combustion Engines . 3-10
3.4.2.1 Mobile Combustion Engines . . 3-10
3.4.2.2 Stationary Combustion Sources
(Steam Boilers) 3-13
3.4.3 Other Sources 3-13
REFERENCES 3-15
4. THE GLOBAL CYCLE OF CARBON MONOXIDE:
TRENDS AND MASS BALANCE 4-1
4.1 INTRODUCTION 4-1
VI
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CONTENTS (cont'd)
4.2 GLOBAL SOURCES, SINKS, AND LIFETIME .......... ::;-... 4-1
4.2.1 Sources ;...'.,. ' 4-2
4.2.2 Sinks ../...........I.. ....r. .....=..,;. .' 4-3
4.2.3 Atmospheric Lifetime ..', . ... , '••. .-.,.' 4-5
= : 4.2.4 Latitudinal Distribution of Sources .;. . . 4-5
4.2.5 Uncertainties and Consistencies ........;..'../.. 4-7
4.3 GLOBAL DISTRIBUTIONS ... ........ .... . . . .'-. •-; -. . ' '• 4-9
r 4.3.1 Seasonal Variations . .;. . 4-9
: 4.3.2 Latitudinal Variation ... . 4-10
.'. > ' 4.3.3 Variations with Altitude ........ . :....'...;'.,. 4-10
: • 4.3.4 Other Variations . . . .-... .... . . .....' .'. . 4-12
4.4 GLOBAL TRENDS ...;...:......;....... 4-12
4.5 ; SUMMARY ........;. . J .-. . . . . / 4-15
REFERENCES . . . ... . . .>. ....... . 4-17
5. MEASUREMENT METHODS FOR CARBON MONOXIDE ; .. , :.. . 5-1
5,1 INTRODUCTION ....... 5-1
5.1.1 Overview of Techniques for Measurement of
Ambient Carbon Monoxide . . . ... . . . . , .... . . 5-3
5.1.2 Calibration Requirements .......... ... .-... . . . . 5-5
5.2 PREPARATION OF STANDARD REFERENCE, '
MATERIALS ; ............. . 5-5
"" 5.2.1 Gas Standards 5-5;
5.2.2 Gravimetric Method 5-5
5.2.3 Volumetric Gas Dilution Methods '< . . . . . . . '. . -. . . . - 5-6
5.2.4 Other Methods . .:. * 5-8
5.3 MEASUREMENT IN AMBIENT AIR . .-.:«,:',..• 5-8
5.3.1 Sampling System Components ..... : . ....'....:' 5-8
5.3.2 Quality Assurance Procedures for Sampling:...-..... 5-10
5.3.3 Sampling Schedules ... . . 5-13
r . 5.3.4 .Continuous Analysis . ... . . . ; . ... . . •: . 5-13'
5.3.4.1 Nondispersive Infrared Photometry . . . . . . 5-13
5.3.4.2 Gas Chromatography-Flame lonization . ... • 5-17
5.3.4.3 Other. Analyzers . 5-18
5.3.5 Intermittent Analysis . . .................. 5-22
5.3.5.1 Colorimetric Analysis . . . •. / 5-22
5.4 MEASUREMENT USING PERSONAL MONITORS ....... 5-24
REFERENCES 5-27
6. AMBIENT CARBON MONOXIDE ...... .'/;.. ... . ..... . . . . .. 6-1
6.1 ESTIMATING NATIONAL EMISSION FACTORS. ......... 6-1
6.2 EMISSION SOURCES AND EMISSION FACTORS BY
SOURCE CATEGORY 6-2
vii
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CONTENTS (cont'd)
Page
6.2.1 Transportation Sources 6-2
6.2.1.1 Motor Vehicles 6-2
6.2.1.2 Aircraft 6-5
6.2.1.3 Railroads . 6-6
6.2.1.4 Vessels . ....... /.. 6-6
6.2.1.5 Nonhighway Use of Motor Fuels ....... 6-6
6.2.2 Stationary Source Fuel Combustion 6-6
6.2.3 Industrial Processes , 6-7
6.2.4 Solid Waste Disposal ......... .V- .... 6-7
6.2.5 Miscellaneous Combustion Sources 6-8
6.2.5.1 Forest Fires . . 6-8
6.2.5.2 Agricultural Burning 6-8
6.2.5.3 Coal Refuse Burning 6-8
6.2.5.4 Structural Fires 6-9
6.3 TREND IN ESTIMATED NATIONAL CARBON MONOXIDE :
EMISSIONS, 1970-1990 ... ....... . 6-9
6.4 OUTDOOR AIR CONCENTRATIONS 6-12
6.4.1 Introduction 6-12
6.4.2 Site Selection . ,-•.•......... ... ... 6-12
6.4.3 United States Data Base .:.... 6-15
6.4.4 Techniques of Data Analysis ........ 6-16
6.4.4.1 Frequency Analyses ............... 6-17
6.4.4.2 Trend Analyses 6-18
6.4.4.3 Special Analyses 6-18
6.4.5 Urban Levels of Carbort Monoxide .......... <. . . 6-20
6.4.5.1 Ten-Year National Carbon Monoxide ,
Trends, 1981-1990 6-20
6.4.5.2 Five-Year Regional Carbon Monoxide
Trends, 1986-1990 6-23
6.4.5.3 Air Quality Levels in Metropolitan
Statistical Areas 6-23
6.4.6 Orcadian and Seasonal Patterns .^ ........ 6-25
6.4.6.1 Eight-Hour Averages 6-25
6.4.6.2 One-Hour Values 6-31
6.4.7 Effects of Meteorology and Topography .......... ; 6-31
6.5 DISPERSION MODEL PREDICTIONS OF
CARBON MONOXIDE CONCENTRATIONS ........... 6-37
6.5.1 Line-Source Modeling . . .- 6-38
6.5.1.1 CALINE3 6-38
6.5.1.2 GMLINE 6-39
6.5.1.3 HIWAY-2 6-39
6.5.1.4 PAL 6-39
6.5.1.5 Model Evaluation 6-40
viii
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CONTENTS (cont'd)
6.5.2 Intersection Modeling 6-40
6.5.2.1 Volume 9 ..................... 6-41
6.5.2.2 Intersection Midblock Model 6-41
6.5.2.3 Georgia Intersection Model ........... 6-42
6.5.2.4 TEXIN2 ........ '. .'....,....-.'... 6-43
6.5.2.5 CAL3Q . . 6-44
6.5.2.6 CALINE4 6-44
6.5.2.7 Comparison of Intersection Models ... ... 6-46
6.5.3 Urban Area Modeling 6-48
6.5.3.1 APRAC-3 ..................... 6-48
6.5.3.2 Urban: Airshed Model .............. 6-50
6.5.3.3 RAM ..,.......; 6-51
REFERENCES . ,- ,• = 6-52
7. INDOOR CARBON MONOXIDE ..... 7-1
7.1 INTRODUCTION ...........;...:............ 7-1
7.2 EMISSIONS FROM INDOOR SOURCES ................ 7-4
7.2.1 Emissions from Gas Cooking Ranges, pas Ovens,
and Gas Appliances ......,.,'..... . : ...... 7-5
7.2.2 Emissions from Unvented Space Heaters . . . 7-12
7.2.3 Emissions from Wood Stoves and Tobacco
Combustion 7-15
7.2.4 Summary of Emission Data ......... ', ....... 7-18
7.3 CONCENTRATIONS IN INDOOR ENVIRONMENTS 7-20
7.3.1 Indoor Concentrations Recorded in Personal
Exposure Studies ................ ^ .. 7-21
7.3.2 Targeted Microenvironmental Studies 7-25
7.3.2.1 Indoor Microenvironmental
Concentrations 7-26
7.3.2.2 Concentrations Associated with
Indoor Sources 7-26
. 7.3.3 Spatial Concentration Variations 7-40
7.3.4 Summary of Indoor Concentrations .....;.„ 7-40
REFERENCES 7-43
8. POPULATION EXPOSURE TO CARBON MONOXIDE 8-1
8.1 INTRODUCTION . . .: 8-1
8.2 EXPOSURE MONITORING IN THE POPULATION ....... 8-4
8.2.1 Personal Monitoring ' 8-5
8.2.2 Carbon Monoxide Exposures Indoors 8-11
8.2.3 Carbon Monoxide Exposures Inside Vehicles . 8-13
8.2.4 Carbon Monoxide Exposures Outdoors . . 8-15
IX
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CONTENTS (cont'd)
Page
8.3 ESTIMATING POPULATION EXPOSURE TO CARBON
MONOXIDE . . ,. . 8-17
8.3.1 Components of Exposure . . ................. 8-17
8.3.2 Relationship to Fixed-Site Monitors .... . ....... 8-20
8.3.3 Alternative Approaches to Exposure Estimation ..... 8-21
8.3.4 Statistical Models Based on Personal Monitoring
Data . . . 8-23
8.3.5 Physical and Physical-Stochastic Models .......... 8-30
8.4 OCCUPATIONAL EXPOSURE TO CARBON MONOXIDE .. 8-43
8.4.1 Historical Perspective ... ..... .... . C .8-44
8.4.2 Exposure Monitoring Techniques . 8-46
8.4.3 Occupational Exposures .....:.............. 8-50
8.5 BIOLOGICAL MONITORING : . . . . .>.....: ; . 8-60
8.5.1 Blood Cafboxyhemoglobin Measurement . . . 8-60
8.5.1.1 Measurement Methods .... . 8-60
8.5.1.2 Carboxyhemoglobin Measurements ;
in Populations ......... ... . .'-. .... 8-74
8.5.2 Carbon Monoxide in Expired Breath ............ 8-79
8.5.52.1 Measurement Methods ...*.. : 8-81
8.5.2.2 * Breath Measurements in Populations 8-87
8.5.3 Potential Limitations ......':' ' 8-96
8.5.3.1 Pulmonary Disease 8-96
8.5.3.2 Subject Age •: . 1 .; . . , . -8-97
8.5.3.3 Effects of Smoking .......... ..:;.' '8-97
8.6 SUMMARY AND CONCLUSIONS ....... . . ;.;..: . . 8-98
REFERENCES ........;../ 8-102
9. PHARMACOKINETICS AND MECHANISMS OF ACTION OF :
CARBON MONOXIDE . i 9-1
9.1 ABSORPTION, DISTRIBUTION, AND PULMONARY ;
ELIMINATION . . . 9-1
9.1.1 Introduction . ..;.... . . ; . .... . . ..'.'. 9-1
9.1.2 Pulmonary Uptake :...... 9-1
9.1.2.1 Mass Transfer of Carbon Monoxide ..... 9-1
9.1.2.2 Effects of Dead Space and Uneven "--•••'•
Distribution of Ventilation and '
Perfusion .......'... '.": '.'. . .....; 9-2
9.1.2.3 Alveolo-Capillary Membrane and
Blood-Phase Diffusion 9-3
9.1.3 Tissue Uptake v ...'.......: 9-5
9.1.31-1- TheBlood ....-........,;....... 9-5
9.1.3.2 The Lung ... .;. ... .... . . . 9-8
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CONTENTS (cont'd)
9.1,3.3 Heart and Skeletal Muscles ,..,.. 9-8
9.1.3.4 Brain and Other Tissues 9-9
9.1.4 Pulmonary and Tissue Elimination ............. 9-9
9.2 TISSUE PRODUCTION AND METABOLISM OF CARBON
MONOXIDE . . 9-10
9.3 MODELING CARBOXYHEMOGLOBIN FORMATION ..... 9-12
9.3.1 Introduction . 9-12
9.3.2 Regression Models ; 9-12
9.3.3 The Cpburn-Forster-Kane Differential Equations ..... 9-14
9.3.3.1 Linear and Nonlinear CFK Differential
Equations 9-14
9.3.3.2 Confirmation Studies of the CFK Model . . . 9-16
9.3.3.3 Modified CFK Models 9-18
9.3.3.4 Application of the CFK Model .......... 9-20
9.3.4 Summary 9-21
9.4 INTRACELLULAR EFFECTS OF CARBON MONOXIDE . . . 9-22
9.4.1 Introduction 9-22
9.4.2 Carbon Monoxide Binding to Myoglobin . * 9-26
9.4.3 Carbon Monoxide Uptake by Cytochrome P-450 .... 9-27
9.4.4 Carbon Monoxide and Cytochrome c Oxidase 9-28
REFERENCES . . . , , 9-32
10. HEALTH EFFECTS OF CARBON MONOXIDE 10-1
10.1 INTRODUCTION . . 10-1
10.2 ACUTE PULMONARY EFFECTS OF CARBON
MONOXIDE 10-4
10.2.1 Introduction 10-4
10.2.2 Effects on Lung Morphology ................ - 10-4
10.2.2.1 Studies in Laboratory Animals 10-5
10.2.2.2 Studies in Humans 10-6
10.2.3 Effects on Lung Function 10-7
10.2.3.1 Lung Function in Laboratory Animals .... 10-7
10.2.3.2 Lung Function in Humans 10-9
10.2.4 Summary 10-13
10.3 CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE . . 10-14
10.3.1 Introduction 10-14
10.3.2 Experimental Studies in Humans 10-15
10.3.2.1 Cardiorespiratory Response to Exercise ... 10-15
10.3.2.2 Arrhythmogenic Effects 10-36
10.3.2.3 Effects on Coronary Blood Flow 10-39
10.3.3 Relationship Between Carbon Monoxide Exposure and
Risk of Cardiovascular Disease in Humans 10-40
XI
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CONTENTS (cont'd)
10.3.4 Studies in Laboratory Animals ................ 10-45
10.3.4.1 Introduction '.'..., . '.'., ... 10-45
10.3.4.2 Ventricular Fibrillation Studies ......... 10-45
10.3.4.3 Hemodynamic Studies . . .'. . . .... . ..... 10-51
10.3.4.4 Cardiomegaly . . .... ... ,". ..... . . .... 10-56
10.3.4.5 Hematology Studies ... ... .'.. . ... .... 10-61
10.3.4.6 Atherosclerosis and,Thrombosis 10-64
10.3.5 Summary and Conclusions 10-72
10.4 CEREBROVASCULAR AND BEHAVIORAL EFFECTS
OF CARBON MONOXIDE . ...... ... , 10-74
10.4.1 Control of Cerebral Blood Flow and Tissue Partial
Pressure of Oxygen .with Carbon Monoxide and
Hypoxic Hypoxia 10-74
• 10.4.1.1, Introduction > 10-74
. 10.4.1.2 .Effects on Global Cerebral Blood Flow ... 10-76
iO.4.1.3 Effects on Regional Cerebral Blood Flow . . 10-86
10.4.1.4 Effect of Low Levels of Carbon Monoxide
on Cerebral Blood Flow ....... , . ... ., 10-90
10.4.1.5 Synergistic Effects of.Carbon Monoxide ,-. T -, -10-95
10.4.1,6 Mechanism of Regulation of Cerebral • • ;-
Blood Flow in Hypoxia . . . ...\ ,......'" iO-101
10.4.1.7 Summary" . .''."..'.'•] 10-104
10.4.2 Behavioral Effects of Carbon Monoxide . . . ... . ...';.';.'• 10-104
10.4.2.1 Introduction ........... .".''.'.-' -.". .•'.-." 10-104
10.4.2.2 Sensory Effects .".'. .... ; ...10-106
10.4.2.3 Motor and Sensorimotor Performance .... 10-116
10.4.2.4 Vigilance , .,,.,. 10-121
10.4.2.5 Miscellaneous Measures of Performance . . . -, - =• „ ,10-123
10.4.2.6 Automobile Driving .......... ....: '10-129
10.4.2.7 Brain Electrical Activity ............... , iO-131
10.4.2.8 Schedule-Controlled Behavior .'..,....,. 10-134
10.4.2.9 Summary and Discussion of Behavioral
Literature . . ,, . .'.'.'. , 10-136
10.4.2.10 Hypotheses ....... ,". .... ... ..... 10-142
10.4.2.11 Conclusions 10-143
10.5 DEVELOPMENTAL TOXICITY OF CARBON MONOXIDE .... 10-144
10.5.1 Introduction . . . . . . ....... . %. . ...... 10-144
10.5.2 Theoretical Basis for Fetal Exposure to Excessive
Carbon Monoxide and for Excess Fetal Toxicity 10-147
10.5.2.1 Evidence for Elevated Fetal. :'
Carboxyhemoglobin Relative to Maternal
Hemoglobin ...... . . 10-147
xn
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CONTENTS (cont'd)
Page
10.5.2.2 Effect of Maternal Carboxyhemoglobin on
Placenta! Oxygen Transport .......... 10448
10.5.3 Measurement of Carboxyhemoglobin Content in
FetalBlood 10449
10.5.4 Consequences of Carbon Monoxide in Development . . 10-150
10.5.4.1 Fetotoxic and Teratogemc Consequence
of Prenatal Carbon Monoxide Exposure ... 10-151
10.5.4.2 Carbon Monoxide and Body Weight ....; ; 10455
10.5.4.3 Alteration in Cardiovascular Development '; *
Following Early Carbon Monoxide
Exposure ............... .Vv. J.V' 10-157
10.5.4.4 Neurobehavioral Consequences of Perinatal
Carbon Monoxide Exposure ....:. . . . t . 10-162
10.5.4.5 Neurochemical Consequences of Prenatal
and Perinatal Carbon Monoxide Exposure . . 10469
10.5.4.6 Morphological Consequences of Acute
Prenatal Carbon Monoxide . . . . .... . . . 10-172
10.5.5 Summary . . . 10-173
10.6 OTHER SYSTEMIC EFFECTS OF CARBON MONOXIDE . . . 10473
10.7 ADAPTATION, HABITUATION, AND COMPENSATORY
; RESPONSES TO CARBON MONOXIDE EXPOSURE 10-177
10.7.1 Short-Term Habituation .................... 10-178
10.7.2 Long-Term Adaptation ...... ....:....:. . .-. ' 10-179
10.7.3 Summary v ....;. .-"; .... 10-182
REFERENCES ......;.....!;..... 10484
11, COMBINED EXPOSURE OF CARBON MONOXIDE WITH OTHER
POLLUTANTS, DRUGS, AND ENVIRONMENTAL FACTORS .... 11-1
11.1 HIGH ALTITUDE EFFECTS OF CARBON MONOXIDE .... 11-1
11.1.1 Introduction ...................... ll-l
11.1.2 Carboxyhemoglobin Formation . ... ........... 11-3
11.1.3 Cardiovascular Effects ........... . . ; . . .... li-4
11.1.4 Chronic Studies 11-9
11.1.5 Neurobehavioral Effects 11-15
11.1.6 Compartmental Shifts .............. ; . . .... 11-17
11.1.7 Conclusions .'.'.' . . •"•.'-. .'V'.'1.'•: . '.-."•'•''• ' 11-18
11.2 CARBON MONOXIDE INTERACTIONS WITH DRUGS ...- >f 11-19
11.2.1 Introduction . . . . . . .VV. . ,\ ''.•*''' 1149
11.2.2 Alcohol ..'....;./.... 11-20
11.2.3 Barbiturates . ... . . .... . 11-23
11.2.4 Other Psychoactive Drugs • • • • H-24
Xlll
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CONTENTS (cont'd)
11.3 COMBINED EXPOSURE TO CARBON MONOXIDE AND
OTHER AIR POLLUTANTS AND ENVIRONMENTAL
FACTORS . . . 11-24
11.3.1 Exposure in Ambient Air 11-25
1.1.3.2 Exposure to Combustion Products 11-29
11.3.3 Exposure to Other Environmental Factors 11-35
11.3.3.1 Environmental Heat . 11-35
11.3.3.2 Environmental Noise 11-36
11.3.4 Summary . . ? 11-37
11.4 ENVIRONMENTAL TOBACCO SMOKE 11-38
REFERENCES '. 11-41
12. EVALUATION OF SUBPOPULATIONS POTENTIALLY AT RISK
TO CARBON MONOXIDE EXPOSURE 12-1
12.1 INTRODUCTION 12-1
12.2 AGE AND GENDER AS RISK FACTORS 12-2
12.3 RISK OF CARBON MONOXIDE EXPOSURE IN
INDIVIDUALS WITH PREEXISTING DISEASE , . . . 12-4
12.3.1 Subjects with Coronary Artery Disease .......... 12-4
12.3.2 Subjects with Congestive Heart Failure 12-5
12.3.3 Subjects with Other Vascular Diseases ........... 12-6
12.3.4 Subjects with Anemia and Other Hematologic
Disorders 12-6
12.3.5 Subjects with Obstructive Lung Disease . 12-7
12.4 SUBPOPULATIONS AT RISK FROM COMBINED
EXPOSURE TO CARBON MONOXIDE AND OTHER
CHEMICAL SUBSTANCES 12-8
12.4.1 Interactions with Psychoactive Drugs 12-8
12.4.2 Interactions with Cardiovascular Drugs 12-9 ,
12.4.3 Mechanisms of Carbon Monoxide Interactions ;
with Drugs: Need for Further Research 12-10
12.4.3.1 Metabolic Effects '....'.. 12-11
12.4.3.2 Central Nervous System Depression . . . . . 12-11
12.4.3.3 Alteration in Cerebral Blood Flow ...... 12-12
12.4.4 Interactions with Other Chemical Substances
in the Environment . . 12-14
12.5 SUBPOPULATIONS EXPOSED TO CARBON MONOXIDE
AT HIGH ALTITUDES .". ... .,, . . 12-15
REFERENCES 12-19
APPENDIX: GLOSSARY OF TERMS AND SYMBOLS A-l
xiv
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LIST OF TABLES
Number Page
1-1 National Ambient Air Quality Standards for Carbon Monoxide . . 1-3
1-2 Key Health Effects of Exposure to Carbon Monoxide 1-21
2-1 National Ambient Air Quality Standards for Carbon Monoxide .. 2-5
2-2 Lowest Observed Effect Levels for Human Health Effects
Associated with Low-Level Carbon Monoxide Exposure 2-9
3-1 Physical Properties of Carbon Monoxide . . . . ...... 3-3
3-2 Reported Room Temperature Rate Constants for the Reaction of
Hydroxyl Free Radicals with Carbon Monoxide 3-5
3-3 Summary of Light-Duty Vehicle Emissions Standards ....... . 3-9
4-1 Sources of Carbon Monoxide . . . . . . . ... . . . 4-4
- ' - '."'.' ''•'-- '* . ' ' .•• i
5-1 Performance Specifications for Automated Analytical Methods
for Carbon Monoxide ................ ... . . . . . . . . 5-2
6-1 Carbon Monoxide National Emission Estimates ' 6-3
6-2 Carbon Monoxide National Emissions from Transportation ..... 6-10
6-3 Probe Siting Criteria for Carbon Monoxide Monitors ..;..... 6-14
6-4 Distribution of Population in Metropolitan Statistical Areas ... . 6-24
6-5 Monthly Variation in Orcadian Patterns of Running Eight-Hour
Carbon Monoxide Averages > 9.5 ppm at Six Selected
Stations, 1988 .................,;. .•.'-:'. 6-27
6-6 Eight Intersection Models Compared for Their Ability To Predict
Measured Carbon Monoxide Concentrations .............. 6-46
6-7 Averages and Ratios of the Highest 25 One-Hour Values
Observed, and Predicted by Eight Dispersion Models,
at an Urban Intersection ..........;.. 6-49
7-1 Carbon Monoxide-Emission Rates for 12 Range-Top Burners
Operating with Blue and Yellow-Tipping Flames by the Direct-
Sampling Method . . . 7-7
xv
-------
LIST OF TABLES (cont'd)
Number
7-2 Carbon Monoxide-Emission Rates for Gas Range Ovens,
Gas Range Pilot Lights, and Gas Dryers 7-8
7-3 Carbon Monoxide-Emission Rates from 18 Gas Ranges,
Gas Ovens, and Gas Pilot Lights for Blue Flame and
Yellow-Tipping Flame by the Direct-Sampling Method . 7-9
7-4 Carbon Monoxide Emissions from Gas Ranges for Studies of
Small Sample Size 7-11
7-5 Carbon Monoxide Emissions from Unvented Gas
Space Heaters 7-14
7-6 Carbon Monoxide Emissions from Unvented Kerosene
Space Heaters 7-16
7-7 Summary of Carbon Monoxide Exposure Levels and Time
Spent per Day in Selected Microenvironments 7-22
7-8 Indoor Microenvironments Listed in Descending Order of
Weighted Mean Carbon Monoxide Concentration 7-23
7-9 Weighted Means of Residential Exposure Grouped According to
the Presence or Absence of Selected Indoor Carbon
Monoxide Sources 7-24
7-10 Average Residential Carbon Monoxide Exposures: Impact
of Combustion Appliance Use and Tobacco Smoking 7-25
7-11 Carbon Monoxide Concentrations Measured in Various Indoor
Environments as a Function of Microenvironments 7-27
7-12 Weighted Summary Statistics for Carbon Monoxide
Concentrations in the Main Living Area by Use for
Selected Sources by County . . . 7-32
7-13 Summary of Continuous Carbon Monoxide Monitoring
Results by Heating Equipment 7-33
7-14 Peak Carbon Monoxide Concentrations by Indoor
Source Measured in Field Studies 7-35
7-15 Measured Concentrations of Carbon Monoxide in Environmental
Tobacco Smoke 7-38
xvi
-------
LIST OF TABLES (cont'd)
Number
8-1 Carbon Monoxide Concentrations in In-Transit
Microenvironments—Denver, Colorado 8-9
8-2 Carbon Monoxide Concentrations in Outdoor
; Microenvironments—Denver, Colorado 8-9
8-3 Carbon Monoxide Concentrations in Indoor
Microenvironments—Denver, Colorado .'.'.- 8-10
8-4 Comparison of Different Approaches to Air Pollution Exposure
Modeling . 8-24
8-5 Models That Have Been Used To Estimate Carbon Monoxide
;;,- Exposure by Model Type 8-25
8-6 Results of Weighted Linear Regression Analyses with Nontransit
'.. Personal Exposure Monitor Value as Dependent Variable and
Simultaneous Value at Nearest Denver Fixed-Site as Independent
Variable 8-27
8-7 Results of Weighted Linear Regression Analyses with In-Transit
Personal Exposure Monitor Value as Dependent Variable and
Simultaneous Value from Denver Composite Data Set as
Independent Variable . 8-28
8-8 Results of Weighted Linear Regression Analyses with Nontransit
Personal Exposure Monitor Value as Dependent Variable and
Simultaneous Value at Nearest Fixed-Site in Washington, DC,
as Independent Variable 8-29
8-9 Results of Weighted Linear Regression Analyses with In-Transit
Personal Exposure Monitor Value as Dependent Variable and
Simultaneous Value from Composite Washington, DC, Data Set
. • " as Independent Variable . 8-30
8-10 Diagnostic Criteria for Carbon Monoxide Intoxication . 8-49
8-11 Comparison of Representative Methods for Analysis of Carbon
Monoxide in Blood . '.• . . .' 8-62
8-12 Evaluation of the Ability of CO-Oximeters to Measure
Low Levels of Carboxyhemoglobin as Compared to Proposed
Reference Methods . 8-72
xvii
-------
LIST OF TABLES (cont'd)
Number
8-13 Regression Parameters for the Relationship Between
Carboxyhemoglobin and Eight-Hour Carbon Monoxide Averages
for 20 Cities 8-78
8-14 Summary of Studies Comparing End-Expired Breath Carbon
Monoxide with Carboxyhemoglobin Levels .............. 8-82
9-1 In Vitro Inhibition Ratios for Henioproteins That Bind
Carbon Monoxide 9-24
10-1 Summary of Effects of Carbon Monoxide on Maximal and
Submaximal Exercise Performance 10-16
10-2 Summary of Effects of Carbon Monoxide Exposure in Patients
with Angina 10-22
10-3 Comparison of Subjects in Studies of the Effect of Carbon
Monoxide Exposure on Occurrence of Angina During
Exercise 10-31
10-4 Ventricular Fibrillation and Hemodynamic Studies in
Laboratory Animals 10-46
10-5 Cardiac Hypertrophy Studies in Laboratory Animals . 10-57
10-6 Hematology Studies in Laboratory Animals .............. 10-62
10-7 Atherosclerotic Studies in Laboratory Animals 10-65
10-8 Brain Regions Ranked from Greatest to Least in Response
to Hypoxia 10-87
10-9 Effects of Carboxyhemoglobin on Absolute Visual Threshold ... 10-107
10-10 Effects of Carboxyhemoglobin on Critical Flicker Fusion 10-109
10-11 Effects of Carboxyhemoglobin on Miscellaneous Visual
Functions 1Q-112
10-12 Effects of Carboxyhemoglobin on Miscellaneous Auditory
Functions 1.0-115
10-13 Effects of Carboxyhemoglobin on Fine Motor Skills . . 10-117
xviii
-------
LIST OF TABLES (cont'd)
Number Page
10-14 Effects of Carboxyhemoglobin on Reaction Time 10-119
10-15 Effects of Carboxyhemoglobin on Tracking .............. 10-120
10-16 Effects of Carboxyhemoglobin on Vigilance 10-122
10-17 Effects of Carboxyhemoglobin on Continuous Performance .... 10-125
10-18 Effects of Carboxyhemoglobin on Time Estimation 10-126
10-19 Effects of Carboxyhemoglobin on Miscellaneous Cognitive
Tasks 10-128
10-20 Effects of Carboxyhemoglobin on Automobile Driving Tasks ... 10-130
10-21 Effects of Carboxyhemoglobin on Brain Electrical Activity ..... 10-132
10-22 Effects of Carboxyhemoglobin on Schedule-Controlled
Behavior 10-135
10-23 Effect of Blind Conditions 10-137
10-24 Effect of Statistical Methodology . 10-137
10-25 Probability of Effects of Carboxyhemoglobin . 10-138
10-26 Effect of Single vs. Multiple Task Performance 10-141
10-27 Effect of Rate of Carboxyhemoglobin Formation 10-141
10-28 Teratogenic Consequences of Prenatal Carbon Monoxide
Exposure in Laboratory Animals 10-152
10-29 Consequences of Prenatal Carbon Monoxide Exposure
on Cardiovascular Development in Laboratory Rats . 10-159
10-30 Neurobehavioral Consequences of Prenatal Carbon Monoxide
Exposure in Laboratory Animals 10-1.64
10-31 Consequences of Human Carbon Monoxide Intoxication During
Early Development 10-166
10-32 Other Systemic Effects of Carbon Monoxide . 10-174
xix
-------
LIST OF TABLES (cont'd) ,
Number Page
11-1 Calculated Equilibrium Values of Percent Carboxyhemoglobin ;
and Percent Oxyhemoglobin in Humans Exposed to Ambient
Carbon Monoxide at Various Altitudes . . , ....... >-.-.••.... . ...•• 11-4
11-2 Summary of Effects of Carbon Monoxide at Altitude ........ 11-5
11-3 Chronic Effects of Altitude and Carbon Monoxide Exposure >... .^ 11-15
11-4 Combined Exposure to Carbon Monoxide and Other
Pollutants -... >.rj. -,.,'. •>... .,.'.-•• Ilr26
11-5 Combined Exposure to Carbon Monoxide and Combustion
Products . . . . ....... .... . :-.>...... 11-31
XX
-------
LIST OF FIGURES
Number '-'•- '--"•• •'• ''•'•''•
1-1 Relationship between carbon monoxide exposure and
carboxyhemoglobin levels in the blbod ..:.,.,: .; I ...:-... 1-9
2*1 Relationship between carbon monoxide exposure and;;'-
carboxyhemoglobin levels in the blood 2-7
2-2 Currently accepted or proposed mechanisms of action of
carbon monoxide resulting from external exposure-sources'can >"
interfere with cellular respiration and cause tissue hypoxia 2-15
3-1 . Effect of air-fuel ratio on exhaust gas carbon monoxide --•••> ; ~
concentrations from three gasoline-fueled test engines 3-11
4-1 r The estimated sources of carbon monoxide as a function
of latitude 4-7
4-2 The global seasonal variations of carbon monoxide . 4-11
4-3 The global concentrations and trends of carbon monoxide 4-13
5-1 Loss of carbon monoxide with time in mild steel cylinders .... 5-7
5-2 Carbon monoxide monitoring system 5-9
5-3 Schematic diagram of gas filter correlation monitor
for carbon monoxide .;.... 5-16
6-1 Estimated emissions of carbon monoxide from gasoline-fueled
highway vehicles, 1970-1990 6-11
6-2 Example of a pollution rose for carbon monoxide . 6-19
6-3 National trend in the composite average of the second
highest nonoverlapping eight-hour average carbon monoxide
concentration, 1981-1990 . . . . . . 6-21
6-4 Box plot comparisons of trends in second highest nonoverlapping
eight-hour average carbon monoxide concentrations at 301 sites,
1981-1990 . . 6-21
6-5 National trend in the composite average of the estimated
number of exceedances of the eight-hour carbon monoxide
NAAQS, 1981-1990 6-22
xxi
-------
LIST OF FIGURES (eont'd)
Number /Page
6-6 Regional comparisons of the 1986 through 1990 composite . ' '
averages of the second highest nonoverlapping eight-hour
average carbon monoxide concentration ...........;. ^ ;• . '•'' 6-23
6-7 United States map of the highest second maximum •
nonoverlapping eight-hour average carbon monoxide concentration v
by Metropolitan Statistical Area for 1990 6-24
6-8 Yearly cumulative circadian patterns of eight-hour average
carbon monoxide concentrations > 9.5 ppm at six
selected stations, 1988 . .'...... 6-26
6-9 Hawthorne, CA, Station 5001, 1988: individual events with
running eight-hour carbon monoxide averages > 9.5 ppm
and precursor one-hour values > 9.5 ppm . . • 6-29
6-10 New York City, NY, Station 0082, 1988: individual events
with running eight-hour carbon monoxide averages > 9.5 ppm
and precursor one-hour values > 9.5 ppm . :....... 6-30
6-11 Monthly and yearly circadian patterns of one-hour carbon
monoxide values > 9.5 ppm at six selected stations, 1988 . ..... 6-32
6-12 Attenuating effect of terrain roughness on a 10 m/s gradient
wind : . 6-34
6-13 Schematic representation of an elevated subsidence inversion .... 6-36
: , , i • • ',.-"-' f
6-14 Hourly variations in inversion height and wind speed for
Los Angeles in summer 6-37
6-15 Schematic of intersecting six-lane streets in Melrose Park, BL,
showing location of nine monitoring sites 6-47
7-1 Cumulative frequency distributions and summary statistics
for indoor carbon monoxide concentrations in three groups
of monitored homes 7-33
7-2 A time history of, carbon monoxide concentrations, two-hotir
averages, winter of 1974 7-37
xxii
-------
LIST OF FIGURES (cont'd)
Number
8-1 Frequency distributions of maximum eight-hour carbon monoxide
population exposures and fixed-site monitor values in Denver,;
CO, and Washington, DC; November 1982 - February 1983 ........ ; 8-7
8-2 Typical individual exposure as a function of time showing.
the instantaneous exposure and the integrated exposure \. .-........ . . 8-18
8-3 Logarithmic-probability plot of cumulative frequency distribution
of maximum one-hour average exposure of carbon monoxide ;
predicted by SHAPE, plus an observed frequency distribution
for Day 2 in Denver ... ,.-, ... 8-37
8-4 Logarithmic-probability plot of cumulative frequency distribution*
of maximum moving average eight-hour exposure ,of carbon
monoxide predicted by SHAPE, plus an observed frequency . ;
distribution for Day 2 in Denver 8-38
8-5 Frequency distributions of carboxyhemoglobin levels in the U.S.
population, by smoking habits .............. . .... .,. . 8-77
8-6 Alveolar carbon monoxide of nonsmoking basement office • , : ;
workers compared to nonsmoking workers in other offices on
Friday afternoon, Monday morning, and Monday afternoon .... 8-88
8-7 Eight-hour average carbon monoxide concentrations in basement
office before and after corrective action ................ 8-89
8-8 Distributions of carbon monoxide in breath of adult nonsmokers
in Denver and Washington . . ...... ... . . . ... . . . * . . . . 8-92
8-9 Percent of Washington sample population with eight-hour
average carbon monoxide exposures exceeding the - •
concentrations shown ....... .•-,.-. . . . ..... , . . . ... . . . 8-93
9-1 Oxyhemoglobin dissociation curves of normal human blood, of
blood containing 50% carboxyhemoglobin, and of blood with a ,.i
50% normal hemoglobin concentration due to anemia ......... 9-7
9-2 Measured and predicted carboxyhemoglobin concentrations from ,
six intermittently exercising subjects ................... 9-19
10-1 Relationship between carboxyhemoglobin level and decrement in
maximal oxygen uptake for healthy nonsmokers 10-19
xxm
-------
LIST OF FIGURES (cont'd)
Number Page
10-2 Regression of the percent change in time to threshold ischemic
ST segment change (ST End Point) between the pre-and
postexposure exercise tests and the carboxyhemoglobin levels
measured after exercise 10-29
10-3 The effect of carbon monoxide exposure on time to onset
of angina . . , 10-33
10-4 Effect of hypoxic hypoxia and carbon monoxide hypoxia
on cerebral blood flow in 13 control and 9 chemodenervated
dogs ..." . .... .. 10-78
10-5 Effects of hypoxic and carbon monoxide hypoxia on cerebral
blood flow, mean arterial blood pressure, and cerebral
vascular resistance in control, carotid baroreceptor-, and
chemoreceptor-denervated animals 10-79
10-6 Effects of hypoxic and carbon monoxide hypoxia on cerebral
blood flow, mean arterial blood pressure, and cerebral vascular
resistance in control and vagotomized animals ............ 10-80
10-7 Cerebral blood flow as a function of fractional arterial
oxygen saturation ............. 10-83
10-8 Comparison of newborn and adult responses of the reciprocal
of the cerebral arteriovenous oxygen-content difference to a
reduction in arterial oxygen content during hypoxic hypoxia .... 10-84
10-9 Profiles of slopes of regional blood flow responses to hypoxic
hypoxia and carbon monoxide hypoxia in adults and newborns . . 10-88
10-10 Effect of hypoxic hypoxia and carbon monoxide hypoxia on
neurohypophyseal and regional cerebral blood flow 10-91
10-11 Effect of complete chemoreceptor denervation on regional
cerebral blood flow in the cerebral hemispheres and
neurohypophysis 10-92
10-12 Effect of increasing carboxyhemoglobin levels on cerebral
blood flow, with special reference to low-level administration
(below 20% carboxyhemoglobin) . , 10-93
10-13 Effect of cyanide and carbon monoxide hypoxia, alone and in ,
combination, on cerebral blood flow 10-98
xxiv
-------
LIST OF FIGURES (cont'd)
Number
10-14 Effect of cyanide and carbon monoxide hypoxia, alone and in
combination, on cerebral oxygen consumption .........
10-15 Relationship of cerebral blood flow to cerebral oxygen
consumption during cyanide and carbon monoxide hypoxia . .
11-1 Increment in percent carboxyhemoglobin over basal (control)
levels at the end of a maximum aerobic capacity test and at
the fifth minute of recovery from the test in a typical male
subject and a typical female subject
11-2 Change in carboxyhemoglobin concentration during eight-hour
exposures to 0 to 9 ppm carbon monoxide for resting and
exercising subjects ...'.' ,
11-3 The effects of altitude and ambient carbon monoxide exposure
on carboxyhemoglobin in Fischer 344 rats
11-4 Relationship between increase in percent carboxyhemoglobin
observed at the end of a five-minute recovery period and
carboxyhemoglobin concentration present at exhaustion after
attainment of maximum aerobic capacity
10-99
10-100
11-10
11-11
11-13
11-18
XXV
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-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHAPTER 1. SUMMARY AND CONCLUSIONS
Principal Authors
Mr. Thomas B. McMullen
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James A. Raub
Environmental Criteria and Assessment
Office (MD-52).
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Reviewer
Mr. William J. Neuffer
Office of Air Quality Planning and
Standards (MD-13)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
CHAPTER 2. INTRODUCTION
Principal Author
Mr. James A. Raub
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Reviewers
Dr. Lester D. Grant
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. William J. Neuffer
Office of Air Quality Planning and
Standards (MD-13)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xxvn
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. Jerzy A. Sokal
Department of Toxicity Evaluation
Institute of Occupational Medicine
8 Teresy Str., P.O. Box 199
90-950 Lodz, Poland
CHAPTER 3. PROPERTIES AND PRINCIPLES OF FORMATION
OF CARBON MONOXIDE ., ;
Principal Authors
Dr. Marcia C. Dodge
Atmospheric Research and Exposure
Assessment Laboratory (MD-84)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711 ,
Dr. Harold G. Richter
Office of Air Quality Planning and =
Standards (MD-14)-, • Ky :,.-: ;-•
U.S. Environmental Protection Agency
Research Triangkpark^NC 2771 L.v^
Contributors and Reviewers
Dr. Aubrey P. Altshuller -.'...-. -,.
Atmospheric Research and Exposure t
Assessment Laboratory (MD-59)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Joseph J. Bufalini
Atmospheric Research and Exposure
Assessment Laboratory (MD-84)
U.S Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. William J. Neuffer ,•:..-.,.;.......< • .,;,
Office of Air Quality Planning .and ,
Standards (MD-13)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
XXVlll
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
CHAPTER 4. THE GLOBAL CYCLE OF CARBON MONOXIDE:
TRENDS AND MASS BALANCE
Principal Author
Dr. Aslam K. Khalil
Institute of Atmospheric Sciences
Oregon Graduate Center
19600 N.W. Von Neumann Drive
Beaverton, OR 97006
Contributors and Reviewers
Dr. Aubrey P. Altshuller
Atmospheric Research and Exposure
Assessment Laboratory (MD-59)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Joseph J. Bufalini
Atmospheric Research and Exposure
Assessment Laboratory (MD-84)
U.S Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Jack Fishnian
Atmospheric Sciences Division
NASA - Langley Research Center
Mail Stop 401A
Hampton, VA 23665
Mr. Samuel A. Leonard
Environmental Activities Staff
General Motors Corporation
General Motors Technical Center
30400 Mound Road
Warren, MI 48090
CHAPTER 5. MEASUREMENT METHODS FOR CARBON MONOXIDE
Principal Author
Mr. Gerald G. Akland
Atmospheric Research and Exposure
Assessment Laboratory (MD-75)
U-S. Environmental Protection Agency
Research Triangle Park, NC 27711
XXIX
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Contributors and Reviewers
Dr. William A. McClenny
Atmospheric Research and Exposure
Assessment Laboratory (MD-44)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Joseph R. Stetter
Transducer Research, Inc.
1228 Olympus Drive
Naperville, IL 60540
CHAPTER 6. AMBIENT CARBON MONOXIDE
Principal Authors
Dr. James N. Braddock
Atmospheric Research and Exposure
Assessment laboratory (MD-46)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Thomas N. Braverman
Office of Air Quality Planning and
Standards (MD-14)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. William B. Petersen
Atmospheric Research and Exposure
Assessment Laboratory (MD-80)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Thomas B. McMullen
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Contributors and Reviewers
Mr. Paul E. Benson
Transportation Laboratory
5900 Folsom Boulevard
Sacramento, CA 95819
Dr. Fred W. Bowditch
Motor Vehicle Manufacturers Association
7430 Second Avenue, Suite 300
Detroit, MI 48202
Dr. Thomas C. Curran
Office of Air Quality Planning and
Standards (MD-14)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Tom Hansen
U.S. Environmental Protection Agency
(4AT Air Program Branch)
345 Courtland Street, NE
Atlanta, GA 30365
Mr. Samuel A. Leonard
Environmental Activities Staff
General Motors Corporation
General Motors Technical Center
30400 Mound Road
Warren, MI 48090
XXX
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Mr. George J. Schewe
PEI Associates, Inc.
11499 Chester Road
Cincinnati, OH 45246
CHAPTER 7. INDOOR CARBON MONOXIDE
Principal Author
Dr. Brian P. Leaderer
John B. Pierce Foundation Laboratory
290 Congress Avenue
New Haven, CT 06519
Contributors and Reviewers
Dr. Irwin H. Billick
Gas Research Institute
8600 West Bryn Mawr Avenue
Chicago, IL 60631
Mr. Tom Hansen
U.S. Environmental Protection Agency
(4AT Air Program Branch)
345 Courfland Street, NE
Atlanta, GA 30365
Mr. Ted Johnson
PEI Associates, Inc.
505 S. Duke Street.
Durham, NC 27701
Dr. P. Barry Ryan
Department of Environmental Sciences and
Physics
Harvard University School of Public
Health
665 Huntington Avenue
Boston, MA 02115
CHAPTER 8. POPULATION EXPOSURE TO CARBON MONOXIDE
Principal Authors
Mr. Gerald G, Akland
Atmospheric Research and Exposure
Assessment Laboratory (MD-75)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Steven D. Colome
Integrated Environmental Services
University Tower, .Suite 1090
4199 Campus Drive
Irvine, CA 92715
XXXI
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. Thomas E. Dahms
Department of Anesthesiology
St. Louis University School of Medicine
3635 Vista Avenue
St. Louis, MO 63110
Mr. Ted Johnson
PEI Associates, Inc.
505 S. Duke Street
Durham, NC 27701
Dr. Brian P. Leaderer
John B. Pierce Foundation Laboratory
290 Congress Avenue
New Haven, CT 06519
Dr. Wayne R. Ott
Office of Research and Development
(RD-680)
U.S. Environmental Protection Agency
Washington, DC 20460
Dr. Lance A. Wallace
U.S. Environmental Protection Agency
Building 166
Vint Hill Farms Station
Bicher Road
Warrenton, VA 22186
Contributors and Reviewers
Dr. William F. BUler
68 Yorktown Road
East Brunswick, NJ 08816
Mr. N. Ogden Gerald
Office of Air Quality Planning and
Standards (MD-14)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Mr. Samuel A. Leonard
Environmental Activities Staff
General Motors Corporation
General Motors Technical Center
30400 Mound Road
Warren, MI 48090
Mr. Thomas R. McCurdy
Office of Air Quality Planning and
Standards (MD-12)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Harvey M. Richmond
Office of Air Quality Planning and
Standards (MD-12)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. P. Barry Ryan
Department of Environmental Sciences and
Physics
Harvard University School of
Public Health
665 Huntington Avenue
Boston, MA 02115
Dr. Carr J. Smith
Bowman Gray Technical Center
RJ. Reynolds Tobacco Company
Winston-Salem, NC 27102
XXXll
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. John Spengler
Harvard School of Public Health
665 Huntington Avenue
Boston, MA 02115
Dr. David K. Stevenson
Department of Pediatrics
Laboratory for Neonatal Metabolism
Stanford University School of Medicine
Stanford, CA 94305
Dr. Henk J. Vreman
Laboratory for Neonatal Metabolism
Department of Pediatrics (S214)
Stanford University School of Medicine
Stanford, CA 94305
CHAPTER 9. PHARMACOKINETICS AND MECHANISMS OF
ACTION OF CARBON MONOXIDE
Principal Authors
Dr. Milan J. Hazucha
Pulmonary Division
Department of Medicine
Center for Environmental Medicine and
Lung Biology
The University of North Carolina
Trailer #4, Medical Building C 224H
Chapel Hill, NC 27599
Dr. Claude A. Piantadosi
Division of Allergy, Critical Care and
.Respiratory Medicine
Department of Medicine, Box 3315
Duke University Medical Center
Durham, NC 27710
Dr. Marjolein V. Smith
2501 Anne Carol Court
Raleigh, NC 27603
Contributors and Reviewers
Dr. Clyde H. Barlow
Laboratory I
Evergreen State College
Olympia, WA 98505
Dr. William F. Biller
68 Yorktown Road
East Brunswick, NJ 08816
Dr. Henry J. Forman
Department of Pediatrics
Cell Biology Group (Box 83)
University of Southern California
Childrens Hospital of Los Angeles
4650 Sunset Boulevard
Los Angeles, CA 90054
XXXlll
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Dr. Robert L. Jensen
LDS Hospital
University of Utah
Salt Lake City, UT 84143
Maj. David Farmer
U.S. Army
Biomedical Research and Development Lab
Fort Detrick, Building 568
Frederick, MD 21701
Dr. Jerzy A. Sokal
Department of Toxicity Evaluation
Institute of Occupational Medicine
8 Teresy Str., P.O. Box 199
90-950 Lodz, Poland
Dr. Peter Tikuisis
Defence and Civil Institute of
Environmental Medicine
1133 Sheppard Avenue, West
North York, Ontario CANADA
M3M3B9
CHAPTER 10. HEALTH EFFECTS OF CARBON MONOXIDE
PrincipalAuthors
Dr. Vernon A. Benignus
Health Effects Research Laboratory
(MD-58)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Lars-Goran Ekelund
Department of Biostatistics
School of Public Health
The University of North Carolina
Suite 203, NCNB Plaza 322A
Chapel Hill, NC 27514
Dr. Laurence D. Fechter
Department of Environmental
Health Sciences
The Johns Hopkins University
School of Hygiene and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Thomas R. Griggs
Division of Cardiology
School of Medicine
The University of North Carolina
349 Clinical Sciences Building 229H
Chapel Hill, NC 27599
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Dr. James J. McGrath
Department of Physiology
School of Medicine
Texas Tech University Health
Sciences Center
Lubbock, TX 79430
XXXIV
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Mr. James A. Raub
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. David S. Sheps
Division of Cardiology
School of Medicine
The University of North Carolina
338 Clinical Sciences Building 229H
Chapel Hill, NC 27599
Dr. Richard J. Traystman
Department of Anesthesiology and
Critical Care Medicine
The Johns Hopkins Medical Institutions
600 N. Wolfe Street
Baltimore, MD 21205
Contributors and Reviewers
Dr. Zoltan Annau
Department of Environmental
Health Sciences
School of Hygiene and Public Health
The Johns Hopkins University
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Steven M. Ayres
Medical College of Virginia, Box 565
Virginia Commonwealth University
Richmond, VA 23298
Dr. Robert L. Balster
Department of Pharmacology and
Toxicology
Medical College of Virginia
Virginia Commonwealth University
Richmond, VA 23298
Dr. Thomas B. Clarkson
Department of Comparative Medicine
Bowman Gray School of Medicine
300 South Hawthorne Road
Winston-Salem, NC 27103
Dr. Steven D. Colome
Integrated Environmental Services
University Tower, Suite 1090
4199 Campus Drive
Irvine, CA 92715
Dr. Thomas E. Dahms
Department of Anesthesiology
St. Louis University School of Medicine
3635 Vista Avenue
St. Louis, MO 63110
Dr. Samuel M. Fox
Georgetown University
3800 Reservoir Road, NW
Washington, DC 20007
Dr. Donald Heistad
Cardiology Division
Department of Internal Medicine
College of Medicine
University of Iowa
Iowa City, IA 52242
Dr. Gregory L. Hirsch
Escondido Pulmonary Medical Group
215 South Hickory St., Suite 112
Escondido, CA 92025
XXXV
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. John R. Holmes
State of California
Air Resources Board
1102 Q Street
P.O. Box 2815
Sacramento, CA 95812
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Dr. Michael T. Kleinman
Department of Community and
Environmental Medicine
California College of Medicine
University of California
Irvine, CA 92717
Dr. Victor G. Laties
Environmental Health Sciences Center
University of Rochester
School of Medicine
Rochester, NY 14642
Mr. Samuel A. Leonard
Environmental Activities Staff
General Motors Corporation
General Motors Technical Center
30400 Mound Road
Warren, MI 48090
Dr. Lawrence D. Longo
School of Medicine
Department of Physiology
Division of Perinatal Biology
Loma Linda University
Loma Linda, CA 92350
Dr. George Malindzak
NIEHS North Campus (MD-3-03)
104 Alexander Drive
Research Triangle Park, NC 27709
Dr. Steve J. McFaul
Letterman Army Institute of Research
Presidio of San Francisco
Blood Research Division
San Francisco, CA 94129
Dr. James J. McGrath
Department of Physiology
School of Medicine
Texas Tech University Health
Sciences Center
Lubbock, TX 79430
Dr. Fathy S. Messiha
Department of Pharmacology
School of Medicine
University of North Dakota
501 North Columbia Road
Grand Forks, ND 58201
Maj. David Partner
U.S. Army
Biomedical Research and Development Lab
Fort Detrick, Building 568
Frederick, MD 21701
Dr. David G. Penney
Department of Physiology
Wayne State University
School of Medicine
Scott Hall, Room 5374
540 East Canfield
Detroit, MI 48201
Mr. Harvey M. Richmond
Office of Air Quality Planning and
Standards (MD-12)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Carr J. Smith
Bowman Gray Technical Center
R.J. Reynolds Tobacco Company
Winston-Salem, NC 27102
XXXVI
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. David K. Stevenson
Department of Pediatrics
Laboratory for Neonatal Metabolism
Stanford University School of Medicine
Stanford, CA 94305
Dr. Jane Warren
Health Effects Institute
141 Portland St., Suite 7300
Cambridge, MA 02139
Dr. Robert Winslow
Combat Trauma Management Directorate
Blood Research Division
Letterman Army Institute of Research
Presidio of San Francisco
San Francisco, CA 94129-6800
Dr. Ronald W. Wood
Department of Environmental Medicine
New York University Medical Center
Lanza Laboratory
Long Meadow Road
Tuxedo, NY 10987
Dr. Henk J. Vreman
Laboratory for Neonatal Metabolism
Department of Pediatrics (S214)
Stanford University School of Medicine
Stanford, CA 94305
CHAPTER 11. COMBINED EXPOSURE OF CARBON MONOXIDE WITH
OTHER POLLUTANTS, DRUGS, AND ENVIRONMENTAL FACTORS
Principal Authors
Dr. Robert L. Balster
Department of Pharmacology and
Toxicology
Medical College of Virginia
Virginia Commonwealth University
Richmond, VA 23298
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Dr. James J. McGrath
Department of Physiology
School of Medicine
Texas Tech University Health Sciences
Center
Lubbock, TX 79430
Mr. James A. Raub
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xxxvii
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Contributors and Reviewers
Dr. Zoltan Annau
Department of Environmental
Health Sciences
School of Hygiene and Public Health
The Johns Hopkins University
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Thomas E. Dahms
Department of Anesthesiology
St. Louis University School of Medicine
3635 Vista Avenue
St. Louis, MO 63110
Dr. Robert F. Grover
216 Mariposa Circle
Arroyo Grande, CA 93420
Dr. Donald H. Horstman
Health Effects Research Laboratory
(MD-58)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Victor G. Laties
Environmental Health Sciences Center
University of Rochester
School of Medicine
Rochester, NY 14642
Mr. Samuel A. Leonard
Environmental Activities Staff
General Motors Corporation
General Motors Technical Center
30400 Mound Road
Warren, MI 48090
Dr. Barbara C. Levin
Center for Fire Research
National Institute for Standards and
Technology
Building 224, Room A363
Gaithersburg, MD 20899
Dr. Lawrence D. Longo
School of Medicine
Department of Physiology '
Division of Perinatal Biology
Loma Linda University
Loma Linda, CA 92350
Dr. Robert Winslow
Combat Trauma Management Directorate
Blood Research Division
Letterman Army Institute of Research
Presidio of San Francisco
San Francisco, CA 94129-6800
Dr. Ronald W. Wood
Department of Environmental Medicine
New York University Medical Center
Lanza. Laboratory '
Long Meadow Road
Tuxedo, NY 10987
xxx vm
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
CHAPTER 12. EVALUATION OF SUBPOPULATIONS POTENTIALLY AT RISK
TO CARBON MONOXIDE EXPOSURE
Principal Authors
Dr. Robert L. Balster
Department of Pharmacology and
Toxicology
Medical College of Virginia
Virginia Commonwealth University
Richmond, VA 23298
Dr. Lars-Goran Ekelund
Department of Biostatistics
School of Public Health
The University of North Carolina
Suite 203, NCNB Plaza 322A
Chapel Hill, NC 27514
Dr. Robert F. Grover
216 Mariposa Circle
Arroyo Grande, CA 93420
Dr. Steven M. Horvath
Environmental Stress Laboratory
Neuroscience Research Institute
University of California
Santa Barbara, CA 93106
Mr. James A. Raub ,
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. DavidS. Sheps
Division of Cardiology
School of Medicine
The University of North Carolina
338 Clinical Sciences Building 229H
Chapel Hill, NC 27599
Contributors and Reviewers
Dr. Zoltan Annau
Department of Environmental
Health Sciences
School of Hygiene and Public Health.
The Johns Hopkins University
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Thomas B. Clarkson
Department of Comparative Medicine
Bowman Gray School of Medicine
300 South Hawthorne Road
Winston-Salem, NC 27103
Dr. Thomas E. Dahms
Department of Anesthesiology
St. Louis University School of Medicine
3635 Vista Avenue
St. Louis, MO 63110
Dr. Samuel M. Fox
Georgetown University
3800 Reservoir Road, NW
Washington, DC 20007
XXXIX
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Dr. John R. Holmes
State of California
Air Resources Board
1101 Q Street
P.O. Box 2815
Sacramento, CA 95812
Dr. Carr J. Smith
Bowman Gray Technical Center
RJ. Reynolds Tobacco Company
Winston-Salem, NC 27102
Dr. Ronald W. Wood
Department of Environmental Medicine
New York University Medical Center
Lanza Laboratory
Long Meadow Road
Tuxedo, NY 10987
xl
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U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
Carbon Monoxide Review
Chairman
Dr. Roger O. McClellan
Chemical Industry Institute of Toxicology
P.O. Box 12137
Research Triangle Park, NC 27709
Members
Dr. Glen R. Cass
Environmental Engineering Science
Department
Mail Code 138-78
California Institute of Technology
Pasadena, CA 91125
Dr. James K. Hambright
Commonwealth of Pennsylvania
Department of Environmental Resources
Bureau of Air Quality Control
P.O. Box 2357
Harrisburg, PA 17105
Dr. Gilbert S. Omenn
School of Public Health and
Community Medicine
University of Washington SC-30
Seattle, WA 98195
Dr. Marc B. Schenker
Division of Occupational and
Environmental Medicine
I.E.H.R. Building
University of California
Davis, CA 95616
Dr. Mark J. Utell
Pulmonary Disease Unit
Box 692
University of Rochester Medical Center
601 Elmwood Avenue
Rochester, NY 14642
Dr. George T. Wolff
General Motors Research Laboratories
Environmental Science Department
Warren, MI 48090
Consultants
Dr. E. Marshall Johnson
Department of Anatomy
Jefferson Medical College
1020 Locust Street
Philadelphia, PA 19107
Dr. David Kane
Health and Welfare Canada
Environmental Substance Division
Environmental Health Center
Room 209
Tunney's Pasture
Ottawa, Ontario CANADA K1AOL2
xli
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CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE (cont'd)
Dr. Victor G. Laties
Environmental Health Sciences Center
University of Rochester
School of Medicine
Rochester, NY 14642
Dr. P. Barry Ryan
Department of Environmental Health
Harvard School of Public Health
677 Huntington Avenue
Boston, MA 02115
Dr. Michael J. Symons
School of Public Health
Room 3104D
McGavran Greenberg Hall
University of North Carolina at
Chapel Hill
Chapel Hill, NC 27599
Dr. Peter Tikuisis
Defence and Civil Institute
of Environmental Medicine
1133 Shepherd Avenue West
North York, Ontario CANADA M3M3B9
Dr. Jerome J. Wesolowski
Air and Industrial Hygiene Laboratory
California Department of Health
Berkeley, CA 94704
Designated Federal Official
Mr. Randall C. Bond
U.S. Environmental Protection Agency
Science Advisory Board (A-101F)
401 M Street, S.W.
Washington, DC 20460
StafiLSecretary
Ms. Carolyn L. Osborne
U.S. Environmental Protection Agency
Science Advisory Board (A-101F)
401 M. Street, S.W.
Washington, DC 20460
xlii
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PROJECT TEAM FOR DEVELOPMENT OF
AIR QUALITY CRITERIA FOR CARBON MONOXIDE
Scientific Staff
Mr. James A. Raub, Project Manager and
Health Effects Coordinator
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Thomas B. McMullen, Air Quality
Coordinator
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Ellie R. Speh, Secretary
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Technical Support Staff
Ms. Frances P. Bradow, Support and
Operations Manager
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Douglas B. Fennell, Technical
Information Specialist
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Allen G. Hoyt, Technical Editor and
Graphic Artist
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Diane H. Ray, Technical Information
Manager (Public Comments)
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xliii
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PROJECT TEAM FOR DEVELOPMENT OF
AIR QUALITY CRITERIA FOR CARBON MONOXIDE (cont'd)
Document Production Staff
Mr. John R. Barton, Document Production
Coordinator
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Ms. Lynette D. Cradle, Lead Word
Processor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Ms. Jorja R. Followill, Word Processor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Ms. Tracy B. Huneycutt, Artist
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Ms. Wendy B. Lloyd, Word Processor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Mr. J. Derrick Stout, Graphic Artist
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Mr. Peter J. Winz, Technical Editor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Technical Reference Staff
Mr. John A. Bennett, Bibliographic Editor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
Ms. Susan L. McDonald, Bibliographic
Editor
Research Information Organizers
P.O. Box 13135
Research Triangle Park, NC 27709
Ms. Carol J. Rankin, Bibliographic Editor
Research Information Organizers
P.O. Box 13135
Research Triangle Park, NC 27709
Ms. Deborah L. Staves, Bibliographic
Editor
Research Information Organizers
P.O. Box 13135
Research Triangle Park, NC 27709
Ms. Patricia R. Tierney, Bibliographic
Editor
ManTech Environmental Technology, Inc.
P.O. Box 12313
Research Triangle Park, NC 27709
xliv
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1. SUMMARY AND CONCLUSIONS
1.1 INTRODUCTION
Carbon monoxide (CO) is a colorless, odorless gas that can be poisonous to humans.
Minute amounts of CO are generated naturally within the human body; with external
exposure to additional amounts, subtle effects can begin to occur, and exposure to higher
levels can result in death. Carbon monoxide is one of the substances covered by the Federal
Clean Air Act (CAA), recently reauthorized by the U.S. Congress (U.S. Code, 1991). The
CAA directs the Administrator of the U.S. Environmental Protection Agency (EPA) to
propose, promulgate, and periodically reexamine National Ambient Air Quality Standards
(NAAQS) that will protect public health and welfare. This document is a requisite step in the
current reexamination of the CO standards; it summarizes the nature, sources, and
environmental concentrations of CO, and focuses on recent studies of low level effects of CO
on human health.
Carbon monoxide is a trace constituent of the troposphere, produced by both natural
processes and human activities. Because plants can both metabolize and produce CO, trace
levels are considered a normal constituent of the natural environment. Although ambient
concentrations of CO in the vicinity of urban and industrial areas can substantially exceed
global background levels, there are no reports of these currently measured levels of CO
producing any adverse effects on plants or microorganisms. Ambient concentrations of CO,
however, can be detrimental to human health and welfare, depending on the levels that occur
in areas where humans live and work and on the susceptibility of exposed individuals to
potentially adverse effects.
This chapter gives an .overview of the document, presenting a brief summary of what is
currently known about the global chemistry and concentration trends of CO in the
troposphere; the sources, emissions, and concentrations of CO found in urban areas and
indoor environments; the assessment" of population exposure to CO; the pharmacokinetics and
mechanisms of action of CO; the health effects that exposure to CO1 may cause; the
interaction of CO with other air pollutants and environmental factors; and the evaluation of
subpopulations at risk to CO exposure.
1-1
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1.2 THE GLOBAL CYCLE OF CARBON MONOXIDE
Limited data on global trends in tropospheric CO concentrations indicate a 1 to 2%
annual increase over the last several decades (Khalil and Rasmussen, 1988; Rinsland and
Levine, 1985; Dvoryashina et al., 1984, 1982; Dianov-Klokov and Yurganov, 1981;
Dianov-Klokov et al., 1978). Global background concentrations fall in the range of
50 to 120 ppb. Higher levels are found in the northern hemisphere, whereas lower levels are
found in the southern hemisphere. Average background concentrations also fluctuate
seasonally. Higher levels occur in the winter months and lower levels occur in the summer
months. About 60% of the CO found in the nonurban troposphere is attributed to human
activities, both directly from combustion processes and indirectly through the oxidation of
hydrocarbons and methane that, in turn, arise from agricultural activities, landfills, and other
similar sources (World Meteorological Organization, 1986; Khalil and Rasmussen, 1984;
Logan et al., 1981). Atmospheric reactions involving CO can produce ozone (O3) in the
troposphere. Other reactions may deplete concentrations of the hydroxyl radical, a key
participant in the global removal cycles of many other natural and anthropogenic trace gases,
thus possibly contributing to changes in atmospheric chemistry and, ultimately, to global
climate change.
1.3 SOURCES, EMISSIONS, AND CONCENTRATIONS OF CARBON
MONOXIDE IN URBAN AREAS
The current NAAQS for CO (Table 1-1) define 1-h and 8-h standards that should not be
exceeded more than once per year. Most CO monitoring conducted in the United States is
for the purpose of determining attainment or nonattainment of the NAAQS. Monitoring data
from fixed-site stations located throughout the country are reported to an Aerometric
Information Retrieval System (AIRS) maintained by EPA. Data in AIRS fall into two major
categories: the National Air Monitoring Stations (NAMS) and the State and Local Air
Monitoring Stations (SLAMS). The NAMS were established through monitoring regulations
promulgated in May 1979 (Federal Register, 1979) to provide EPA with accurate and timely
data on a national scale. The NAMS are located at sites expected to incur high pollutant
1-2
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TABLE 1-1. NATIONAL AMBIENT AIR QUALITY STANDARDS
FOR CARBON MONOXIDE
Date of Promulgation Primary NAAQS Averaging Time
September 13, 1985 9 ppma (10 mg/m3) 8 hb
35 ppma (40 mg/m3) 1 hb
al ppm = 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm @ 25 °C, 760 mm Hg.
bNot to be exceeded more than once per year.
concentrations and to typify areas with the potential for high population exposure. These
stations meet uniform criteria for site location; quality assurance; and equivalent analytical
methodology, sampling intervals, and instrument selection to assure consistent data reporting
nationwide. The SLAMS, in general, meet the same rigid criteria but, in addition to the
above siting criteria for highest concentrations and population exposure potential, they may be
located to monitor a greater diversity of urban neighborhoods.
The most reliable method for measurement of CO is the nondispersive infrared (NDIR)
optical transmission technique, the technique on which the EPA-designated reference
analytical method is based. One category of NDIR monitor, the gas filter correlation
monitor, is currently the single most widely used NDIR-type analyzer for fixed-site
monitoring stations. In general, NDIR monitors have significant advantages, including small
size, good sensitivity and specificity for CO, and reliability of operation under typical
network monitoring conditions. An associated recorder compiles and stores hourly averages
for subsequent computer storage and analysis.
Ambient CO data from the NAMS must be reported each calendar quarter to AIRS, in
accordance with requirements of the CAA and EPA regulations for State Implementation
Plans (Code of Federal Regulations, 1991). State and local agencies report most of the data
from their SLAMS stations as well. As a result, continuous measurements of ambient CO
concentrations from numerous cities throughout the United States are available from the EPA.
The most recently available data reported from fixed-site monitoring stations (U.S.
Environmental Protection Agency, 1991a) indicate that the 1-h NAAQS of 35 ppm is almost
never exceeded in the United States. Trends in air quality data also show a general decline in
1-3
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CO concentrations exceeding the 8-h NAAQS of 9 ppm over the 10-year period 1981 to
1990, from an average of about five exceedances per monitoring station per year to about one
exceedance per monitoring station per year. This decline reflects the efficacy of emission
control systems on newer vehicles. In 1981, highway vehicle emissions of CO accounted for
about 62% of total U.S. emissions; in 1990, it was 50%. During this same period, there was
a 37% increase in highway vehicle miles traveled. Nonhighway transportation sources
contributed 13%. The other categories of CO emissions are other fuel combustion sources,
such as steam boilers (12%), industrial processes (8%), solid waste disposal (3%), and
miscellaneous other sources (14%) (U.S. Environmental Protection Agency, 199Ib).
1.4 POPULATION EXPOSURE TO CARBON MONOXIDE
The U.S. Environmental Protection Agency's primary mandate under the CAA (U.S.
Code, 1991) is to monitor and regulate pollutants, like CO, that are found in the ambient air.
The term "ambient air" currently is interpreted to mean outdoor air. A great majority of
people, however, spend most of their time indoors. A realistic assessment of ambient
exposure to CO, therefore, must be set in the context of total exposure, a major component
of which is exposure while indoors.
The current NAAQS for CO are designed to protect against actual and potential human
exposures in ambient air that would cause adverse health effects. As noted previously,
compliance with the NAAQS is determined by measurements taken at fixed-site ambient
monitors, the use of which is intended to provide some measure of the general level of
exposure of the population represented by the CO monitors. The development of small,
portable electrochemical personal exposure monitors (PEMs) has made possible the
measurement of CO concentrations incurred by individuals as they move through numerous
diverse indoor and outdoor microenvironments that cannot be monitored by fixed-site ambient
stations. Results of both exposure monitoring in the field and modeling studies indicate that
individual personal exposure determined by PEMs does not directly correlate with CO
concentrations determined by using fixed-site monitors alone (Akland et al., 1985; Wallace
and Ziegenfus, 1985; Wallace and Ott, 1982; Dockery and Spengler, 1981; Cortese and
Spengler, 1976). This observation is due to the mobility of people and to the spatial and
1-4
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temporal variability of CO concentrations. Although they fail to show a correlation between
individual personal monitor exposures ancf simultaneous nearest fixed-site monitor
concentrations, large-scale CO human exposure field studies do suggest that aggregate
personal exposures are lower on days of lower ambient CO levels as determined by the fixed-
site monitors and higher on days of higher ambient levels (Akland et al., 1985). These
studies point out the necessity of having personal CO measurements to augment fixed-site
ambient monitoring data when total human exposure is to be evaluated. Data from these field
studies can be used to construct and test models of human exposure that account for time and
activity patterns known to affect exposure to CO (Sexton and Ryan, 1988; Pandian, 1987; Ott
et al., 1986; Fugas, 1986; Ott, 1985; Repace et al;, 1980). Models developed to date have
not been able to successfully predict individual exposures. The models may be modified and
adjusted using information from field monitoring studies in order to capture the observed
distribution of CO exposures, including the higher exposures found in the tail of the exposure
distribution. The models also are useful for evaluating the relative merits of alternative
pollutant control strategies.
During typical daily activities, people encounter CO in a variety of microenvironments
that include traveling in motor vehicles, working at their jobs, visiting urban locations
associated with combustion sources, or cooking over a gas range. Overall, the most
important CO exposures for a majority of individuals occur in the vehicle and indoor
microenvironments. Indoor concentrations of CO are a function of outdoor concentrations,
indoor sources, infiltration, ventilation, and air mixing between and within rooms. In
residences without sources, average CO concentrations are approximately equal to average
outdoor levels. The highest indoor CO exposures are associated with combustion sources and
include enclosed parking garages, service stations, restaurants, and stores. The lowest indoor
CO concentrations are found in homes, churches, and health care facilities. The exposure ,
studies conducted by EPA in Denver (Akland et al., 1985) showed that passive cigarette .
smoke is associated with increasing a nonsmoker's exposure by an average of about 1.5 ppm
and that use of a gas cooking range is associated with about 2.5 ppm increase at home.
Other sources that may contribute to CO in the home include combustion space heaters and
wood-burning stoves. The available data on the spatial and temporal variability of indoor CO
1-5
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concentrations as a function of microenvironments and associated sources are not adequate,
however, to properly assess exposures in these environments.
Studies of human exposure have shown that among all of the microenvironmental
settings, the motor vehicle is the most important for regularly encountered elevations of CO.
Studies by Flachsbart et al. (1987) indicated that CO exposures while commuting in
Washington, DC, average 9 to 14 ppm at the same time that fixed station monitors record
concentrations of 2.7 to 3.1 ppin. Similar studies conducted by EPA in Denver, CO, and
Washington, DC, have demonstrated that the motor vehicle interior has the highest average
CO concentrations (averaging 7 to 10 ppm) of all microenvironments (Johnson, 1984). In
these studies, 8% of all commuters experienced 8-h exposures greater than 9 ppm, whereas
only 1% of noncommuters received exposures over that level. Furthermore, commuting
exposures have been shown to be highly variable, with some commuters breathing CO in
excess of 25 ppm (Flachsbart and Ah Yo, 1989).
Another important setting for CO exposures is the workplace. In general, exposures at
work exceed CO exposures during nonwork periods, apart from commuting to and from
work. Average concentrations may be elevated during this period because workplaces are
often located in congested areas that have higher background CO concentrations than do many
residential neighborhoods. Occupational and nonoccupational exposures may overlay one
another and result in a higher concentration of CO in the blood. Most importantly, the
nature of certain occupations carries an increased risk of high CO exposure (e.g., those
occupations involved directly with vehicle driving, maintenance, and parking). Occupational
groups exposed to CO by vehicle exhaust include auto mechanics; parking garage and gas
station attendants; bus, track, or taxi drivers; police; and warehouse workers. Certain
industrial processes can expose workers to CO produced directly or as a by-product; they
include steel production, cook ovens, carbon black production, and petroleum refining.
Firefighters, cooks, and construction workers also may be exposed at work to high CO
levels. Occupational exposure in industries or settings with CO production represent some of
the highest individual exposures observed in field monitoring studies. For example, in EPA's
CO exposure study in Washington, DC (Akland et al., 1985), of the approximately 4%
(29 of 712) of subjects working in jobs classified as having a high potential for CO exposure,
seven subjects (or approximately 25%) experienced 8-h CO exposures in excess of 9 ppm.
1-6
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1.5 PHARMACOKINETICS AND MECHANISMS OF ACTION OF
CARBON MONOXIDE
The exchange of CO between,the air we breathe and the human body is controlled by
both physical (e.g., mass transport and diffusion) and physiological (e.g., alveolar ventilation
and cardiac output) processes. Carbon monoxide is readily absorbed from the lungs into the
blood stream. The final step hi this process involves competitive .binding between CO and
oxygen (O^ to hemoglobin (Hb) hi the red blood cell, forming carboxyhemoglobin (COHb)
and oxyhemoglobin (O2Hb), respectively. The toxic effects of CO are due to its high affinity
for Hb, which is 240 times greater than the affinity of O2 for Hb (Wyman et al., 1982). The
presence of COHb in the blood causes tissue hypoxia by reducing the O2-carrying capacity of
blood and by impairing release of O2 from O2Hb to extravascular tissues. The brain and
heart are particularly sensitive to the resultant drop in O2 from CO-induced hypoxia.
A unique feature of CO exposure, therefore, is that the blood COHb level represents a
useful biological marker of the dose that the individual has received. The amount of COHb
formed is dependent on the concentration and duration of CO exposure, exercise (which
increases the amount of air inhaled per unit time), ambient temperature, health status, and the
characteristic metabolism of the individual exposed. The formation of COHb is a reversible
process, but because of the tight binding of CO to Hb, the elimination half-time is quite long,
varying from 2 to 6.5 h depending on the initial levels of COHb (Landaw, 1973; Peterson
and Stewart, 1970). This might lead to accumulation of COHb, and even relatively low
concentrations of CO might produce substantial blood levels of COHb.
The level of COHb in the blood may be determined directly by blood analysis or
indirectly by measuring CO hi exhaled breath. The use of CO-Oximeters to measure low
levels of COHb can provide useful information regarding mean values in populations being
studied. It has been shown, however, that the range of values obtained with this optical
method will be greater than that obtained with other methods. For example, in a group of
subjects with cardiovascular disease, the standard deviation of the percent COHb values for
nonsmoking, resting subjects was 2 to 2.5 times larger for the CO-Oximeter values than for
the gas chromatograph values on paired samples (Allred et al., 1989b). Therefore, the
potential exists with the CO-Oximeter for having an incorrect absolute value for COHb as
well as an incorrectly broadened range of values. In addition, it is not clear exactly how
1-7
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sensitive the CO-Oximeter techniques are to small changes in COHb at the low end of the CO
dissociation curve. Allred et al. (1989b) have noted that the interference from changing
O2 saturation can have a very significant influence on the apparent COHb reading in a
sample. This suggests nonUnearity or a disproportionality in the absorption spectrum of
different species of Hb. It is also a potential source of considerable error in the estimation of
COHb by optical methods.
The measurement of exhaled breath has the advantages of ease, speed, precision, and
greater subject acceptance than measurement of blood COHb. However, the accuracy of the
breath measurement procedure and the validity of the Haldane relationship between breath
and blood at low environmental CO concentrations remains in question. There appears to be
a clear research need to validate the breath method at low CO exposures. In view of the
possible problems with the CO-Oximeter, such validation should be done using gas
chromatography for the blood COHb measurements.
Because COHb measurements are not readily available in the exposed population,
mathematical models have been developed to predict COHb levels from known CO exposures
under a variety of circumstances (see Figure 1-1). The best all-around model for COHb
prediction is still the equation developed by Coburn, Forster, and Kane (1965). The linear
solution is useful for examining air pollution data leading to relatively low COHb levels,
whereas the nonlinear solution shows good predictive power even for high CO exposures.
The two regression models might be useful only when the conditions of application closely
approximate those under which the parameters were estimated.
It is important to remember that almost all of the available modeling studies assumed a
constant rate of CO uptake and elimination, which is rarely true. A number of physiological
factors, particularly changes in ventilation associated with exercise activity, will affect both
rates. The predicted COHb values also will differ from individual to individual due to
smoking, age, or lung disease. There does not appear to be a single optimal averaging time
period for ambient CO; however, the shorter the period, the greater the precision.
Although the principal cause of CO toxicity is tissue hypoxia due to CO binding to Hb,
certain physiological aspects of CO exposure are not explained well by decreases in the
intraceUular oxygen partial pressure related to the presence of COHb. For many years, it has
been known that CO is distributed to extravascular sites, such as skeletal muscle (Coburn
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not intracellular uptake of CO in the presence of Hb is sufficient to cause either acute organ
system dysfunction or long-term health effects. The virtual absence of sensitive techniques
capable of assessing intracellular CO binding under physiological conditions has resulted in a
variety of indirect approaches to the problem as well as many negative studies.
Current knowledge pertaining to intracellular CO-binding proteins suggests that the most
likely ones to be inhibited functionally at relevant levels of COHb are myoglobin (Mb),
found predominantly in heart and skeletal muscle, and cytochrome oxidase. The
physiological significance of CO uptake by Mb is uncertain at this time, but sufficient
concentrations of carboxymyoglobin could potentially limit maximal O2 uptake of exercising
muscle. Although there is suggestive evidence for significant binding of CO to cytochrome
oxidase in heart and brain tissue, it is unlikely that any significant CO binding would occur at
low COHb levels. Therefore, further research is needed to determine if secondary,
intracellular mechanisms will occur at exposure concentrations found in ambient air.
1.6 HEALTH EFFECTS OF EXPOSURE TO CARBON MONOXIDE
Concerns about the potential health effects of exposure to CO have been addressed in
extensive studies with various animal species as subjects. Under varied experimental
protocols, considerable information has been obtained on the toxicity of CO, its direct effects
on the blood and other tissues, and the manifestations of these effects in the form of changes
in organ function. Many of these studies, however, have been conducted at extremely high
levels of CO (i.e., levels not found in ambient air). Although severe effects from exposure
to these high levels of CO are not directly germane to the problems from exposure to current
ambient levels of CO, they can provide valuable information about potential effects of
accidental exposure to CO, particularly those exposures occurring indoors.
1.6.1 Acute Pulmonary Effects
It is unlikely that CO has any direct effects on lung tissue except for extremely high
concentrations associated with CO poisoning. Currently available studies on the effects of
CO exposures producing COHb concentrations of up to 39% fail to find any consistent effects
on pulmonary cells and tissue or on the vasculature of the lung (Chen et al., 1982; Hugod,
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1980; Fisher et-al., 1969; Weissbecfcer et al., 1969). Human studies on the pulmonary
function effects of CO are complicated by the lack of adequate exposure information, the
small number of subjects studied, and the short exposures explored. Occupational or
accidental exposure to the products of combustion and pyrolysis, particularly indoors, may
lead to acute decrements in lung function if the COHb levels are high (Evans et al., 1988;
Sheppard et al., 1986; Hagberg et al., 1985; Cooper and Alberti, 1984). It is difficult,
however, to separate the potential effects of CO from those due to other respiratory irritants
in the smoke and exhaust. Community population studies on. CO in ambient air (Lebowitz
et al., 1987; Robertson and Lebowitz, 1984; Lutz, 1983) have not found any significant
relationship with pulmonary function, symptomatology, and disease.
1.6.2 Cardiovascular Effects
Previous assessments of the cardiovascular effects of CO performed by EPA (U.S.
Environmental Protection Agency, 1979, 1984) have identified what appears to be a linear
relationship between the level of COHb in the blood and decrements in human maximal
exercise performance, measured as maximal O2 uptake. Exercise performance consistently
decreases at a blood level of about 5% COHb in young, healthy, nonsmoking individuals
(Klein et al., 1980; Stewart et al., 1978; Weiser et al., 1978). Some studies have even
observed a decrease in short-term maximal exercise duration at levels as low as 2.3 to 4.3%
COHb (Horvath et al., 1975; Drinkwater et al., 1974; Raven et al., 1974a); however, this
decrease is so small as to be of concern mainly for competing athletes rather than for
ordinary people conducting the activities of daily life. Cigarette smoking has a similar effect
on cardiopulmonary response to exercise in nonathletic human subjects, indicating a reduced
ability for sustained work (Hirsch et al., 1985; Klausen et al., 1983).
Five key studies (Allred et al., 1989a,b, 1991; Kleinman et al., 1989; Adams et al.,
1988; Sheps et al., 1987; Anderson et al., 1973) have investigated the potential for CO
exposure to enhance the development of myocardial ischemia during exercise in patients with
coronary artery disease. An early study by Anderson et al. (1973) found that exercise
duration was significantly decreased by the onset of chest pain (angina) in patients with
angina pectoris at postexposure COHb levels as low as 2.9%, representing a 1.6% increase
over the baseline. Results of a large multicenter study reported by Allred et al. (1989a,b,
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1991) demonstrated effects in patients with reproducible exercise-induced angina at
postexposure COHb levels of 3.2%, corresponding to an increase of 2.0% from the baseline.
Sheps et al. (1987) and Adams et al. (1988) also found similar effects in patients with
obstructive coronary artery disease and evidence of exercise-induced ischemia at postexposure
COHb levels of 4.1 and 5.9%, respectively, representing 2.2 and 4.2% increases over the
baseline. Kleinman et al. (1989) studied subjects with angina and found an effect at 3%
COHb, representing an increase of 1.5% from the baseline. Thus, the lowest observed-effect
level in patients with exercise-induced ischemia is somewhere between 3 and 4% COHb,
representing a 1.5 to 2.2% increase from the baseline. Effects on silent ischemia episodes,
which represent the majority of episodes in these patients, have not been studied.
The adverse health consequences of low-level CO exposure effects in patients with
ischemic heart disease are very difficult to predict in the at-risk population of individuals with
heart disease. There exists a distribution of professional judgments on the clinical
significance of small exercise-performance decrements occurring with the levels of exertion
and CO exposure defined in these five studies. The decrements in performance that have
been described at the lowest levels (< 3% COHb) are in the range of reproducibility of the
exercise stress test and may not be alarming to some physicians. On the other hand, the
consistency of the responses in time to onset of angina across the studies and the dose-
response relationship reported in one of the studies (AUred et al., 1989a,b, 1991) would
strengthen the argument in the minds of other physicians that, although small, the effects
could limit the activity of these individuals and affect the quality of their life. In addition, it
has been argued by Bassan (1990) that 58% of cardiologists believe that recurrent episodes of
exertional angina are associated with a substantial risk of precipitating a heart attack, a fatal
arrhythmia, or slight but cumulative myocardial damage.
Exposure to CO that is sufficient to achieve 6% COHb recently has been shown to
adversely affect exercise-induced arrhythmia in patients with coronary artery disease (Sheps
et al., 1990, 1991). This finding, combined with epidemiologic work of Stern et al. (1988)
in tunnel workers who are routinely exposed to automobile exhaust, is suggestive but not
conclusive evidence that CO exposure may provide an increased risk of sudden death from
arrhythmia in patients with coronary artery disease.
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There is also evidence from both theoretical considerations and experimental studies in
laboratory animals that CO can adversely affect the cardiovascular system, depending on the
exposure conditions utilized in these studies. Although disturbances in cardiac rhythm and
conduction have been noted in healthy and cardiac-impaired animals, results from these
studies are not conclusive. The lowest level at which effects have been observed varies,
depending upon the exposure regime used and species tested. Results from animal studies
also indicate that inhaled CO can increase Hb concentration and hematocrit ratio, which
probably represents a compensation for the reduction hi oxygen transport caused by CO. At
high CO concentrations, excessive increases in Hb and hematocrit may impose an additional
workload on the heart and compromise blood flow to the tissues.
There is conflicting evidence that CO exposure will enhance development of
atherosclerosis in laboratory animals, and most studies show no measurable effect. Similarly,
the possibility that CO will promote significant changes hi lipid metabolism that might
accelerate atherosclerosis is suggested in only a few studies. Any such effect must be subtle
at most. Finally, CO probably inhibits rather than promotes platelet aggregation. In general,
there is little data to indicate that an atherogenic effect of exposure would be likely to occur
hi human populations at commonly encountered levels of ambient CO.
1.6.3 Cerebrovascular and Behavioral Effects
Under normal circumstances, the brain can increase blood flow or tissue O2 extraction
to compensate for the hypoxia caused by exposure to CO. The overall responses of the
cerebrovasculature are similar in the fetus, newborn, and adult animal; however, the
mechanism of the increase in cerebral blood flow is still unclear. In fact, several mechanisms
working simultaneously to increase blood flow appear likely and these may involve metabolic
and neural aspects as well as the O2Hb dissociation curve, tissue O2 levels, and even a
histotoxic effect of CO. These potential mechanisms of CO-induced alterations hi the
cerebral circulation need to be investigated further. Whether these compensatory mechanisms
will continue to operate successfully in a variety of conditions where the brain or its
vasculature are compromised (i.e., stroke, head injury, atherosclerosis, hypertension) is also
unknown and requires further investigation. Aging increases the probability of such injury
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and disease. It is also possible that there exist individual differences with regard to COHb
sensitivity and compensatory mechanisms.
Behaviors that require sustained attention or sustained performance are most sensitive to
disruption by COHb. The group of human studies (Benignus et al., 1987, 1990; Putz et al.,
1976, 1979) on hand-eye coordination (compensatory tracking), detection of infrequent events
(vigilance), and continuous performance offer the most consistent and defensible evidence of
COHb effects on behavior at levels as low as 5%. These effects at low CO-exposure
concentrations, however, have been very small and somewhat controversial. Nevertheless,
the potential consequences of a lapse of coordination, vigilance, and the continuous
performance of critical tasks by operators of machinery such as public transportation vehicles
could be serious. Therefore, additional research is necessary to provide a better
understanding of the behavioral mechanisms of action of CO and compensatory changes in
the vascular bed that may act to maintain an adequate O2 supply to the brain.
1.6.4 Developmental Toxicity
Studies in laboratory animals of several species provide strong evidence that maternal
CO exposures of 150 to 200 ppm, leading to approximately 15 to 25% COHb, produce
reductions in birth weight, cardiomegaly, delays in behavioral development, and disruption in
cognitive function (Singh, 1986; Storm et al., 1986; Storm and Fechter, 1985a,b; Mactutus
and Fechter, 1984, 1985; Fechter et al., 1980; Penney et al., 1980, 1983; Fechter and
Annau, 1980a,b, 1977, 1976). Isolated experiments suggest that some of these effects may
be present at concentrations as low as 60 to 65 ppm (approximately 6 to 11% COHb)
maintained throughout gestation (Abbatiello and Mohrmann, 1979; Prigge and Hochrainerj
1977). The current data (Hoppenbrouwers et al., 1981) from human children suggesting a
link between environmental CO exposures and sudden infant death syndrome are weak, but
further study should be encouraged. Human data from cases of accidental high CO exposures
(e.g., Klees et al., 1985; Crocker and Walker, 1985; Yenning et al., 1982) are difficult to
use in identifying a lowest observed-effect level for CO because of the small numbers of
cases reviewed and problems in documenting levels of exposure. However, such data, if
systematically gathered and reported, could be useful in identifying possible ages of special
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sensitivity to CO and cofactors or other risk factors that might identify sensitive
subpopulations.
1.6.5 Other Systemic Effects of Carbon Monoxide
Laboratory animal studies suggest that enzyme metabolism of xenobiotic compounds
may be affected by CO exposure (Roth and Rubin, 1976a,b; Pankow et al., 1974; Swiecicki,
1973; Martynjuk and Dacenko, 1973; Pankow and Ponsold, 1972, 1974; Kustov et al., 1972;
Montgomery and Rubin, 1971). Most of the authors of these studies have concluded,
however, that effects on metabolism at low COHb levels (< 15%) are attributable entirely to
tissue hypoxia produced by increased levels of COHb because they are no greater than the
effects produced by comparable levels of hypoxic hypoxia. At higher levels of exposure,
where COHb concentrations exceed 15 to 20%, there may be direct inhibitory effects of CO
on the activity of mixed-function oxidases, but more basic research is needed. The decreases
in xenobiotic metabolism shown with CO exposure might be important to individuals
receiving treatment with drugs.
Inhalation of high.levels of CO, leading to COHb concentrations greater than 10 to
15%, have been reported to cause a number of other systemic effects in laboratory animals as
well as effects in humans suffering from acute CO poisoning. Tissues of highly active
O2 metabolism, such as heart, brain, liver, kidney $ and muscle, may be particularly sensitive
to CO poisoning. The impairment of function in the heart and brain caused by CO exposure
is well known and has been described above. Other systemic effects of CO poisoning are not
as well known and are, therefore, less certain. There are reports in the literature of effects
on liver, kidney, bone, and immune capacity in the lung and spleen (Zebro et al., 1983;
Katsumata et al., 1980; Kuska et al.> 1980; Snella and Rylander, 1979). It generally is
agreed that these effects are caused by the severe tissue damage occurring during acute CO
poisoning due to one or more of the following: (1) ischemia resulting from the formation of
COHb, (2) inhibition of O2 release from O2Hb, (3) inhibition of cellular cytochrome function
(e.g., cytochrome oxidases), and (4) metabolic acidosis.
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1.6.6 Adaptation
The only evidence for short- or long-term compensation to increased COHb levels in the
blood is indirect. Experimental animal data indicate that COHb levels produce physiological
responses that tend to offset other deleterious effects of CO exposure. Such responses are
(1) increased coronary blood flow, (2) increased cerebral blood flow, (3) increased Hb
through increased hemopoiesis, and (4) increased O2 consumption in muscle.
Short-term compensatory responses in blood flow or O2 consumption may not be
complete or might even be lacking in certain persons. For example, from the laboratory
animal studies it is known that coronary blood flow is increased with increasing COHb, and
from human clinical studies it is known that subjects with ischemic heart disease respond to
the lowest levels of COHb (6% or less). The implication is that in some cases of cardiac
impairment, the short-term compensatory mechanism is impaired.
From neurobehavorial studies, it is apparent that decrements due to CO have not
occurred consistently in all subjects, or even in the same studies, and have not demonstrated a
dose-response relationship with increasing COHb levels. The implication from these data is
that there might be some threshold or time lag in a compensatory mechanism such as
increased blood flow. Without direct physiological evidence in either laboratory animals, or
preferably humans, this concept only can by hypothesized.
The mechanism by which long-term adaptation would occur, if it could be demonstrated
in humans, is assumed to be an increased Hb concentration via a several day increase in
hemopoiesis. This alteration in Hb production has been demonstrated repeatedly in
laboratory animal studies, but no recent studies have been conducted indicating or suggesting
that some adaptational benefit has or would occur. Furthermore, even if the Hb increase is a
signature of adaptation, it has not been demonstrated to occur at low ambient concentrations
of CO.
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1.7 COMBINED EXPOSURE OF CARBON MONOXIDE WITH OTHER
POLLUTANTS, DRUGS, AND ENVIRONMENTAL FACTORS
1.7.1 High Attitude Effects
Although there are many studies comparing and contrasting the separate effects of ' •
inhaling CO with those produced by exposure to altitude, there are relatively few reports on
the combined effects of inhaling CO at altitude. There are data (Horvath etah, 1988a,b;
McFarland, 1970; Pitts and Pace, 1947; McFarland et al., 1944) to support the possibility"
that the effects of these two hypoxia episodes are at least additive. These data were obtained
at CO concentrations that are too high to have much significance for regulatory concerns. •
There are even fewer studies of the long-term effects of CO at high altitude. These
studies (McGrath, 1988, 1989; McDonagh et al., 1986; Cooper et al., 1985; James et al.,
1979) indicate few changes at CO concentrations below 100 ppm and altitudes below 4,572 m;
(15,000 ft). The fetus, however, may be particularly sensitive to the effects of CO at
altitude; this is especially true with the high levels of CO associated with maternal smoking '
(Moore etal., 1982). •..•.-•.••..
1.7.2 Carbon Monoxide Interaction with Drugs
There remains little direct information on the possible enhancement of CO toxicity by
concomitant drug use or abuse; however, there are some data suggesting cause for concern.
There is some evidence that interactions of drug effects with CO exposure can occur in both
directions; that is, CO toxicity may be enhanced by drug use and the toxic or other effects of
drugs may be altered by CO exposure. Nearly all the published data that are available on CO
combinations with drugs concern psychoactive drugs (e.g., Knisely et al., 1989; McMillan
and Miller, 1974). r
The use and abuse of psychoactive drugs and alcohol is ubiquitous in society. Because
of the effect of CO on brain function, interactions between CO and psychoactive drugs could
be anticipated. Unfortunately, very little systematic research has addressed this question. In
addition, very little of the research that has been done has utilized models for expected effects
from treatment combinations. Thus, it often is not possible to assess whether the combined
effects of drugs and CO exposure are additive or differ from additivity. It is important to
recognize that even additive effects of combinations can be of clinical significance, especially
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when the individual is unaware of the combined hazard. The greatest evidence for a
potentially important interaction of CO comes from studies with alcohol in both laboratory
animals and humans, where at least additive effects have been obtained (Knisely et al., 1989;
Rockwell and Weir, 1975). The significance of this is augmented by the high probable
incidence of combined alcohol use and CO exposure.
1.7.3 Combined Exposure of Carbon Monoxide with Other Air Pollutants
and Environmental Factors
Much of the data concerning the combined effects of CO and other pollutants found in
the ambient' air are based on animal experiments. Only a few human studies are available.
Early studies in healthy human subjects on common air pollutants such as CO, nitrogen
dioxide, O3, or peroxyacetylnitrate failed to show any interaction from combined exposure
(DeLucia et al., 1983; Hackney et al., 1975a,b; Gliner et al., 1975; Raven et al., 1974a,b;
Drinkwater et al., 1974). In animal studies, no interaction was observed following combined
exposure of CO and common ambient air pollutants such as nitrogen dioxide or sulfur dioxide
(Hugod, 1979; Murray et al., 1978; Busey, 1972). However, an additive effect was
observed following combined exposure of high levels of CO and nitric oxide (Groll-Knapp
et al., 1988), and a synergistic effect was observed after combined exposure to CO and
O3 (Murphy, 1964).
Toxicological interactions of combustion products, primarily CO, CO2, and hydrogen
cyanide (HCN), at levels typically produced by indoor and outdoor fires, have shown a
synergistic effect following CO plus CO2 exposure (Levin et al., 1987a; Rodkey and
Collison, 1979) and an additive effect with HCN (Levin et al. 1987b). Additive effects were
also observed when CO, HCN, and low O2 were combined; adding CO2 to this combination
was synergistic (Levin et al., 1988). Additional studies are needed, however, to evaluate the
effects of CO under conditions of hypoxic hypoxia.
Finally, laboratory animal studies (Yang et al.., 1988; Fechter et al., 1988; Young
et al., 1987) suggest that combinations of environmental factors such as heat stress and noise
may be important determinants of health effects occurring in combination with exposure to,
CO. Of the effects described, the one potentially most relevant to typical human exposures is
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a greater decrement in the exercise performance seen when heat stress is combined with
50 ppm CO (Gliner et al., 1975; Drinkwater et al., 1974; Raven et al., 1974a,b).
1.7.4 Environmental Tobacco Smoke
Although tobacco smoke is another source of CO for smokers as well as nonsmokers, it
is also a source of other chemicals with which environmental CO levels could interact.
Available data (Glantz and Parmley, 1991; National Research Council, 1986; Surgeon
General of the United States, 1983, 1986) strongly suggest that acute and chronic CO
exposure attributed to tobacco smoke can affect the cardiopulmonary system, but the potential
interaction of CO with other products of tobacco smoke confounds the results. In addition, it
is not clear if incremental increases in COHb caused by environmental exposure would
actually be additive to chronically elevated COHb levels due to tobacco smoke, because some
physiological adaptation may take place. There is, therefore, a need for further research to
describe these relationships better.
1.8 EVALUATION OF SUBPOPULATIONS POTENTIALLY AT RISK
TO CARBON MONOXIDE EXPOSURE
Most of the information that is known about the health effects of CO involves two
carefully defined population groups—young, healthy, predominantly male adults and patients
with diagnosed coronary artery disease. On the basis of the known effects described, patients
with reproducible exercise-induced ischemia appear to be best established as a sensitive group
within the general population that is at increased risk for experiencing health effects of
concern (i.e., decreased exercise duration due to exacerbation of cardiovascular symptoms) at
ambient or near-ambient CO-exposure concentrations that result in COHb levels of less than
or equal to 6%. t A smaller, sensitive group of healthy individuals experience decreased
exercise duration at similar levels of CO exposure, but only during short-term maximal
exercise. Decrements in exercise duration in the healthy population, therefore, would mainly
be of concern to competing athletes rather than for nonathletic people carrying out the
common activities of daily life.
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It can be hypothesized, however, from both theoretical work and from experimental
research on laboratory animals, that certain other groups in the population may be at potential
risk to exposure from CO. Another purpose of the health assessment provided by the EPA is
to explore the potential effects of CO in population groups that have not been adequately
studied, but which could be expected to be susceptible to CO because of underlying
physiological status. Identifiable probable risk groups can be categorized by gender
differences; by age (e.g., fetuses, young infants, and the elderly); by preexisting diseases,
either known or unknown, that already decrease the availability of O2 to critical tissues; or by
the use of medications, recreational drugs, or alterations in environment (e.g., exposure to
other air pollutants or to high altitude). Unfortunately, little empirical evidence currently is
available by which to specify health effects associated with ambient or near-ambient CO
exposures for most of these probable risk groups.
1.9 SUMMARY
Carbon monoxide is a by-product of both natural processes and human activities.
Although low levels of CO have always been a normal constituent of our natural
environment, high levels produced in the vicinity of urban and industrial areas can affect
humans by combining with Hb in the blood to form increased levels of COHb that reduce the
availability of O2 to critical tissues and organs. Key health effects most clearly demonstrated
to be associated with varying blood COHb concentrations are summarized in Table 1-2. The
current U.S. NAAQS for CO are intended to keep COHb levels below 2.1% in order to
protect the most sensitive members of the general population (i.e., individuals with ischemic
heart disease). There is evidence that these individuals experience an exacerbation of their
symptoms (i.e., angina) when the COHb levels are as low as 3 to 6% (See Table 1-2).
Several hours of exposure to peak ambient CO concentrations often found at downtown urban
sites during periods of heavy traffic would be required to produce these COHb levels in
nonsmokers. It would, therefore, be advisable that individuals with cardiovascular disease
avoid more heavily polluted urban areas. Carbon monoxide levels occurring outside the
downtown urban locations would be expected to be lower and are probably representative of
levels found hi residential areas where most people live. Significant health effects from
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TABLE 1-2. KEY HEALTH EFFECTS OF EXPOSURE TO CARBON MONOXIDE
Target Organ
Health Effect(s)3
Sensitive
Population1
Individuals with
ischemic heart
disease
Healthy individuals
Healthy individuals
Healthy individuals
Heart Reduced exercise duration due to increased chest
pain (angina) with peak ambient exposure
(3-6% COHb)c
Heart/ Reduced maximal exercise performance with
Lungs 1-h peak ambient exposures (> 2.3% COHb)
Brain Equivocal effects on visual perception, audition,
motor and sensorimotor performance, vigilance,
and other measures of neurobehavioral performance
with 1-h peak exposures (> 5% COHb)
Neurological symptoms can occur ranging from
(1) headache, dizziness, weakness, nausea,
confusion, disorientation, and visual disturbances to
(2) unconsciousness and death with continued
exposure to high levels in the workplace or in
homes with faulty or unvented combustion ,
appliances (> 10% COHb)
*EPA has set significant harm levels of 50 ppm (8-h average), 75 ppm (4-h average), and 125 pprri
(1-h average). Exposure under these conditions could result in COHb levels of 5 to 10% and cause significant
health effects.
bFetuses; infants; pregnant women; elderly people; and people with anemia or with a history of cardiac,
respiratory, or vascular disease may be particularly sensitive to CO.
°Carboxyhemoglobin levels were determined by the optical method (CO-Qximeter).
ambient CO exposure would not be likely under these latter conditions unless outdoor
activities occur near internal combustion engines. Other sources of CO, however,
particularly those found indoors, may cause significant health effects in exposed individuals.
Cigarette smokers are at increased risk for the development of cardiovascular and pulmonary
disease and should quit smoking. Passive smoking can elevate COHb levels in nonsmokers
under conditions of poorly ventilated indoor spaces, putting nonsmoking co-workers and
family members at increased risk. Therefore, it is advisable to limit, where possible,
cigarette smoking in all public areas (e.g., workplaces and schools), as well as voluntarily at
home. It is also advisable to avoid poorly ventilated indoor spaces where the concentrations
of CO can be increased due to faulty or unvented combustion appliances.
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Allred, E. N.; Bleecker, E. R.; Chairman, B. R.; Dahms, T. E.; Gottlieb, S. O.; Hackney, J. D.; Pagano, M.;
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Anderson, E. W.; Andelman, R. J.; Strauch, J. M.; Fortuin, N. J.; Knelson, J. H. (1973) Effect of low-level
carbon monoxide exposure on onset and duration of angina pectoris: a study in ten patients with ischemic
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Bassan, M. M. (1990) Sudden cardiac death [letter to the editor]. N. Engl. J. Med. 322: 272.
Benignus, V. A.; Muller, K. E.; Barton, C. N.; Prah, J. D. (1987) Effect of low level carbon monoxide on
compensatory tracking and event monitoring. Neurotoxicol. Teratol. 9: 227-234.
Benignus, V. A.; Muller, K. E.; Smith, M. V.; Pieper, K. S.; Prah, J. D. (1990) Compensatory tracking in
humans with elevated carboxyhemoglobin. Neurotoxicol. Teratol. 12: 105^110.
Busey, W. M. (1972) Chronic exposure of albino rats to certain airborne pollutants [unpublished material].
Vienna, VA: Hazleton Laboratories, Inc. [as cited in U.S. Environmental Protection Agency, 1979].
Chen, S.; Weller, M. A.; Penney, D. G. (1982) A study of free lung cells from young rats chronically exposed
to carbon monoxide from birth. Scanning Electron Microsc. 2: 859-867.
Coburn, R. F.; Forster, R. E.; Kane, P. B. (1965) Considerations of the physiological variables that determine
the blood carboxyhemoglobin concentration in man. J. Clin. Invest. 44: 1899-1910.
Cobum, R. F.; Wallace, H. W.; Abboud, R. (1971) Redistribution of body carbon monoxide after hemorrhage.
Am. J. Physiol. 220: 868-873.
Coburn, R. F.; Ploegmakers, F.; Gondrie, P.; Abboud, R. (1973) Myocardial myoglobin oxygen tension. Am.
J. Physiol. 224: 870-876.
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Code of Federal Regulations. (1991) Requirements for preparation, adoption, and submittal of implementation
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Yang, L.; Zhang, W.; He, H.; Zhang, G. (1988) Experimental studies on combined effects of high temperature
and carbon monoxide. J. Tongji Med. Univ. 8: 60-65.
Young, J. S.; Upchurch, M. B.; Kaufman, M. J.; Fechter, L. D. (1987) Carbon monoxide exposure potentiates
high-frequency auditory threshold shifts induced by noise. Hear. Res. 26: 37-43.
Zebro, T.; Wright, E. A.; Littleton, R. J.; Prentice, A. I. D. (1983) Bone changes in mice after prolonged
continuous exposure to a high concentration of carbon monoxide. Exp. Pathol. 24: 51-67.
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2. INTRODUCTION
2.1 ORGANIZATION AND CONTENT OF THIS DOCUMENT
This revised air quality criteria document for carbon monoxide (CO) reviews and
evaluates the scientific information on the health effects associated with exposure to the
concentrations of CO found in ambient air. Although the document is not intended to be an
exhaustive literature review, it is intended to cover all the pertinent literature through early
1991. The references cited in this document are, therefore, reflective of the current state of
knowledge on those issues relevant to the subsequent review of the National Ambient Air
Quality Standards (NAAQS) for CO, currently set at 9 ppm (10 mg/m3) for 8 h and 35 ppm
(40 mg/m3) for 1 h. Major gaps hi knowledge also are identified. Although emphasis is
placed on the presentation of health effects data, other scientific data are presented and
evaluated in order to provide a better understanding of the nature, sources, distribution,
measurement, and concentrations of CO in the environment, as well as the measurement of
population exposure to CO.
The primary focus of air pollution control in the United States has been on the
regulation of pollutants such as CO that are found in the ambient air. The term "ambient air"
currently is interpreted to mean outdoor air. Current criteria standards, therefore, should
protect against most effects of CO found in the outdoor environment. Potential exposures
that exceed the standards, however, may be of greater concern to public health. For
example, exceedances of the ambient standards occur outdoors as a result of CO emissions
from transportation sources, primarily highway motor vehicles, and from stationary sources
producing industrial combustion gases. Transient concentrations of CO also can be high in
tunnels and parking garages due to the accumulation of engine exhaust fumes. In addition,
the results of time activity/pattern analyses have indicated that most of the public spends an
average of 90% of their time indoors where exposures to CO emitted from combustion
sources such as wood stoves, fireplaces, kerosene heaters, and other fossil fuel-burning
appliances are becoming more of a problem. In 1986, the U.S. Environmental Protection
Agency (EPA) was directed by Congress under Section 403 of the Superfund Amendments
and Reauthorization Act (Statutes-at-Large, 1986) to establish a comprehensive indoor air
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quality research program. Unlike most EPA research that supports regulatory agendas,
research on indoor environments is directed toward the identification of serious public health
risks in the indoor environment and the development and dissemination of practical
information that can be used by the public to avoid or mitigate these risks. This document,
therefore, includes information on indoor air sources, emissions, and concentrations of CO.
Information on the health effects of CO at higher-than-ambient levels, including effects from
CO poisoning, also was reviewed for inclusion in this document.
The identification of subpopulations potentially at risk from exposure to CO is another
issue directly pertinent to standard-setting that is addressed in this document. On the basis of
controlled or natural laboratory investigations, the health effects chapters in this document
describe effects of CO exposure in young, healthy, predominantly nonsmoking, male adults
and in patients with diagnosed coronary heart disease. Identification of other population
groups at risk, however, often requires information that is not derived directly from human
CO-exposure studies and is, therefore, more speculative. This document will explore the
potential effects of CO in population groups that have not been studied yet, but which could
be expected to be sensitive to CO because of underlying physiological status either due to
gender differences, aging, preexisting disease, or because of the use of medications or
alterations in their environment.
Certain issues of relevance to standard setting are not addressed explicitly in this
document. Such issues include (1) discussion of what constitutes an "adverse health effect,"
(2) assessment of risk, and (3) discussion of factors to be considered in providing an adequate
margin of safety. Although the scientific information presented in this document contributes
significantly to decisions regarding these issues, resolution of these issues cannot be achieved
solely on the basis of experimentally derived data. Final decisions on these issues are made
by the Administrator of the EPA.
Li addition, issues resulting from standard setting, such as those pertaining to the
attainment of standards, the techniques or strategies for controlling the emissions of CO, or
the monitoring of progress for implementation of control techniques, are not discussed in this
document. These topics are addressed by other offices and through other documents released
by EPA. . ,. - -
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Most of the scientific information selected for review and comment in this document
comes from the more recent literature published since completion of the previous criteria
document (U.S. Environmental Protection Agencyj 1979). Some of the these newer studies
were reviewed briefly in the addendum to that document (U.S. Environmental Protection
Agency, 1984a). Emphasis has been placed on studies conducted at or near CO
concentrations found in ambient air. Other studies, however, were included if they contained
unique data, such as the documentation of a previously unreported effect or a mechanism of
an effect; or if they were multiple-concentration studies designed to provide exposure-
response relationships relevant to total human exposure to CO. Studies that were presented in
the previous criteria document and whose data are still, considered relevant are summarized in
tables or reviewed briefly in the text. , Older studies were considered for discussion in the
document if they were (1) judged to be significant because of their usefulness in deriving the
current NAAQS, (2) open to reinterpretation because of newer data, or (3) potentially useful;
in deriving revised standards for CO. Generally, only published information that has
undergone scientific peer review is included in this criteria document.. Some newer studies
not published in the open literature but meeting high standards of.-scientific reporting also are
included.
2.2 LEGISLATIVE HISTORY OF NAAQS
Two sections of the Clean Air Act (CAA) govern the establishment, review, and
revision of NAAQS. Section 108 (U.S. Code, 1991) directs the Administrator of the EPA to
identify pollutants that reasonably may be anticipated to endanger public health or welfare
and to issue air quality criteria for them. These air quality criteria ate to reflect the latest
scientific information useful in indicating the kind and extent of all identifiable effects on
public health or welfare that may be expected from the presence of the pollutant in ambient
air/ • . .•"...•" • •- • • . : .-.-,.
Section 109(a) of the CAA (U.S. Code, 1991) directs the Administrator of EPA to
propose and promulgate primary and secondary NAAQS for pollutants identified under
Section 108. Section 109(b)(l) defines a primary standard as one the attainment and
maintenance of which in the judgment of the Administrator, based on the criteria and
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allowing for an adequate margin of safety, is requisite to protect the public health. The
secondary standard, as defined in Section 109(b)(2), must specify a level of air quality the
attainment and maintenance of which in the judgment of the Administrator, based on the
criteria, is requisite to protect the public welfare from any known or anticipated adverse
effects associated with the presence of the pollutant in ambient air. Section 109(d) of the
CAA (U.S. Code, 1991) requires periodic review and, if appropriate, revision pf existing
criteria and standards. If, in the Administrator's judgment, the Agency's review and revision
of criteria make appropriate the proposal of new or revised standards, such standards are to
be revised and promulgated in accordance with Section 109(b). Alternately, the
Administrator may find that revision of the standards is inappropriate and may conclude the
review by leaving the existing standards unchanged.
In keeping with the requirements of the CAA, the Environmental Criteria and
Assessment Office of EPA's Office of Health and Environmental Assessment has started to
review and revise once again the criteria for CO. New data on the health and air quality
aspects of CO exposure have become available since completion of the previous Air Quality
Criteria Document (U.S. Environmental Protection Agency, 1979) and an addendum to that
document (U.S. Environmental Protection Agency, 1984a).
2.3 REGULATORY BACKGROUND FOR CARBON MONOXIDE
NAAQS*
On April 30, 1971, EPA promulgated identical primary and secondary NAAQS for CO
at levels of 9 ppm for an 8-h average and 35 ppm for a 1-h average, not to be exceeded more
than once per year. The scientific basis for the level of the primary standard, as described in
the first criteria document (National Air Pollution Control Administration, 1970), was a study
suggesting that low levels of CO exposure resulting in carboxyhemoglobin (COHb)
concentrations of 2 to 3% were associated with neurobehavioral effects in exposed subjects
(Beard and Wertheim, 1967).
"This text is excerpted and adapted from "Review of the National Ambient Air Quality Standards for Carbon
Monoxide; Final Rule" (Federal Register, 1985).
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In accordance with Sections 108 and 109 of the CAA, EPA has reviewed and revised
the criteria upon which the existing NAAQS for CO (Table 2-1) are based. On August 18,
1980, EPA proposed certain changes in the standards (Federal Register,, 1980) based on
scientific evidence reported in the revised criteria document for CO (U.S. Environmental
Protection Agency, 1979). Such evidence indicated that the Beard and Wertheim (1967)
study was no longer considered to be a sound scientific basis for the standard. Additional
medical evidence accumulated since 1970, however, indicated that aggravation of angina
pectoris and other cardiovascular diseases would occur at COHb levels as low as 2.7 to
2.9%. The proposed changes included (1) retaining the 8-h primary standard level of 9 ppm;
(2) revising the 1-h primary standard level from 35 ppm to 25 ppm; (3) revoking the existing
secondary CO standards (because no adverse welfare effects have been reported at or near
ambient CO levels); (4) changing the form of the primary standards from deterministic to
statistical; and (5) adopting a daily interpretation for exceedances of the primary standards, so
that exceedances would be determined on the basis of the number of days on which the 8- or
1-h average concentrations are above the standard levels.
TABLE 2-1. NATIONAL AMBIENT AIR QUALITY STANDARDS
FOR CARBON MONOXIDE
Date of Promulgation Primary NAAQS Averaging Time
September 13, 1985 9 ppma (10 mg/m3) 8 hb
35 ppma (40 mg/m3) 1 hb
al ppm = 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm @ 25°C, 760 mm Hg.
bNot to be exceeded more than once per year.
See glossary of terms and symbols for abbreviations and acronyms.
The 1980 proposal was based in part on health studies conducted by Dr. Wilbert
Aronow. In March of 1983, EPA learned that the U.S. Food and Drug Administration
(FDA) had raised serious questions regarding the technical adequacy of several studies
conducted by Dr. Aronow on experimental drugs, leading FDA to reject use of the Aronow
drug study data. Therefore, EPA convened an expert committee to examine the Aronow CO
studies before any final decisions were made on the NAAQS for CO. The committee
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concluded that EPA should not rely on Dr. Aronow's data due to concerns regarding the
research, which substantially limited the validity and usefulness of the results.
An addendum to the 1979 criteria document for CO (U.S. Environmental Protection
Agency, 1984a) reevaluated the scientific data concerning health effects associated with
exposure to CO at or near ambient exposure levels in light of the committee recommendations
and taking into account new findings reported beyond those previously reviewed. (These data
are summarized in the following section.) On September 13, 1985, EPA issued a final notice
(Federal Register, 1985) announcing retention of the existing primary NAAQS for CO and
rescinding the secondary NAAQS for CO.
2.4 SCIENTIFIC BACKGROUND FOR THE CURRENT CARBON
MONOXIDE NAAQS
The following is a summary of the scientific basis for the current CO NAAQS. These
key points were derived from a revised evaluation of the health effects of CO that was
released as an addendum (U.S. Environmental Protection Agency, 1984a) to the previous air
quality criteria document for CO (U.S. Environmental Protection Agency, 1979).
2.4.1 Mechanisms of Action
The binding of CO to hemoglobin (Hb), producing COHb and decreasing the oxygen
(O^-carrying capacity of blood, appears to be the principal mechanism of action .underlying
the induction of toxic effects of low-level CO exposures. The precise mechanisms by which
toxic effects are induced via COHb formation are not understood fully, but likely include the
induction of a hypoxic state in many tissues of diverse organ systems. Alternative or
secondary mechanisms of CO-induced toxicity (besides COHb) have been hypothesized, but
none have been demonstrated to operate at relatively low (near-ambient) CO-exposure levels.
Blood COHb levels, then, currently are accepted as representing a useful physiological
marker by which to estimate internal CO burdens due to the combined contribution of
(1) endogenously derived CO and (2) exogenously derived CO resulting from exposure to
external sources of CO. Carboxyhemoglobin levels likely to result from particular patterns
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(concentrations, durations, etc.) of external CO exposure can be estimated reasonably well
from equations developed by Coburn et al. (1965) as demonstrated in Figure 2-1.
14
I
0)
OL
ja
8
A 8 h, 20 L/min
8h, 10L/min
1 h, 20 L/min
1 h, 10 L/min
20
I
40 60
Carbon Monoxide, ppm
100
Figure 2-1. Relationship between carbon monoxide exposure and carboxyhemoglobin
(COHb) levels in the blood. Predicted COHb levels resulting from 1- and
8-h exposures to carbon monoxide at rest (alveolar ventilation rate of
10 L/min) and with light exercise (20 L/min) are based on the Coburn-
Forster-Kane equation (Coburn et al., 1965) using the following assumed
parameters for nonsmoking adults: altitude = 0 ft, initial COHb level =
0.5%, Haldane coefficient = 218, blood volume = 5.5 L, hemoglobin
level = 15 g/100 mL, lung diffusivity = 30 mL/torr/min, endogenous
rate = 0.007 mL/min. See glossary of terms and symbols for abbreviations
and acronyms.
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2,4.2 Carbon Monoxide Exposure Levels
Evaluation of human CO-exposure situations indicates that occupational exposures in
some workplaces or exposures in homes with faulty combustion appliances can exceed
100 ppm CO, often leading to COHb levels of 10% or more with continued exposure. In
contrast, such high exposure levels are encountered much less commonly by the general
public exposed under ambient conditions. More frequently, exposures to less than 25 to
50 ppm CO for any extended period of time occur among the general population and, at the
low exercise levels usually engaged in under such circumstances, the resulting COHb levels
most typically remain 2 to 3 % among nonsmokers. Those levels can be compared to the
physiologic norm for nonsmokers, which is estimated to be in the range of 0.3 to 0.7%
COHb. Baseline COHb concentrations in smokers, however, average 4% with a usual range
of 3 to 8%, reflecting absorption of CO from inhaled smoke.
2.4.3 Health Effects of Low-Level Carbon Monoxide Exposures
Four types of health effects reported or hypothesized to be associated with CO
exposures (especially those producing COHb levels below 10%) were evaluated in the last
review of the CO NAAQS (U.S. Environmental Protection Agency, 1984a): (1) cardio-
vascular effects, (2) neurobehavioral effects, (3) fibrinolysis effects, and (4) perinatal effects.
Data available at that time (Table 2-2) demonstrated an association between cardiovascular
and neurobehavioral effects at relatively low-level CO exposures. Much less clear evidence
existed to indicate that other types of health effects were associated with low-level CO
exposures.
2.4.3.1 Cardiovascular Effects
In regard to cardiovascular effects, decreased oxygen uptake and resultant decreased
work capacity under maximal exercise conditions clearly have been shown to occur in healthy
young adults starting at 5.0% COHb; and several studies observed small decreases in work
capacity at COHb levels as low as 2.3 to 4.3%. These cardiovascular effects may have
health implications for the general population in terms of potential curtailment of certain
physically demanding occupational or recreational activities under circumstances of
sufficiently high CO exposure. However, of greater concern at more typical ambient
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TABLE 2-2. LOWEST OBSERVED EFFECT LEVELS FOR EfUMAN HEALTH
EFFECTS ASSOCIATED WITH LOW-LEVEL CARBON MONOXIDE EXPOSURE
Effects
COHb
Concentration
(Percent)8
References
Statistically significant decreased
(3-7 %) work time to exhaustion in exercising,
young, healthy men
Statistically significant decreased
exercise capacity (i.e., shortened
duration of exercise before onset of
pain) in patients with angina pectoris
and increased duration of angina attacks
No statistically significant vigilance decrements
after exposure to CO
Statistically significant decreased
maximal oxygen consumption and exercise time
during strenuous exercise
in young, healthy men
Statistically significant diminution of visual
perception, manual dexterity,
ability to learn, or performance in complex
sensorimotor tasks (such
as driving)
2.3-4.3
2.9-4.5
Below 5
5-5.5
5-17
Statistically significant decreased
maximal oxygen consumption during strenuous
exercise in young, healthy men
7-20
Horvath et al. (1975)
Drinfcwater et al. (1974)
Anderson et al. (1973)
Haider et al. (1976)
Winneke (1974)
Christensen et al. (1977)
Benignus et al. (1977)
Putz et al. (1976)
Klein et al. (1980)
Stewart et al. (1978)
Weiser et al. (1978)
Bender et al. (1971)
Schulte (1963)
O'Donnell et al. (1971)
McFarland et al. (1944)
McFarland (1973)
Putz et al. (1976)
Salvatore (1974)
Wright et al. (1973)
Rockwell and Weir (1975)
Rummo and Sarlanis (1974)
Putz et al. (1979)
Putz (1979)
Ekblotn and Huot (1972)
Pirnay et al. (1971)
Vogel and Gleser (1972)
The physiologic norm (i.e., COHb levels resulting from the normal catabolism of hemoglobin and other
heme-containing materials) has been estimated to be in the range of 0.3 to 0.7% (Coburn et al., 1963). See
glossary of terms and symbols for abbreviations and acronyms.
Source: U.S. Environmental Protection Agency (1984b).
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CO-exposure levels were certain cardiovascular effects (i.e., aggravation of angina symptoms
during exercise) likely to occur in a smaller, but sizeable, segment of the general population.
This group, chronic angina patients, is presently viewed as the most sensitive risk group for
CO-exposure effects, based on evidence for aggravation of angina occurring in patients at
COHb levels of 2.9 to 4.5%. Such aggravation of angina is thought to represent an adverse
health effect for several reasons articulated in the 1980 proposal preamble (Federal Register,
1980), and the Clean Air Scientific Advisory Committee concurred with EPA's judgment on
this matter. Dose-response relationships for cardiovascular effects in coronary artery disease
patients remain to be defined more conclusively, and the possibility cannot be ruled out at
this time that such effects may occur at levels below 2.9% COHb (as hinted at by the results
of the now-questioned Aronow studies). Therefore, new studies published since the last
review cycle are evaluated in this revised criteria document to determine the effects of CO on
aggravation of angina at levels in the range of 2 to 6% COHb.
2.4.3.2 Neurobehavioral Effects
No reliable evidence demonstrating decrements in neurobehavioral function in healthy,
young adults has been reported at COHb levels below 5%. Results of studies conducted at or
above 5% COHb are equivocal. Much of the research at 5% COHb did not show any effect
even when behaviors similar to those affected in other studies at higher COHb levels were
involved. However, investigators failing to find CO decrements at 5% or higher COHb
levels may have utilized tests not sufficiently sensitive to reliably detect small effects of CO.
From the empirical evidence, then, it can be said that COHb levels >5% do produce
decrements in neurobehavioral function. It cannot be said confidently, however, that COHb
levels lower than 5% would be without effect. One important point made in the 1979 criteria
document should be reiterated here. Only young, healthy adults have been studied using
demonstrably sensitive tests and COHb levels at 5% or greater. The question of groups at
special risk for neurobehavioral effects of CO, therefore, has not been explored. Of special
note are those individuals who are taking drugs that have primary or secondary depressant
effects that would be expected to exacerbate CO-related neurobehavioral decrements. Other
groups at possibly increased risk for CO-induced neurobehavioral effects are the aged and ill,
but these groups have not been evaluated for such risk.
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2.4.3.3 Other Health Effects
Only relatively weak evidence points toward possible CO effects on fibrinolytic activity,
generally only at rather high CO-exposure levels. Similarly, whereas certain data also
suggest that perinatal effects (e.g., reduced birth weight, slowed postnatal development,
sudden infant death syndrome) are associated with CO exposure, insufficient evidence
presently exists by which to either qualitatively confirm such an association in humans or to
establish any pertinent exposure-effect relationships.
2.5 CRITICAL ISSUES IN REVIEW OF THE NAAQS FOR CARBON
MONOXIDE
Based on the scientific evidence currently evaluated in air quality criteria documents
(U.S. Environmental Protection Agency, 1979, 1984a), potentially adverse health effects of
CO have been demonstrated to occur at COHb levels in the range of 2.3 to 20% (see
Table 2-2). However, several critical issues have developed during the current review of the
scientific criteria for CO air quality standards that will need to be resolved in order to
determine the extent to which adverse effects are occurring in the population, particularly at
the lower COHb levels of greatest interest to standard setting (<5 percent). The following
section will focus on specific issues pertaining to (1) exposure assessment in the general
population, including the measurement of CO in ambient air and in blood; (2) mechanisms of
action of CO; (3) health effects from exposure to CO; and (4) groups of individuals
considered to be at greatest risk to CO at ambient or near-ambient exposure levels.
2.5.1 Exposure Assessment in the Population
The 1989 trends in ambient air quality reported by EPA (U.S. Environmental Protection
Agency, 1991) summarize fixed-site monitoring data for CO but only focus on 8-h averages.
The rationale for this approach is that the 8-h standard of 9 ppm is typically the controlling
standard and the 1-h standard of 35 ppm is rarely exceeded. For example, only three
exceedances of the CO 1-h standard were recorded in the United States during 1989 and these
occurred at two sites that are affected by localized, nonmobile sources. In contrast, 41 areas
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failed to meet the CO 8-h standard for .the years 1988-89, a decrease of three areas from the
1987-88 period (U.S. Environmental Protection Agency, 1991). ,
Ambient CO-concentration data from fixed-site monitors alone will not necessarily give
a good estimate of potential total exposure to the population, based on experience from the
Denver, CO, and Washington, DC, human-exposure field studies using personal monitors. It
is estimated that over 10% of the residents in Denver and 4% of the residents in Washington
were exposed to CO levels above 9 ppm for 8 h during the winter of 1982-83 (Akland et al.,
1985). The effects of personal activity, indoor sources, and time spent commuting contribute
greatly to an individual's total exposure to CO. Available 1-h CO concentrations taken at
fixed-site monitors in these field studies did not correlate well (0.14 < r < 0.27) with
measurements made by personal monitors.
The best available study for determining relevant exposure to the most susceptible target
population, that is, individuals with ischemic heart disease (IHD), is the work of Lambert
et al. (1991). A total of 36 nonsmoking men with IHD were followed during personal-
exposure monitoring. A wide range of .peak exposures to CO were measured. The highest
CO exposures were found while the subjects were commuting and when the subjects were
near internal combustion engines. For example, CO exposures on freeways in Los Angeles
averaged 10 to 12 ppm. The average personal exposure for all time spent in automobiles was
8.6 ppm with a maximum 1-min average of 239 ppm. Concentrations of CO, averaging
7.9 ppm, also were found in parking lots, parking structures, service stations, and motor
repair facilities. Residential CO exposure was. much lower, averaging 2.0 ppm. In typical
outdoor residential activities, transient peaks as high as 134 ppm were observed for
woodcutting with a gas-powered chain saw and 226 ppm for gardening activity where a two-
stroke, gasoline-powered engine was utilized. Exposures under these conditions would be
expected, based on equations developed by Coburn et al. (1965), to cause COHb levels in
excess of 2.5%.
The best indicator of exposure to CO continues to be the direct measurement of COHb
in blood. There are, however, several issues regarding measurement techniques for COHb
that have been raised during the current review of the CO air quality criteria. For many
years, routine clinical laboratory measurements of COHb commonly have been made using
the IL 182 and it successor, the IL 282 CO-Oximeter (Instrumentation Laboratory, Inc.,
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Lexington, MA), which is a spectrophotometric instrument. The CO-Oximeter and other
similar optical methods of COHb measurement, however, are limited in sensitivity,
particularly in the range of 0 to 5%, where the lowest observed health effects associated with
CO exposure have been described. Other, more sensitive techniques require the release of
CO from Hb into a gas phase that can be detected directly. One method for COHb
measurement that has become more widely used in laboratory settings is gas chromatography.
Recent efforts to compare COHb measurement by spectrophotometry versus gas
chromatography have indicated that the high correlation over a wide range of concentrations
(0 to >20%) becomes much worse at COHb levels <5% because of an apparent instrument
offset or potential error. Thus, there has been concern about the relative accuracy and
precision of the COHb measurements at levels that are of particular concern to the CO
NAAQS review. Further, ongoing work is needed in order to determine (1) which method
should be used to accurately quantify low levels of COHb, (2) if there is a scientifically
acceptable way to compare COHb measurements made by different instruments across
different laboratories, and (3) the relationship of measured COHb values to those derived
from modeling efforts based on actual CO exposures in the general population.
Most "real-life" exposures to CO are to concentrations that vary with time and those
exposures are experienced by people with differing physiological attributes and at varying
exercise levels. Direct measurements of COHb are not readily available in the general
population exposed to CO under these conditions. Mathematical models, therefore, have
been developed to predict COHb levels from known CO exposures under a variety of
circumstances. The most used model for COHb formation is still the Coburn-Forster-Kane
equation (CFKE) developed by Coburn et al. (1965). The COHb levels predicted by this
equation generally have been accepted as the best available estimates of COHb levels likely to
result from varying CO concentrations, exposure durations, and exercise levels. Further
research, however, is needed to evaluate the predictive capabilities of the CFKE in
individuals exposed to low concentrations of CO leading to COHb levels of less than 10%.
Of particular interest is the variation of predicted COHb in a population whose pattern of CO
exposure involves frequent concentration variations. In addition, the CFKE needs to be
evaluated for applicability to CO-susceptible subjects, such as patients with cardiovascular or
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pulmonary disease. CJinieal evaluation of CO uptake by these individuals should be
considered.
Epidemiology studies have suggested the possibility that increased mortality from heart
attacks and increased cardiovascular complaints may be associated with elevated ambient
concentrations of CO. Unfortunately, due to inadequate characterization of exposure as well
as other limitations, inconclusive results have been obtained from existing studies. The
availability of both personal-exposure monitors for CO and ambulatory electrocardiogram
(EKG) monitoring techniques have made it possible to design epidemiology studies to
determine whether ambient CO exposures are related to serious or irreversible cardiovascular
effects. It would be desirable, therefore, to obtain CO exposure data on CO-susceptible
individuals in order to characterize their risk from elevated levels of COHb. Potentially
susceptible individuals include infants, the elderly, and patients with known cardiovascular
diseases.
2.5.2 Mechanisms of Action of Carbon Monoxide
The accepted mechanisms of action underlying the potentially toxic effects of low-level
CO exposure continue to be the decreased O2-carrying capacity of blood and subsequent
interference of O2 release at the tissue level that is caused by the binding of CO with Hb,
producing COHb (Figure 2-2). The resulting impaired delivery of O2 can interfere with
cellular respiration and cause tissue hypoxia.
Review of the newer information on mechanisms of action of CO has focused on the
possibility that secondary mechanisms that also can impair cellular respiration may be
occurring at relatively low (near-ambient) CO-exposure levels. Approximately 10 to 50% of
the total-body burden of CO can be distributed to extravascular sites, suggesting that
intracellular uptake of CO may contribute to CO-induced toxicity. It is uncertain, however,
if intracellular uptake of CO occurs at low levels of COHb or if it would be likely to
contribute to the physiological effects of CO.
Carbon monoxide will bind to intracellular hemoproteins such as myoglobin (Mb), ,
eytochrome oxidase, mixed-function oxidases (e.g., cytochrome P-450), tryptophan
oxygenase, and dopamine hydroxylase. Binding to CO would be favorable under conditions
of low intracellular partial pressure of oxygen (PO2), particularly in brain and myocardial
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MECHANISMS OF ACTION OF CARBON MONOXIDE
Source
Internal
storage
compartment
Target
organ
External Exposure
Carbon
Monoxide
Ambient
Indoor
Occupational
Halogenated
Hydrocarbons
e.g., CH2CI2
Decreased O2 Delivery
Decreased 0^- carrying capacity
Left-shifted OaHb dissociation curve
Compensatory
vasodilation
and increased
blood flow
to maintain
O2 consumption
Decreased cellular respiration
Tissue hypoxla
Ischemlc cascade
Figure 2-2. Currently accepted or proposed mechanisms of action of carbon monoxide
resulting from external exposure sources can interfere with cellular
respiration and cause tissue hypoxia (see text for details). See glossary of
terms and symbols for abbreviations and acronyms.
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tissue where intracellular PO2 decreases with increasing COHb levels. The most likely
hemoproteins to be inhibited functionally at relevant levels of COHb are Mb, found
predominantly in heart and skeletal muscle, and cytochrome oxidase. The physiological
significance of CO uptake by Mtr is uncertain at this time, but sufficient concentrations of
carboxymyoglobin could potentially limit maximal O2 uptake of exercising muscle. Although
there is suggestive evidence for significant binding of CO to cytochrome oxidase in heart and
brain tissue, it is unlikely that any significant CO binding would occur at low COHb levels.
Therefore, further research still is needed to determine if secondary, intracellular mechanisms
will occur at exposure concentrations found in ambient air.
2.5.3 Health Effects from Exposure to Carbon Monoxide
2.5.3.1 Effects on the Cardiovascular System
Scientific support for the current NAAQS for CO is based primarily on studies of
patients with stable angina pectoris (chest pain) from coronary artery disease. Although it is
assumed that the development of angina reflects adverse effects of CO on myocardial
metabolism, more specific research supporting the validity of this assumption is needed. For
example, little is known about the reproducibility or reoccurrence of this disease. Time to
onset of angina and the duration of angina are measurable outcomes that need to be defined
more precisely. Research al§o is needed on niore objective measures of myocardial ischemia,
such as continuous BKG tracing for ST segment depression and arrhythmias, and on
measurement of ventricular function using a gamma camera or thallium scan.
In view of questions concerning the validity of angina studies by Aronow et al.
reviewed in the previous criteria document, additional data were clearly needed in order to
(1) provide more reliable dose-response information in individuals with stable angina,
(2) allow a better determination of the level of COHb necessary to cause adverse effects in
the sensitive population, and (3) ultimately set an appropriate level for the CO NAAQS. In
response to this need, additional studies recently have been completed by a number of
independent laboratories to identify the relationship between COHb and aggravation of
preexisting chronic heart disease. Four of these studies now have been published (Sheps
et al., 1987; Adams et al., 1988; Kleinman et al., 1989; Allred et al., 1989;1991).
Collectively, all four studies provide new information on the likelihood that patients exposed
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to CO will experience angina earlier during exercise when compared to clean-air exposure.
Levels of COHb across the studies range from 2.9 to 5.9%, as measured by the >
spectrophotometric method (CO-Oximeter). An evaluation of these data is provided in this
document as part of the overall review of the scientific basis for the CO NAAQS. Any
potential differences in the results between these studies primarily will be due to either the
patient population studied or to the experimental design of the study itself.
Heart attack is the leading cause of death in the United States. In 1987 alone, more
than 513,700 deaths were attributed to coronary artery disease and more than 5 million
people alive at that time were estimated to have a history of heart attack, angina, -or both
(American Heart Association, 1989). Today that estimate may be as high as 7 million
individuals afflicted with ischemic heart disease (U.S. Department of Health and Human
Services, 1990). A major question that will become important in the evaluation of all the
clinical studies involving subjects with coronary heart disease is whether the study population
is representative of this broad group of patients with IHD and, therefore, is applicable to the
subpopulation of potentially susceptible individuals that are exposed .routinely to ambient
levels of CO. The possibility of studying the effects of CO in a more representative group of
patients with coronary heart disease should be investigated. Recent changes in the treatment
of coronary artery disease indicate that the sensitive subpopulation of angina patients may be
changing from one of untreated patients to one of angina patients who have had coronary
artery bypass or balloon angioplasty. The susceptibility of this new population to CO may
not be the same. In addition, there is a greater likelihood of increased risk to CO exposure
in a virtually unknown group of individuals who have silent ischemia (no symptomatic
episodes of chest pain).
Additional research is needed to determine dose-response relationships for the acute
effects of CO in other potentially susceptible groups. Patients with arteriosclerosis of the
arteries of the lower limbs who develop intermittent claudication are analogous to patients
with angina and could be studied in a similar manner. Research is needed to determine dose-
response relationships for cardiovascular effects in individuals with ventricular arrhythmias.
Patients with anemia may be susceptible to increased levels of COHb, because CO would
further reduce the already compromised arterial 02 content of the blood. Patients with
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chronic obstructive pulmonary disease and those with congestive heart failure also should be
studied to determine if they are at increased risk to low levels of CO exposure.
Other cardiovascular effects of low-level CO exposure, particularly with prolonged or
chronic exposure, have not been demonstrated. Previous studies on laboratory animals that
were reviewed in the last criteria document failed to clearly link CO exposure with
atherogenesis and the development of arteriosclerosis. Newer data published since then still
fail to prove conclusively an atherogenic effect of exposure to low concentrations of CO
despite strong evidence from epidemiology studies showing an association between cigarette
smoke and increased risk for arteriosclerosis. Other components of cigarette smoke (e.g.,
nicotine) as well as other risk factors (e.g., diet) also may promote atherogenesis, making it
difficult to attribute the atherogenic effects of cigarette smoke to CO alone.
2.5.3.2 Neurobehavioral Effects
Neurobehavioral effects of CO exposure, such as changes in (1) hand-eye coordination
(compensatory tracking), (2) detection of infrequent events (vigilance), and (3) visual system
sensitivity, have been reported in healthy young adults at COHb levels as low as 5%. These
effects at low CO-exposure concentrations, however, have been very small and somewhat
controversial. The newer data on neurobehavioral effects of CO discussed in this document
apparently have provided little help in resolving this controversy. Nevertheless, the potential
consequences of a lapse of coordination, vigilance, and visual sensitivity in the performance
of critical tasks by operators of machinery such as public transportation vehicles could be
serious. Therefore, additional research is necessary to provide a better understanding of the
mechanisms of action of CO and compensatory changes in the vascular bed that may act to
maintain an adequate oxygen supply to the brain.
Certain subgroups of the population are at increased risk from the neural and behavioral
effects of elevated COHb. For example, any condition that would reduce O2 supply to the .
brain also would potentially exacerbate the effects of CO exposure. A very large subgroup
that is known to have a reduced O2 supply to the brain is the aged. Therefore, it is important
to determine COHb dose-response functions for neurobehavioral variables in older subjects.
Other conditions that might reduce O2 supply to the brain include certain cerebrovascular,
cardiovascular, and pulmonary disease states mentioned above.
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Another large subgroup that may be at increased risk from neurobehavioral effects of
CO exposure are those people who take prescription or over-the-counter medications that
reduce alertness or motor abilities, such as antihistamines, sedatives, anitipsychotics,
antiseizure drugs, antiemetics, and analgesics. The effects of ethanol, caffeine, nicotine, and
other nonprescription drugs should not be overlooked. Individuals taking nonprescription or
over-the-counter drugs already would be affected behaviorally so that any further impairment
due to elevated COHb might have serious consequences.
2.5.3,3 Perinatal Effects
The fetus and newborn infant are theoretically susceptible to CO exposure for several
reasons. Fetal circulation is likely to have a higher COHb level than the maternal circulation
due to differences in uptake and elimination of CO from fetal Hb. Because the fetus also has
a lower O2 tension in the blood than adults, any further drop in fetal O2 tension due to the
presence of COHb could have a potentially serious effect. The newborn infant with a
comparatively high rate of O2 consumption and lower O2-transpprt capacity for Hb than most
adults also would be potentially susceptible to the hypoxic effects of increased COHb. Newer
data from laboratory animal studies on the developmental toxicity of CO suggest that
prolonged exposure to high levels (> 100 ppm) of CO during gestation may produce a
reduction in birthweight, cardiomegaly, and delayed behavioral development. Human data
are scant and more difficult to evaluate, but further research is warranted. Therefore,
additional studies are needed in order to determine if chronic exposure to CO, particularly at
low, near-ambient levels, can compromise the already marginal conditions existing in the
fetus and newborn infant.
The effects of CO on maternal-fetal relationships are not understood well; In addition
to fetuses and newborn infants, pregnant women also represent a susceptible group because
pregnancy is associated with increased alveolar ventilation and an increased rate of
O2 consumption that serves to increase the rate of CO uptake from inspired air. Perhaps a
more important factor is that pregnant women experience hemodilution due to the
disproportionate increase in plasma volume as compared to erythrocyte volume. This group,
therefore, should be studied to evaluate the effects of CO exposure and elevated COHb
levels.
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2.5.4 Population Groups at Greatest Risk for Ambient Carbon Monoxide
Exposure Effects
Angina patients or others with obstructed coronary arteries, but not yet manifesting
overt symptomatology of coronary artery disease, appear to be best established as a sensitive
group within the general population that is at increased risk for experiencing health effects
(i.e., exacerbation of cardiovascular symptoms) of concern at ambient or near-ambient
CO-exposure levels. Several other probable risk groups were identified: (1) fetuses and
young infants; (2) pregnant women; (3) the elderly, especially those with compromised
cardiopulmonary or cerebrovascular functions; (4) individuals with obstructed coronary
arteries, but not yet manifesting overt symptomatology of coronary artery disease;
(5) individuals with congestive heart faijure; (6) individuals with peripheral vascular or
cerebrovascular disease; (7) individuals with hematological diseases (e.g., anemia) that affect
C>2-carrying capacity or transport in the blood; (8) individuals with genetically unusual forms
of Hb associated with reduced O2-carrying capacity; (9) individuals with chronic obstructive
lung diseases; (10) individuals using medicinal or recreational drugs having central nervous
system (CNS) depressant properties; (11) individuals exposed to other pollutants (e.g.,
methylene chloride) that increase endogenous formation of CO; and (12) individuals who
have not been adapted to high altitude and are exposed to a combination pf high altitude and
CO. However, little empirical evidence currently is available by which to specify health
effects associated with ambient or near-ambient CO exposures in these probable risk groups.
2.6 CARBON MONOXIDE POISONING
The majority of this document deals with the relatively low concentrations of CO that
induce effects in humans at or near the lower margin of detection by current medical
technology. Yet, the health effects associated with exposure to this pollutant range from the
more subtle cardiovascular and neurobehavioral effects at low-ambient concentrations, as
identified in the preceding sections, to unconsciousness and death after prolonged chronic
exposure or after acute exposure to high concentrations of CO. The morbidity and mortality
resulting from the latter exposures are described briefly here to complete the picture of CO
exposure in present-day society.
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Carbon monoxide is responsible for more than half of the fatal poisonings that are
reported in the United States each year (Cobb and Etzel, 1991; National Safety Council,
1982). At sublethal levels, CO poisoning occurs in a small but important fraction of the
population. Certain conditions exist in both the indoor and outdoor ambient environments
that cause a small percentage of the population to become exposed to dangerous levels of CO.
Outdoors, concentrations of CO are highest near intersections, in congested traffic, near
exhaust gases from internal combustion engines and from industrial combustion sources, and
in poorly ventilated areas such as parking garages and tunnels. Indoors, CO concentrations in
the workplace or in homes that have faulty appliances or downdrafts and backdrafts have
been measured in excess of 100 ppm, resulting in COHb levels of greater than 10% for 8 h
of exposure. In addition, CO is found in the smoke produced by all types of fires. Of the
6,000 deaths from burns in the United States each year, more than half are related to
inhalation injuries where victims die from CO poisoning, hypoxia, and smoke inhalation
(Heimbach and Waeckerle, 1988).
Carbon monoxide poisoning is not new, although more attention to this problem has
been addressed recently in the scientific literature as well as in the popiular media. The first
scientific studies of the hypoxic effects of CO were described by Claude Bernard (1865).
The attachment of CO to Hb, producing COHb, was evaluated by Douglas et al. (1912),
providing the necessary tools for studying human response to CO. During the next half
century, numerous studies were conducted with the principal emphasis being on high
concentrations of COHb. Carbon monoxide poisoning as an occupational hazard (Grut,
1949) received the greatest attention due to the increased use of natural gas and the potential
for leakage of exhaust fumes in homes and industry. Other sources of CO have become more
important and more insidious. The clinical picture of CO poisoning, as described by Grut
(1949), relates primarily to the alterations in cardiac and CNS function due to the extreme
hypoxia induced.
Mortality from CO exposure is high. In 1985, 1,365 deaths due to CO exposure were
reported in England and Wales (Meredith and Vale, 1988). In the United States, more than
3,800 people die annually from CO (accidental and intentional), and more than 10,000
individuals seek medical attention or miss at least one day of work because of a sublethal ,
exposure (U.S. Centers for Disease Control, 1982). The per capita mortality and morbidity
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statistics for CO are surprisingly similar for the Scandinavian countries and for Canada, as
well. However, not all instances of CO poisoning are reported and complete up-to-date data
are difficult to obtain. Often the individuals suffering from CO poisoning are unaware of
their exposure because symptoms are similar to those associated with the flu or with clinical
depression. This may result in a significant number of misdiagnoses by medical professionals
(Heckerling et al., 1988, 1987; Kirkpatrick, 1987; Dolan et al., 1987; Barret
et al., 1985; Fisher and Rubin, 1982; Grace and Platt, 1981). Therefore, the precise number
of individuals who have suffered from CO intoxication is not known, but it is certainly larger
than the mortality figures indicate. Nonetheless, the reported literature available for review
indicates the seriousness of this problem.
The symptoms, signs, and prognosis of acute poisoning correlates poorly with the level
of COHb measured at the time of arrival at the hospital (Meredith and Vale, 1988).
Carboxyhemoglobin levels below 10% usually are not associated with symptoms. At the
higher COHb saturations of 10 to 30%, neurological symptoms of CO poisoning can occur,
such as headache, dizziness, weakness, nausea, confusion, disorientation, and visual
»
disturbances. Exertional dyspnea, increases in pulse and respiratory rates, and syncope are
observed with continuous exposure producing COHb levels in excess of 30 to 50%. When
COHb levels are higher than 50%, coma, convulsions, and cardiorespiratory arrest may
occur.
Different individuals experience very different clinical manifestations of CO poisoning
and, therefore, have different outcomes even under similar exposure conditions. Norkool and
Kirkpatrick (1985) found that COHb levels in individuals who had never lost consciousness
ranged from 5 to 47%. In individuals who were found unconscious but regained
consciousness at hospital arrival, the range was 10 to 64%; for those remaining unconscious,
COHb levels varied from 1 to 53%. The large differences in COHb levels found in these
individuals most likely resulted from differences in time elapsing from exposure to CO and
admission to the hospital. Considerable differences in exposure duration may also be
responsible for the lack of correlation between blood COHb and the clinical severity of CO
poisoning (Sokal, 1985; Sokal and Kralkowska, 1985). These data clearly indicate that
COHb saturations correlate so poorly with clinical status that they have little prognostic
significance.
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The level of CO in the tissues may have an equal or greater impact on the clinical status
of the patient than the blood level of CO (Broome et al., 1988). The extent of tissue
toxicity, which becomes significant under hypoxic conditions or with very high levels of CO,
is likely determined by the length of exposure. For example, a short exposure to CO at high
ambient concentrations may allow insufficient time for significant increases in tissue levels of
CO to occur. The syncope observed in individuals with CO poisoning who were exposed in
this manner may be the result of simple hypoxia with rapid recovery despite high COHb
levels. On the other hand, prolonged exposure to CO prior to hospital arrival may allow
sufficient uptake of CO by tissues to inhibit the function of intracellular compounds such as
Mb. This effect, in combination with the existing reduction in tissue O2, may cause
irreversible CNS or cardiac damage.
Patients with CO poisoning respond to treatment with 100% O2 (Pace et al., 1950). If
available, treatment with hyperbaric O2 (HBO) at 2.5 to 3 times atmospheric pressure for
90 min is preferable (Myers, 1986), but the precise conditions requiring treatment have been
a topic of debate in the literature (Thorn and Keim, 1989; Roy et al., 1989; Raphael et al.,
1989; Brown et al., 1989; James, 1989; Van Hoesen et al., 1989; Broome et al., 1988;
Norkool and Kirkpatrick, 1985; Mathieu et al., 1985). It has been suggested that if COHb is
above 25%, HBO treatment should be initiated (Norkool and Kirkpatrick, 1985), although
treatment plans based on specific COHb saturations is not well founded (Thorn and Keim,
1989). Most hyperbaric centers treat patients with CO intoxication when they manifest loss
of consciousness or other neurological signs and symptoms (excluding.headache) regardless of
the COHb saturation at presentation (Piantadosi, 1990). The half time elimination of CO
while breathing air is approximately 320 min; when breathing 100% O2, it is 80 min; and
when breathing O2 at 3 atmospheres, it is 23 min (Penney et al., 1983; Myers et al., 1985).
Successful removal of CO from the blood does not ensure an uneventful recovery with
no further clinical signs or symptoms., Neurological problems may develop insidiously weeks
after recovery from the acute episode of CO poisoning (Meredith and Vale, 1988). These
problems include intellectual deterioration; memory impairment; and cerebral, cerebellar, and
midbrain damage. Up to two-fifths of patients develop memory impairment and a third
suffer late deterioration of personality. Arrhythmias are a common complication of CO
poisoning. Conduction defects also are found, possibly from cardiomyopathies, but the
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precise mechanisms by which these occur are not understood. Other systemic complications,
such as skeletal muscle necrosis, renal failure, blood dyscrasias, pulmonary edema, and
hemorrhage in various tissues also can occur as a result of CO poisoning.
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Salvatore, S. (1974) Performance decrement caused by mild carbon monoxide levels on two visual functions.
J. Saf. Res. 6: 131-134.
Schulte, J. H. (1963) Effects of mild carbon monoxide intoxication. Arch. Environ. Health 7: 524-530.
Sheps, D. S.; Adams, K. F., Jr.; Bromberg, P. A.; Goldstein, G. M.; O'Neil, J. J.; Horstman, D.; Koch, G.
(1987) Lack of effect of low levels of carboxyhemoglobin on cardiovascular function in patients with
ischemic heart disease. Arch. Environ. Health 42: 108-116.
Sokal, J. A. (1985) The effect of exposure duration on the blood level of glucose pyruvate and lactate in acute
carbon monoxide intoxication in man. J. Appl. Toxicol. 5: 395-397.
Sokal, J. A.; Kralkowska, E. (1985) The relationship between exposure duration, carboxyhemoglobin, blood
glucose, pyruvate and lactate and the severity of intoxication hi 39 cases of acute carbon monoxide
poisoning in man. Arch. Toxicol. 57: 196-199.
Statutes-at-Large. (1986) Supermnd Amendments and Reauthorization Act of 1986, PL 99-499, October 17,
1986, title IV, §403: radon gas and indoor air quality research program. Stat. 100: 1758-1760.
f
Stewart, R. D.; Newton, P. E.; Kaufman, J.; Forster, H. V.; Klein, J. P.; Keelen, M. H., Jr.; Stewart, D. J.;
Wu, A.; Hake, C. L. (1978) The effect of a rapid 4% carboxyhemoglobin saturation increase on maximal
treadmill exercise. New York, NY: Coordinating Research Council, Inc.; report no.
CRC-APRAC-CAPM-22-75. Available from: NTIS, Springfield, VA; PB-296627.
Thorn, S. R.; Keim, L. W. (1989) Carbon monoxide poisoning: a review. Epidemiology, pathophysiology,
clinical findings, and treatment options including hyperbaric oxygen therapy. J. Toxicol. Clin. Toxicol.
27: 141-156.
U.S. Centers for Disease Control. (1982) Carbon monoxide intoxication - a preventable environmental health
hazard. Morb. Mortal. Wkly. Rep. 31: 529-531.
2-28
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U.S. Code. (1991) Clean Air Act, §108, air quality criteria and control techniques, §109, national ambient air
quality standards. U.S. C. 42: §§7408-7409.
U.S. Department of Health and Human Services. (1990) Vital and health statistics: current estimates from the
National Health Interview Survey, 1989. Hyattsville, MD: Public Health Service, National Center for
Health Statistics; DHHS publication no. (PHS) 90-1504. (Series 10: data from the National Health
Survey no. 176).
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monoxide exposure: an addendum to the 1979 EPA air quality criteria document for carbon monoxide.
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Triangle Park, NC: Office of Air Quality Planning and Standards; EPA report no. EPA-450/4-91-003.
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oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? A case report and
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Weiser, P. C.; Morrill, C. G.; Dickey, D. W.; Kurt, T. L.; Cropp, G. J. A. (1978) Effects of low-level carbon
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Wright, G.; Randell, P.; Shephard, R. J. (1973) Carbon monoxide and driving skills. Arch. Environ. Health
27: 349-354.
2-29
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-------
3. PROPERTIES AND PRINCIPLES OF FORMATION
OF CARBON MONOXIDE
3.1 INTRODUCTION
Carbon monoxide (CO) was first discovered to be a minor constituent of the earth's
atmosphere by Migeotte (1949) in 1948. While taking measurements of the solar spectrum,
he observed a strong absorption band in the infrared region at 4.7 pm, which he attributed to
CO (Lagemann et al., 1947). On the twin bases of the belief that the solar contribution to
that band was negligible and bis observation of a strong day-to-day variability in absorption,
Migeotte concluded that an appreciable amount of CO was present in the terrestrial
atmosphere of Columbus, Ohio. In the 1950s many more observations (Benesch et al., 1953;
Faith et al., 1959; Locke and Herzberg, 1953; Migeotte and Neven, 1952; Robbins et al.,
1968; Sie et al., 1976) of CO were made, with measured concentrations ranging from 0.08 to
100 ppm. On the basis of these and other measurements available in 1963, Junge (1963)
stated that CO appeared to be the most abundant trace gas, other than, carbon dioxide (CO^,
in the atmosphere. The studies of Sie et al. (1976) indicated higher mixing ratios near the
ground than in the upper atmosphere, implying a source in the biosphere, but Junge
emphasized that knowledge of the sources and sinks of atmospheric CO was extremely poor.
It was not until the late 1960s that concerted efforts were made to determine the various
production and destruction mechanisms for CO in the atmosphere.
Eveii far from human habitation in remote areas of the Southern Hemisphere, natural
o
background CO concentrations average around 0.05 mg/m , primarily as a result of natural
processes such as forest fires and the oxidation of methane. In the Northern Hemisphere,
background concentrations are 2 to 3 times higher because of more extensive human
activities. Much higher concentrations occur in cities, arising from technological sources
such as automobiles and the production of heat and power. Carbon monoxide emissions are
increased when the fuel is burned in an incomplete or inefficient way. The physical and
chemical properties of CO suggest that its atmospheric removal occurs primarily by reaction
of CO with hydroxyl (OH*) radicals.
3-1
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The remainder of this chapter focuses on the physical properties and formation
principles of CO that contribute to its release into the atmosphere. In Chapter 4, other source
and sink estimates as well as the global cycle of CO are described; in Chapter 6, the various
factors that determine the technological emission source strengths are discussed., ,-
3.2 PHYSICAL PROPERTIES
Carbon monoxide is a tasteless, odorless, colorless diatomic molecule that exists as a
gas in the earth's atmosphere. Radiation in the visible and near ultraviolet regions of the
electromagnetic spectrum is not absorbed by CO, although the molecule does have weak
absorption bands between 125 and 155 nm. It absorbs radiation in the infrared regipn
corresponding to the vibrational excitation of its electronic ground state. Carbon monoxide
has a low electric dipole moment (0.10 debye); short interatomic distance (1.23 A); and high
heat of formation from atoms, or bond strength (2072 kJ/mol). These observations suggest
that the molecule is a resonance hybrid of three structures (Perry et al., 1977), all of which
contribute nearly equally to the normal ground state. General physical properties of CO are
given in Table 3-1.
3.3 GASEOUS CHEMICAL REACTIONS OF CARBON MONOXIDE
In the atmosphere, carbon monoxide reacts with OH* radicals to produce CO2 and
hydrogen (H*) atoms.
OH* + CO •* CO2 + H* (3-1)
The H* atoms formed in this process react very rapidly with oxygen (O^ to produce
hydroperoxyl radicals (HO*/). ,. ..
- H* + O2 (+M) •* HO*. (+M) (3-2)
3-2
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TABLE 3-1. PHYSICAL PROPERTIES OF CARBON MONOXIDEa
Molecular weight 28.01
Critical point -140° C at 34.5 atm ' A
Melting point -199 °G
Boiling point -191.5 °C
Density
atO °C, latm 1.250g/L
at 25 °C, latm 1.145 g/L
Specific gravity relative to air 0.967
Solubility in waterb
atO°C 3.54 mL/100 mL (44.3 ppmm)c
at20°C 2.32 mL/100 mL (29 .,0 ppmm)c
at 25 °C 2.14 mL/100 mL (26,, 8 ppmm)c
Explosive limits in air 12.5-74.2%
Fundamental vibration transition 2,143.3 cm"1
+, v1 = 1 Ev"O)(4.67
Conversion factors
at 0 °C, 1 atm 1 mg/m3 = 0.800 ppmd
at 25 °C, latm 1 ppm = 1.250 mg/in3
Img/m3 = 0.873 ppmd
1 ppm = 1.145 mg/m3
aNational Research Council (1977).
Volume of carbon monoxide is at 0 °C, 1 atm (atmospheric pressure at sea level = 760 torr).
cPartsper million by mass (ppmm = ftg/g). • ,
Parts per million by volume (ppm = mg/L).
See glossary of terms and symbols for abbreviations and acronyms.
The liberated HO*, radicals can react with nitric oxide to form nitrogen dioxide (NO^ and
regenerate OH* radicals.
HO*, + NO -+ NO2 + OH* (3-3)
The photolysis of NO2 leads to the formation of ozone; hence, CO c;m contribute to the
production of photochemical smog in the lower troposphere, but this path is thought to play
an important role only in areas remote from urban pollution. Other radicals besides OH* also
can react with CO.
3-3
-------
CO + HO2 •* CO2 + OH* (3-4)
CO + NO^ -> CO2 + NO2 (3-5)
CO + CH3O2-> product (3-6)
The rates of these reactions, however, are so slow that their contribution to the overall
chemistry occurring in the atmosphere is expected to be very slight. Hampson and Garvin
(1978), in their review of chemical kinetics data, recommended a rate constant of less than
10"19 cm3/molecule-s for Reaction 3-4. DeMore et al. (1987), based on their analysis of rate
data, suggested a rate constant of less than 4.0 x 10~19 cm3/molecule-s for Reaction 3-5 and
Heicklen (1973) recommended a value of 4 x 10~17 cm3/molecule-s for Reaction 3-6. In
contrast, the rate constant for the CO + OH* reaction is of the order of
10"13 cm3/molecule-s, a factor of at least 104 to 106 greater than other known reactions
between CO and atmospheric constituents. Thus, the reaction with OH* is the only reaction
involving CO that is expected to be of any consequence in the atmosphere.
The reaction of CO with OH* is one of the most studied of all atmospheric reactions.
Table 3-2 summarizes the results obtained in a few of these studies. More complete reviews
of the kinetics of this reaction can be found in Hampson and Garvin (1978), Baulch et al.
(1980), and DeMore et al. (1987). As seen in Table 3-2, the rate constants obtained in the
late 1960s and early 1970s agreed fairly well and led the National Bureau of Standards
(Hampson and Garvin, 1975) to recommend a value of 1.4 x 10"13 cm3/molecule-s for the
rate constant. Af that time, there did not appear to be either a substantial temperature or
pressure dependency for this reaction. In the mid 1970s, however, Cox et al. (1976) studied
the reaction at 700 torr using a mixture of nitrogen (N2) and O2 as the diluent gas. They
obtained a rate constant of 2.7 X 10"13 cm3/molecule-s and suggested that the reaction might
be subject to a pressure effect. At approximately the same time, Sie et al. (1976) studied the
CO + OH* reaction as a function of pressure. When molecular hydrogen was used as the
diluent gas, they found that the rate constant increased from 0.9 x 10"13 cm3/molecule-s at a
10*2 • ' •
pressure of 20 torr to 3.3 x 10"1 cm /molecule-s at 700 torr. When argon was used as the
diluent gas, however, the rate of the reaction was found to be insensitive to pressure changes.
Subsequent research has supported this finding. In general, it appears that there is no
pressure effect if noble gases (for example, helium or argon) are used as the carrier gas, but
3-4
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TABLE 3-2. REPORTED ROOM TEMPERATURE RATE CONSTANTS FOR THE
REACTION OF HYDROXYL FREE RADICALS WITH CARBON MONOXIDE
Reference
No observed pressure dependence
Greiner (1969)
Stuhl and NM (1972)
Westenberg and deHaas (1973)
Smith and Zellner (1973)
Howard and Evenson (1974)
Davis et al. (1974)
Gordon and Mulac (1975)
Atkinson et al. (1976)
Pressure dependence observed
Cox et al. (1976)
Sie et al. (1976)
Perry et al. (1977)
Chan et al. (1977)
Biermann et al. (1978)
Paraskevopoulos and Irwin (1984)
DeMore (1984)
Hofzumahaus and Stuhl (1984)
Hyries et al. (1986)
NiM et al. (1984)
Hynes et al. (1986)
Pressure
(ton)
100
20
1-3
10-20
0.3-6
20
730
25-650
700
20-700
25-600
100-700
25-750
20-700
200-730
20-700
50-700
700
50-700
Diluent
He
He
He or Ar
He or N2O + H2
He, Ar, or N2
He or N2
Ar
Ar
N2 + 02
H2
SF6
Air
N2
N2
N2 '
N2
N2
Air
Air
Rsite constant X 10 , 13
(cm3/molecule-s)
1.4 ± 0.2
1.3 ±0.2
1.3
1.4
1.6 ±0.2
1.6
1.5 ± 0.1
1.5 ± 0.2
2.7 ± 0.2
3.3 ±0.2
3.4 ± 0.3
3.0 ±0.2
2.8 ± 0.3
2.2 ± 0.1
2.1 ± 0.4
2.3 ± 0.2
2.1 ±0.2
2.4 ± 0.1
2.3 ± 0.2
*Rate constants listed are the values obtained at the highest pressure used in each study.
See glossary of terms and symbols for abbreviations and acronyms.
3-5
-------
when other gases are used, such as N2 or O2, which are more representative of the
atmosphere, the CO + OH* reaction rate exhibits a strong pressure dependency. In all cases,
the rate constant listed in Table 3-2 for the pressure dependent studies is the value obtained at
the highest pressure used in each study. Excellent agreement is noted for the studies
conducted in 1984 and later years.
The National Aeronautics and Space Administration Date Evaluation Panel (DeMore
et al., 1987) recently examined the kinetics date for the CO + OH* reaction. They first
analyzed all of the direct, low-pressure determinations to derive a zero pressure value for the
rate constant. They then performed a weighted squares analysis of all the pressure-dependent
date obtained since 1984 and fitted it to the expression
K = K°X(l + CPatir) (3-7)
where K° is the zero pressure value for the rate constant, C is a constant, and Patm is the
pressure in atmospheres.
They found that the data were best fit using the expression
K = (1.50 ± 0.45) X 10~13 (1 + 0.6Patm ) (3-8)
At a pressure of 760 torr, this corresponds to a rate constant of 2.4 + 0.7 x
10~~13 cm3/molecule~s, independent of temperature. Thus, the rate constant at atmospheric
pressure is substantially larger than the value that previously had been assumed for this '
reaction. The larger value has led to important changes in our understanding of the global
CO cycle. This point is discussed in more detail in Chapter 4.
3.4 PRINCIPLES OF FORMATION BY SOURCE CATEGORY
Carbon monoxide is produced at the earth's surface during the combustion of fuels and
in the atmosphere during the oxidation of anthropogenic and biogenic hydrocarbons. The
3-6
-------
role of man-made and natural hydrocarbons in CO production is discussed in Chapter 6; only
the production of CO from combustion sources is addressed here.
The burning of any carbonaceous fuel produces two primary products:, CQ2 and CO.
The production of CO2 predominates when the air or O2 supply is in excess of the
stoichiometric needs for complete combustion. If burning occurs under fuel-rich conditions,
with less air or O2 than is needed, CO will be produced in abundance. In past years, -most of
the CO and CO2 formed simply was emitted into the atmosphere. In recent years, concerted
efforts have been made to reduce ambient-air concentrations of materials that are potentially
harmful to humans. Much CO, most notably from mobile sources, is converted to CO2, then
that is emitted into the atmosphere. ,
In the Northern Hemisphere, the background concentration of CO contributes less than
0.23 mg/m3 (0.20 ppm) to the ambient-air concentration at a given urban location. The
natural component in this background CO level, resulting from processes such as forest fibres,
oxidation of methane, and biological activity, is estimated to be about 0.05 mg/m3
(0.04 ppm) (Seller and Junge, 1970). See Chapter 4 for a discussion of global background
concentrations.
Considerable effort has been made to reduce emissions of CO and other pollutants to the
atmosphere. Because the automobile engine is recognized to be the major source of CO in
most urban areas, special attention is given to the control of automotive emissions. Generally
the approach has been technological: reduction of CO emissions to the atmosphere either by
improving the efficiency of the combustion processes, thereby increasing the yield of CO2
and decreasing the yield ,of CO; or by applying secondary catalytic combustion reactors to the
waste gas stream to convert CO to CQ2.
The development and application of control technology to reduce emissions of CO from
combustion processes generally have been successful and are continuing to receive deserved
attention. The reduction of CO emissions from 7.0 to 3.4 g/mi, scheduled for the 1981
model year, was delayed 2 years, reflecting in part the apparent difficulty encountered by the
automobile industry in developing and supplying the required control technology. The,CO
emission limit for light-duty vehicles (LDVs) at low altitude has,been 3.4 g/mi since 1983;
since 1984, this limit applied to LDVs at all altitudes.
3-7
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Table 3-3 shows the automobile emissions control schedules that have resulted from the
1970 Clean Air Act (CAA) (U.S. Code, 1991) and subsequent amendments, notably the 1977
and 1981 CAA Amendments.
The problems encountered in mass producing and marketing effective control technology
for automobile engines are complex because a number of simultaneous requirements are
involved (i.e., control of multiple air pollutants, fuel economy and efficiency, durability and
quality control of components, and maintenance). Emission factor program testing conducted
by EPA during the 1980s indicates that the durability of emission control systems continues ,/
to present a problem for in-use vehicles intended to comply with the 1983 and later ,
requirement that CO emissions be limited to not more than 3.4 g/mi through the 50,000-mile,
useful-life compliance period. (CO emissions are less than 3.4 g/mi for new, low-mileage
automobiles.)
The following subsections present a brief discussion of the general principles and
mechanisms of CO formation and control of emissions associated with the many combustion
processes. The processes commonly are classified in two broad types, mobile sources and
stationary sources, because this division generally does separate distinct types of major
combustion devices. Control techniques for CO emissions from mobile and stationary
sources are detailed in Control Techniques for Carbon Monoxide Emissions (U.S.
Environmental Protection Agency, 1979). .•----.„>.
3.4.1 General Combustion Processes
Incomplete combustion of carbon-containing compounds creates varying amounts of
CO. The chemical and physical processes that occur during combustion are complex because
they depend not only on the type of carbon compound reacting with O2 but also on the
conditions existing in the combustion chamber (Mellor, 1972; Pauling, 1960). Despite the
complexity of the combustion process, certain general principles regarding the formation, of. ,
CO from the combustion of hydrocarbon fuels are accepted widely. ,
Gaseous or liquid hydrocarbon fuel reacts with O2 in a chain of reactions that result in
CO. Carbon monoxide then reacts with OH* radicals to form CO2. The second reaction is ,
approximately 10 times slower than the first. In coal combustion, too, the reaction of carbon
3-8
-------
TABLE 3-3. SUMMARY OF LIGHT-DUTY VEHICLE
EMISSIONS STANDARDS8'1*
Year
Test
Procedure0
Hydrocarbons
Carbon
Monoxide
Oxides of
Nitrogen
Evaporative
Particulates Hydrocarbons6
Gasoline-fueled LDVs
Prior to controls
1968-69-
1970 .
1971
1972
1973-74
7-mode
7-mode
CVS-75
7-mode
50-100 CID
101-140 CID
> 140 CID
7-mode
7-mode
CVS-72
CVS-72
850 ppm
11 g/mi ...
8.8 g/mi
410 ppm
350 ppm
275 ppm
2.2 g/mi
2.2 g/mi
3.4 g/mi
3. 4 g/mi
3.4 %
80 g/mi
87 g/mi
2.3 »
2.0 %
1.5 %
23 g/mi
23 g/mi
39 g/mi
39 g/mi
1000 ppm
4 g/mi
3.6 g/mi
-
-
-
-
-
- - .
-
-
. ,-
-
-
. . .
-
- . . - -
6.0 g/testf
2.0g/test
2.0 g/test
Gasoline-fueled and Diesel LDVs
1975-76
1977S
1978-79
1980
1981
1982k
1983k
1984-86"1
1987 & later1"
CVS-75
, CVS-75
CVS-75
CVS-75
CVS-75
CVS-75
CVS-75
CVS-75
CVS-75
1.5 g/mi
1.5 g/mi
1.5 g/mi
0.41 g/mi
0.41 g/mi
0.41 g/mi
(0.57)
0.41 g/mi
(0.57)
0.41 g/mi
0.42 g/mi
(0.41)
15 g/mi
15 g/mi
15 g/mi
7.0 g/mi
3.4g/mih
3.4g/mih
(7.8)1
3.4 g/mi
(7.8)
3.4 g/mi
3.4 g/mi
(3.4)
3.1 g/mi
2.0 g/mi
2.0 g/mi
2.0g/mi
1.0 g/mi'J
l.Og/mi'J
(l.O/J
1.0 g/mi'
a.oy
1.0 g/mi1
1.0 g/mi
(1.0)
2.0 g/test
2.0 g/test
6.0 g/test
- 6.0 g/test
2.0 g/test
0.60 g/mi 2.0 g/test
(-) (2.6)
0.60 g/mi 2.0 g/test
(0.60) (2.6)
0.60 g/mi 2.0 g/test
0.20 g/min 2.0 g/test
(0.20)n (2-0)
Standards do not apply to LDVs with engines less than 50 CID from 1968 through 1974.
See glossary of terms and symbols for abbreviations and acronyms.
cDifferent test procedures, which vary in stringency, have been used since the early years of emission control. The appearance that the
standards were relaxed from 1971 to 1972 is incorrect; the 1972 standards actually are more stringent because of the 1972 test
procedure.
Applies only to diesel LDVs.
Evaporative emissions determined by carbon-trap method through 1977, SHED procedure beginning in 1978. Applies only to gasoline-
fueled LDVs.
Evaporative standard does not apply to off-road utility LDVs for 1971.
SLDVs sold in specified high-altitude counties are required to meet these standards at high altitude.
^Carbon monoxide standard is waived to 7.0 g/mi for 1981-82 for certain LDVs.
JQxides of nitrogen standard is waived to 7.0 g/mi for 1981-82 for certain LDVs.
^Oxides of nitrogen standard for 1981-82 is 2.0 g/mi for American Motors Corporation LDVs.
^Standards in parentheses apply to LDVs sold in specified high-altitude counties.
LDVs eligible for a carbon monoxide waiver to 7.0 g/mi at low altitude are eligible for a waiver to 11 g/mi at high altitude,
"'The same numerical standards apply to LDVs sold in high-altitude areas. Exemptions from compliance at high-altitude are provided for
qualifying low-performance vehicles.
"Emissions averaging may be used to meet this standard, provided that emissions from LDVs produced for sale in California or in
designated high-altitude areas may be averaged only within each of those areas.
Source: U.S. Environmental Protection Agency (1985).
3-9
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and O2 to form CO is one of the primary reactions, and a large fraction of carbon atoms go
through the CO form. Again, the reaction of CO to CO2 is much slower.
Four basic variables control the concentration of CO produced in the combustion of all
hydrocarbon gases. These are (1) O2 concentration, (2) flame temperature, (3) gas residence
time at high temperatures, and (4) combustion chamber turbulence. Oxygen concentration
affects the formation of both CO and CO2 because O2 is required in the initial reactions with
the fuel molecule and in the formation of the OH* radical. As the availability of
O2 increases, more complete conversion of CO to CO2 results. Flame and gas temperatures
affect both the formation of CO and the conversion of CO to CO2 because both reaction rates
increase exponentially with increasing temperature. Also, the OH* radical concentration in
the combustion chamber is very temperature-dependent. The conversion of CO to CO2 also
is enhanced by longer residence time, because this is a relatively slow reaction in comparison
with CO formation. Increased gas turbulence in the combustion zones increases the actual
reaction rates by increasing the mixing of the reactants and assisting the relatively slower
gaseous diffusion process, thereby resulting in more complete combustion.
3.4.2 Combustion Engines
3.4.2.1 Mobile Combustion Engines
Most mobile sources of CO are internal combustion engines of two types: (1) gasoline-
fueled, spark-ignition, reciprocating engines (carbureted or fuel-injected); and (2) diesel-
rueled reciprocating engines. The CO emitted from any given engine is the product of the
following factors: (1) the concentration of CO in the exhaust gases, (2) the flow rate of
exhaust gases, and (3) the duration of operation.
Internal Combustion Engines (Gasoline-Fueled, Spark-Ignition Engines)
Exhaust concentrations of CO increase with lower (richer) air-to-fuel (A/F) ratios, and
decrease with higher (leaner) A/F ratios, but remain relatively constant with ratios above the
stoichiometric ratio of about 15:1 (Hagen and Holiday, 1964). The behavior of gasoline
automobile engines before and after the installation of pollutant control devices differs
considerably. Depending on the mode of driving, the average uncontrolled engine operates at
A/F ratios ranging from about 11:1 to a point slightly above the stoichiometric ratio. During
3-10
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the idling mode, at low speeds with light load (such as low-speed cruise), during the full-
open throttle mode until speed picks up, and during deceleration, the A/F ratio is low in
uncontrolled cars and CO emissions are high. At higher speed cruise and during moderate
acceleration, the reverse is true. Cars with exhaust controls generally remain much closer to
stoichiometric A/F ratios in all modes, and thus the CO emissions are kept lower. The
relationship between CO concentrations in engine exhaust and A/F ratios is shown in
Figure 3-1. The exhaust flow rate increases with increasing engine power output.
.2
I
of
T>
1
14 15
Air-Fuel Ratio
16
17
18
19
Figure 3-1. Effect of air-fuel ratio on exhaust gas carbon monoxide concentrations from
three gasoline-fueled test engines.
Source: Hagen and Holiday (1964).
The decrease in available oxygen with increasing altitude has the effect of enriching the
A/F mixture and increasing CO emissions from carbureted engines. Fuel-injected gasoline
engines, which predominate in the vehicle fleet today, have more closely controlled -
3-11
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A/F ratios and are designed and certified to comply with applicable emission standards
regardless of elevation (U.S. Environmental Protection Agency, 1983).
Correlations between total emissions of CO in grams per vehicle mile and average route
speed show a decrease in emissions with increasing average speed (Simonaitis and Heieklen,
1972; Stuhl and NiM, 1972; U.S. Environmental Protection Agency, 1985). During low-
speed conditions (below 32 km/h or 20 mi/h average route speed), the greater emissions per
unit of distance traveled are attributable to (1) an increased frequency of acceleration,
deceleration, and idling encountered in heavy traffic; and (2) the consequent increase in the
operating time per mile driven.
The CO and the unburned hydrocarbon exhaust emissions from an uncontrolled engine
result from incomplete combustion of the fuel-air mixture. Emission control on new vehicles
is being achieved by engine modifications, improvements in engine design, and changes in
engine operating conditions. Substantial reductions in CO and other pollutant emissions result
from consideration of design and operating factors such as leaner, uniform mixing of fuel and
air during carburetion; controlled heating of intake air; increased idle speed; retarded spark
timing; improved cylinder head design; exhaust thermal reactors; oxidizing and reducing
catalysts; secondary air systems; exhaust recycle systems; electronic fuel injection; A/F ratio
feedback controls; and modified ignition systems (National Academy of Sciences, 1973).
Internal Combustion Engines (Diesel Engines)
Diesel engines in use are primarily the heavy-duty type that power trucks and buses.
Diesel engines allow more complete combustion and use less volatile fuels than do spark-
ignition engines. The operating principles are significantly different from those of the
gasoline engine. In diesel combustion, CO concentrations in the exhaust are relatively low
because high temperature and large excesses of oxygen are involved in normal operation.
The exhaust emissions from diesel engines have the same general components as gasoline
engine emissions, though the concentrations of different pollutants vary considerably. For
example, the diesel emits larger quantities of nitrogen oxides and polycyclic organic
participates than gasoline engines; it emits less CO.
3-12
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3.4.2.2 Stationary Combustion Sources (Steam Boilers)
This section refers to fuel-burning installations such as coal-, gas-, or oil-fired heating
or power generating plants (external combustion boilers).
In these combustion systems, the formation of CO is lowest at a ratio near or slightly
above the stoichiometric ratio of air to fuel. At lower than stoichiometric A/F ratios, high
CO concentrations reflect the relatively low O2 concentration and the possibility of poor
reactant mixing from low turbulence. These two factors can increase emissions even though
flame temperatures and residence time are high. At higher than stoichiometric A/F ratios,
increased CO emissions result from decreased flame temperatures and shorter residence time.
These two factors remain predominant even when O2 concentrations and turbulence increase.
Minimal CO emissions and maximum thermal efficiency, therefore, require combustor
designs that provide high turbulence, sufficient residence time, high temperatures, and near
stoichiometric A/F ratios. Combustor design dictates the actual approach to that minimum.
The measurement of CO in effluent gas is used as an indication of improper and
inefficient operating practice for any given combustor, or of inefficient combustion.
3.4.3 Other Sources
There are numerous industrial activities that result in the emission of CO at one or more
stages of the process (Walsh and Nussbaum, 1978; U.S. Environmental Protection Agency,
1979, 1985)., Manufacturing pig iron can produce as much as 700 to 1,050 kg CO/metrie ton
of pig iron. Other methods of producing iron and steel can produce CO at a rate of 9 to
118.5 kg/metric ton. However, most of the CO generated is normally recovered and used as
fuel. Conditions such as "slips," abrupt collapses of cavities in the coke-ore mixture, can
cause instantaneous emissions of CO that temporarily exceed the capacity of the control
equipment. Slips have been reduced greatiy with modern equipment. Grey-iron foundries
can produce 72.5 kg CO/metric ton of product, but an efficient afterburner can reduce the
CO emission to 4.5 kg/metric ton.
Charcoal production results in average CO emissions of 172 kg/metric ton. Emissions
from batch Mlns are difficult to control, although some may have afterburners. Afterburners
can more easily reduce, by an estimated 80% or more, the relatively constant CO emissions
from continuous charcoal production. Emissions from carbon black manufacture can range
3-13
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from 5 to 3,200 kg CO/metric ton depending on the efficiency and quality of the emission
control systems.
Some chemical processes, such as phthalic anhydride production, give off as little as
6 kg CO/metric ton with proper controls or as much as 200 kg CO/metric ton if no controls
are installed. There are numerous other chemical processes that produce relatively small CO
emissions per metric ton of product: sulfate pulping for paper produces 1 to 30 kg
CO/metric ton, lime manufacturing normally produces 1 to 4 kg CO/metric ton, and CO
from adipic acid production is zero or slight with proper controls. Other industrial chemical
processes that cause CO emissions are the manufacture of terephthalic acid and the synthesis .
of methanol and higher alcohols. As a rule, most industries find it economically desirable to
install suitable controls to reduce CO emissions.
Even though some of these CO emission rates seem excessively high, they are, in fact,
only a small part of the total pollutant load. Mention of these industries is made to
emphasize the concern for localized pollution problems when accidents occur or proper
controls are not used.
In some neighborhoods, wintertime CO emissions include a significant component from
x
residential fireplaces and wood stoves. Emissions of CO can vary from 18 to 140 g/kg
depending on design, fuel type, and skill of operation.
Although the estimated CO emissions resulting from forest wildfires in the United States
have fluctuated between about 4 and 9 x 106 metric tons per year since 1970 and were
6.2 X 106 metric tons in 1989, the estimated total industrial process CO emissions have
declined from 8.9 x 106 metric tons in 1970 to 4.6 x 106 metric tons in 1989 (U.S.
Environmental Protection Agency, 1991). Emissions of CO from all sources are summarized
in Chapter 6.
3-14
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Howard, C. J.; Evenson, K. M. (1974) Laser magnetic resonance study of the gas phase reactions of OH with
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Migeotte, M.; Neven, L. (1952) Recents progres dans Pobservation du spectre infra-rouge du soleil a la station
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Perry, R. A.; Atkinson, R.; Pitts, J. N., Jr. (1977) Kinetics of the reactions of OH radicals with Cft and CO.
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Robbins, R. C.; Borg, K. M.; Robinson, E. (1968) Carbon monoxide in the atmosphere. J. Air Pollut. Control
Assoc. 18: 106-110.
Seiler, W.; Junge, C. (1970) Carbon monoxide in the atmosphere, J. Geophys. Res. 75: 2217-2226. ,.
Sie, B, K. T.; Simonaitis, R.; Heicklen, J. (1976) The reaction of OH with CO. Int. J. Chem. Kinet. 8: 85-98.
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reactions of OH with CO, C2H4 and Cf^. J. Chem. Soc. Faraday Trans. 2: 69: 1617-1627.
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4. THE GLOBAL CYCLE OF CARBON MONOXIDE:
TRENDS AND MASS BALANCE
4.1 INTRODUCTION
In the troposphere, carbon monoxide (CO) may control the removal, and therefore the
concentrations, of hydroxyl (OH*) radicals (Crutzen, 1974; Khalil and Rasmussen, 1985;
Levine et al., 1985; Sze, 1977; Thompson and Cicerone, 1986). The chemical reactions of
CO alsp may produce substantial amounts of ozone (O3) in the troposphere (Conrad and
Seiler, 1982; Fishman and Crutzen, 1978; Fishman et al., 1980; Fishman and Seller, 1983;
Seiler and Fishman, 1981). If the concentrations of CO increase, O3 may increase; at the
same time, OH* may be depleted, thus affecting the global cycles of many natural and
anthropogenic trace gases that are removed from the atmosphere by reacting with OH*.
Therefore, increasing CO may indirectly affect the global climate and contribute to
widespread changes in atmospheric chemistry.
The purpose of this chapter is to review the present understanding of the sources and
sinks of CO and the resulting global distributions and trends. The first section is a review of
the global sources and sinks and the estimated atmospheric lifetime of CO. The next section
deals with the global distribution of CO resulting from the sources and sinks, including
variations with seasons, altitude, and latitude. Next, there is an analysis of the current
evidence for global trends that reflect an imbalance of the sources and sinks probably caused
by steadily increasing emissions from anthropogenic sources. The chapter is concluded with
a summary.
4.2 GLOBAL SOURCES, SINKS, AND LIFETIME
The mass balance of a trace gas in the atmosphere can be described as a balance
between the rate of change of the global burden added to the annual rate of loss on the one
side and balanced by the global emissions on the other side (d concentration/dt + loss rate =
source emissions). In steady state, the atmospheric lifetime (T) is the ratio of the global
burden to the loss rate. The global burden is the total number of molecules of a trace gas in
4-1
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the atmosphere or its total mass. The concentration of a trace gas can vary (dC/dt is not 0)
when either the loss rate or the emissions vary cyclically in time, representing seasonal
variations, or vary over a long time, often representing trends of human industrial activities
and increasing population. For CO, both types of trends exist. There are large seasonal
cycles mostly driven by seasonal variations in the loss rate but also affected by seasonal
variations of emissions, and there are indications of long-term trends probably caused by
increasing anthropogenic emissions.
It appears that the largest sources of CO in the global atmosphere are combustion
processes and the oxidation of hydrocarbons. Carbon monoxide is produced in the
atmosphere by reactions of OH* with methane (CH^ and other hydrocarbons, both manmade
and natural, and also from the reactions of alkenes with O3 and of isoprene and terpenes with
both OH* and O3. Most of the CO is removed from the atmosphere by reacting with
tropospheric OH* radicals.
4.2.1 Sources
Carbon monoxide comes from both natural and anthropogenic processes. About half of
the CO is released at the earth's surface and the rest is produced in the atmosphere. Many
papers on the global sources of CO have been published over the last 15 years; whether most
of the CO in the atmosphere is from human activities or from natural processes has been
debated for nearly as long. Before 1970, it was believed that CO in the troposphere was
almost all man-made (Jaffe, 1968, 1973). Later, based on the theory that oxidation of CH4
produces large amounts of CO, it was suggested that much of the CO in the nonurban
troposphere was of natural origin (Levy, 1971, 1973; McConnell et al., 1971; National
Research Council, 1977; Weinstock and Niki, 1972; Wofsy, 1976; Wofsy et al., 1972).
However, this view was controversial (Newell, 1977; Stevens et al., 1972). At that time, it
commonly was believed that CH4 came from natural processes, although the existing
tabulation of the sources suggested otherwise (Ehhalt and Schmidt, 1978). Even now, the
source of CO from the oxidation of CH4 often is regarded as natural as opposed to the direct
emissions of CO from combustion processes. However, there is good evidence that about
half the CH4 in the atmosphere is from human activities, particularly rice paddies, cattle,
urban areas, landfills, and other sources (Khalil and Rasmussen, 1983). Therefore^
4-2
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regardless of how much CO is estimated to come from the oxidation of CH4, about half of it
could be considered to come indirectly from anthropogenic activities. In recent years, the
estimates of the average level of OH* radicals have been revised downward so that the
production of CO from CH4 and other hydrocarbons no longer is thought to be the dominant
source (Hameed and Stewart, 1979; Logan et al., 1981; Pinto et al., 1983).
The recent budgets that take into account previously published date suggest that human
activities are responsible for about 60% of the CO in the nonurban troposphere and natural
processes account for the remaining 40%. It also appears that combustion processes directly
produce about 40% of the annual emissions of CO (Jaffe, 1968, 1973; Robinson and
Robbins, 1969, 1970; Swinnerton et al., 1971), and oxidation of hydrocarbons make up most
of the remainder (Greenberg et al., 1985; Hanst et al., 1980; Rasmussen and Went, 1965;
Went, 1960, 1966; Zimmerman et al., 1978) (about 50%) along with other sources such as
the oceans (Bauer et al., 1980; DeMore et al., 1985; Lamontagne et al.,, 1971; Logan et al.,
1981; Linnenbom et al., 1973; Liss and Slater, 1974; National Research Council, 1977;
Seller, 1974; Seller and Junge, 1970; Seiler and Schmidt, 1974; Swinnerton et al., 1969;
Swinnerton and Lamontagne, 1974) and vegetation (Bauer et al., 1980; Bidwell and Fraser,
1972; DeMore et al., 1985; Krall and Tolbert, 1957; Logan et al., 1981; National Research
Council, 1977; Seiler, 1974; Seiler and Giehl, 1977; Seiler et al., 1978; Seiler and Junge,
1970; Siegel et al., 1962; Wilks, 1959). Some of the hydrocarbons that eventually end up as
CO also are produced by combustion processes, constituting an indirect source of CO from
combustion. These conclusions are summarized in Table 4-1, which is adapted from the
1981 budget of Logan et al. (1981) in which most of the previous work was incorporated
(Logan et al., 1981; World Meteorological Organization, 1986), including the CO budget of
Seiler (1974). The total emissions of CO are about 2,600 Tg/year. Other budgets by Volz
et al. (1981) and by Seiler and Conrad (1987) are reviewed by Warneck (1988). Global
emissions between 2,000 and 3,000 Tg/year are consistent with these budgets.
4.2.2 Sinks
It is believed that reaction with OH* radicals is the major sink for removing CO from
the atmosphere. The cycle of OH* itself cannot be uncoupled from the cycles of CO, CH4,
4-3
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TABLE 4-1. SOURCES OF CARBON MONOXIDE
(Teragrams per year)
; • Anthropogenic Natural
I.
II.
m.
Directly from Combustion
Fossil Fuels
Forest Clearing '
Savanna Burning
Wood Burning
Forest Fires ,, >, .
Oxidation of Hydrocarbons
Methane t ,
Nonmethane HCs
Other Sources
Plants
Oceans
TOTALS (Rounded)
500
400
200
50
:• * "
l •
.300
90
•-•'•
--
1,500
—
—
—
--
30
300
600
100
40
1,100
Global
500
400
200
50
; 30
:. 600
690
100
40
2,600
Range
400
200
100
25
10
400
300
50
20
2,000
- 1,000
- 800
- 400.
- 150
- 50
- 1,000
- 1,400
- 200
80
- 3,000
Notes: " > .•,;,'
1. Table adapted from Logan et al. (1981) and revisions reported by World Meteorological Organization
(1986). All estimates are in Tg/year of CO. Tg/year = megatons/year = 1012 g/year.
2. All estimates are expressed to one significant figure. The sums are rounded to two significant digits.
3. Half the production of CO from the oxidation of,CH4 is attributed to anthropogenic sources and the other
half to natural sources based on the budget of CH4 from KhalU and Rasmussen (1984c).
water (H2O), and O3. In the troposphere, OH* radicals are produced by the photolysis of
O3 (ho + C?3 > O^D) + Cy followed by the reaction of the excited oxygen atoms
with H2O vapor to produce two OH* radicals (O^D) + H2O _.> OH* + OH*), The,
production of OH* radicals is balanced by their removal principally by reactions with CO and
CH4. On a global scale, CO may remove more OH* radicals than CH4; however, CH4
becomes more important in the Southern Hemisphere where there is much less CO than in the
Northern Hemisphere but the amount of CH4 is only slightly less.
The amount of CO that is removed by reactions with OH* radicals can be estimated by
calculating the loss as loss = Ke^OH*'\av^CO\ave, where Kejfis the effective reaction rate
•i - ' ". , ,.'-'.,,-•, '. = • ': - ". - • - "
constant, [OH*]ave is the average concentration of OH*; and [CO]ave is the average
concentration of CO. The reaction rate constant of CO + OH* is K = (1.5 x 10~13)
(1 + 0.6 Patm) cm3/molecule-s (DeMore et al., 1987), where P tm is the atmospheric
4-4
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pressure. The constant K^ describes the effective reaction rate, taking into account the
decreasing atmospheric pressure and decreasing CO concentrations with height. Estimating
Keffto be 2 x 10~13 cm3/molecule-s and taMng [OH*}ave to be 8 x 105 molecules/cm3 and
[CO\ave to be 90 ppbv, the annual loss of CO from reactions with OH" is about 2,200
Tg/year. The values adopted for [OH?]ave and \CO\ave are discussed in more detail later in
this chapter.
Uptake of CO by soils has been documented and may amount to about 250 Tg/year, or
about 10% of the total emitted into the atmosphere (Bartholomew and Alexander, 1981;
Ingersoll et al., 1974; Inman et al., 1971; Seiler and Schmidt, 1974), although arid soils may
release CO into the atmosphere (Conrad and Seiler, 1982). Another 100 Tg (5%) or so are
probably removed annually in the stratosphere (Seiler, 1974).
4.2.3 Atmospheric Lifetime
Based on the global sources and sinks described above, the average r of CO can be
calculated to be about 2 months with a range of between 1 and 4 months, which reflects the
uncertainty in the annual emissions of CO (T = C/S, where C is the tropospheric mixing
ratio and S is the total annual emissions). The lifetime, however, can vary enormously with
latitude and season compared to its global average value. During winters at high and middle
latitudes, CO has a lifetime of more than a year, but during summers at middle latitudes, the
lifetime may be closer to the average global lifetime of about 2 months. Moreover, in the
tropics, the average lifetime of CO is probably about 1 month. These calculated variations
reflect the seasonal cycles of OH* at various latitudes.
4.2.4 Latitudinal Distribution of Sources
When the sources, sinks, transport, and observed concentrations are combined into a
mass balance model, it is possible to calculate any one of these four components if the others
are known. In the case of CO, the sources can be estimated assuming that the sinks (OH*
reaction and soils), transport, and concentrations are known. The latitudinal distribution of
sources can be described in a one-dimensional model as follows:
4-5
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(4.1)
where S represents emissions, fjt, is the sine of latitude, £ is a factor to account for the lower
concentrations of CO in the stratosphere, r is the lifetime, H is a factor to account for the
variation of the tropopause height with latitude, K is the zonally and height averaged transport
coefficient, R is the radius of the earth, and C is the tropospheric mixing ratio.
This model is similar to that described by Czeplak and Junge (1974) and Fink and Klais
(1978). A time-averaged version was applied to the CO budget by Hameed and Stewart
(1979) and a somewhat modified and time-dependent version shown above was applied by
Khalil and Rasmussen (1990b) to derive the latitudinal distribution of CO shown in
Figure 4-1. Calculations by Khalil and Rasmussen (1990b) also suggest that emissions are
higher in spring and summer compared with the other seasons, particularly in the middle
northern latitudes. This is expected for three reasons: (1) oxidation of CH4 and other
hydrocarbons is faster during the summer because of the seasonal variation of OH* , (2) other
direct emissions are also greater during spring and summer, and (3) at middle and higher
latitudes methane and nonmethane hydrocarbons build up during the winter and this reservoir
is oxidized when OH* concentrations rise during the spring.
From Figure 4-1, the emissions from the northern and southern tropical latitudes sum
up to 480 Tg/year and 330 Tg/year, respectively; the emissions from the northern and
southern middle latitudes are 960 Tg/year and 210 Tg/year, respectively; some 50 Tg are
emitted each year from the Arctic, and some 10 Tg/year come from the Antarctic. The
largest fluxes of CO are from the industrial band of latitudes between 30° to 50° north.
From this region some 620 Tg/year are emitted, representing about 30% of the total
emissions of 2,050 Tg/year. The model does not distinguish between the anthropogenic or ,
natural sources, nor does it distinguish between direct emissions and photochemical
production of CO from the oxidation of hydrocarbons. Much of estimated fluxes from the
mid-northern latitudes and from tropical regions are likely to be of anthropogenic origin.
The latitudinal distribution in Figure 4-1 is compatible with the estimate (Table 4-1) that
about 60% of the total emissions are from anthropogenic activities. .
4-6
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-1.0
-0.6
50
Sine of Latitude
-0.2 0.2 0.6
i i I i i i I i i i l i i i l i i i l i i i l i
-53 -36 -23 -11 Eq 11 23 36 53 N
Figure 4-1. The estimated sources of carbon monoxide as a function of latitude. The
sources are in teragrams per year (Tg/year) in each latitude band 0.02 units
in sine of latitude. The dashed lines are estimates of uncertainties as
hydroxyl free radical concentrations and the rate of dispersion are varied
simultaneously so that the maximum values of each of these parameters are
twice the minimum values.
Source: Khalil and Rasmussen (1990b).
4.2.5 Uncertainties and Consistencies
The first consistency one notes is that the total emissions of CO estimated from the
various sources are balanced by the estimated removal of CO. The approximate balance
between sources and sinks is expected because the trends, to be discussed later, are only
showing an increase of about 4 to 8 Tg/year compared to the total global emission rate of
more than 2,000 Tg/year. On the other hand, there are many uncertainties in the sources and
sinks.
4-7
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There are large uncertainties in the estimates of emissions from individual sources as
expressed in Table 4-1. In most cases, the stated uncertainty is a qualitative expression of the
likely range of emissions and it cannot be interpreted statistically. Therefore, the resulting
uncertainty in the total emissions, obtained by adding up the uncertainties in individual
sources, appears to be large.
There are two difficulties in improving the estimates of CO from individual sources.
First, although many critical experiments to determine the production and emissions of CO
from individual sources are yet to be done, there is a limit to the accuracy with which
laboratory data can be extrapolated to the global scale. Second, the cycle of CO may be so
intimately tied up with the cycles of hydrocarbons that accurate global estimates of CO
emissions may not be possible until the cycles of the hydrocarbons are better understood.
Whereas the global distribution and seasonal variations of OH* can be calculated, there
are no direct measurements of OH* that can be used to estimate the removal of CO. The
effective average concentration of OH* that acts on trace gases can be estimated indirectly
from the cycles of other trace gases with known global emissions. Therefore, the total
emissions of CO are constrained by the budgets of other trace gases, even though the
estimates of emissions from individual sources may remain uncertain. The most notable
constraint may be the budget of methylchloroform (CH3CC13). Methylchloroform is a
degreasing solvent that has been emitted into the atmosphere in substantial quantities for more
than 20 years. It is thought to be removed principally by reacting with OH* radicals and to a
lesser extent by photodissociation in the stratosphere. Because industry records on CH3CC13
production and sales have been kept for a long time, it can be used to estimate the average
amount of OH* radicals needed to explain the observed concentrations compared to the
emissions. The accuracy of the source estimates of CH3CC13 is improved by the patterns of
its uses; most of it tends to be released shortly after purchase, so that large unknown or
unquantified reservoirs probably do not exist. The recent budgets of CH3CC13 suggest that
on an average there are about 8 x 105 molecules of OH* per cubic centimeter, although
significant uncertainties remain (see for example Khalil and Rasmussen, 1984c). This is the
value used earlier in estimating the loss of CO from reaction with OH*. The same average
value of OH* also explains the CH4 concentrations compared to estimated sources, lending
4-8
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more support to the accuracy of the estimated OH* concentrations. Neither of these
constraints is very stringent; however, if the total global emissions of GO from all sources are
much different from the estimated 2,600 Tg/year, then revisions of the budgets of both CH^
and CH3CC13 may be required.
There are other sources and sinks of CO, believed to be of lesser importance on a
global scale, which are reviewed in the previous EPA criteria document on CO (Chan et al.,
1977; Swinnerton et al., 1971).
4.3 GLOBAL DISTRIBUTIONS
Atmospheric concentrations, and thus the global distribution, generally are the most
accurately known components of a global mass balance of a trace gas because direct
atmospheric measurements can be taken (Dianov-Klokov and Yurganov, 1981; Ehhalt and
Schmidt, 1978; Fraser et al., 1986; Heidt et al., 1980; Hoell et al., 1984; Khalil and
Rasmussen, 1988, 1990a; Pratt and Falconer, 1979; Rasmussen and Khalil, 1982; Reichle
et al., 1982; Seiler, 1974; Seiler and Fishman, 1981; Wilkniss et al., 1973). Much has been
learned about the global distribution of CO over the last decade. The experiments leading to
the present understanding range from systematic global observations at ground level for the
last 8 to 10 years, reported by Khalil and Rasmussen (1988, 1990a) and Seiler (Seiler, 1974;
Seiler and Junge, 1970), to finding the instantaneous global distribution of CO from remote-
sensing instruments on board NASA's space shuttle as reported by Reichle et al. (1982,
1990).
4.3.1 Seasonal Variations
The seasonal variations of CO are well established (Dianov-Klokov and Yurganov,
1981; Fraser etal., 1986; Khalil and Rasmussen, 1990a; Seiler etal., 1984). High
concentrations are observed during the winters in each hemisphere and the lowest
concentrations are seen in late summer. The amplitude of the cycle is largest at high northern
latitudes and diminishes as one moves towards the equator until it is reversed in the southern
hemisphere, reflecting the reversal of the seasons. The seasonal variations are small in the
equatorial region. These patterns are expected from the seasonal variations of OH*
4-9
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concentrations and CO emissions. At mid and high latitudes, diminished solar radiation,
water vapor, and O3 during winters cause the concentrations of OH* to be much lower than
during summer. The removal of CO is slowed down and its concentrations build up. In
summer, the opposite effect exists, causing the large seasonal variations of CO. These
variations are apparent in the observed global seasonal cycles shown in Figure 4-2a.
On the hemispherical scale, the seasonal variation of CO is approximately proportional
to the concentration. Therefore, because there is much more CO in the Northern Hemisphere
than in the Southern Hemisphere, the decline of concentrations during the summer of the
Northern Hemisphere is not balanced by the rise of concentrations in the Southern
Hemisphere. This causes a global seasonal variation. The total amount of CO in the earth's
atmosphere undergoes a remarkably large seasonal variation; the global burden is highest
during northern winters, lowest during northern summers. This feature is shown in
Figure 4-2b.
4.3.2 Latitudinal Variation
The global seasonal variation of CO in the earth's atmosphere also creates a seasonal
variation in the latitudinal distribution (Khalil and Rasmussen, 1988, 1990a; Newell et al.,
1974; Reichle et al., 1982, 1986; Seller, 1974). During northern winters, CO levels are at
their highest in the Northern Hemisphere, whereas Southern Hemisphere concentrations are at
a minimum. The interhemispheric gradient, defined as the ratio of the amount of CO in the
Northern and Southern Hemispheres, is at its maximum of about 3.2 during Northern
Hemisphere winters and falls to about 1.8 during Northern Hemisphere summers, which is
about half of the winter value. The average latitudinal gradient is about 2.5, which means
that on an average there is about 2.5 times as much CO in the Northern Hemisphere as in the
Southern Hemisphere. Earlier data on the latitudinal variations did not account for the
seasonal variations.
4.3.3 Variations with Altitude
In the Northern Hemisphere troposphere, the concentrations of CO generally decline
with altitude, but in the Southern Hemisphere, the vertical gradient may be reversed due to
the transport of CO from the Northern Hemisphere into the Southern Hemisphere. Above the
4-10
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£
I
o
-10-
-20
B
T I
I I
GL
J F
M A M J J ASONDJ
Time of year
Figure 4-2. The global seasonal variations of carbon monoxide (CO). Figure 4-2A
shows the seasonal cycle at six sites hi polar, middle, and tropical latitudes
of both hemispheres (AK = Alaska, OR = Oregon, HA = Hawaii, SA =
Samoa, TA = Tasmania, SP = South Pole). Figure 4-2B shows the
seasonal variation of the global burden of atmospheric CO. The
atmospheric content of CO is much higher during Northern Hemisphere
winters compared to summers.
Sources: Khalil and Rasmussen (1990a).
4-11
-------
tropopause, concentrations decline rapidly so that there is very little CO between 20 km and
40 km; at still higher altitudes, the mixing ratio may increase again (Fabian et al., 1981;
Setter and Junge, 1969; Seiler and Warneck, 1972).
4.3.4 Other Variations
The concentration of CO generally is higher over populated continental areas compared
to the air over oceans, even though oceans release CO into the atmosphere. Other regions,
such as tropical forests also may be a source of isoprene and other hydrocarbons that may
form CO in the atmosphere. Such sources produce shifting patterns of high CO
concentrations over regional and perhaps even larger spatial scales. Concentrations are
representative of the middle troposphere and were measured during the 1984 flights of the
space shuttle, as reported by Reichle et al. (1990). Eventually, CO in the lower troposphere
may be measured from space using the techniques described by Reichle et al. (1989). -The
new method uses gas correlation filter radiometry at 2.3 jum in addition to the 4.67 jum line
used earlier to obtain mid-tropospheric concentrations of CO.
Occasionally, in some locations, significant diurnal variations of CO also may occur.
For instance, diurnal variations have been observed over some parts of the oceans, with high
concentrations during the day and low concentrations at night. Because similar patterns also
exist in the surface sea water, the diurnal variations in the air can be explained by emissions
from the oceans.
Finally, after the repeating cycles and other trends are subtracted, considerable random
fluctuations still remain in time series of measurements. These fluctuations reflect the short
lifetime of CO and the vicinity of the sources, and they complicate the detection of long-term
trends (see Figure 4-3).
4.4 GLOBAL TRENDS
Because some 60% of the global emissions of CO are believed to come from
anthropogenic sources with increasing emissions, it stands to reason that the global
concentration of CO should be increasing. At present, there are several independent pieces of
evidence for an increasing trend, although none are definitive. First, direct atmospheric
4-12
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Q.
Q.
•*
Tasmania, + Antarctic.
Sources: Khalil and Rasmussen (1988).
4-13
-------
observations reported by Khalil and Rasmussen (1984a) showed a detectable trend at Cape
Meares in Oregon between 1979 and 1982. Over these 3 years, the rate of increase was
about 5% per year. Subsequent data from the same site showed that the rate was not
sustained for long and a much smaller trend of a somewhat less than 2% per year emerged
over the longer period of 1970 to 1987 (Khalil and Rasmussen, 1988). Similar data from
other sites distributed worldwide now show that there is evidence for a global increase of
about 1% per year as shown in Figure 4-3 (Khalil and Rasmussen, 1988). This is the only
study in which trends from different parts of the world are evaluated. It shows that the
trends are strongest in the mid-northern latitudes where most of the sources are located and
becdme smaller and weaker in the Southern Hemisphere. At the mid-southern latitude site,
the trends persist but are not statistically significant (Khalil and Rasmussen, 1988). Second,
Rinsland and Levine (1985) have reported estimates of CO concentrations from spectroscopic
plates from Europe that show that between 1950 and 1984, CO increased at about 2% per
year. Finally, spectroscopic measurements of CO taken by Dvoryashina et al. and Dianov-
Klokov et al. in the Soviet Union also suggest an increase of about 2% per year between
1974 and 1982 (Dianov-Klokov et al., 1978; Dianov-Klokov and Yurganov, 1981;
Dvoryashina et al., 1982, 1984; Khalil and Rasmussen, 1988; Khalil and Rasmussen, 1984b).
There is good evidence that the concentrations of CO are increasing in the nonurban
troposphere; however, the rate of increase still is not well known and may vary considerably
over time. The random variability is so large and the trends are so small that there are just
enough data to detect the increase, but not enough to estimate the long-term rate of increase
with confidence. Such increases of tropospheric CO can cause a reduction of OH*
concentrations and thus reduce the oxidizing capacity of the atmosphere, causing other trace
gases, including CH4, to build up more rapidly in the atmosphere and reach higher levels.
This occurrence could add to the greenhouse effect and deplete the stratospheric O3 layer. In
the troposphere, increased CO in the presence of nitrogen oxides also could result in an
increase of O3 concentrations.
All the studies show increases of 1 to 2% per year over the last several decades. These
- ; •- . •• «--,.-' .-- •- - • ,. - -j
trends and the sources shown in Table 4-i suggest that the anthropogenic sources, both direct
and indirect, probably were very small until this century. Therefore, the average CO
concentration may have doubled over the last 50 years or so. This change could be a
4-14
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significant contributing factor to increasing levels of O3 in the nonurban troposphere.
Because the influence of CO on tropospheric O3 is not understood fully, the role of
increasing CO on tropospheric O3 also remains uncertain.
The likely future global scale concentrations of CO are completely unknown at present.
It is possible that in the next decade CO concentrations will remain stable or even decline
rather than continue to increase. Emissions from automobiles are probably on the decline
worldwide, emissions from biomass burning may be stabilizing and the contribution from
CH4 oxidation may no longer be increasing as rapidly as before. Because the atmospheric
lifetime of CO is short compared to other contributors to global change, the ambient
concentrations adjust rapidly to existing emissions of CO or it precursors.
4.5 SUMMARY
The annual global emissions of CO are estimated to be about 2,600 + 600 Tg, of which
about 60% are from human activities, including combustion of fossil fuels and oxidation of
hydrocarbons, including CH4. The remaining 40% of the emissions are from natural
processes, mostly from the oxidation of hydrocarbons, but also from plants and the oceans.
Almost all the CO emitted into the atmosphere each year is removed by reactions with OH*
radicals (85%), by soils (10%), and by diffusion into the stratosphere. There is a small
unbalance between annual emissions and removal, causing an increase of about 1% per year.
It is very likely that the imbalance is due to increasing emissions from anthropogenic
activities. The average concentration of CO is about 90 ppbv, which amounts to about
400 Tg in the atmosphere and the average lifetime is about 2 months. This view of the
global cycle of CO is consistent with the present estimates of average OH* concentrations and
the budgets of other trace gases, including CH4 and CH3CC13.
There are large remaining uncertainties that in the future may upset the apparently
cohesive present budget of CO. Although the patterns of the global distribution are becoming
established, there still are uncertainties about the absolute concentrations. Estimates of
emissions from individual sources are very uncertain; however, the total annual emissions are
likely to be more accurate.
4-15
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There are just sufficient data on the trends to suggest that CO is increasing, but the rates
are not certain. However, if the present view of the global cycle of CO is correct, then it is
likely that, in time, increasing levels of CO will contribute to widespread changes in
atmospheric chemistry and the global climate.
4-16
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Seller, W. (1974) The cycle of atmospheric CO. Tellus 26: 116-135.
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4: 329-332.
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Seiler, W.; Junge, C. (1970) Carbon monoxide in the atmosphere. J. Geophys. Res. 75: 2217-2226.
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Seiler, W.; Schmidt, U. (1974) Dissolved nonconservative gases in seawater. In: Goldberg, E. D., ed. The sea:
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5. MEASUREMENT METHODS FOR
CARBON MONOXIDE
5.1 INTRODUCTION
To promote uniform enforcement of the air quality standards set forth under the Clean
Air Act as amended (U.S. Code, 1991), the U.S. Environmental Protection Agency (EPA)
has established provisions under which analytical methods can be designated as "reference" or
"equivalent" methods (Code of Federal Regulations, 199la). A reference method or
equivalent method for air quality measurements is required for acceptance of measurement
data. An equivalent method for monitoring carbon monoxide (CO) can be so designated
when the method is shown to produce results equivalent to the approved reference monitoring
method based on absorption of infrared radiation from a nondispersed beam.
EPA-designated reference methods are automated, continuous methods utilizing the
nondispersive infrared (NDIR) technique, which generally is accepted as being the most
reliable method for the measurement of CO in ambient air. The official EPA reference
methods are described in Code of Federal Regulations, 199la. Eleven reference methods for
CO have been designated for use in determining compliance, and all of these methods employ
the NDIR technique (Code of Federal Regulations, 199la). Before a particular NDIR
instrument can be used in a reference method, it must be designated by the EPA as approved
in terms of manufacturer, model number, components, operating range,, etc. Several NDIR
instruments have been so designated (Code of Federal Regulations, 199la), including the gas
filter correlation (GFC) technique, which was developed through EPA-sponsored research
(Burch et al., 1976). No equivalent methods that use a principle other than NDIR have as of
January 1988 been designated for measuring CO in ambient air. The performance
specifications for automated CO analyzers are shown in Table 5-1 (Code of Federal
Regulations, 1991a).
The normal full scale operating range for reference methods is 0 to 50 ppm (0 to
58 mg/m3). Some instruments offer higher ranges, typically 0 to 100 ppm (0 to 116 mg/m3),
or lower ranges such as 0 to 20 ppm (0 to 23 mg/m3). A narrower range up to 1 ppm may
be needed to measure background levels in unpolluted atmospheres. Higher ranges up to
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TABLE 5-1. PERFORMANCE SPECIFICATIONS FOR AUTOMATED
ANALYTICAL METHODS FOR CARBON MONOXIDE
(CODE OF FEDERAL REGULATIONS, 1991a)
Range 0 to 57 mg/m3 (0 to 50 ppm)
Noise 0.6 mg/m3 (0.50 ppm)
Lower detectable limit" 1.2 mg/m3 (1.0 ppm)
Interference equivalent
Each interfering substance +1.2 mg/m3 (+1.0 ppm)
Total interfering substances 1.7 mg/m3 (1.5 ppm)
Zero drift
12 h ±1.2 mg/m3 (±1.0 ppm)
24 h ±1.2 mg/m3 (+1.0 ppm)
Span drift, 24 h
20% of upper range limit ± 10.0%
80% of upper range limit + 2.5%
Lag time 10 min
Rise time 5 min
Fall time 5 min
Precision
20% of upper range limit 0.6 mg/m3 (0.5 ppm)
80% of upper range limit 0.6 mg/m3 (0.5 ppm)
Definitions:
Range: Nominal minimum and maximum concentrations that a method is capable of
measuring.
Noise: The standard deviation about the mean of short duration deviations in output that are
not caused by input concentration changes.
Lower detectable limit: The minimum pollutant concentration that produces a signal of
twice the noise level.
Interference equivalent: Positive or negative response caused by a substance other than the
one being measured.
Zero drift: The change in response to zero pollutant concentration during continuous
unadjusted operation.
Span drift: The percent change in response to an upscale pollutant concentration during
continuous unadjusted operation.
Lag time: The time interval between a step change in input concentration and the first
observable corresponding change in response.
Rise time: The time interval between initial response and 95% of final response.
Fall time: The time interval between initial response to a step decrease in concentration and
95% of final response.
Precision: Variation about the mean of repeated measurements of the same pollutant
concentration expressed as one standard deviation about the mean.
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**t
1,000 ppm (1,150 mg/m ) are used to measure CO concentrations in vehicular tunnels and
parking garages. ,, ,
5.1.1 Overview of Techniques for Measurement of Ambient Carbon
Monoxide
There have been several excellent reviews on the measurement of CO in the atmosphere
(National Research Council, 1977; Driscoll and Berger, 1971; Harrison, 1975; American
Industrial Hygiene Association, 1972; Leithe, 1971; Repp, 1977; Schnakenberg, 1976;
Stevens and Herget, 1974; National Air Pollution Control Administration, 1970; National
Institute for Occupational Safety and Health, 1972; Verdin, 1973). The NDIR method is •
discussed widely in the literature (Dailey and Fertig, 1977; Houben, 1976; McKee and
Childers, 1972; McKee et al., 1973; Perez et al., 1975; Pierce and Collins, 1971; Sehunek,
1976; Scott, 1975; Smith and Nelson, 1973; Smith, 1969; Luft, 1975). Currently, the most
commonly-used measurement technique is the type of NDIR method referred to as GFC
(Acton et al., 1973; Bartte and Hall, 1977; Burch and Gryvnak, 1974; Burch et al., 1976;
Chaney and.McClenny, 1977; Goldstein et al., 1976; Gryvnak and Bureh, 1976a,b; Herget
et al., 1976; Ward and Zwick, 1975). This technique was developed to a commercial
prototype stage through EPA sponsored research (Burch et al., 1976).
The NDIR method is an automated, continuous method that generally is accepted as
being the most reliable method for the measurement of CO in ambient air. Nondispersive
infrared analyzers are based on the specific absorption of infrared radiation by the CO
molecule (Feldstein, 1967). Most commercially available analyzers incorporate a gas filter to
minimize interferences from other gases; they operate at atmospheric pressure and the most
sensitive analyzers are able to detect minimum CO concentrations of about 0.05 mg/m3.
Interferences due to carbon dioxide (CO^) and water vapor can be dealt with so as not to
affect the data quality. Nondispersive infrared analyzers with Luft-type detectors are
relatively insensitive to flow rate, require no wet chemicals, are sensitive over wide
concentration ranges, and have short response times. Nondispersive infrared analyzers of the
newer GFC type have overcome zero and span problems and minor problems due to
vibrations.
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A more sensitive method for measuring low, background levels is gas ehromatography
(Bergman et al., 1975; Bruner et al., 1973; Dagnall et al., 1973; Porter and Volman, 1962;
Feldstein, 1967; Smith et al., 1975a; Swinnerton et al., 1968; Tesarik and Krejci, 1974).
This technique is an automated, semicontinuous method where CO is separated from water,
CO2» and hydrocarbons other than methane (CB^) by a stripper column. Carbon monoxide
and CH4 then are separated on an analytical column and the CO is passed through a catalytic
reduction tube, where it is converted to CH4. The CO (converted to CH^ passes through a
flame ionization detector (FID), and the resulting signal is proportional to the concentration
of CO in the air. This method has been used throughout the world. It has no known
interferences and can be used to measure levels from 0.03 to 50 mg/m3. These analyzers are
expensive and require continuous attendance by a highly trained operator to produce valid
results. For high levels, a useful technique is catalytic oxidation of the CO by Hopcalite or
other catalysts (Stetter and Blurton, 1976), either with temperature-rise sensors (Naumann,
1975; Benzie et al., 1977; Schnakenberg, 1976) or with electrochemical sensors (Bay et al.,
1972, 1974; Bergman et al., 1975; Dempsey et al., 1975; Repp, 1977; Schnakenberg, 1975).
Other analytical schemes used for CO in air include dual-isotope infrared fluorescence,
another technique derived from NDIR (Link et al., 1971; McClatchie, 1972; McClatchie
et al., 1972); reaction with hot mercuric oxide to give elemental mercury vapor (Beckman
etal., 1948; MeCuUough et al., 1947; Mueller, 1954; Palanos, 1972; Robbins et al., 1968);
reaction with heated iodine pentoxide @2O5) to give elemental iodine (Adams and Simmons,
1951; Moore et al., 1973; Newton and Morss, 1974; van Dijk and Falkenburg, 1976;
VoPberg and Pochina, 1974); and color reactions (Allen and Root, 1955; Bell et al., 1975;
Feldstein, 1965; Jones, 1977; Lambert and Wiens, 1974; Levaggi and Feldstein, 1964; Ray
et al., 1975; Simonescu et al., 1975; Smith et al., 1975b), as with palladium salts or the
silver salt of _p-sulfamoylbenzoate. Many of these methods are described in Section 5.3,
Measurement in Ambient Air. A classical procedure for many decades was to use gasometric
apparatus such as the Orsat or Haldane (Cormack, 1972), in which the CO present in a gas
sample is absorbed by cuprous chloride solution and the decrease in volume or pressure is
measured. This method, however, is not sensitive enough for trace amounts. -
Microwave rotational spectroscopy is an analytical technique with high specificity
(Hrubesh, 1973; Morgan and Morris, 1977). Other possible ways to determine CO include
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chemiluminescent reaction with ozone (v. Heusden and Hoogeveen, 1976), X-ray excited
optical fluorescence (Goldstein et al., 1974), radiorelease of radiolabeled krypton from the
kryptonates of mercuric oxide (HgO) or I2O5 (Goodman, 1972; Naoum et al., 1974), and
utilization of narrow-band infrared laser sources (Chaney et al., 1979; Optical Society of
America, 1975; Golden and Yeung, 1975).
5.1.2 Calibration Requirements
Whichever method or instrument is used, it is essential that the results be validated by
frequent calibration with samples of known composition similar to the unknowns (Commins
et al., 1977; Goldstein, 1977; National Bureau of Standards, 1975). Chemical analyses can
be relied on only after the analyst has achieved acceptable accuracy in the analysis of such
standard samples through an audit program.
5.2 PREPARATION OF STANDARD REFERENCE MATERIALS
5.2.1 Gas Standards
A set of reliable gas standards for CO in air, certified at levels of approximately 12, 23,
<3
and 46 mg/cm (10, 20, and 40 ppm) is obtainable from the National Institute of Standards
and Technology (NIST) (formerly the National Bureau of Standards), Washington, DC
(National Bureau of Standards, 1975). These Standard Reference Materials (SRMs) are
supplied as compressed gas (at about 1,700 psi) in high-strength aluminum cylinders
containing 31 ft3 of gas at dry standard temperature and pressure and are accurate to better
than 1 % of the stated values. Because of the time and effort required in their preparation,
SRMs are not intended for use as daily working standards, but rather as primary standards
against which transfer standards can be calibrated.
5.2.2 Gravimetric Method
The gravimetric method used by NIST for preparing primary standards of CO (Hughes,
1975, 1976) is as follows. An empty gas cylinder is tared on an analytical balance, then 2 g
of pure CO, weighed accurately to ±2 mg, is added from a high-pressure tank. Next, 100 g
of pure air (accurately weighed) is added from a pressure tank, and the concentration of CO
5-5
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is calculated from the sum of the respective weights added to the molecular weights of the
two gases. Not only the average "molecular weight" of the air, but also the requisite careful
check of purity, is obtained by mass spectrometry and gas chromatography analyses of the air
and the CO. Lower concentration primary standards are prepared by serial dilutions (not
more than a fector of 100 for each step) by the same technique.
The commercial suppliers of compressed gases are another source of air samples
containing CO in the mffligrani-per-cubic-meter or parts-per-million range. However, the
nominal values for CO concentration supplied by the vendor should be verified by
intercomparison with an SRM or other validated standard sample. A three-way
intercomparison has been made among the NIST SRMs, commercial gas blends, and an
extensive set of standard gas mixtures prepared by gravimetric blending at the Environmental
Protection Agency (Paulsell, 1976). Results of the comparison showed that commercial gas
blends are within ±2% of the true value represented by a primary standard. Another study
on commercial blends (Elwood, 1976) found poorer accuracy. To achieve compatible results
in sample analyses, different laboratories should interchange and compare their respective
working standards frequently.
In making and using standards, many precautions are needed (Hughes, 1975): One
deserves special mention. liarge but unpredictable decreases in CO concentration occur
within a few months in mixtures prepared in ordinary mild steel gas cylinders, as shown in
Figure 5-1. This may be due to carbonyl formation or oxidation of CO to CO2. The
difficulty can be avoided by, the use of gas cylinders made of stainless steel or aluminum.
A special treatment for aluminum, which includes enhancement of the aluminum oxide
surface layer, has been recommended (Wechter,, 1976). . . . ...... -:
In addition to the set of SRMs for CO in air, another set of SRMs is available from
NIST for CO in nitrogen (N^. This second set covers concentrations from 10 to 957 ppm.
5.2.3 Volumetric Gas Dilution Methods
Standard samples of CO in air also can be prepared by volumetric gas dilution
techniques. In a versatile system designed .for this purpose (Hughes et al., 1973), air at a
pressure of 10 to 100 psi is first purified and dried by passage through cartridges of charcoal
5-6
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50
o
100
200
Time, days
300
400
Figure 5-1. Loss of carbon monoxide with time in mild steel cylinders (Hughes, 1975).
and silica gel, then is passed through a sintered metal filter into a flow control and flowmeter
system. The CO (or a mixture of CO in air that is to be diluted further), also under
pressure, is passed through a similar flow control and flowmeter system.
Both gas streams are fed into a mixing chamber, which is designed to mix the gas
streams rapidly and completely before passage into the sampling manifold from which the
standard samples will be withdrawn. From the air flow rate, FA, and the CO flow rate, Fco,
the concentration of CO in the sample, Cco, is readily calculated by the expression
'CO
-co
FCO+FA
(5-1)
5-7
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For samples prepared by dilution of a more concentrated bulk mixture, the concentration is - .
given by
where Fb and Cb are the values of flow rate and concentration of CO, respectively, for the
" ' t
bulk mixture.
5.2.4 Other Methods
Permeation tubes have been used for preparing standard mixtures of such pollutant gases
as sulfur dioxide (SO^ and nitrogen dioxide (NO^ (O'Keeffe and Ortman, 1966; Scaringelli
et al., 1970). Permeation tubes are not used routinely in the United States for making CO
standard samples. In the permeation tube techniques, a sample of the pure gas under pressure
is allowed to diffuse through a calibrated partition at a defined rate into a diluent gas stream
to give a standard sample of known composition.
Another possible way to liberate known amounts of CO into a diluent gas is by thermal
decomposition of nickel tetracarbonyl [Ni(CO)4]. However, an attempt to use this as a ' :
gravimetric calibration source showed that the relation between CO output and weight loss of
the Ni(CO)4 is nonstoichiometric (Stedman et al., 1976).
5.3 MEASUREMENT IN AMBIENT AIR
Ambient CO monitoring is an expensive and time-consuming task, requiring skilled
personnel and sophisticated analytical equipment. This section discusses several important
aspects of the continuous and intermittent measurement of CO in the atmosphere, including
sampling techniques, sampling schedules, and recommended analytical methods for CO
measurement.
5.3.1 Sampling System Components
Carbon monoxide monitoring requires a sample introduction system,, an analyzer
system, and a data recording system, as illustrated in Figure 5-2 (Smith and Nelson, 1973).
5-8
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While the "heart" of any air pollution monitoring system is the air pollution analyzer,
Figure 5-2 shows that there is a considerable amount of supportive equipment necessary for
continuous air monitoring.
Sample Introduction System
O
Sample Intake Port i«jr 1^
Intake
Manifold
Analyzer System
Data Recording
and
Display System
Gauge \
.-. \ .
Cylinder
.1 I—V y^X
Second Stage
assure Gauge
Second Stage
Pressure Valve
Zero Gas
Span Gas
Figure 5-2. Carbon monoxide monitoring system (Smith and Nelson, 1973).
A sample introduction system consists of a sampling probe, an intake manifold, tubing,
and air movers. This system is needed to collect the air sample from the atmosphere and to
transport it to the analyzer without altering the original concentration. If; also may be used to
introduce known gas concentrations in order to periodically check the reliability of the
analyzer output. Construction materials for the sampling probe, intake manifold, and tubing
should be tested to demonstrate that the test atmosphere composition or concentration is not
altered significantly. It is recommended that sample introduction systems be fabricated from
5-9
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borosilicate glass or fluorinated ethylene propylene Teflon® (Code of Federal Regulations,
1991b) if several pollutants are to be monitored. However, in monitoring for CO only, it has
been reported (Wohlers et al., 1967) that no measurable pollutant losses were observed at the
high (> 1 L/min) sampling flow rates when sampling systems were constructed of tygon,
polypropylene, polyvinylchloride, aluminum, or stainless steel piping. The sample
introduction system should be constructed so that it presents no pressure drop to the analyzer.
At low flow and low concentrations, such operation may require validation.
The analyzer system consists of the analyzer itself and any sample preconditioning
components that may be necessary. Sample preconditioning might require a moisture control
system to help minimize the false positive response of the analyzer (e.g., the NDIR analyzer)
to water vapor, and a particulate filter to help protect the analyzer from clogging and possible
chemical interference due to particulate buildup in the sample lines or analyzer inlet. The
sample preconditioning system also may include a flow metering and flow control device to
control the sampling rate to the analyzer. As for the analyzer, there are several analytical
methods for the continuous measurement of CO. These are described in Section 5.3.4,
Continuous Analysis.
A data recording system is needed to record the output of the analyzer. Data recording
systems range from simple strip chart recorders to digital magnetic tape recorders to
computerized telemetry systems that transfer data from remote stations to a central location
via telephone lines or radio waves.
5.3.2 Quality Assurance Procedures for Sampling
The accuracy and validity of data collected from a CO monitoring system must be
ensured through a quality assurance program. Such a program consists of procedures for
calibration, operational and preventive maintenance, data handling, and auditing; the
procedures should be documented fully in a quality assurance program manual maintained by
the monitoring organization.
Calibration procedures consist of periodic multipoint primary calibration and secondary
calibration, both of which are prescribed to minimize systematic error. Primary calibration
involves the introduction of test atmospheres of known concentration to an instrument in its
normal mode of operation for the purpose of producing a calibration curve.
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A calibration curve is derived from the analyzer response obtained by introducing
several successive test atmospheres of different known concentrations. One recommended
method for generating CO test atmospheres is to use zero air (containing no. CO) along with
several known concentrations of CO in air or nitrogen contained in high-pressure gas
cylinders and verified by NIST-certified SRMs wherever possible (Code of Federal
Regulations, 1991a). The number of standard gas mixtures (cylinders) necessary to establish
a calibration curve depends on the nature of the analyzer output. A multipoint calibration at
five or six different CO concentrations covering the operating range of the analyzer is
recommended by EPA (Code of Federal Regulations, 199Ib; Federal Register, 19.78). ,.
Alternatively, the multipoint calibration is accomplished by diluting a known high-
concentration CO standard gas with zero gas in a calibrated flow dilution system.
Primary calibrations should be performed when the analyzer is first purchased and every
30 days thereafter (Smith and Nelson, 1973). Primary calibratipn also is recommended after
the analyzer has had maintenance that could affect its response characteristics or when results
from auditing show that the desired performance standards are not being met (Smith and
Nelson, 1973).
Secondary calibration consists of a zero and upscale span of the analyzer. This is
recommended to be performed daily (Federal Register, 1978). If the analyzer response ,
differs by more than 2% from the:Certiiied concentrations, then the analyzer is adjusted
accordingly. Complete records of secondary calibrations should be kept to aid in data , ,
reduction and for use in auditing.
Operational and preventive maintenance procedures consist of operational checks to
ensure proper operation of the analyzer and a preventive maintenance schedule necessary to
prevent unexpected analyzer failure and the associated loss of data (PEDCo Environmental
Specialists, Inc., 1971). Operational checks include checks of zero and span control settings,
sample flow rate, gas cylinder pressures, sample cell pressure, shelter temperature, water
vapor control, the paniculate filter, the sample introduction system, the recording system, and
the strip chart record. These checks may indicate the need for corrective/remedial action.
They usually are performed in conjunction with secondary calibrations. In addition to
operational checks, a routine schedule of preventive maintenance should be developed.
Maintenance requirements for the analyzer usually are specified in the manufacturer's
5-11
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instrument manual. Routine maintenance of supportive equipment (i.e., the sample
introduction system and the data recording system) also is required. This may include sample
line filter changes, water vapor control changes, sample line cleaning, leak checks, and chart
paper supply changes.
Date handling procedures consist of date generation, reduction, validation, recording,
and analysis and interpretation. Date generation is the process of generating raw,
unprocessed, and unvalidated observations as recorded on a strip chart record. Date
reduction is the conversion, by use of calibration records, of raw date to concentration units.
Date validation involves final screening of date before recording. Then, questionable date
"flagged" by the monitoring technician are reviewed with the aid of daily calibration and
operation records to assess their validity. Specific criteria for date selection and several
instrument checks are available (Smith and Nelson, 1973). Data recording involves recording
in a standard format for date storage, interchange of date with other agencies, and/or date
analysis. Date analysis and interpretation usually include a mathematical or statistical analysis
of air quality date and a subsequent effort to interpret results in terms of exposure patterns,
meteorological conditions, characteristics of emission sources, and geographic and
topographic conditions.
Auditing procedures consist of several quality control checks and subsequent error
.analyses to estimate the accuracy and precision of air quality measurements. The quality
control checks for CO include a date processing check, a control sample check, and a water
vapor interference check, which should be performed by a qualified individual independent of
the regular operator. The error analysis is a statistical evaluation of the accuracy and
precision of air quality data. Guidelines have been published by EPA (Smith and Nelson,
1973) for calculating an overall bias and standard deviation of errors associated with data
processing, measurement of control samples, and water vapor interference, from which the ,
accuracy and precision of CO measurements cari be determined. Since January 1, 1983, all
state and local agencies submitting date to EPA must provide estimates of accuracy and
precision of the CO measurements based on primary and secondary calibration records
(Federal Register, 1978). The precision and accuracy audit results through 1985 indicate that
the 95% national probability limits for precision are ±9% and the,95% national probability
limits for accuracy are within ±1.5% for all audit levels from 3 to 8 ppm to 80 to 90 ppm.
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The results for CO are better than comparable results for the other pollutants with national air
quality standards (Rhodes and Evans, 1987).
5.3.3 Sampling Schedules
Carbon monoxide concentrations in the atmosphere exhibit large temporal variations due
to changes in the time and rate that CO is emitted by different sources and due to changes in
meteorological conditions that govern the amounts of transport and dilution that take place.
During a 1-year period, an urban CO station may monitor hourly concentrations of CO
ranging from 0 to as high as 50 mg/m3 (45 ppm). The National Ambient Air Quality
Standards (NAAQS) for CO are based on the second highest 1- and 8-h average
concentrations; violations represent extreme events when compared to the 8,760 hours that
constitute a year. In order to measure the highest two values from the distribution of 8,760
hourly values, the "best" sampling schedule to employ is continuous monitoring 24 hours per
day, 365 days per year. Even so, continuous monitors rarely operate for long periods
without data losses due to malfunctions, upsets, and routine maintenance. Data losses of 5 to
10% (438 to 876 hours per year) are not uncommon. Consequently, the data must be
interpreted in terms of the "likelihood" that the NAAQS were attained or violated. Statistical
methods can be employed to interpret the results (Garbarz et al., 1977; Larsen, 1971).
Compliance with 1- and 8-h NAAQS requires continuous monitoring. Statistically valid
sampling could be performed on random or systematic schedules, however, if annual averages
or relative concentration levels were of importance. Most investigations of various sampling
schedules have been conducted for particulate air pollution data (Hunt, 1972; Ott and Mage,
1975; Phinney and Newman, 1972), but the same schedules also could be used for CO
monitoring. However, most instruments do not perform reliably in intermittent sampling.
5.3.4 Continuous Analysis
5.3.4.1 Nondispersive Infrared Photometry
Carbon monoxide has a characteristic infrared absorption near 4.6 ^tm: The absorption
of infrared radiation by the CO molecule therefore can be used to measure CO concentration
in the presence of other gases. The NDIR method is based on this principle.
5-13
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Nondispersive infrared systems have several advantages. They are not sensitive to flow
rate, they require no wet chemicals, they are reasonably independent of ambient air
temperature changes, they are sensitive over wide concentration ranges, and they have short
response times. Further, NDIR systems may be operated by nontechnical personnel.
Nondispersive infrared analyzers using Luft-type detectors were widely used in the 1970s,
whereas GFC analyzers are most commonly used now in documenting compliance with
ambient air standards.
NDIR Using Lvft-Type Detectors
The Luft-type detector is the primary'distinguishing feature for the type of NDIR
monitor that was widely used in the 1970s. This type of analyzer contains a hot filament
source of infrared radiation, a rotating sector (chopper), a sample cell, reference cell, and'a
detector. The reference cell contains a non-infrared-absorbing gas, whereas the sample cell is
continuously flushed with the sample atmosphere. The detector consists of a two-
compartment gas cell (both filled with CO under pressure) separated by a diaphragm whose
movement causes a change of electrical capacitance in an external circuit that generates an
amplified electrical signal suitable for input to a servo-type recorder.
During analyzer operation, a mechanical chopper alternately exposes the reference and
sample cells to the infrared sources. At the frequency imposed by the chopper, infrared
energy passes unattended through the reference cell to one compartment of the detector cell.
Transmission through the sample cell is adjusted with no CO present so that the two beams
are matched. Subsequently, when a sample is introduced into the sample cell, infrared
energy is attenuated by CO absorption, causing an imbalance in the energy reaching the two
compartments of the detector cell. These unequal amounts of infrared energy differentially
heat the absorbing gas in the detector cell and the resulting pressure difference inside the cells
causes movement of the diaphragm that forms their common wall. A signal is generated at
the chopping frequency with an amplitude related to the concentration of CO in the sample.
This in turn produces the electrical signal previously discussed.
Because water vapor is the principal interfering substance in determining CO by NDIR
techniques, a moisture control or compensation^ system is particularly important. Water vapor
can be removed by absorption using in-line drying agents or by removal of condensate in a
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cooled inlet line. Alternatively, the water vapor concentration can be measured
independently; its contribution is then subtracted from the total signal.
Gas-Filter Correlation Spectroscopy
A GFC monitor (Burch et al., 1976) is in essence a modern NDIR monitor. It has all
the advantages of an NDIR instrument and the additional advantages of ismaller size, no
interference from CO2, and very small interference from water vapor. It is not sensitive to
flow rate, requires no wet chemicals, has a very fast response, and is relatively independent
of normal ambient temperature changes.
A top view of the GFC monitor is presented schematically in Figure 5-3A, showing the
components of the optical path for CO detection. During operation, sample ah* is
continuously pushed through the sample cell. Radiation from the source is directed by optical
transfer elements through the two main optical subsystems: the rotating gas filter (designated
as the correlation cell in Figure 5-3A) and the optical multipass (sample) cell. The beam
exits the sample cell through interference filter FC, which limits the spectral passband to a
few of the strongest CO absorption lines in the 4.6-/mi region. Detection of the transmitted
radiation occurs at the infrared detector, C.
Although the passband of filter FC is chosen to minimize interference from other gases,
some residual water vapor interference occurs. This residual interference is not significant at
criteria pollutant levels, but can be corrected by independent measurement of water vapor in
the same cell.
The gas correlation cell is constructed with two compartments (Figure 5-3B): One
compartment (Gas Cell 1) is filled with 0.5 atm CO, and the other compartment (Gas Cell 2)
is filled with pure N2. Radiation transmitted through Cell 1 is completely attenuated at
spectral positions where CO absorbs strongly. The radiation transmitted by Cell 2 is reduced
by coating the exit window of the cell with a neutral attenuator. In this way, the amounts of
radiation transmitted by the two cells are made approximately equal in the spectral passband
that reached detector C through filter FC.
In operation, radiation passes alternately through the two cells as they are rotated by a
synchronous motor drive. This establishes a signal modulation frequency. Transmission to
the detector is constant if no absorption by the ambient sample occurs. If CO is present in
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Plated pattern
Chopper
Cell containing r^ Neutral
Attenuator
Cell containing
Carbon Monoxide
Figure 5-3. Schematic diagram of gas filter correlation (GFC) monitor for carbon
monoxide. A: Optical layout (M denotes mirror reflector; L denotes lens);
B: Detail of correlation cell.
Source: Chaney and McClenny (1977).
the sample, the radiation transmitted through Cell 1 is not appreciably changed, while that
through Cell 2 is changed. This imbalance is linearly related to CO concentration for small
concentrations. Other gas species absorb the radiation transmitted by Cells 1 and 2 in
approximately equal amounts because their absorption structure does not correlate with that of
CO.
Superimposed on the entrance window of the cell is a typical light chopper pattern
(Figure 5-3B) that creates a carrier frequency 12 times the signal modulation frequency (i.e.,
a carrier frequency of 400 Hz). The detector output from the CO channel is fed to two
phase-sensitive amplifiers that separate the detector response at the signal frequency from the
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detector response at the reference (carrier) frequency. The signal due to CO is divided by the
reference signal to substantially reduce many of the causes of sensitivity change, such as
accumulation of material on optical components and variation in detector sensitivity.
5.3.4.2 Gas Chromatography-Flaine lonization
In this type of system, CO is separated from other trace gases by'gas chromatography
and catalytically converted to CH4 prior to detection. A gas sampling valve, a back flush
valve, a precolumh, a gas chromatographic column, a catalytic reactor, and an FID comprise
the gas chromatography-flame ionization system. In operation, measured volumes of air are
delivered 4 to 12 times per hour to a hydrogen FID that measures the total hydrocarbon
content. A portion of the same air sample, injected into a hydrogen carrier gas stream, is
passed through the precolumn where it is separated from water, CO2, and hydrocarbons other
than CH4. Methane then is separated from CO on a second gas chromatographic column.
The CH4, which is eluted first, is unchanged after passing through a catalytic reduction tube
into the FID. The CO eluted into a catalytic reduction tube is reduced to CH4 before passing
through the FID (Porter and Volman, 1962). Between analyses, the precolumn is flushed
out. Nonmethane hydrocarbon concentrations also can be determined by subtracting the CH4
value from the total hydrocarbon (TH) value. ,
There are two possible modes of operation. One of these is a complete
chromatographic analysis showing the continuous output from the detector for each sample
injection. In the other, the system is programmed for both automatic zero and span settings
to display selected elution peaks as bar graphs. The peak height is then the measure of the
concentration. The first operation is referred to as the chromatographic or "spectro" mode
and the second as the barographic or "normal" mode. ' :
Because measuring CO entails only small increases in cost, instrument complexity, and
analysis time, these instruments customarily are used to measure three pollutants: CH4, THs,
and CO.
' Q
The instrumental sensitivity for each of these three components is 0.023 mg/m
(0.02 ppm). The lowest full-scale range available is usually 2.3 mg/m3 (2 ppm) to
"3 " ' *2 -" -"
5.7 mg/m (5 ppm), although at least one instrument has a 1.2 mg/m (1 ppm) range.
Because of the complexity of these instruments, continuous maintenance by skilled technicians
5-17
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is required to minimize downtime. This maintenance requirement may be considered a
possible disadvantage of the system. Depending on the frequency of analysis and the
temporal variability of CO, the representativeness over short averaging times may not be
accurate (Chancy and McClenny, 1977).
5.3.4.3 Other Analyzers
Contmlled-Potential Electrochemical Analysis
Carbon monoxide is measured by means of the current produced in aqueous solution by
its electro-oxidation by an electro-catarytieally active noble metal. The concentration of CO
reaching the electrode is controlled by its rate of diffusion through a membrane. This is
dependent on its concentration in the sampled atmosphere (Bay et al., 1974, 1972). Proper
selection of both the membrane and such cell characteristics as the nature of the electrodes,
the electrode potential, and the solution make the technique selective for various pollutants.
A similar technique has been reported by Yamate and Inoue (1973).
The generated current is linearly proportional to the CO concentration from 0 to
115 mg/m3 (0 to 100 ppm). A sensitivity of 1.2 mg/m3 (1 ppm) and a 10-s response time
(to reach 90% of full scale) are claimed for currently available commercial instruments.
Acetylene and ethylene are the chief interfering substances: 1 part acetylene responds
as 11 parts CO, and 1 part ethylene responds as 0.25 part CO. For hydrogen, ammonia,
hydrogen sulfide, nitric oxide, NO2, SO2, natural gas, and gasoline vapor, interference is less
than 0.03 part CO per 1 part interfering substance.
Galvanic Analyzer
Galvanic cells employed in the manner described by Hersch (1966, 1964) can be used to
measure atmospheric CO continuously. When an air stream containing CO is passed into a
chamber packed with I2O5 and is heated to 150 °C, the following reaction takes place:
SCO + I2O5 > 5CO2 + J2 (5-3)
The liberated iodine is absorbed by an electrolyte and is transferred to the cathode of a
galvanic cell. At the cathode, the iodine is reduced and the resulting current is measured by
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a galvanometer. Instruments with this detection system have been used successfully to
measure GO levels in traffic along freeways (Haagen-Smit, 1966).
Mercaptans, hydrogen sulfide, hydrogen, olefins, acetylenes, and water vapor cause
interference. Water may be removed by sampling through a drying column; hydrogen,
hydrogen sulfide, acetylene, and olefin interferences can be minimized by sampling through
an absorption tube containing mercuric sulfate on silica gel. : .-• •
Coidometric Analyzer
A coulometric method employing a modified Herseh-type cell has been used for
continuous measurement of CO in ambient air (Dubois et al., 1966). The reaction of I2O5
with CO liberates iodine, which then is'passed into a Ditte cell, and the current generated is
measured by an electrometer-recorder combination. Interferences are the same as those
discussed above for the galvanic analyzer.
This technique may be used for a minimum detectable concentration of 1.2 mg/m3
(1 ppm) with good reprodueibility and accuracy if flow rates and temperatures are controlled
well. This method requires careful column preparation and use of filters to remove '
interferences. Its relatively slow response time may be an added disadvantage in some work.
Mercury Replacement
Mercury (Hg) vapor formed by the reduction of HgO by CO is detected photometrically
by its absorption of ultraviolet light at 253.7 nm. The reaction involved is as follows: '
(210° Q
CO + HgO ^> CO2 + Hg . . ;(5-4)
This is potentially a much more sensitive method than infrared absorption because the
oscillator strength of Hg at 253.7 nm is 2,000 times greater than that of CO at 4.6 jEtm.
Hydrogen and hydrocarbons also reduce HgO to Hg, and there is some thermal
decomposition of the oxide. Operation.of the detector at constant temperature results in a
regular background concentration of Hg from thermal decomposition. The instrument is
rt
portable and can analyze CO concentrations of 0.025 to 12 mg/m3 (0.020 to 10.0 ppm).
Changes of 0.002 mg/m3 (0.002 ppm) are detectable. For this reason., this instrument has
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been used to determine global CO levels. McCullough et al. (1947) and Beckman et al.
(1948) recommended a detector operating temperature of 175 °C to minimize hydrogen
interference. A commercial instrument employing these principles was made and used during
the middle 1950s (Mueller, 1954). The technique recently has been used for measuring
background CO concentrations. Robbins et al. (1968) have described an instrument in which
the HgO chamber is operated at 210 °C, and the amount of hydrogen interference is assessed
by periodic introduction of a tube of silver oxide into the intake air stream. At room
temperature silver oxide quantitatively oxidizes CO, but not hydrogen. Thus, the baseline
hydrogen concentration can be determined. Additional minor improvements are discussed by
Seiler and Junge (1970), who gave the detection limit for CO as 0.003 mg/m3 (0.003 ppm).
More recently, Palanos (1972) described a less sensitive model of this instrument
intended for use in urban monitoring. It has a range of 0 to 23 mg/m3 (20 ppm),, a
sensitivity of about 0.58 mg/m3 (0.5 ppm), and a span and zero drift of less than 2% per
day. As in other similar instruments, specificity is achieved by removal of the potentially
interfering substances (which are less than 10% of the sample) other than hydrogen.
With all of these instruments, a constant geophysical hydrogen concentration is
assumed. In unpolluted atmospheres, the hydrogen concentration is roughly 46.5 /*g/m3
(0.56 ppm). However, the automobile not only is a source of CO but also of hydrogen.
Therefore, if this technique is used in polluted areas, it will be necessary to measure the
hydrogen concentration frequently.
Dual-Isotope Fluorescence
This instrumental method utilizes the slight difference in the infrared spectra of isotopes.
The sample is alternately illuminated with the characteristic infrared wavelengths of the
common CO isotope, carbon monoxide-16 (12C16O), and the rare isotope, carbon monoxide-
18 (12C18O). Any CO in the sample, having the normal isotope ratio of nearly 100%
12C16O, absorbs only the 12C16O wavelengths; the essentially unimpeded 12C18O
wavelengths constitute a reference signal. Therefore, there is a cyclic variation hi the
intensity of the fluorescent light that is dependent on the 12C16O content of the sample (Link
et al., 1971; McClatchie, 1972; McClatchie et al., 1972).
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Full-scale ranges of 0 to 23 mg/m3 (0 to 20 ppm) and up to 0 to 230 mg/m3 (0 to
200 ppm) with a claimed sensitivity of 0.23 mg/m3 (0.2 ppm) are available in this
instrument. The response time (to reach 90% of full scale) is 25 s, but a 1-s response time
also is available. An advantage of this technique is that it minimizes the effects of interfering
substances.
Catalytic Combustion-Thermal Detection
Determination of CO by this method is based on measuring the temperature rise
resulting from catalytic oxidation of the CO in the sample air.
The sample air is pumped first into a furnace that brings it to a preset, regulated
temperature and then over the catalyst bed in the furnace. A thermopile assembly measures
the temperature difference between the air leaving the catalyst bed and the air entering it.
The output of the thermopile, which is calibrated with known concentrations of CO in air, is
read on a strip chart recorder as parts of CO per million parts of air. The sensitivity is about
1.2 mg/m3 (1 ppm). Most hydrocarbons are oxidized by the same catalyst, and will interfere
unless removed. These systems are widely used in enclosed spaces; their applicability for
ambient air monitoring is limited because they function best at high CO concentrations.
Second-Derivative Spectrometry
A second-derivative spectrometer processes the transmission-versus-wavelength function
of an ordinary spectrometer to produce an output signal proportional to the second derivative
of this function. Ultraviolet light of continuous wavelength is collected and focused onto an
oscillating entrance slit of a grating spectrometer. When the grating orientation is changed
slowly, a slowly scanning center wavelength with sinusoidal wavelength modulation is created
in the existing light by the oscillating entrance slit. This radiation passes through a gas
sample and is detected with a photomultiplier tube. The signal then is electronically
processed to produce a second-derivative spectrum (Lawrence Berkeley Laboratory, 1973).
This method has the advantage that it can be used to measure other pollutants as well as CO.
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Fourier-Transform Spectroscopy
Fourier-transform spectroscopy is an extremely powerful infrared spectroscopic
technique (Bell, 1972) that has developed in the past 20 years and has been applied in the last
10 years to air pollution measurement problems (Hanst et al., 1973; Lawrence Berkeley
Laboratory, 1973). The advantage of this technique over a standard grating or prism
spectrometer is that it has a higher throughput, which means that the available energy is used
more effectively and that a much higher resolving power is obtainable. In air pollution
measurements, individual absorption lines can be resolved.
A special advantage for air pollution measurements is that all the data required to
reconstruct the entire absorption spectrum are acquired at the same time. The spectrum as a
function of wavelength is generated by a built-in computer. This means that several gases
can be measured simultaneously. Several commercial instruments now are available with
resolutions of 0.06/cm or better. These instruments are capable of clearly defining the
spectrum of any gaseous pollutant, including CO, and currently are being used for special air
pollution studies.
5.3.5 Intermittent Analysis
Intermittent samples may be collected in the field and later analyzed in the laboratory by
the continuous analyzing techniques described above. Sample containers may be rigid (glass
cylinders or stainless steel tanks) or they may be nonrigid (plastic bags). Because of location
or cost, intermittent sampling at times may be the only practical method for air monitoring.
Samples can be taken over a few minutes or accumulated intermittently to obtain, after
analysis, either "spot" or "integrated" results. Additional techniques for analyzing
intermittent samples are described below.
5.3.5.1 Colorimetric Analysis
Colored Silver Sol Method
Carbon monoxide reacts in an alkaline solution with the silver salt of /7-sulfamoyl-
benzoate to form a colored silver sol. Concentrations of 12 to 23,000 mg/m3 (10 to
20,000 ppm) CO may be measured by this method (Ciuhandu, 1958, 1957, 1955; Ciuhandu
and Krall, 1960; Ciuhandu et al., 1965; Levaggi and Feldstein, 1964). The method has been
5-22
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modified to determine CO concentrations in incinerator effluents. Samples are collected in an
evacuated flask and are reacted. The absorbance of the resulting colloidal solution is
measured spectrophotometrically. Acetylene and formaldehyde interfere, but can be removed
by passing the sample through mercuric sulfate on silica gel. Carbon monoxide
concentrations of 5.8 to 20,700 mg/m3 (5 to 18,000 ppm) may be measured with an accuracy
of 90 to 100% of the true value.
National Institute of Standards and Technology Colorimetric Indicating Gel
A NIST colorimetric-indicating gel (incorporating palladium and molybdenum salts) has
been devised to measure CO in the laboratory and in the field (Shepherd, 1947; Shepherd
et al., 1955). The laboratory method involves colorimetric comparison with freshly prepared
indicating gels exposed to known concentrations of CO. The method has an accuracy range
of 5 to 10% of the amount of CO involved, and the minimum detectable concentration is
o
1.2 mg/m (1 ppm). This technique requires relatively simple and inexpensive equipment;
however, oxidizing and reducing gases interfere, and the preparation of the indicator tube is a
tedious and time-consuming task.
Lengih-of-Stain Indicator Tube
An indicator tube that uses potassium palladosulfite is a commonly employed manual
method (Silverman and Gardner, 1965). Carbon monoxide reacts with the contents of the
tube and produces a discoloration.
The length of discoloration is an exponential function of the CO concentration. This
method and other indicator tube manual methods are estimated to be accurate to within
±25% of the amount present, particularly at CO concentrations of'about 115 mg/m3
(100 ppm). Such indicator tube manual methods have been used frequently in air pollution
studies. Ramsey (1966) used the technique to measure CO at traffic intersections, and Brice
and Roesler (1966) estimated CO concentrations with an accuracy of ±15% by means of
color-shade detector tubes.
Colorimetric techniques and length-of-stain discoloration methods are recommended for
use only when other physicochemical monitoring systems are not available. They may be
5-23
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used in the field for gross mapping where accuracy is not required and may possibly be of
great value during emergencies.
Fronted Analysis
Air is passed over an adsorbent until equilibrium is established between the
concentration of CO in the air and the concentration of CO on the adsorbent. The CO then is
eluted with hydrogen, reduced to CH4 on a nickel catalyst at 250 °C, and determined by
flame ionization as CH4.
"2 " ' - •
Concentrations of CO as low as 0.12 mg/m (0.10 ppm) can be measured. This
method does not give instantaneous concentrations, but does give averages over a six-minute
or longer sampling period (Dubois and Monkman, 1972, 1970).
5.4 MEASUREMENT USING PERSONAL MONITORS
Until the 1960s, most of the data available on ambient CO concentrations came from
fixed monitoring stations operated routinely in urban areas. The accepted measurement
technique was by NDIR spectrometry, but the instruments were large and cumbersome, often
requiring vibration-free, air-conditioned enclosures. Without a portable, convenient monitor
for CO, it was extremely difficult to measure CO concentrations accurately in the
microenvironments that people usually visited. In the late 1960s, studies were initiated to
investigate the CO concentrations within vehicles (Brice and Roesler, 1966; Lynn et al.,
1967). In 1971, an investigator walked on congested downtown streets alongside pedestrians
to measure their exposures (Ott, 1971). With a portable pump, the investigator filled
sampling bags in various locations, then transported them to the laboratory where the contents
were analyzed by NDIR spectrometry.
In the early 1970s, portable electrochemical monitors about the size of a shoe box
became available. Using the Ecolyzer monitor, CO concentrations were measured in traffic
in Boston, MA (Cortese and Spengler, 1976). In the late 1970s, smaller personal monitors
using electrochemical sensing systems became available and were deployed in specialized
field surveys involving a few people (Jabara et al., 1980).
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As CO monitors continued to evolve, they were used in studies of indoor
microenvironments. Many of the microenvironmental CO data on indoor concentrations were
collected as an integral part of multipollutant indoor health or dosage studies in homes,
offices, or rooms (Berglund et al., 1982; Hoffmann et al., 1984; Hugod, 1984), or as more
narrowly focused multipollutant exposure field studies in homes (Quackenboss et a}., 1984;
Koontz and Nagda, 1984; Traynor et al., 1984) and in buildings (Konopinski, 1984;
MalaspinaetaL, 1984; Clarkson, 1984).
Although the CO personal monitors evolved rapidly, they were not used in large-scale
field surveys of indoor microenvironments until the early 1980s. Personal monitors have
been used in studies of CO concentrations in sustained-use vehicles (Ziskind et al., 1981) and
in passenger compartments of vehicles traveling on highways (Ott and Willits, 1981;
Flachsbart and Ah Yo, 1986).
Ultimately, small personal exposure monitors (PEMs) were developed that could
measure CO concentrations continuously over time and store the readings automatically on
internal digital memories (Ott et al., 1986). These small PEMs made possible the large-scale
CO human exposure field studies in Denver, CO, and Washington, DC, in the winter of
1982 to 1983 (Akland et al., 1985). The PEM employed in these studies uses an aqueous
solid polymer ion exchange material as the electrolyte in which CO is converted to CO2 by
an electrochemical reaction at a noble metal electrode, thereby generating an electrical
current. The signal (current) is proportional to the quantity of CO present in the gas stream,
and the continuous electrical signal is recorded in internal memory. A small pump operates
continuously to send air into the sensing cell, and chemical filters in the intake stream remove
interfering chemicals, such as ethanol. The pump operates on batteries for up to 40 h with a
drift of no more than 2 ppm. Zero and span checks are required before and after field
service. Other studies have employed the CO detector and combined it with small computers
such as the HP-41CV to enhance the utility of the detector for studying factors that affect CO
concentration variability (Fitz-Simons and Sauls, 1984). These monitors proved effective in
generating 24-h CO exposure profiles on more than 1,600 persons. By breaking up the
profiles into the microenvironments visited by these people, it was possible to develop CO
concentration readings on more than 40 indoor and in-transit microenvironments (see
Chapter 8).
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Detector tubes also can be used in studies where high concentrations occur (above
5 mg/m3) or long exposure times are possible and only cumulative exposures are required.
Air is drawn through specifically manufactured tubes containing an absorbent impregnated
with a chemical reagent that changes color if CO is present (Jacobs, 1949). The length of the
stain produced in the tube after exposure is read on a chart to give the concentration of CO.
Unfortunately, interferences also may produce color changes, unless additional precautions
are taken to filter out particles and to absorb interfering gases such as oxides of nitrogen,
SO2, hydrocarbons, ammonia, hydrogen sulfide, and water vapor. Techniques such as the
detector tube may have the greatest utility to the researcher by providing inexpensive
approximate value for screening purposes, which would require confirmation found about
some predetermined "action" level.
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6. AMBIENT CARBON MONOXIDE
Ambient pollutant concentrations can be measured at selected locations, or they can be
estimated through mathematical models using inventories of source emissions and scenarios of
meteorological conditions. A network of measurement instruments, plus their laboratory and
data analysis support, provides concrete information, but for a necessarily limited number of
locations because of cost. Modeled results can cover a broader scale of geographic areas, but
require detailed, accurate emissions data and representative meteorological data. Models also
require verification by comparison with measured concentrations. Measurements and
modeling are, thus, complementary. Data on carbon monoxide (CO) emissions, used to
identify principal source categories, and measurements of ambient CO concentrations, used
principally to assess compliance with national standards, are summarized here. The various
models, which are used primarily to design and evaluate control options, are described
briefly.
6.1 ESTIMATING NATIONAL EMISSION FACTORS
The national CO emission estimates presented here are taken from the U.S.
Environmental Protection Agency (EPA) report: National Air Pollutant Emission Estimates,
1940-1990 (U.S. Environmental Protection Agency, 1991b). These data are most useful as
indicators of overall national emission trends; they are not necessarily the best guide for
estimating or predicting specific trends in local areas. The emission data represent calculated
estimates based on standard emission inventory procedures developed by the Office of Air
Quality Planning and Standards of the U.S. Environmental Protection Agency (1991b).
These procedures either estimate the emissions directly or estimate the magnitude of other
variables that can then be related to emissions. For CO, these indicators include fuel
consumption, vehicle population, vehicle miles traveled (VMT), sales of new vehicles, tons
of refuse burned, raw materials processed, etc., which are then multiplied by the appropriate
CO emission factor(s) to obtain the CO emission estimate(s). It should be noted that
emission factors have specific limitations and applicability. Emission factors, in general, are
• 6-1
-------
not precise indicators of emissions from a single source; rather, they are quantitative
estimates of the average rate of pollutant released as a result of some activity. They are most :
valid when applied to a large number of sources and processes. Emission factors thus relate '••
quantity of pollutants emitted to indicators such as those noted above, and are EPA's
approach for determining national estimates of emissions from various source categories.
6.2 EMISSION SOURCES AND EMISSION FACTORS BY SOURCE
CATEGORY
Emission source categories, as presented in Table 6-1, are divided into five individual
categories: (1) transportation, (2) stationary source fuel combustion, (3) industrial processes^
(4) solid waste disposal, and (5) miscellaneous. The methodology used in the generation of
emission estimates for the individual source categories is summarized below. .
6.2.1 Transportation Sources
Transportation sources, include'emissions from all mobile sources, including highway
and other off-highway motor vehicles. Highway motor vehicles include passenger cars,
trucks, buses, and motorcycles. Off-highway vehicles include aircraft; railroads; vessels; and
miscellaneous engines such as farm equipment, industrial and construction machinery,
lawnmowers, and snowmobiles. - '-.
6.2.1.1 Motor Vehicles
Emission estimates from gasoline- and diesel-powered motor vehicles are based upon
vehicle-mile tabulations and emission factors. Eight vehicle categories are considered:
(1) light duty gasoline (mostly passenger cars), (2) light duty diesel passenger cars, (3) light
duty gasoline trucks (weighing less than 6,000 pounds), (4) light duty gasoline trucks
(weighing 6,000 to 8,500 pounds), (5) light duty diesel trucks, (6) heavy duty gasoline trucks
and buses, (7) heavy duty diesel trucks and buses, and (8) motorcycles. The emission factors
used are based on EPA's mobile source emission factor model, developed by the EPA Office
of Mobile Sources, which uses; the latest available data to estimate average in-use emissions .
from highway vehicles. The. most recent update of the model, MOBILE4.1, was released in
6-2
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TABLE 64. CARBON MONOXIDE NATIONAL EMISSIONS ESTIMATES (teragrams/year)a
Source Category
Transportation
Highway Vehicles
Aircraft
Railroads
Vessels
Other, Off Highway
Transportation Total
Stationary Source Fuel Combustion
Electric Utilities
Industrial
Commercial-Institutional
Residential
Fuel Combustion Total
Industrial Processes
Solid Waste Disposal
Incineration
Open Burning
Solid Waste Total
Miscellaneous
Forest Fires
Other Burning
Miscellaneous Organic Solvent
Miscellaneous Total
Total of All Sources
1970
65.3
0.9
0.3
1.2
6.8
74.4
0.2
0.7
0.1
3.5
4.5
9.0
2.7
3.7
6.4
5.1
2.1
0.0
7.2
101.4
1975
57.2
0.9
0.2
1.4
5.4
65.0
0.3
0.7
0.1
3.3
4.3
6.9
1.8
1.3
3.1
4.0
0.8
0.0
4.8
84.1
1980
48.7
1.0
0.3
1.4
4.7
56.1
0.3
0.7
0.1
6.4
7.4
6.3
1.2
1.0
2.2
6.9
0.7
f\ /\
u.u
7.6
79.6
1981
48.0
1.0
0.3
1.4
4.7
55.4
0.3
0.6
0.1
6.7
7.7
5.9
1.2
0.9
2.1
5.8
0.6
0.0
6.4
77.5
1982
45.9
1.0
0.2
1.4
4.4
52.9
0.3
0.6
0.1
7.3
8.2
4.4
1.1
0.9
2.0
4.3
0.6
A /\
U.U
4.9
72.5
1983
45.9
1.0
0.2
1.4
3.9
52.4
0.3
0.6
0.1
7.2
8.2
4.3
1.0
0.9
1.9
7.1
0.6
0.0
7.8
74.5
1984
43.5
1.0
0.2
1.7
4.2
50.6
0.3
0.6
0.1
7.3
8.3
4.7
1.0
0.9
1.9
5.7
0.6
0.0
6.4
71.9
1985
40.7
1.1
0.2
1.4
4.5
47.9
0.3
0.6
0.1
6.5
7.5
4.4
1.1
0.9
1.9
6.5
0.6
A n
7.1
68.7
1986
37.5
1.1
0.2
1.5
4.4
44.6
0.3
0.6
0.1
6.6
7.5
4.2
0.9
0.8
1.8
4.5
0.6
n i\
5.1
63.2
1987
36.0
1.1
0.2
1.6
4.4
43.3
0.3
0.6
0.1
6.6
7.6
4.3
0.9
0.8
1.8
5.8
0.6
n n
6.4
63.4
1988
34.1
1.0
0.2
1.6
4.2
41.2
0.3
0.6
0.1
6.6
7.6
4.6
0.9
0.8
.1.7
8.9
0.6
0.0
9.5
64.7
1989
32.7
1.1
0.2
1.7
4.4
40.0
0.3
0.7
0.1
6.7
7.8
4.6
0.9
0.8
1.7
5.8
0.6
0.0
6.3
60.4
1990
30.3
1.1
0.2
1.7
4.4
37.6
0.3
0.7
0.1
6.4
7.5
4.7
0.9
0.8
1.7
8.1
0.6
ft n
8.6
60.1
*Note: Due to rounding, sums of subcategories may appear not to equal totals shown.
'! -'
Source: U.S. Environmental Protection Agency (1991b).'", t
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1991 (U.S. Environmental Protection Agency, 1991c). Earlier versions of the model
(MOBELE2, MOBILES, and MOBELE4) have been used in the development and evaluation of
some of the intersection models discussed in Section 6.5.2, below. Because each update of
the emission factor model reflects the results of analyses of much additional data on in-use
vehicles' emission performance, as well as revisions to correction factors and other
information used in the model, the release of a new version supersedes all previous versions,
References to MOBILE2, MOBILES, and MOBILE4 in the sections below reflect the version
of the model that was used at the time; all future work and analyses should be based on the
most recent version of (the model (currently MOBILE4.1).
The MOBILE model is used to calculate emission factors for each model year. The
emission factors are weighted to consider the approximate amount of motor vehicle travel in
low- and high-altitude areas to obtain overall national average emission factors. For each
area, a representative average annual temperature (low altitude average annual temperature =
57 "F, high altitude = 54 *F, California = 65 °F), together with national averages for
motor vehicle registration distributions in the eight categories listed above, and annual
mileage accumulation rates by age and hot/cold start vehicle operation percentages were used
to calculate the emission factors. Average speed is taken into account according to the
published distribution of VMT (U.S. Department of Transportation, 1988). These published
VMT are divided into three road categories with assumed average speeds: (1) 55 mph for
interstates and other primary highways, (2) 45 mph for rural roads, and (3) 19.6 mph for
urban streets.
MOBELE4.1 provides four emission factors in grams per mile: (1) hydrocarbons,
exhaust; (2) hydrocarbons, evaporative; (3) CO, exhaust; and (4) nitrogen oxides, exhaust.
The emission factors represent a composite driving pattern at a given average speed, which
includes variations in speed, stops and starts, and idling periods. Idle emission factors
represent emission rates for stabilized vehicle operation at 75 °F (fully warmed-up engine and
catalytic converter). Adjustments of the idle emission factors to other conditions, such as
cold start or low temperatures, must be performed outside of MOBILE model calculations
(U.S. Environmental Protection Agency, 1989b).
6-4
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In a 1987 California study, CO emissions measured in a tunnel were compared with
predicted emissions using a vehicle emissions model (EMFAC7C) similar to MOBILES.
Recorded emissions of CO averaged 2.7 times greater (range: 1.1 to 3.6) than the model
predictions (Ingalls et al., 1989; Pierson et'al., 1990). This underprediction of tunnel CO
emissions by a factor of 2.7 is due to the chosen limitations and assumptions in the designs of
the EMFAC7C and MOBILES emissions models themselves. These emissions models do not
adequately take into account vehicle fleets containing "super CO emitters" (i.e., grossly
polluting vehicles, which are predominantly found among pre-1980 model cars and trucks).
For example, roadway emission tests in Los Angeles and Denver showed Ihat at least 50% of
total vehicle emissions of CO derived from approximately 10% of the sampled vehicle fleet,
a group composed largely of pre-1980 models (Lawson et al., 1990; Stephens and Cadle,
1991). On the other hand, in the Denver study, 1988 and 1989 model vehicles, 12% of the
vehicle fleet, contributed only 2% of the total vehicular emissions of CO (Stephens and
Cadle, 1991). More importantly, the MOBILES model and its successors, MOBILE4 and
now MOBILE4.1, are intended to estimate emission factors for an entire in-use vehicle fleet
over several major operating modes in a broad geographic area for an entire day rather than
the physical and temporal microscale of a 1/8 mi tunnel, an essentially constant operating
mode, and sampling periods of 60 to 90 min. Subsequent trial calculations with MOBILE4,
adjusted to accommodate several of the more prominent experimental aspects in which the
tunnel study differed from typical MOBILE4 scenarios (e.g., model year/mileage
proportions), reduced the disparity between measured and predicted CO emissions to about
1.4. Additional model refinements would reduce the difference further. MOBILE4.1 still
may underpredict actual CO emissions to some extent, but the disparity is not as great as the
California tunnel study initially seemed to suggest.
6.2.1.2 Aircraft
Aircraft emissions are based on emission factors and aircraft activity statistics reported
by the Federal Aviation Administration (1988). Emissions are based on the number of
landing-takeoff cycles. Any emissions in cruise mode, which is defined to be above
3,000 feet (1,000 meters), are ignored. Average emission factors for each year, which take
6-5
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into account the national mix of aircraft types for general aviation, military, and commercial
aircraft, are used to compute the emissions.
6.2.1.3 Railroads
The Department of Energy reports consumption of diesel fuel and residual fuel oil by
locomotives (U.S. Department of Energy, 1988a). Average emission factors applicable to
diesel fuel consumption were used to calculate emissions.
6.2.1.4 Vessels
Vessel use of diesel fuel, residual oil, and coal is reported by the Department of Energy
(U.S. Department of Energy, 1988a,b). Gasoline use is based on national boat and motor
registrations, coupled with a use factor (gallons/motor/year) (Hare and Springer, 1973) and
marine gasoline sales (U.S. Department of Transportation, 1988). Emission factors from
AP-42 are used to compute emissions (U.S. Environmental Protection Agency, 1985).
6.2.1.5 Nonhighway Use of Motor Fuels
Gasoline and diesel fuel are consumed by off-highway vehicles in substantial quantities.
The fuel consumption is divided into several categories, including farm tractors, other farm
machinery, construction equipment, industrial machinery, snowmobiles, and small general
utility engines such as lawnmowers and snowthrowers. Fuel use is estimated for each
category from estimated equipment population and an annual use factor of gallons per unit
per year (Hare and Springer, 1973), together with reported off-highway diesel fuel deliveries
(U.S. Department of Energy, 1988a) and off-highway gasoline sales (U.S. Department of
Transportation, 1988).
6.2.2 Stationary Source Fuel Combustion
Stationary combustion equipment, such as coal-, gas-, or oil-fired heating or power
generating plants, generate CO as a result of improper or inefficient operating practices or
inefficient combustion techniques. The specific emission factors for stationary fuel
combustors vary according to the type and size of the installation and the fuel used, as well
6-6
-------
as the mode of operation. The EPA compilation of air pollutant emission factors provides
emission data obtained from source tests, material balance studies, engineering estimates, and
so forth, for the various common emission categories. For example, coal-fired electricity-
generating plants report coal use to the Department of Energy (U.S. Department of Energy,
1988b,c). Distillate oil, residual oil, kerosene, and natural gas consumed by stationary
combustors are also reported by user category to the U.S. Department of Energy (1988a,
1989a,b). Average emission factors from AP-42 (U.S. Environmental Protection Agency,
1985) were used to calculate the emission estimates. The consumption of wood in residential
wood stoves has likewise been estimated by the U.S. Department of Energy (1982, 1984).
6.2.3 Industrial Processes
In addition to fuel combustion, certain other industrial processes generate and emit
varying quantities of CO into the air. The lack of published national data on production, type'
of equipment, and controls, as well as an absence of emission factors, makes it impossible to
include estimates of emissions from all industrial process sources.
Production data for industries that produce the great majority of emissions were derived
from literature data. Generally, the Minerals Yearbook (U.S. Department of the Interior,
annual), published by the Bureau of Mines, and Current Industrial Reports (U.S. Department
of Commerce, annual), published by the Bureau of the Census, provide adequate data for
most industries. Average emission factors were applied to production data to obtain
emissions. Control efficiencies applicable to various processes were estimated on the basis of
published reports (Vandegrift et al., 1971a,b; Shannon et al., 1971) and from National
Emissions Data System data (NEDS, National Emissions Data System, no date).
6.2.4 Solid Waste Disposal
Solid waste CO emissions result from the combustion of wastes in municipal and other
incinerators, and also from the open burning of domestic and municipal refuse. Specific
emission estimates for the various waste combustion procedures in use were taken from a
study conducted in 1968 concerning solid waste collection and disposal practices (U.S.
Department of Health, Education, and Welfare, 1968). Results of this study indicate that the
average collection rate of solid waste is about 5.5 Ibs per capita per day in the United States.
6-7
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It has been stated that a conservative estimate of the total generation rate is 10 Ibs per capita
per day. The results of this survey were updated based on data reported hi NEDS and used
to estimate, by disposal method, the quantities of solid waste generated (NEDS, National
Emissions Data System, no date). Average emission factors were applied to these totals to
obtain estimates of total emissions from the disposal of solid wastes.
6.2.5 Miscellaneous Combustion Sources
Miscellaneous CO emissions results from the burning of forest and agricultural
materials, smoldering coal refuse materials, and structural fires.
6.2.5.1 Forest Fires
The Forest Service of the Department of Agriculture publishes information on the
number of forest fires and the acreage burned (U.S. Forest Service, 1988). Estimates of the
amount of material burned per acre are made to estimate the total amount of material burned.
Similar estimates are made to account for managed burning of forest areas. Average
emission factors were applied to the quantities of materials burned to calculate emissions.
6.2.5.2 Agricultural Burning
A study was conducted by EPA (Yamate, 1974) to obtain, from local agricultural and
pollution control agencies, estimates of the number of acres and estimated, quantity of
material burned per acre in agricultural burning operations. These data have been updated
and used to estimate agricultural burning emissions, based on average emission factors.
6.2.5.3 Coal Refuse Burning
Estimates of the number of burning coal-refuse piles existing in the United States are
made in reports by the Bureau of Mines (McNay, 1971). This publication presents a detailed
discussion of the nature, origin, and extent of this source of pollution. Rough estimates of
the quantity of emissions were obtained using this information by applying average emission
factors for coal combustion. It was assumed that the number of burning refuse piles
decreased to a negligible amount by 1975.
6-8
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6.2.5.4 Structural Fires
The United States Department of Commerce publishes, in their statistical abstracts,
information on the number and types of structures damaged by fire (U.S. Department of
Commerce, 1987). Emissions were estimated by applying average emission factors for wood
combustion to these totals.
6.3 TREND IN ESTIMATED NATIONAL CARBON MONOXIDE
EMISSIONS, 1970-1990
Table 6-1 lists the estimated total annual CO emissions from the various source
categories for 1970, 1975, and 1980-1990 (U.S. Environmental Protection Agency, 1991b).
The CO estimations cited herein are the result of current methodology and refined emission
factors and should not be compared with data reported earlier. These data indicate that CO
emissions from all man-made sources hi the United States declined from 101.4 Tg in 1970
(1 Tg = 1012g = 103Gg = 106 metric tons, or approximately 1.1 X 10b short tons) to
60.1 Tg in 1990. The majority, about 63%, of the CO emissions total comes from
transportation sources, 12% comes from stationary source fuel combustion, 8% comes from
industrial processes, 3% comes from solid waste, and 14% comes from miscellaneous
sources. Table 6-2 contains a more detailed listing of CO emissions from the dominant
category, transportation sources.
The single largest contributing source of CO emissions is highway vehicles, which
emitted an estimated 50% of the national total in 1990. Because of the implementation of the
Federal Motor Vehicle Control Program (FMVCP), CO emissions from highway vehicles
have declined 54%, from 65.3 Tg to 30.3 Tg, in the period 1970 to 1990. Figure 6-1
displays the trend hi estimated CO emissions from the major highway vehicle categories from
1970 to 1990. Although the total annual VMT continues to increase in the United States (by
37% just in the period 1981-1990), total CO emissions from highway vehicles have continued
to decrease as a result of the FMVCP-mandated air pollution control devices on new vehicles.
Carbon monoxide emissions from other sources have also generally decreased. In 1970,
emissions from burning of agricultural crop residues were greater than in more recent years.
6-9
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TABLE 6-2. CARBON MONOXIDE NATIONAL MISSIONS EROM TRANSPORTATION (gigagrams/year)e
Source Category
1970 1975 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989
1990
Highway vehicles
Gasoline-powered
Passenger cars
Light trucks -1
Light trucks - 2
Heavy duty vehicles
Motorcycles
Total - Gasoline
Diesel-powered
Passenger cars
Light trucks
Heavy duty vehicles
Total - Diesel
Highway Vehicle Total
i—»
o Aircraft
Railroads
Vessels
Farm machinery
Construction machinery
Industrial machinery
Other off-highway vehicles
Transportation Total
49,090 41,430 31,850 30,160 30,150 29,510 27,790 25,409 23,650 22,531 21,219 20,198 18,571
5,800 5,730 5,810 6,370 5,760 6,190 6,050 6,279 6,059 6,103 5,769 5,677 5,408
2,070 2,450 4,210 4,700 4,220 4,610 4,450 4,329 4,036 3,793 3,539 3,363 3,072
7,810 6,610 5,870 5,780 4,910 4,720 4,380 3,749 2,918 2,797 2,735 2,588 2,379
260 540 370 2§0_ 200 . 190 170 128 124 126 121 122 122
65,030 56,760 48,110 47,290 45,240 45,220 42,840 39,894 36,787 35,349 33,384 31,948 29,553 -
0 08 10 10 20 20 17 17 15 13 11 11
0 0 3 6 6 5 3,4-4 3 4 4 4
300 390 610 700 680 650 650 769 675 "• 682 719 730 715
300 390 621 716 " 696 - 675 673 790 695 700 ,736 745 729
65,330 57,150 48,731 48,006 45,936 45,895 43,513 40,684 /37,482 36,050 34,119 32,692 30,282
900 880 990 960 950 980 1,010 1,086 1,082 1,062 1,048 1,067 1,078
250 240 270 250 240 190 200 190 183 186 193 193 164
1,150 1,360 1,380 1,440 1,390 1,410 1,700 1,396 1,498 1,565 1,617 1,662 1,670
3,570 2,930 2,040 1,880 1,780 1,470 1,900 2,117' 1,914 '1,828 1,645 1,640 1,697
580 370 460 370 320 260 250 414 451 524 526 558 622
1,780 1,060 1,110 1,330 1,190 1,040 900 848 839 877 882 937 888
840 990 1.100 1,150 1,130 1.140 1.130 1,153 1.169 1.190 1.194 1.224 1.210
74,400 64,980 56,081 55,386 52,936 52,385 50,603 47,887 44,616 43,281 41,222 39,974 37,611
"Note: Due to rounding, sums of subcategories may appear not to equal totals shown.
Source: U.S. Environmental Protection Agency (1991b).
-------
70 -T
60
50
'SO "81 '82 '83 '84 '85 '86 '87 '88 '89 '90
Year
Figure 6-1. Estimated emissions of carbon monoxide from gasoline-fueled highway
vehicles, 1970-1990.
Source: Adapted from U.S. Environmental Protection Agency (1991a).
Solid waste disposal emissions have also decreased as the result of implementation of
regulations limiting or prohibiting burning of solid waste in many areas. Emissions of CO
from stationary source fuel combustion occur mainly from the residential sector. These
emissions were reduced somewhat through the mid-1970s as residential consumers converted
to natural gas, oil, or electric heating equipment. Recent growth in the use of residential
wood stoves has reversed this trend, but increased CO emissions from residential sources
continue to be small compared to highway vehicle emissions. Nevertheless, in 1990
residential wood combustion accounted for about 10% of national CO emissions, more than
any source category except highway vehicles. Carbon monoxide emissions from industrial
processes have generally been declining since 1970 as the result of the obsolescence of a few
high-polluting processes such as manufacture of carbon black by the channel process and
installation of controls on other processes.
6-11
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6.4 OUTDOOR AIR CONCENTRATIONS
6.4.1 Introduction
Ambient concentrations of CO in urban communities vary widely with time and space.
Actual human exposure to CO in various indoor and outdoor activities is affected by highly
localized microenvironments, which are influenced by nearness to sources, including vehicles;
occupations; and by personal activities, such as smoking. Indoor sources and concentrations
are summarized in Chapter 7. Exposure information is presented in Chapter 8. This section
presents information about ambient concentrations. It will describe observed diurnal,
seasonal, and annual patterns of ambient urban CO levels and will explain the importance of
air monitoring site selection, of meteorological and geographic effects on CO exposures,
techniques of CO trend analyses, and special CO exposure situations.
6.4,2 Site Selection
Site selection is one of the most complex and critical elements in the design of CO air
monitoring programs. This is especially important for CO monitoring because the proximity
of the monitor to traffic will influence the magnitude of CO concentrations. Naturally, the
choice of monitoring sites depends greatly on the objective of the monitoring to be
performed. The U.S. Environmental Protection Agency (1971) recognizes the following as
general objectives for monitoring:
1. To judge compliance with and/or progress made toward meeting ambient air quality
standards. .
2. To activate emergency control procedures to ameliorate air pollution episodes.
3. To observe pollution trends throughout the region, including the nonurban areas.
(Information from nonurban areas is needed to evaluate whether air quality in the
cleaner portions of a region is deteriorating significantly and to gain knowledge
about background pollutant levels.)
4. To provide a date base for application in the evaluation of effects; in urban, land
use, and transportation planning; in development and evaluation of abatement
strategies; and in development and validation of diffusion models.
6-12
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In addition to these general objectives, site selection is also based on the scale of
representativeness that will meet the objectives. Data representativeness, like measures of
concentration at a site, is dependent on the proximity of the monitor to the CO source but,
further, is influenced by the intended use to which the data will be put. Ground level
concentrations of CO within an urban area vary widely because the principal source of CO in
cities is automobiles which, obviously, move and are more concentrated in some areas at
some times than at other times. Monitoring sites at the edge of a highway will measure CO
concentrations representative of a fairly small area. Sites well removed from highways can
be representative of a fairly large-scale area. The EPA has defined six scales of spatial
representativeness for CO monitoring sites: (1) microscale, (2) middle scale,
(3) neighborhood scale, (4) urban scale, (5) regional scale, and (6) national and global scale
(Federal Register, 1979).
Most CO monitoring conducted in the United States is for the purpose of determining
attainment or nonattainment of air quality standards. Because monitoring resources have been
and continue to be severely limited, monitoring sites are usually selected by, a "worst case"
principle; that is, they are set up where maximum CO concentrations are expected because
the National Ambient Air Quality Standards (NAAQS) focus on peaks. As a result, many
CO sites are located in close proximity to major highways, arterials, and downtown street
canyons. This means that they are situated where maximum CO levels occur, but that their
scale of representativeness is small. Monitoring results may thus relate primarily to
pedestrian exposure near the monitor. Sites located away from the major roadways, but
within highly populated neighborhoods with high traffic densities, may be more representative
of the maximum CO concentrations to which a large portion of the population of a city may
be exposed.
The EPA has published guidelines (Federal Register, 1979) for CO monitor siting
(Table 6-3). EPA guidelines (U.S. Environmental Protection Agency, 1971) give the highest
priority to microscale sites within street canyons and to neighborhood sites where maximum
concentrations are expected.
The variability of CO concentration with height in the vicinity of a highway is
sufficiently large that the representativeness of measurements will be strongly affected by
variability of the inlet probe height. It is, therefore, necessary to standardize the height of
6-13
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TABLE 6-3. PROBE SUING CRITERIA FOR CARBON MONOXIDE MONITORS
Site Type
Microscale
(Street canyon and
traffic corridor)
Middle scale
Neighborhood scale
Height Above Horizontal Proximity
Ground to Buildings Separation from Influencing Sources
3 ± 0.5 m 1m >2 to ^10 m from, nearest traffic lane;
>10 m from intersection, preferably
midblock
3-15 m 1m Same as microscale, but closer than
neighborhood scale, below
3-15 m 1 m Avg. Traffic, Probe-to-
vehicles per day Roadway, m
< 10,000 > 10
15,000 25
20,000 45
30,000 80
40,000 115 '
50,000 135
> 60,000 150
General
Remarks
No interposed
vegetation
> 10 m from
dripline of large
trees
Same as middle
scale
Source: Code of Federal Regulations (1991b).
-------
the inlet probe so that data collected at one air monitoring station are comparable to data
collected at others. In an effort to characterize typical human exposure, the sample inlet
probe height should ideally be at breathing level. However, as a compromise between
representation of breathing height and practical considerations, such as prevention of
vandalism, it is recommended that inlets for most kinds of sampling be at a height of
3 ± 0.5 m (Altshuller et al., 1966; Bach et al., 1973). A 1-m minimum separation of the !
probe from adjacent structures is also recommended to avoid the frictional effects of surfaces
on the movement of air (Code of Federal Regulations, 199 lb).
Site selection for monitors used for purposes other thdn trend analysis and determination
of compliance with air quality standards may not follow the specific criteria that apply to
continuous monitoring sites. In fact, special purpose studies in which CO concentrations are '
measured at many locations provide information about the spatial variations of ambient CO
that form the basis for setting site-selection criteria. Among the principal types of special ;
purpose monitoring are research studies for diffusion model development anddmprovement
and for source surveillance studies. . ,
6.4.3 United States Data Base
Monitoring stations reporting data to BPA's Aerometric Information Retrieval System, •'.
(AIRS) fall into two major categories;. (1) the National Air Monitoring Stations (NAMS) and
(2) the State and Local Air Monitoring Stations (SLAMS). The NAMS were established ,
through monitoring regulations promulgated in May 1979 (Federal Register, 1979) to provide
EPA with accurate and timely data on a national scale. The NAMS are located at sites
expected to incur high pollutant concentrations and to typify areas with the potential for high
population exposure. These stations meet uniform criteria for site location; quality assurance;
and equivalent analytical methodology, sampling intervals, and instrument selection to assure ;
consistent data reporting nationwide. The SLAMS, in general, meet the same rigid criteria
but, in addition to the above siting criteria for highest concentrations arid population exposure
potential, they may be located to monitor a greater diversity of urban neighborhoods.
In accordance with requirements of the Clean Air Act and EPA regulations for State
Implementation Plans (SIPs) (Code of Federal Regulations, 199/la), ambient GO data from
Federal networks must be reported each calendar quarter to AIRS. State and local agencies
?6-15
-------
report most of the data from their SLAMS stations as well. As a result, continuous
measurements of ambient CO concentrations from numerous cities throughout the United
States are available from the U.S. EPA.
Computer retrievals of raw data submitted to the EPA's AIRS data bank and published
data summaries such as the National Air Quality and Emission Trends Report (U.S.
Environmental Protection Agency, 1976e, 199 la) and Air Quality Data—Annual Statistics
(U.S. Environmental Protection Agency, 1974a,b, 1976a,b,c,d, 1977a) are available.
However, state and local air pollution control agencies are not required to submit all CO data
collected from their monitoring network. These agencies may also conduct special studies for
certain "in-house" purposes. State departments of transportation and local metropolitan
planning commissions are sources of CO data for the preparation of environmental impact
statements for proposed transportation projects and/or in the preparation of SIP revisions.
Air quality impact research sponsored by the EPA, the Federal Highway Administration,
universities, and private industries also are sources of CO data.
6.4.4 Techniques of Data Analysis
Air quality surveys inherently involve taking a limited number of samples from a highly
variable and uncontrolled population (i.e., the environment). For this reason, air quality data
should be analyzed through statistical methods, which can be used to describe the behavior of
the total population on the basis of a finite number of samples. In particular, statistical
parameters can be calculated to describe the typical values observed, the maximum or peak
values observed, and the range of values observed.
Although intermittent sampling is an important research tool for conducting special
studies, the majority of CO monitoring instruments in use today are intended to operate
continuously and to yield successive hourly averages. These data are applied for two
principal uses: (1) characterizing environmental conditions by describing short-term (hourly,
daily, seasonal) and long-term (year-to-year) urban CO concentration patterns, and
(2) evaluating, for statutory purposes, an area's status with respect to the 1-h and 8-h average
NAAQS for CO.
At a minimum, an analysis of CO air quality data should include a comparison of the
highest (or second highest) observed pollution concentration to established air quality
6-16
-------
standards. In addition, an analysis of CO data may include calculation of population
statistics, patterns of occurence that relate to exposure potential, frequency analyses, <
averaging time analyses, trend analyses, and case analyses. ,
6.4.4.1 Frequency Analyses
In most areas of air pollution monitoring modeling, we do not have enough knowledge
about the generation, dispersion, and transport of air pollutants to formulate a convincing
theoretical model for air quality data. Air pollutant concentrations are often generated by
autocorrelated stochastic processes. In most situations we never know which of several
hypothetical models may be "correct." Fortunately, it is usually possible to identify time
periods and pollutant averaging times when observations are approximately stationary .and can
be treated as independent sequences of concentrations. Horowitz and Barakat (1979) showed
that autocorrelation does not significantly affect the validity of the usual methods for
estimating the parameters of the maximum pollutant concentration distribution. The most
widely used model has been the two-parameter lognormal distribution, which has played a
major role in the formulation of air quality standards for many pollutants (Georgopoulos and
Seinfeld, 1982). However, there are many data sets for which some other distribution fits
better. These candidate models include the three-parameter lognormal, Weibull, exponential,
and gamma distributions (Bencala and Seinfeld, 1976; Ott et at, 1979; JPollack, 1975;
Simpson et al., 1984). This variety of distribution types probably reflects the phenomenon
that an air pollution concentration is the superposition of a random number of point, line, and
area sources of different emission strengths.
The NAAQS for CO are currently based on a 1-h and an 8-h averaging time. Carbon
monoxide data are most frequently collected in time averages of 1 h. Evaluating compliance
with the 1-h standard simply requires rank-ordering 1-h values for a year and comparing the
^
second highest value with the 1-h standard, which is currently 35 ppm (40 mg/m ), not to be
exceeded more than once per year. If the second highest 1-h value is less than 35 ppm, the
standard has been met.
Evaluating compliance with the 8-h standard involves the calculation of moving 8-h
averages from the 1-h data set. These 8-h averages are also rank-ordered to obtain the
second highest nonoverlapping value for comparison with the 8-h standard, which is currently
6-17
-------
<2
9 ppm (10 mg/m ). For enforcement purposes, only nonoverlapping 8-h intervals are
counted as violations, as discussed in the Guidelines for the Interpretation of Air Quality
Standards (U.S. Environmental Protection Agency, 19775). It has been shown, however,
that the full set of moving 8-h averages should be examined in order to properly identify
maximum values before demarcating nonoverlapping violations (McMullen, 1975). Proposed
simplifications, such as calculating only three consecutive nonoverlapping 8-h averages per
day, can easily miss peak 8-h intervals and may not afford equitable comparisons among
stations with differing diurnal patterns. .
6.4.4.2 Trend Analyses
Carbon monoxide ambient concentrations vary considerably from hour to hour, day to
day, season to season, and year to year. These variations are usually not random but follow
fairly predictable temporal patterns according to season of the year, day of the week, and
hour of the day. Long-term, statistical patterns in CO concentrations are referred to as
trends. Carbon monoxide trends are best illustrated by graphs that can show diurnal, daily,
seasonal, or yearly CO concentration comparisons. Examples of the different ways trends
can be shown are provided in Section 6.4.5. Carbon monoxide concentrations also follow
fairly predictable spatial patterns. Spatial distributions of CO concentrations can be illustrated
by the use of isopleth maps.
6.4.4,3 Special Analyses
An understanding of how concentration patterns vary from hour to hour throughout the
day, by day of the week, and from month to month through the seasons is important in
evaluating the potential for human exposure. Examples of circadian and seasonal patterns are
discussed in Section 6.4.6.
Another useful analysis technique is the "pollution rose," as illustrated in Figure 6-2.
The pollution rose presents the joint frequency distribution of wind direction versus ambient
CO concentration. The pollution rose is very helpful in determining the wind direction
associated with the highest ambient CO concentrations and, inferentially, the location of high
CO emissions sources.
6-18
-------
North
West
10% of wind
vectors
East
South
Legend
Carbon Monoxide Concentration, mg/m3
0-6.8 6.8-9.1 >9.1
Figure 6-2. Example of a pollution rose for carbon monoxide.
6-19
-------
Another analysis technique is case analysis, which can be used to characterize the
meteorological or emission conditions associated with observed CO concentrations. For
example, in order to characterize the meteorological conditions associated with the occurrence
of high CO levels, meteorological records can be evaluated for the days when Hie highest CO
concentrations were observed concurrently at several monitoring sites throughout an urban
area. The results of the analysis can then be used to develop a meteorological scenario for
input to a mathematical model for the purpose of modeling "worst-case" CO concentrations.
6.4.5 Urban Levels of Carbon Monoxide
The ambient CO data cited in this document were obtained from EPA's Air Quality and
Emissions Trend Report (U.S. Environmental Protection Agency, 199la) and directly from
AIRS (Aerometric Information Retrieval System, no date). To be included in the 10-year
trend analyses, a given station had to report data for at least 8 of the 10, years in the period
1981-1990; 301 stations qualified.
6.4.5.1 Ten-Year National Carbon Monoxide Trends, 1981-1990
Figure 6-3 illustrates the national 1981-1990 composite average trend for the second
highest nonoverlapping 8-h CO value for the 301 long-term sites and the subset of 92 NAMS
sites (U.S. Environmental Protection Agency, 1991a). In this 10-year period, the national
average for all 301 stations decreased 29%; for the NAMS subset of 92 stations, it decreased
by 32%.
A Box plot of the second-high 8-h data for all 301 stations (Figure 6-4) provides a
measure of the distribution changes (U.S. Environmental Protection Agency, 1991a). Each
horizontal line of a Box plot represents a percentile value. Starting at the top, each line
represents the 95th, 90th, 75th, 50th (median), 25th, 10th, and 5th percentile values. The
composite average is represented by an " x " near the median value. Although certain
percentiles fluctuate from year to year, the general long-term improvement is clear.
The 10-year trend of the composite average of the estimated number of nonoverlapping
8-h CO average concentrations that exceed the 8-h NAAQS .across all stations is shown ..in
Figure 6-5 (U.S. Environmental Protection Agency, 199la). The trend is clearly decreasing,
6-20
-------
12
10 -
8 -
6 -
4 -
2 -
All Sites (301)
NAMS Sites (92)
T :—I i ' I I I I . I : i~~ T^
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990
Figure 6-3, National trend in the composite average of the second highest
nonoverlapping 8-h average carbon monoxide concentration, 1981-1990.
Bars show 95% confidence intervals.
Source: U.S. Environmental Protection Agency (1991a).
20 -p
o.
Q.
§
I
o
O
15 -
10 -
5 -
301 Sites
NAAQS
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990
Figure 6-4. Box plot comparisons of trends in second highest nonoverlapprng 8-h
average carbon monoxide concentrations at 301 sites, 1981-1990.
Source: U.S. Environmental Protection Agency (1991a).
6-21
-------
15
10 -I
a
s -
All Sites (301)
NAMS Sites (92)
I I I I I I II I !
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990
Kgure 6-5. National trend in the composite average of the estimated number of
exceedances of the 8-h carbon monoxide NAAQS, 1981-1990. Bars show
95% confidence intervals.
Source: U.S. Environmental Protection Agency (199 la).
with an 87% improvement for the 301 long-term stations; the 92 NAMS showed a 86%
decrease. Note that these percentage improvements for exceedances are typically much larger
than those found for the second maximum 8-h concentrations depicted in Figure 6-4. The
concentrations data are more likely to reflect percentage change in emission levels.
National CO emission estimates (Table 6-1) show a 22% decrease over the 10-year
period (U.S. Environmental Protection Agency, 1991b). The predominant CO emission
source, transportation, accounted for about 71% of total CO emissions in 1981, but had
decreased to about 63% in 1990. This result provides further evidence that the FMVCP has
been effective on a national scale, with controls more than offsetting the growth during the
period. It should be noted that CO monitors are typically located to identify potential
problems and are placed in areas of high traffic densities that may not experience significant
increases in traffic. Thus, CO levels at these locations may improve at a faster rate than the
nationwide reduction in emissions.
6-22
-------
6.4.5.2 Five-Year Regional Carbon Monoxide Trends, 1986-1WO
Composite regional averages for 1986 through 1990 of the second highest
nonoverlapping 8-h CO averages are shown in Figure 6-6. All regions show some net
improvement; the largest decreases occurred in Regions n, Vm, and X,
6.4.5.3 Air Quality Levels in Metropolitan Statistical Areas
Metropolitan Statistical Areas (MSAs) consist of a central urban county or counties and
any adjacent counties with at least 50% of their population within the urban perimeter. The
nation's 341 MSAs, grouped by population range in Table 6-4, include 78% of the U.S.
population. Figure 6-7 compares the highest second-high nonoverlapping 8-h value recorded
during 1990 for the 90 largest MSAs in the continental United States (not shown: Honolulu,
HI, and San Juan, PR), containing approximately 55% of the U.S. population. Twelve of
these MSAs exceeded the current 8-h standard of 9 ppm in 1990.
\£.
11 -
10-
9 -
8 -
1 7-
AR
50
K
1 i ,
egion
3 .-
"
v. X
X X
K X
E 1
VI
s
30
3 x <
< x <
X X X
Mi
>
xxS
1 1 1
/I!
22
1 1 1.
X X
X K
< X
, l-
VIII
18
<
x
I I
F
X
X >
I I
IX
8(
'
I t I
3
I
x!* K
Kjx X
bh
1 1 .
X
2
K
<
X X
i !
2
Figure 6-6. Regional comparisons of the 1986 through 1990 composite averages of the
second highest nonoverlapping 8-h average carbon monoxide concentration.
Source: U.S. Environmental Protection Agency (1990, 1991a).
6-23
-------
TABLE 6-4. DISTRIBUTION OF POPULATION IN METROPOLITAN
STATISTICAL AREAS (Based on 1987 estimates)
Population Range
No. of MS As
Total Population
^100,000
100,000 £ 250,000
250,000 £ 500,000
500,000 £ 1,000,000
1,000,001 <, 2,000,000
> 2,000,000
Total
28
148
73
48
26
18
341
2,367,600
23,513,000
25,218,000
34,367,000
,38,685,000
65,747,000
189,897,600
Source: U.S. Environmental Protection Agency (199 la).
Figure 6-7. United States map of the highest second maximum nonoverlapping 8-h
average carbon monoxide concentration by Metropolitan Statistical Area for
1990.
Source: U.S. Environmental Protection Agency (1991a).
6-24
-------
6.4.6 Orcadian and Seasonal Patterns
This discussion of patterns of elevated concentrations of CO is based on 1988 data from
outdoor, fixed-site monitors, and will focus primarily on 8-h averages exceeding the current
9-ppm NAAQS (U.S. Code, 1970-1981)(U.S. Environmental Protection Agency, 1979).
Because the 1-h standard, 35 ppm, was exceeded on only six occasions at two stations in
1988, 1-h patterns will be discussed only briefly.
6.4.6.1 Eight-Hour Averages
For this examination of patterns in the exceedances of the current NAAQS 8-h average
CO standard, the six stations were selected that reported 20 or more exceedances of that
standard in 1988; they are located in Hawthorne and Lynnwood, CA; Las Vegas, NV; New
York, NY; Steubenville, OH; and Spokane, WA.
From a legal perspective, it has been considered judicious to formally count
exceedances of the 8-h average CO NAAQS standard (values equal to or greater than
9.5 ppm, in actual practice) only when their averaging periods do not overlap one another.
For the purpose, here, of compiling and comparing patterns of protracted high levels of CO,
however, it is deemed necessary to include every hour that culminates an 8-h average
concentration exceeding the standard.
One way of assessing the potential for exposure to this 8-h cumulative measure of CO is
to sum up the numbers of events by hour of the day over the course of a year. Figure 6-8
depicts, for 1988, the aggregated circadian patterns of the numbers of days when the 8-h CO
concentration equalled or exceeded 9.5 ppm at the six selected stations. The important aspect
of these graphs is the diversity of patterns. Also of note are the numerous 8-h average
exceedances that culminate in nighttime hours, the 6 PM to 5 AM period.
This depiction of cumulative circadian incidence profiles by clock hour, however,, does
not convey either seasonal patterns, or the variability in the course of individual events.
Seasonal variation is summarized in Table 6-5± The diverse patterns, even in this small set of
6-25
-------
HAWTHORNS CA (5001) 1988
•PM
I
BAM
30d«y»
2Sdsyt
20 days
16d>yt
Stkyi
LYNNWOOD,CA (1301) 1988
0PM
Hday.
2Ddty»
8AM + P
1i&
IAS VEQAS.NV (0557) 1988
«AM 4- 0
30*y»
Sdayt
20*y»
ISdtyt
NEW YORK CITY, NY (0082) 1988
• ZStfays
SAM
15dl>-8
• lOifays
Sdtyi
Ji
7
6AM
• 25dayi
• ZOdayi
• 16dayt
10d«ys
• 6d
I I t
1 1 1 1 1 1 1 1 1 1 1 i 1 T
SPOKANE, WA (0040) 1988
~i 1 1 1 1 1 1 1 1 \ 1 1 r
6AM
30itay»
ZSdnyt
20 days
15 day.
Sdayt
jure 6-8. Yearly cumulative circadian patterns of 8-h average carbon monoxide concentrations
> 9.5 ppm at six selected stations, 1988. Nighttime bars (6 PM to 5 AM) are shaded.
6-26
-------
TABLE 6-5. MONTHLY VARIATION IN ORCADIAN PATTERNS OF RUNNING
EIGHT-HOUR CARBON MONOXIDE AVERAGES > 9,5 PPM AT SIX
SELECTED STATIONS, 1988
HAWTHORNE, CA 1988
J
F
M
A
M
J
J
A
S
0
N
D
Sum:
M
1
3
4
1
1
1
2
4
8
LYNNUOOO
J
F
M
A
M
J
J
A
S
0
N
D
Sum:
J
F
M
A
M
J
J
A
S
0
N
D
M
8
3
3
13
27
LAS
M
4
1
3
10
1
9
3
4
13
29
2
2
2
2
4
10
. CA
2
9
4
5
13
31
3 4
2 4
3 3
2 2
5 6
12 15
1988
3 4
7 8
3 4
1 1
5 5
12 12
28 30
VEGAS, NV 1988
1
5
1
4
9
a
2
1
4
7
3 4
1 1
2 1
5 4
8-h CO
5
5
3
1
2
5
16
8-h
5
8
5
1
4
11
29
8-
5
1
4
6
4
3
2
6
15
CO
6
8
6
1
1
5
7
28
h CO
6
1
3
7
4
3
2
7
16
7
8
4
1
2
4
7
26
7
1
2
HOUR
8 9 10 11 12 13 14
6551
3 3 34 1
233111
6443221
17 15 15 94 3 1
HOUR
8 9 10 11 12 13 14
8744211
564333
1
221111
5444432
6654441
27 25 18 16 14 12 4
HOUR
8 9 10 11 12 13 14
2
Monthly
15 16 17 18 19 20 21 22 23
1 1
1
000000012
Sum
39
32
1
0
0
0
0
0
0
0
28
63
163
Max.. own
12.7
15.6
9.6
4.9
3.4
2.2
2.1
2.6
5.9
7.3
14.7
15.9
Monthly
15 16 17 18 19 20 21 22 23
124
1 3
2 3' 3 3
3 5 7 11
00 00 05 9 13 21
Sum
99
60
0
0
0
0
0
0
3
• 14
72
144
392
Max. . Don
15.1
15.9
9.4
6.5
5.7
3.7
2.8
4.4
10.1
11.7
19.6
27.5
Monthly
15 16 17 18 19 20 21 22 23
1 1
1 2
1 359
Sum
18
0
0
0
0
0
0
0
0
3
17
64
Max. , POT
12.8
9.2
6.6
6.4
3.6
5.2
5.1
5.7
6.8
10.0
12.2
18.2
Sura: 18 19 14 8
7 12
102
6-27
-------
TABLE 6-5 (cont'd). MONTHLY VARIATION IN ORCADIAN PATTERNS
EIGHT-HOUR CARBON MONOXIDE AVERAGES > 9.5 PPM AT
SELECTED STATIONS, 1988
OF RUNNING
SIX
NEU YORK
J
F
H
A
H
J
J
A
S
0
H
D
Sun;
H
1
1
1
1
4
1
1
1
2
CITY, HY 1988 8-h CO •
2
0
STEJBEHVILLE.
J
F
8
A
H
J
J
A
5
3
1
>
Sum:
H
1
1
3
S
1
1
1
1
2
5
SPOKANE.
1
:
1
V
1
1
1
t
;
i
i
H
1
4
3
2
2
3
1
2
2
1
1
3
2
1
1
1
1
1
5
WA
2
1
1
2
HOUR
3 4 5 6 7 8 9 10 11 12 13
1 2 2
p
000000001 22
OH 1988 8-h CO
HOUR
3 4 5 6 7 8 9 10 11 12 13
1111
22212333332
11111111111
11222111
133211
1 11111
1 23333332
2
1 1 222233333
8 5 8 9 14 15 15 13 13 11 8
1988 8-h CO
HOUR
3 4 5 6 7 8 9 10 11 12 13
1 1
1 1
1
Monthly
14 15 16 17
1 1 3
4455
1223
2 2
1 1
5 7 11 14
18
3
4
3
2
12
19 20
3 2
5 5
4 4
2 2
14 13
21 22
1 1
1
2 1
5 5
4 4
1 1
1 1
14 14
23
1
1
2
3
1
8
Sum
0
4
0
4
16
50
32
13
2
0
2
0
123
Max.. DPffl
9.3
10.4
9.2
10.5
10.7
13.9
13.5
11.6
10.3
' 6.4
9.7
7.6
Monthly
14 15 16 17
1
1
322
5220
14 15 16 17
2
1 .
1
1 2
1 1
2 6
18
0
18
2
2
2
2
1
7
19 20
f
00
19 20
3 1
4. 4
3 4
4 4
2 1
5 6
21 22
1
1 1
1 2
21 22
2 . 2
5. 5
4 4
5 5
2 2
5 3
23
1
1
4
6
23
1
5
3
4
2
3
Sun
4
0
31
17
0
11
11
7
23
4
44
0
152
Sun
14
32
0
0
0
• 0
0
0
29
32
16
46
Max., ppm
11.6
5.8 ,
13.5
21.0
9.0
11.9
12.0
11.6
19.6
10.4
17.6
9.1
Monthly
Max., ppm
11.5
13.0
8.1
8.1
8.3
6.8
7.1
8.9
13.8
13.0
11.3
14.3
:um; 15 9 4 2 1
1 1
4 13 16 21 20 23 21 18
169
6-28
-------
stations, show that influences from seasonal sources, meteorology, and natural and manmade
topography can differ considerably with location. ,;
Individual 8-h average events equalling or exceeding 9.5, ppm are depicted in
Figures 6-9 and 6-10 for two of the stations with conspicuously contrasting circadian patterns:
the Hawthorne and New York stations. Many events span midnight, therefore each line
includes parts of two days; note, however, that in order not to break the continuity of
CLOCK HOUR
Dates Ml 16 17|18J9 ZQ_21 222300 1 2 54 5|6 7 8 9 10 11 12 13 14
1/6-7
1/8-9
1/14-15
1/19-20
ttflllllllll
1/27-28
2/4-5
2/5-6
2/7-8
2/8-9
2/10-11
2/19-20
mmimimisiiaiiiiiiimsttin
4HllIllill
-WJttimillll
II!
11/21-22
11/28-29
11/30-12/1
12/5-6
12/6-7 !
12/9-10
12/10-11
imiiMiiniiiniiiiiBitiiniiiiiB
iniimiiiniiiiniiniiiifHW
nnminniiiiiiiiiiiiiiiiiiiisiim
— in i-
mwtttiimniiiii
-HHIHtfllllllll
12/12-13
8-h
Max.
opra
1Q.T
'10.0
9.9 '
10.4
'11.0 •'
12.7
10.0
10.4
15.6
11.1
10.0
9.6
12.1
10.9
9.6
9.7
14.7
12.4
13.8
13.3
10.6
12.7
10.4
11,3
h
3
9
5 •--•••
10
8
5,
6-7
9
8
4
10
11
8
4
5, "
9
8
2-4
2
9
8-9
4
5-7
8
DOT
12
14
11
16
14
15
11
15
23
13
16
16
21
12
12
' 14
21
15
19
17
15
14
11
16
1-h
Max.
h
23-M,9
7
-'•' 1
7
7
1
M,3,5
8
7
10-11
7
• 8
7
1
11
- ' 7 '
7
M,7
9-10
8
8
11-H
H-3
7 '
15.9
Total: 0 0 0 0| 0 0 0 ,0 1 2 4 8 10 12 15 16[15 16 17,15 15 9 43 1
21
Figure 6-9. Hawthorne, CA, Station 5001, 1988: individual events with running 8-h
carbon monoxide averages > 9.5 ppm (HI) and precursor 1-h values
> 9.5 ppm ( ). Nighttime hours (1800 to 0500) are in bold.
6-29
-------
Pates
2/1-2
4/4-5
5/5-6
5/24-25
5/31-6/1
6/1-2
6/13-14
6/14-15
6/15-16
6/21-22
6/22-23
7/8-9
7/11-12
7/21-22
7/26-27
7/29-30
8/12-13
8/15-16
9/13-14
11/26-27
Total;
CLOCK HOUR
3 4 5| 6 7 8 9 10 11 12 13 14 15 16 171 18 19 20 21 22 23 00 1 2
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8-h
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10.4
10.5
9.9
10.7
10.5
10.5
10.4
10.1
13.9
10.6
13.5
9.7
10.6
11.3
9.9
11.6
10.3
9.7
h
22
18
18
18
21
20
20
15
17
22
20
22-M
17
20
17
22
1-h
Max.
DDffl
13.8
14.4
13.7
17.7
15.1
14.7
13.4
14.4
13.7
12.9
23.0
13.4
21.7
17.1
12.7
16.7
16.8
19.4
18.6
12.8
h
20
22
16
16
15
10-11
20
11
16
17
17
15
10
18
Elgure (J-10. New York City, NY, Station 0082, 1988: individual events with running
8-h carbon monoxide averages >: 9.5 ppm (III) and precursor 1-h values
> 9.5 ppm ( ). Nighttime hours (1800 to 0500) are in bold.
individual events, the horizontal axis for the Hawthorne station begins at 3 p.m. and the
horizontal axis for the New York station begins at 3 a.m. Note, also, that some of the
overlapping 8-h events in Figures 6-9 and 6-10 extend 9 or more hours, generating two
formally counted, nonoverlapping exceedances within one event.
In addition to marking the days containing 8-h averages equalling or exceeding 9.5 ppm
(25 events at the Hawthorne station, 20 at the New York station), these figures also show, for
these event days, the periods when the 1-h values reached the 9.5-ppm level, a necessary but
6-30
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not sufficient precondition for an 8-h exceedance. At the Hawthorne station, there were
29 additional days when a 1-h value reached at least 9.5 ppm, but an 8-h average did not; at
the New York station, there were 94 such days.
Based on even tMs limited examination of CO in the vicinity of fixed-site monitors, it
seems clear that concentration patterns should be examined on a site-by-site basis; a single
generalized model is not currently feasible. Further, a substantial fraction of the 8-h averages
above the standard can occur overnight, when a smaller percentage of the population is out of
doors.
6.4.6.2 One-Hour Values
As mentioned above, the 1-h standard is rarely exceeded; however, examination of the
circadian patterns of 1-h values above'some reference level is instructive. The chosen 1-h
reference concentration is 9.5 ppm, again simply because this is the precursor level for a
possible exceedance of the 8-h average; no health effects are attributed to this 1-h level.
Figure 6-11 presents a qualitative comparison of monthly and yearly circadian patterns
for the six selected stations. The Hawthorne, Lynnwood, Las Vegas, and Spokane stations
generally show patterns above the reference level in winter months, and riot in the summer
months. The winter month patterns at the two CaEfbrnia stations and the Las Vegas station
peak overnight and in the early morning; whereas at the Spokane station, the primary peak is
in the afternoon. The New York station also has its primary peak in the afternoon, but
concentrated in the summer months. The Steubenville station's values peak in the morning,
and in most months of the year.
6.4,7 Effects of Meteorology and Topography
Meteorology governs the transport and dispersion of CO emissions in the atmosphere
and thus has a strong influence on the ground level CO concentrations .detected at receptor:
points downwind of emission sources. Meteorological parameters that determine CO
transport and, dispersion patterns include wind speed, wind direction, atmospheric stability,
and mixing depth. The relative importance of each parameter depends on the scale of the ;•••
analysis. For example, concentration patterns around an intersection would not be greatly
6-31
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HAWIHORN£CAP1)1988
WS VEGAS, NV(0557) 1988
NEWYOflKCIW;NY(Mffi)1988
~ MDtyt
L 10
M
SPOKlE.WApOjIW
BODayi
figure 6-11. Monthly and yearly circadian patterns of 1-h carbon monoxide values > 9.5 ppm at
six selected stations, 1988. Rows 1-12 portray monthly patterns (Jan - Dec);
Row 13 portrays the cumulative annual pattern.
6-32
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influenced by mixing depth. However, concentration patterns over the whole urban area
would be.
Wind direction determines the direction of horizontal transport of CO emissions and,
consequently, the impact that CO emissions from one area will have on air quality in another
area. If emissions are uniform across the urban area, as air flows across the whole urban
area, the additive effect of the CO emissions being transported downwind will result in higher
CO concentrations at the downwind edge of the urban area. However, concentrations at a
particular location may be dominated by local emissions. Concentrations adjacent to a
highway will be higher than urban levels away from large highways. Wind directions nearly
parallel to a highway will allow for an accumulation of CO emissions in the downwind
direction, resulting in CO concentrations higher than would be expected for winds
perpendicular to the highway under the same conditions.
Low wind speeds provide little atmospheric dilution, allowing CO emissions to build
up, resulting in higher CO concentrations. Conversely, high wind speeds aid in the
dispersion of CO emissions by increasing the amount of dilution that takes place, thus
decreasing CO concentrations. The effect of surface roughness (i.e., mountains, buildings,
etc.) on the wind speed profile over several types of topographic features is illustrated in
Figure 6-12 (Benson, 1979). With increased surface roughness, either natural or man-made,
the depth of the affected layer is increased. The winds affected by frictional drag are
reduced, but the turbulence induced by mechanical effects in increased. The net effect of
increased surface roughness over an urban area is to mix the CO emissions through a larger
depth in the atmosphere, which aids in the dispersion of CO emissions. Thermal forces in
the atmosphere either enhance or suppress the production of turbulent motion in the
atmosphere. The dispersive properties of the atmosphere are correlated with atmospheric
stability, which is generally easier to characterize.
Radiation and thermal properties of topographic features influence the heating and
• cooling of the atmosphere near the ground surface. The most notable of these effects is the
urban "heat island" effect. Heat sources, including the asphalt and concrete associated with
an urban area, tend to radiate heat, causing a "heat island" compared to the cooler
surrounding terrain. The buoyant effect of warmer air over the city tends to induce thermal
6-33
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600
500
400
-------
The depth through which pollutants are routinely mixed affects the total ventilation •
capacity of the atmosphere. When the potential temperature lapse rate is positive, the
resulting increase in temperature with increase in height produces an inversion or inversion
lid that limits vertical mixing, and thereby limits the dilution capacity of the atmosphere.
An important form of inversion for CO dispersion is the surface or radiation inversion.
This usually occurs at night with light winds and clear skies, when the loss of heat by
longwave radiation from the ground surface cools the surface and subsequently the air
adjacent to it. With the proper relative humidity, these same conditions will lead to the
formation of radiation fog. The presence of early morning fog is often associated with a
surface-based temperature inversion. The surface inversion usually persists for hours, and
because it typifies stable atmospheric conditions, it tends to result in high microscale and
mesoscale CO concentrations.
Another type of inversion is the subsidence inversion. It is caused by a gradual descent
of air aloft, which results in adiabatic warming of the descending layer. ITie resulting
subsidence inversion is illustrated in Figure 6-13, which shows the temperature decreased
with height and the capping by a subsidence inversion layer, above which there is a normal
decrease of temperature with height. The subsidence inversion can persist for days and tends
• . • '-'.•:".• . •*?.""-•-.<• '
to contribute to high urban background CO concentrations. The subsidence inversion is
usually more persistent during summer and fall than in winter or spring.
The shape of typical plots of hourly CO concentrations can be attributed in large part to
the effect of changing wind speeds, atmospheric stability, and inversion height during the
course of a day. Figure 6-14 shows average hourly wind speeds and inversion heights
occurring in Los Angeles during summer (Tiao et al., 1975). The higher wind speeds and
inversion height during early afternoon are typical throughout the continental United States
and play a significant role in lowering urban CO concentrations at midday. Traffic volumes,
and subsequently CO emissions from cars, would still be expected to be high at this time of
day. Around midnight, when traffic volumes are relatively low, the effects of low wind
speeds and low inversion heights tend to confine emissions and cause increases in CO
concentrations. In some local areas, during the colder months, wood-burning stoves and
fireplaces can be signficant contributors to neighborhood CO concentrations. Many
6-35
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1000 _
"
500
0
I I
J I
2nd Mixing Layer
Inversion "Lid"
1st Mixing Layer
l I i r
i i r r
i r
10
Temperature
20
Figure 6-13. Schematic representation of an elevated subsidence inversion.
monitoring stations in the United States observe these relatively high CO concentrations late
at night.
Ambient surface temperature also has a unique effect on the production rate of CO
emissions from automobiles. Using a variety of automobiles tested at artificially controlled
ambient temperatures of 20, 50, 75, and 110 °F, the EPA (Bullin et al., 1986) found that the
lowest CO emissions were produced at 75 °F and tend to increase with colder and warmer
temperatures. Colder temperatures coupled with a strong surface-based radiative inversion
are generally associated with poor dispersion in the atmosphere. The combined effect of
higher emission rates and poor dispersive conditions results in higher ambient CO
concentrations than would be expected for warmer temperatures.
6-36
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10-
o.
E
OL
CO
•o
i 5-
Inversion Height
Wind Speed
r-20
X
— 15
II I I II I
12 18 24
Time, h
Figure 6-14. Hourly variations in inversion height and wind speed for Los Angeles in
summer.
Source: Tiao et al. (1975).
6.5 DISPERSION MODEL PREDICTIONS OF CARBON MONOXIDE
CONCENTRATIONS
A dispersion model relates pollutant emissions to ambient air quality by providing a
mathematical description of the transport, dispersion, and chemical transformations that occur
in the atmosphere. This ability to relate source emissions to receptor air quality is very
important to air quality maintenance planning and environmental impact assessment.
Dispersion models vary in complexity from simple empirical or statistical relationships
to sophisticated multisource models that describe the transport and dispersion of CO
throughout an urban area. For estimates of ambient CO concentrations, a line-source model
is needed to estimate the CO levels near a highway, an intersection model is needed to
estimate CO levels near an intersection, and an urban model is needed to estimate CO levels
that result from the cumulative effects of urban sources such as roadways and wood stoves.
6-37
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The types of models used will depend mainly on the source configuration to be modeled (i.e.,
highway, intersection, or urban area).
6.5.1 Line-Source Modeling
Several models have been used to estimate CO concentrations from line sources. The
guideline on Air Quality Models (Revised) (U.S. Environmental Protection Agency, 1986)
makes specific recommendations on procedures to utilize for line-source modeling. Refer to
the latest version of this document for these recommendations. Available line-source models
are CALINE-3 (Benson, 1979), GMLINE (Chock, 1978), HIWAY-2 (Petersen, 1980), and
PAL (Petersen, 1978). A brief description of each of the line source models excerpted from
"Evaluation of Mobile Source Air Quality Simulation Models" (Wackier and Bbdner, 1986)
follows.
6.5.1.1 CALINE3
The CALINE3 model was developed by the California Department of Transportation.
It simulates dispersion of highway emissions by dividing individual roadway links into a
series of elements from which incremental concentrations are computed using a finite line-
source equation. The incremental concentrations are summed to obtain a total concentration
estimate at a particular receptor location.
CAIJNE3 simulates the region directly over the roadway as a zone of uniform
emissions and turbulence called the "mixing zone." This zone experiences increased
dispersion due to mechanical turbulence created by moving vehicles as well as thermal
turbulence created by hot vehicle exhaust. CALINE3 adjusts the level of turbulence as a
function of wind speed. At low wind speeds, residence time of an air parcel within the
mixing zone is increased, resulting in turbulence enhancement through the use of a larger
initial vertical sigma value.
The CALINE3 model includes options for simulating dispersion from four types of
roadways: (1) at grade, (2) elevated filled sections, (3) elevated bridges, and (4) cut or
depressed sections. Multiple lanes, links, and orientations can be simulated.
6-38
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6.5.1.2 GMLINE
GMLINE (Chock, 1978) was developed by General Motors Research- Laboratories to
describe dispersion near straight-line, at-grade highways. Multiple parallel or crossing
roadway links can be simulated and the model allows for a variable emissions height. The ;
model was not designed to treat cut-sections. ,
GMLINE simulates dispersion of vehicle emissions by dividing the.roadway into , ,
separate, straight-line sources, each with a uniform emission rate. Downwind concentrations
at a receptor are calculated for each infinite line source, then summed to obtain a total
concentration. The model accounts for plume rise due to heated exhaust and includes a wind
speed correction to account for increased turbulence created by traffic wakes.
6.5.1.3 HIWAY-2
HIWAY-2 (Petersen, 1980) was developed by EPA to replace the HIWAY model
(Zimmerman and Thompson, 1975) for estimating roadway pollutant impacts. The model
was designed to determine concentrations at receptors downwind of at-grade roadways and
cut sections (outside of the cut only).
HIWAY-2 simulates dispersion by treating highway .emissions as a series of finite line
sources, each with a uniform emission rate. Concentrations downwind are calculated.b.y
numerically integrating a Gaussian point-source plume along each line segment. The primary
differences between HIWAY-2 and HIWAY are that HIWAY-2 includes a new set of
dispersion curves and an aerodynamic drag factor to account for dispersion due to vehicle
motion under low wind speed conditions. , ,
6.5.1.4 PAL
The PAL model (Petersen, 1978) was developed by EPA to estimate pollutant
dispersion from point, area, and line sources. It was designed to simulate dispersion .from ...
several types of roadway geometries, including straight or curved horizontal lines and straight
or curved elevated lines with variable emissions along each line segment. Model ,
documentation specifies that treatment of elevated line sources is appropriate for open bridge
type road segments but not for elevated filled roadways. Cut or depressed roadway sections
are not treated by PAL.
6-39
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PAL determines concentrations at a receptor due to a line source by numerically
integrating the Gaussian point-source equation. Calculations are made for a number of points
along the finite line, assuming a linear change in concentration between these points.
Subsequent estimates of concentrations are made by including additional points along the line.
When the difference between succeeding estimates becomes smaller than a prescribed value,
the calculations are considered complete.
6.5.1.5 Model Evaluation
A comprehensive evaluation of CALINE3, GMLINE, HIWAY-2, and PAL was
undertaken using five field measurement programs and is described in "Evaluation of Mobile
Source Air Quality Simulation Models" (Wackier and Bodner, 1986). This report contains
numerous tabulations of each model's performance in terms of statistical measures
recommended by the American Meteorological Society. The results indicate that the
GMLINE model performed the best most often, whereas the PAL model ranked lowest most
frequently. All the models tended to overpredict for light wind speeds and near parallel:
wind/road angles, whereas underproductions occurred for high wind speeds.
6.5.2 Intersection Modeling
Several models have been used to estimate CO concentrations from intersections. The
Guideline on Air Quality Models (Revised)(U.S. Environmental Protection Agency, 1986)
makes specific recommendations on procedures to utilize for intersection modeling. Refer to
the latest version of this document for these recommendations. As discussed in
Section 6.2.1.1, references below to MOBELE2, MOBILES, or MOBILE4 reflect the version
of that mobile source emission factor model in use at the time the work was originally done.
The current version is MOBILE4.1 (U.S. Environmental Protection Agency, 1991c).
Available intersection models are: "Volume 9" (U.S. Environmental Protection Agency,
1978), CAL3Q (Smith, 1985), CALINE4 (Benson, 1984), Georgia Intersection Model (GIM)
(EMI Consultants, 1985), Intersection Midblock Model (IMM) (New York State Department
of Transportation, 1980), and TEXIN2 (Buffin et al., 1986). A brief description of each of '
these models excerpted from the above references follows.
6-40
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6.5.2.1 Volume 9
Carbon monoxide concentrations are calculated in a three-step process (U.S.
Environmental Protection Agency, 1978; Wolcott, 1986). In the first step, the network
description and traffic demand volume are used to estimate the traffic flow characteristics.
Emissions are then computed as the sum of two parts: cruise emissions produced by
nonstopping vehicles and excess emissions emitted by stopping/starting vehicles. Lastly, the
effect of atmospheric dispersion on actual concentrations at the specified receptor locations is
estimated.
Excess emissions consist of deceleration, idle, and acceleration emissions due to
vehicles stopping and starting at intersections. Idle emissions rates are determined using
MOBDLE4.1. Acceleration, deceleration, and cruise emission rates are determined using
modal emission factors based on the updated (December 1977) version of the Modal
Emissions Model (Kunselman et al., 1974). MOBBLE4.1 correction factors to the modal
emission factors can then be utilized to adjust for calendar year, cold starts, hot starts, speed,
temperature, and vehicle mix.
The traffic model contained in Volume 9 calculates the length over which excess
emissions apply. This calculation is based on the proportion of vehicles mat stop and the
number of vehicles subject to queuing delay. It should be noted that the traffic model
contained in Volume 9 is not applicable for overcapacity intersections; thus, Volume 9 cannot
be utilized for such intersection scenarios.
6.5.2.2 Intersection Midblock Model
The Intersection Midblock Model (IMM) (New York State Department of .
Transportation, 1980) is a combination of signalization and vehicle queuing estimation
procedures using accepted traffic engineering principles. It also predicts emissions using the
Modal Analysis Model and the MOBILE4.1 program, and models dispersion with the
HIWAY-2 model.
The IMM first calculates various traffic parameters. Once the traffic calculations have
been performed, the estimation of emission rates is carried out. Using the input parameters
of speed into the queue, speed out of the queue, deceleration into the queue and acceleration
6-41
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out of the queue, the IMM utilizes the Modal Analysis Model as a subroutine to calculate
cruise and acceleration/deceleration emissions for all approaches. Idle emissions are
calculated by use of the MOBBLE4.1 program. Based on the previously calculated queue
lengths, a set of pseudolinks is constructed. These pseudolinks lie along the actual links with
the same termination points and center lines as the actual links, but each has a length equal to
the calculated queue length for that approach. The only emissions assigned to the actual links
are the cruise emissions (calculated with the Modal Analysis Model). The emissions assigned
to the pseudolinks are the excess emissions due to, accelerating, decelerating and idling.
A correction factor is applied to the emissions calculated from the Modal Analysis
Model because these apply only for 1977 emission rates from stabilized light-duty vehicles.
The correction factor used is the ratio of the MOBILE4.1 composite emission estimate for the
specified scenario to the MOBILE4.1 composite emission estimate for 1977 stabilized light-
duty vehicles.
Once the traffic calculations have been performed and emission rates have been assigned
to each lane, the HIWAY-2 model is employed as a subroutine to calculate CO concentrations
at selected receptors. For the special case of a "street canyon" intersection between tall
buildings in a highly urban area, a special dispersion routine is used.
6.5.2.3 Georgia Intersection Model
The Georgia Intersection Model (GIM) (EMI Consultants, 1985) uses a computer
program to calculate the average vehicle delay, the average route speed, and the emission rate
of CO of vehicles traveling through the intersection over a distance called the "effective
length" where speeds are lower due to the effect of vehicles slowing and stopping during red
light cycles. It eliminates the need for using modal emission factors and allows for the
analysis of overcapacity intersections.
GIM uses many of the same assumptions and equations as in the Volume 9 approach,
with few modifications. The procedure can be summarized briefly as follows. GIM
calculates the effected length of roadway upstream of the intersection where vehicle speeds
are reduced due to delays caused by vehicle slowing and stopping. It calculates the CO
emissions for vehicles traversing the effected length, based on average speed over the length
6-42
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and MOBILE4.1 emission factors. Using this approach, modal emission factors (i.e.,
acceleration mode emissions, deceleration mode emissions, idle emissions, and cruise
emissions) are not utilized. The output of GM defines finite line-source segments with their
associated CO emission rates, which can be input to the CALINE3 line source dispersion
model.
6.5.2.4 TEXIN2
The TEXIN2 Model (Bullin et al., 1986) follows a general three-step process:
(1) estimation of traffic parameters,
(2) estimation and distribution of vehicle emissions, and
(3) modeling downwind dispersion of pollutants.
Traffic parameters are calculated using either the modified Planning or Operations and
Design procedures of the Critical Movement Analysis (CMA) (Transportation Research
Board, 1985) for signalized intersections. Basically, the difference between the two traffic
algorithms concerns the different adjustment factors present in the CMA (Operations and
Design algorithm. These adjustment factors tend to decreased the calculated capacity of a
given intersection. Therefore, the Operations and Design technique will occasionally
calculate that an intersection is over capacity while the Planning procedure indicates that the
intersection is below capacity.
Research has provided adjustment factors for a number of elements that affect traffic
flow and hence modify critical volumes. These elements are (1) left turns, (2) bus and truck
volume, (3) peaking characteristics, (4) lane width, (5) bus stop operations, (6) right turns
with pedestrian activity, and (7) parking activity. In the TEXIN2 Model, the CMA Planning
procedure utilizes only the left turn adjustment factor, whereas the CMA Operations and
Design procedure uses the first four adjustment factors listed above with no additional user
input. In both algorithms, left turns are treated in detail for the simple reason that left turns
have a large impact on intersection capacity. This effect is created using passenger car
equivalency values. Passenger car equivalency values are multiplicative adjustment factors
applied to the left turning traffic volumes.
6-43
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The second function performed by TEXIN2 is the estimation of vehicle emissions. The
emissions are modeled as the sum of two components: cruise and excess emissions. Cruise
emissions and excess emissions are released by free-flowing and delayed vehicles,
respectively. Initially, cruise emissions are assumed to be released along the entire length of
each intersection leg. The emissions are subsequently redistributed to better reflect actual
traffic movement. A modified version of the MOBILE4.1 program is used to estimate cruise
emissions and an idle emission factor, whereas acceleration and deceleration emissions are
calculated using modal emission factors as suggested by Ismart (1981). As an alternative, a
shortcut method combining the MOBILE4.1 estimation of the idle emission factor with values
for individual vehicle emission rates based on speed, temperature, percent hot/cold starts, and
the vehicle scenario is available to the user (Federal Highway Administration, no date).
As used in TEXIN2, the MOBILE4.1 program provides inspection/maintenance and
antitampering program options. To conserve computer time, several sizable portions of the
extremely large MOBILES program were deleted, namely the nitrogen oxide and hydrocarbon
emission factors modeling and user-supplied corrections to the emission rates.
6.5.2.5 CAL3Q
The CAL3Q model (Smith, 1985) utilizes the Connecticut Department of Transportation
queuing model to calculate traffic parameters including queue length. The average speed of
vehicles through the intersection is estimated so a composite MOBILE4.1 emission factor;can
be applied over the length of the queue. In addition, the MOBILE4.1 idle emission rate is
applied over the queue length. No modal emission factors are utilized in CAL3Q and the
model cannot handle overcapacity intersections. The emissions and queue, length are input to
the CALINE3 dispersion model to calculate CO concentrations at selected receptors.
6.5.2.6 CALBSE4
The CALINE4 intersection model (Benson, 1984) focuses on a rather complex concept
of spatially resolved modal emissions over links. A CALINE4 intersection link encompasses
the acceleration and deceleration zones created by the presence of the intersection. Each link
can treat only one direction of traffic flow, so that four links are required to model a full
intersection.
6-44
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Four cumulative modal emission profiles representing the deceleration, idle, acceleration
and cruise modes of operation are constructed for each intersection link. These profiles are
determined using the following input variables: :
SPD = Cruise speed (mph)
ACCT = Acceleration time (seconds)
DCLT = Deceleration time (seconds)
IDT1 = Maximum idle time (seconds)
IDT2 = Minimum idle time (seconds) .
NCYC = Total number of vehicles per cycle per lane
HDLA = Number of vehicles delayed per cycle per lane.
NCYC and NDLA are chosen to represent the dominant movement for the link. The
model assumes a uniform vehicle arrival rate, constant acceleration and deceleration rates,
and full stops for all delayed vehicles. Acceleration and deceleration rates (ACCR, DCLR)
and acceleration and deceleration lengths (LACC, LDCL) are determined using the input
values for SPD, ACCT and DCLT. By assuming an "at rest" vehicle spacing (VSP) of
7 meters, the average queue length (LQU) is also determined. IDTI represents the delay at
full stop experienced by the first vehicle in the queue. Similarly, IDT2 represents this same
measure for the last vehicle. IDT2 is used to model a platooned arrival and.should be
assigned au value of zero for nonplatoohed applications.
The time rate modal emission factors over the link are computed by a rather complex
-method. To develop these factors, the model must be provided with composite emission rates
for average route speeds of 0 (idle) and 16 mph. The resulting time rate factors are denoted
as EFA (acceleration), BFD (deceleration), EFC (cruise), and EFI (idle).
The cumulative emission profile for a given mode is developed by determining the time
in mode for each vehicle as a function of distance from link endpoint 1 (ZD), multiplying the
time by the respective modal emission rate and summing the results over the NCYC. The
elementary equations of motion are used to relate time to ZD for each mode. The assumed
VSP is used to specify the positional distribution of the vehicles. The total cumulative
emissions per cycle per lane at distance ZD from XL1, YL1 are denoted as EGUM^ZD) in
the CALINE4 coding, where the subscript, k, signifies the mode (l=aecelerating,. •
2=decelerating, 3=cruise, 4=idle). ,
6-45
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The CALINE4 model handles atmospheric dispersion, somewhat similarly to that in the
CALINE3 model. The most significant difference is that CALINE4, unlike CALINE3,
requires the input of site-specific wind direction, fluctuation, and sigma-theta data.
6.5.2.7 Comparison of Intersection Models
Six currently used intersection models and two proposed models have been compared in
a short study conducted for EPA by PEI Associates (1990). The models do not encompass
the entire "emissions -* traffic -* dispersion" process and require either internal or external
input and/or subsequent processing by other modeling components. For example, all use
MOBILE4 emissions estimates at some point. Table 6-6 lists the principal models evaluated
in flu's study and shows their interaction with supplementary models to produce final analyses
comparable with one another.
TABLE 6-6. EIGHT INTERSECTION MODELS COMPARED FOR THEIR ABILITY
TO PREDICT MEASURED CARBON MONOXIDE CONCENTRATIONS
Principal Model As Used with Auxiliary Models
1:EPA Intersection Model (Proposed) HCMa+ MOBILE4 + EPAINT + CALINE3
2:Federal HighWay Administration HCMa + MOBILE4 + FHWAINT + CALINE3
Intersection Model (Proposed)
3:VoIume 9 modified by MOBILE4 HCMa + MOBILE4 + VOL9MOB4 + CALINE3
4:Georgia Intersection Model HCMa + MOBILE4 + GIM + CALIME3
5:CAL3Q modified by 1985 Highway MOBILE4 + CAL3QHC
Capacity Manual
6:CALINE Ver. 4 including modal MOBILE4 + CALINE4
emission calculations
7:Texas Transportation Institute TEXIN2 (includes MOBILE4)
Ver. 2
8:lhtersection Midblock Model EMM (includes MOBILE4)
'HCM = Highway Capacity Man.ua! (Transportation Research Board, 1985).
6-46
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The data'used in this comparison were collected during an intensive 11-day study in the
fall of 1978 at an intersection in Melrose Park, IL, west of downtown Chicago. The
intersecting streets, six lanes each, run north-south and east-west in flat, level terrain. Eight
sampling sites were positioned around the east leg of the intersection; a ninth, background
site was placed some 140 meters southeast of the intersection (see Figure 6-15). One-hour
bag samples were collected consecutively from 7 a.m. to 7 p.m.
3 x8
x8
x
.100 m
Figure 6-15. Schematic of intersecting 6-lane streets in Melrose Park, EL, showing
location of nine monitoring sites.
Predictions of CO concentrations from traffic through such an intersection depend on
many variables, each of which can take on a spectrum,of values; computer modeling for,a
representative set of scenarios can become quite time consuming. Principal variables include
numbers of vehicles, makes, ages, speeds, etc.; intersection design and capacity, numbers of
lanes, signal timing, diurnal speed and volume patterns, etc.; and meteorological parameters.
6-47
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Comparisons between predicted and observed concentrations for the eight models were
made in two contexts: (1) unpaired 1-h maxima, and averages of the 25 highest 1-h
values, also unpaired, and (2) paired 1-h values and 8-h averages. Averages of the unpaired
25 highest 1-h values, and the ratios of those predicted and observed averages, are
summarized for the eight models in Table 6-7. By the measure of the average of the
25 highest values, unpaired, the CALINE4 and the TEXIN2 models gave the most consistent
results. At Site 6, which is the only site that meets the regulatory siting criteria for routine
monitoring, the CAL3QHC model also performed reasonably well. •
6.5.3 Urban Area Modeling
Several models have been used to model the cumulative effects of urban CO sources
such as roadways and wood stoves. The Guideline on Air Quality Models (Revised) (U.S.
Environmental Protection Agency, 1986) does not recommend one specific model for
urbanwide CO analysis; instead, it recommends these analyses be considered on a case-by-
case basis.
Urban exceedances of the 8-h CO NAAQS result primarily from the cumulative effects
of motor vehicle emissions throughout the urban area. The APRAC-3 model (Simmon et al.,
1981), which is briefly described below, was developed to handle this situation.
6.5.3.1 APRAC-3
APRAC-3 is a Gaussian-plume diffusion model that computes hourly average CO
concentrations for any urban location. The model calculates contributions from dispersion on
various scales: extraurban, mainly from sources upwind of the city of interest; intraurban,
from freeway, arterial, and feeder street sources; and local, from dispersion within a street
canyon. APRAC-3 requires an extensive traffic inventory for the city of interest.
Traffic links may have arbitrary length and orientation. Off-link traffic is allocated to
2-mi-square grids. Link traffic emissions are aggregated into a receptor-oriented area source
array. The boundaries of the area sources actually treated are (1) arcs at radial distances
from the receptor that increase in geometric progression, (2) the sides of a 22.5° sector
oriented upwind for distances greater than 1,000 m, and (3) the sides of a 45° sector oriented
6-48
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TABLE 6-7. AVERAGES AND RATIOS OF THE HIGHEST 25 ONE-HOUR
VALUES OBSERVED, AND PREDICTED* BY EIGHT DISPERSION
MODELS, AT AN URBAN INTERSECTION
Model Predictions (ppm)
SITE
ALL
Off*
1
0/f*
2
O//*
3
ox**'
4
O/P*
5
O/f*
6C
C»/Pb
7
8
0/Pb
OBS (ppm)
35.34
25.60
28.89
29.99
11.52
18.90
24.62
7.48
9.96
EPAINT
16.03
0.45
9.99
0,39
8.34
0.29
11.87
0.40
4.68
0.41
5.92
0.31
12.57
O.51
3.48
0.47
4.91
0.49
FWHAINT
11.30
0.32
6.64
0.2<5
7.87
0.27
8.94
0.30
4.30
0.37
5.81
0.3.Z
6.74
a 27
3.68
0.49
5.69
0.57
GM
16.60
0.47
8.44
0.33
9.32
0.32
13.45
0.45
4.39
0.38
5.83
0.3J
10.58
0.45
3.54
0.47
£45
0.55
VOL9MOB4
13.40
0.38
7.36
0.29
8.03
0.25
11.61
0.39
4.12
0.36"
4.98
0.26"
9.51
0.39
3.36
0.45
4.19
0.42
CAL3QHC
24.15
0.68
13.04
0.51
9.49
0.33
19.24
0.64
3.81
. 0.33
5.87
0.31
20.05
0.81
2.90
0.39
4.44
0.45
CALINE 4
44,35
1.25
30.54
1,19
26,18
0.91
33J4
1.13
7.57
0.66
12.07
0.64
26,07
1..O6
5.60
0.75
(5.14
0.62
TEXIN2
31.17
0.88
18.04
0.70
25.22
0.87
30.29
1.01
7.33
0.64
11.81
0.62
15.57
0.(53
4.36
0.5S
£78
0.55
MM4
14.53
0.41
7.93
0.31
7.60
0.26"
10.41
0.35
2.43
0.2J
3.84
0.20
12.22
O.5O
1.27
0.17
3.08
0.3J
"Underlined averages lie within the range of one-half to twice the observed average.
bO/P is the ratio of observed value to predicted value.
"Site 6 meets regulatory siting criteria for routine monitoring.
Source: PEI Associates (1990).
upwind for distances less than 1,000 m. A similar area source array is established for each
receptor. Up to 625 receptors are accepted for a single hour.
Meteorological data requirements are hourly wind direction (nearest 10°), hourly wind
speed, and hourly cloud cover for stability calculations. Constant, uniform (steady-state)
wind is assumed within each hour. The model can interpolate winds at receptors if more than
6-49
-------
one wind is provided. Mixing height is ignored until the concentration equals that calculated
using a box model. A box model (uniform vertical distribution) is used beyond that distance.
A secondary contributor to some urban exceedances of the 8-h CO NAAQS is the
cumulative effect of wood-stove emissions throughout the urban area. These emissions are
trapped under the nighttime radiation inversion along with evening traffic emission on cold
clear nights with light and variable winds. This situation can be handled best by either a
Gaussian model or a model that uses numerical approximations to the diffusion equation.
A numerical model provides a better treatment than a Gaussian model of the time dependent
changes in meteorology under these conditions. However, use of numerical models is
extremely data and resource intensive. Thus, numerical models have only been applied in
very large cities. One numerical model that has been used in a few cases is the Urban
Airshed Model (Ames et al., 1985). An acceptable Gaussian model for urban area
applications is RAM (Catalano et al., 1987). A brief description of the Urban Airshed Model
and RAM follows.
6.5.3.2 Urban Airshed Model
The Urban Airshed Model (Ames et al., 1985) simulates the major physical and
chemical processes in the polluted troposphere. These include gas-phase chemistry, advective
transport, and turbulent diffusion. The modeling domain is divided into a large array of grid
cells. Horizontally the cells are uniformly sized squares 3 to 5 km on a side. Typically, four
or five layers of cells represent the vertical domain. The depth of the layers is scaled by the
height of the mixed layer and the height of the top of the modeling domain (region top). The
latter typically ranges from 500 m in the morning hours to 1,000 m or more in the afternoon.
Emissions are injected into individual cells depending on the location of the sources, their
height of release, and the buoyant rise of individual stack gas plumes.
The theoretical basis for the Urban Airshed Model rests of the conservation of mass
equation for atmosphere diffusion. Primary inputs to the Urban Airshed Model are point-
and area-source emissions, initial and boundary concentrations both at the surface and aloft,
and a variety of meteorological data. These include a three-dimensional wind field, mixing
depths, surface temperature, and exposure class, the latter an indicator of thermal instability.
6-50
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6.5.3.3 RAM
RAM (Catalano et al., 1987) provides a readily available computer program based on
the assumptions of steady-state Gaussian dispersion for short-term (1 h to 1 day)
determination of urban air quality resulting from pollutants released from point and/or area
sources.
RAM is applicable for locations with level or gently rolling terrain where a single wind
vector for each hour is a reasonable approximation of the flow over the source area
considered. Calculations are performed for each hour. Hourly meteorological data required
are wind direction, wind speed, temperature, stability class, and mixing height.
Computations are performed hour by hour as if the atmosphere had achieved a steady-
state condition. Therefore, errors will occur where there is a gradual buildup (or decrease) in
concentrations from hour to hour, such as with light wind conditions. Also under light wind
conditions, the definition of wind direction is likely to be inaccurate, and variations in the
wind flow from location to location in the area are quite probable.
Considerable time is saved in calculating concentrations from area sources by using a
narrow plume simplification, which considers sources at various distances on a line directly
upwind from the receptor to be representative in the crosswind direction of the sources at
those distances affecting the receptor. Area source sizes are used as given in the emission
inventory in lieu of creating an internal inventory of uniform elements.
6-51
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6-57
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7. INDOOR CARBON MONOXIDE
7.1 INTRODUCTION
The activities of individuals are the most important determinants of their exposure to
airborne contaminants. In the course of a day, individuals spend varying amounts of time in
a variety of microenvironments (residences, industrial and nonindustrial workplaces,
automobiles, public access buildings, outdoors, etc.). Exposures across all
microenvironments need to be assessed in evaluating adverse health or comfort effects and in
formulating cost-effective mitigation measures to reduce or minimize the risks associated with
exposure. Exposure can be assessed by direct methods (personal monitoring or by measuring
biomarkers of exposure) or by indirect methods (microenvironmental monitoring and
questionnaires combined with an appropriate human exposure model).
In recent years, there has been a growing recognition of the importance of nonindustrial
indoor microenvironments in assessing exposures to a wide range of air contaminants
(National Research Council, 1981; World Health Organization, 1985). This recognition
reflects the fact that concentrations for many important air contaminants are higher in many
indoor microenvironments than outdoors and that most individuals spend little time outdoors.
Carbon monoxide (CO) is introduced to indoor environments through emissions from a
variety of combustion sources and in the infiltration or ventilation air from outdoors. The
resulting indoor concentration, both average and peak, is dependent on a complex interaction
of several interrelated factors affecting the introduction, dispersion, and removal of CO.
These factors include, for example, such variables as (1) the type, nature (factors affecting
the generating rate of CO), and number of sources; (2) source-use characteristics;
(3) building characteristics; (4) infiltration or ventilation rates; (5) air mixing between and
within compartments in an indoor space; (6) removal rates and potential remission or
generation by indoor surfaces and chemical transformations; (7) existence and effectiveness of
air contaminant removal systems; and (8) outdoor concentrations. The interaction of these
factors to produce the resulting indoor concentrations usually is considered within the
framework of the mass balance principle.
7-1
-------
In its simplest form, where steady-state or equilibrium conditions are assumed for a
single compartment with complete mixing and no air cleaner, the mass-balance model can be
represented by the following equation.
C- = C + C (7-1)
where:
PAC0
C± = = outdoor air contribution n v\
S/V
Q> = = indoor source contribution , ,„ ..
• 2 (A+K) (7-3)
and where Cf represents the steady-state indoor concentration of CO in micrograms per cubic
meter, Cj represents the contribution to indoor CO from outdoor air in micrograms per cubic
meter, C2 represents the contribution to indoor CO from indoor sources in micrograms per
cubic meter, P is the fraction of outdoor CO that penetrates the building shell, A. is the air-
exchange rate in air changes per hour (ACH or h"1), C0 is the outdoor CO concentration, in
micrograms per cubic meter, K is the removal rate of CO by indoor surfaces or chemical
transformations (equivalent ACH), S is the generation rate or source strength of CO in
micrograms per hour, and V is the volume of the indoor space in cubic meters. This :
simplified form of the model generally is used to evaluate CO levels indoors. In actuality,
however, indoor spaces often are multicompartments with incomplete mixing where the
source-generation and contaminant-removal rates and air-contaminant concentrations vary .
considerably in time. Equation 7-1 is useful particularly for determining the impact on .:-„ „
indoor air-contaminant concentrations from sources that are used over relatively long periods
of time (e.g., unvented kerosene or gas space heaters) where steady-state or equilibrium /-..-,
conditions are reached. When applied to sources that are intermittent in their use (e.g., gas
range or tobacco combustion), Equation 7-1 averages over the off/on periods of the sources
to determine average input parameters for the model. Short-term indoor concentrations of air
contaminants associated with sources whose use varies considerably with time can be modeled
with the differential version of Equation 7-1, when detailed information on the time
variability of the source use, mixing, and removal terms are available. Field data on
7-2
-------
short-term variability of contaminant concentrations and associated variables, however, are
not available.
Carbon monoxide generally is assumed have low reactivity indoors (Yamanaka, 1984;
Leaderer et al., 1986; Traynor et al., 1982; Borrazzo et al., 1987; Caeeres et al., 1983); that
is, CO removal by indoor surfaces or chemical transformations is approximately equal to zero
for typical indoor CO residence times (K=Q in Equations 7-2 and 7-3). There are no
chamber or field studies that have measured the penetration factor for CO. Given the low
CO reactivity, P generally is assumed equal to one (P=l) for conditions where outdoor levels
of CO do not vary rapidly. Under these typical assumptions (£==0 and P=l), indoor
concentrations of CO can be represented by the following simplified form of Equations 7-1,
7-2, and 7-3.
In the case where there are no indoor sources, then the average indoor concentration is equal
to the average outdoor concentration. With short Variations in outdoor concentrations,
however, indoor CO concentrations will lag outdoor concentrations and will be dependent on
the air-exchange rate in a space. When an indoor source exists, the indoor CO concentration
will be equal to the outdoor concentration plus the contribution of the indoor source, which Is
a function of the source strength (CO emission rate), volume of the indoor environment, and
air-exchange rate.
Source emissions from indoor combustion are usually characterized in terms of emission
rates, defined as the mass of pollutant emitted per unit of fuel input (micrograms per
Mlojoule). They provide source strength data as input for indoor modeling, promote an
understanding of the fundamental processes influencing emissions, guide field study designs
assessing indoor concentrations, identify and rank important sources, and aid in developing
effective mitigation measures. Unfortunately, source emissions can vary widely, as
demonstrated in this chapter. Although it would be most useful to assess the impact of each
of the sources on indoor air concentrations of CO by using models, the high variability hi the
source emissions and other factors impacting the indoor levels do not :make such an effort !
7-3
-------
very useful. Such an estimate will result in predicted indoor concentrations ranging over
several orders of magnitude, making them of no practical use, and may be misleading.
This chapter will first summarize the data currently available on emissions of CO from
sources commonly found indoors. Estimates of the contribution of each source to indoor
concentrations measured in a variety of indoor microenvironments are summarized in the
remainder of this chapter.
7.2 EMISSIONS FROM INDOOR SOURCES
Carbon monoxide emitted directly into the indoor environment is one of several air
contaminants resulting from combustion sources. Such emissions into occupied spaces can be
unintentional or the result of accepted use of unvented or partially vented combustion sources.
Faulty or leaky flue pipes, backdrafting and spillage from combustion appliances that draw
their air from indoors (i.e., Moffatt, 1986), improper use of combustion sources (i.e., use of
a poorly maintained kerosene heater), and air intake into a building from attached parking
garages are all examples of unintentional or accidental indoor sources of CO. The National
Center for Health Statistics (1986) estimates between 700 and 1,000 deaths per year in the
United States alone are due to accidental CO poisoning. The number of individuals
experiencing severe adverse health effects at sublethal CO concentrations from accidental
indoor sources is no doubt many times the estimated deaths. Although the unintentional or
accidental indoor sources of CO represent a serious health hazard, little is known about the
extent of the problem. Such sources cannot be characterized for CO emissions in any
standard way that would make the results extendable to the general population. Unintentional
or accidental sources are not considered in this review of emissions of CO from indoor
sources.
The major indoor sources of CO emissions that result from the accepted use of unvented
or partially vented combustion sources include gas cooking ranges and ovens, gas appliances,
unvented gas space heaters, unvented kerosene space heaters, cigarette combustion, and
wood-burning stoves. This section of the chapter will summarize the available CO-emission
data for the major indoor sources of CO. The experimental design, measurement methods,
and results of studies of indoor-source CO emissions will be discussed.
7-4
-------
The characterization of CO emissions from indoor sources is essential in providing
source strength input data for indoor modeling, understanding fundamental processes
influencing emissions, guiding field study designs aimed at assessing indoor CO exposures,
identifying and ranking important sources, and developing cost-effective mitigation measures
that will minimize exposures.
7.2.1 Emissions from Gas Cooking Ranges, Gas Ovens, and Gas
Appliances
Estimates indicate that gas (natural gas and liquid propane) is used for cooking, heating
water, and drying clothes in approximately 45.1% of all homes in the United States (U.S.
Bureau of the Census, 1982) and in nearly 100% of the homes in other countries (e.g., the
Netherlands). Unvented, partially vented, and improperly vented gas appliances, particularly
the gas cooking range and oven, represent an important source category of CO emissions into
• - - • • • - ' • "..-.-' ' ' 'f ; "" - ; ,...-.
the indoor residential environment. Emissions of CO from these gas appliances (the source
term S in Equation 7-4) are a function of a number of variables relating the source type
(range top or oven, water heater, dryer, number of pilot lights, burner design, etc.), source
condition (age, maintenance, combustion efficiency, etc.), source use (number of burners
used, frequency of use, fuel consumption rate, length of use, improper use, etc.) and venting
of emissions (existence and use of outside vents over ranges, efficiency of vents, venting of
gas dryers, etc.).
A number of chamber studies have investigated CO emissions from gas cooking ranges,
ovens, and appliances. The studies have used two basic approaches. The first is called the
direct or sampling-hood approach (Moschandreas et al., 1985; ffimmel and DeWerth, 1974)
and the second is the mass-balance or chamber approach (Moschandreas et al., 1985; Traynor
et al., 1982; Leaderer, 1982). In the direct approach, emissions are sampled using a quartz
hood through which the combustion emissions pass and are sampled. Because the effluent
gases measured by this method contain substantial amounts of excess air that can vary
considerably from run to run, the measured concentrations are converted to a hypothetical
undiluted or "air-free" basis for calculating CO emission rates. This method is used in both
chamber and field evaluations of emission rates (Moschandreas et al., 1985; Borrazzo et al.,
1987). The mass-balance approach utilizes a well-mixed environmental chamber where the
7-5
-------
relationship between changes in concentration of CO over time in relation to outdoor
concentration, source-emission rate, air-exchange rate, and removal rate are evaluated (mass-
balance equation). Both approaches yield source emission rates for CO, usually expressed as
micrograms per kilojoule.
Emissions from gas range-top burners typically are evaluated using a standardized water
load in a cooking pot (American National Standards Institute, 1982) or a modification of it
(Borrazzo et al., 1987). The cooking pot has a top that is sealed, except for a 3/4 in. pipe
that extends from the center of the top to allow steam to escape.
Using both the direct-sampling hood and mass-balance approach and a standardized
water load, Mosehandreas et al. (1985) evaluated CO emissions from three new gas ranges
(including pilot and non-pilot light and self-cleaning oven and conventional oven) with 6 h of
conditioning before use in actual testing. The data of Cole and ZawacM (1985) are
incorporated into the Mosehandreas et al. (1985) report. The range CO emissions were
evaluated for appliance type, the conditions of blue-flame operation (burner air shutter set at
the manufacturer's recommended level), and yellow-tipping (air shutters are closed—worst
condition). Two natural gas mixes were evaluated: lean mix (983 Btu/sef) and rich mix
(1,022 Btu/scf).
A total of 116 direct-sampling experiments were conducted in which CO emissions were
measured for all 12 burners (four burners per stove) using rich and lean fuels. Thirty direct-
sampling experiments were conducted with the burners operating with yellow tipping. No
significant differences (criterion: p < 0.05) were found by fuel type. The results of the tests
using blue- and yellow-flame settings are shown in Table 7-1. The improper operation of the
burners (yellow-tipping flame) resulted in an approximately two- to fivefold increase in CO
emissions. Considerable variation in CO emissions from burner to burner within and between
ranges were noted by the authors for blue-flame operation, although overall CO emission
averages for burners by each range were within a factor of 2.
A total of 144 mass-balance experiments on the three ranges were conducted in a 33-m3
chamber to evaluate the impact of fuel composition, range type, primary aeration level (blue
or yellow flame), fuel-consumption rate (high, 9,149 Btu/h; medium, 7,673 Btu/h; low,
1,492 Btu/h; and warm, 807 Btu/h), test chamber air-exchange rate, temperature and
humidity (range of 15 to 50%), and temporal effects on CO-emission rates. Carbon
7-6
-------
TABLE 7-1. CARBON MONOXIDE-EMISSION RATESa FOR 12 RANGE-TOP
BURNERS OPERATING WITH BLUE AND YELLOW-TIPPING FLAMES BY THE
DIRECT-SAMPLING METHOD (calculated from Moschandreas et aL, 1985)
Number
of Tests
25
33
58
11
9
12
Gas Range
1
2
3
1
2
3
Flame
Condition15
Blue
Blue
Blue
Yellow
Yellow
Yellow
Emission Rate (^g/kJ)
Average
50.7
34.3
70.9
190.0
196.9
108.4
SD
9.46
4.93
12.9
5.8
3.8
5.6
Range
17.2
15.1
15.1
53.8
60.2
94.6
- 107.5
- 71.4
-215.0
- 344.0
- 344.0
- 227.9
"Lean and rich fuel mixtures combined.
bBlue-flame condition—well tuned. Yellow-tipping flame—improperly tuned.
monoxide emissions showed little variation by fuel composition (lean vs. rich), range type,
test chamber air-exchange rate, and time. Yellow-tipping-flame conditions resulted in a 2- to
10-fold increase in CO emissions over blue-flame operation conditions. No changes in
emissions were noted as a function of changes in chamber temperature and relative humidity.
Little change in CO emissions were noted for the high, medium, and low fuel-consumption
rates, whereas a sevenfold increase in emissions was observed for the warm setting. In a
comparison of CO emission results obtained from both the direct-sampling and mass-balance
experiments (Moschandreas et al., 1985), for blue-flame and yellow-tipping-flame conditions,
differences were observed. No clear trend emerged, however, because CO emissions varied
among experimental runs by as much as an order of magnitude.
As part of the above study CO emissions from gas ovens, gas range pilot lights and a
gas dryer were evaluated for blue-flame operating conditions. The results of these
experiments are shown in Table 7-2. Pilot light emissions are comparable to those of gas
range burners (Table 7-1). Variability by oven use was observed but the limited data is not
sufficient to draw any conclusions. Gas dryer CO emissions appear to be comparable to
those from gas range burners.
7-7
-------
TABLE 7-2. CARBON MONOXIDE-EMISSION RATES* FOR GAS RANGE OVENS,
GAS RANGE PILOT LIGHTS, AND GAS DRYERS
(calculated from Moschandreas et al., 1985)
Average Emission Rates 0*g/kJ)
Gas Range
1
1
2
3
3
3
1
1
2
Burner
Bake
Broil
Broil
Bake
Broil
Self-clean
Oven door open0
Oven door closed0
Pilot lightd
Gas dryer6
Number of Tests
4
4
9
2
7
3
3
3
20
4/3
Direct Methodb
19.1 (6.7)
13.8 (3.9)
13.2 (2.1)
68.5(6.1)
21.5 (1.0)
16.0 (2.2)
40.4 (3.0)
Mass Balanceb
' 54.6 (2.6)
127.3(3.5)
40.4(5.2)
68.8(14.2)
'Combined and rich and lean fuel and no oven load.
'Numbers in parentheses represent the standard deviation.
"Broiler operated. .
""Results are on a per pilot light basis, experiments covered various pilot light combinations.
"Using Association of Home Appliance Manufacturers Standard HLD-2EC, four tests are by the direct method
and three tests are by the mass-balance method.
Eighteen different gas ranges, representing greater than 90% of the gas stoves in use at
the time, were tested for CO emissions by the American Gas Association Laboratories
(Himmel and Dewerth, 1974). Carbon monoxide emissions were evaluated for top burners,
ovens and broilers, burner pilot lights, and oven pilot lights. The protocol utilized the direct
measurement method for both blue-flame (well-adjusted flame) and yellow-tipping-flame
(poorly adjusted flame) operating conditions. Range-top burner evaluations, a total of 72,
were made with a standard water pot load centered on the grate (American National
Standards Institute, 1974). Oven tests, 27 in all, were conducted without a cooking load
because the substantial thermal,mass of the cavity itself makes a load unnecessary.
A summary of the CO-emission rates measured in the Himmel and Dewerth (1974)
study are shown in Table 7-3. Yellow-tipping-flame operating conditions resulted in higher
CO emissions for burners and ovens than the blue-flame conditions. Considerable variability
existed from burner to burner within and between gas ranges and among ovens, yet the
7-8.
-------
TABLE 7-3. CARBON MONOXIDE-EMISSION RATES FROM 18 GAS RANGES,
GAS OVENS, AND GAS PILOT LIGHTS FOR BLUE FLAME AND
YELLOW-TIPPING FLAME BY THE DIRECT-SAMPLING METHOD
Average and Range of Emissions (jtg/kJ)a
Burner Type Blue Flame Yellow-Tipping Flame
Top burners 22.6 (8.0-64.2)b 156.6 (58.0-421.0)
Ovens and broilers 15.7 (6.3-38.8) 62.0(11.1-349.2)
Top burners with thermostat 51.8 (11.9-228.8)
Top burners (142 kJ/min) 15.3 (6.6-35.4)
Top burners (190 kJ/min) 26.1 (9.4-72.0)
Infrared burners 77.4
Ovens and broilers with 11.9 (4.9-29.1) 53.5(11.8-243.4)
catalytic clean
Pyrolytie self-clean oven 87.7
Pilot lights-burner
a. Free standing 44.0 (30.4-63.8)
b. Baffle around flame 35.7
c. Baffle around flame and 28.3
shield above flame 56.1 (39.6-69.7)b
Pilot lights-oven
a. Constant horizontal 248.3 (146.5-420.0)
b. Constant horizontal 322.2 (158.5-491.2)b
operates in two modes 208.8 (135.8-281.8)b
'Values in parentheses are the range of emission rates that contain two-thirds of the measured values.
bValues at the low and high measured level.
Source: Himmel and Dewerth (1974).
average emission rates for blue-flame operation among top burners, ovens, and burner pilot
lights were generally within a factor of 4 or 5 of each other. The authors noted that the
CO emission-rate distributions were skewed, leading them to average the emission data using
a log-normal transform and to present the average concentration and an interval representing
66% of the measurements. The infrared burner, pyrolytic self-cleaning oven, and oven pilot
light emission rates were considerably higher than the typical range-top burner.
Himmel and Dewerth (1974) noted that significant differences (p > 0.05) for the range
averages for all four burners existed for 3 of the 18 ranges tested. Emissions from front
burners were found to average 13% higher than back burners. Significant CO emission
7-9
-------
differences (p £ 0.05) were noted between oven burners. Type of cooking pot (material),
size of cooking pot, and physical properties of the individual pots (density, thermal
conductivity, etc.) did not have a pronounced impact on emissions. Burner cap design was
found to influence GO emissions.
Using the indirect measurement method and the standard water pot load (American
National Standards Institute, 1982), Tikalsky et al. (1987) reported the results of
CO-emission measurements made on gas ranges in 10 homes with each home having a
different range make, spanning a use age of from 7 to 30 years. The sample of homes was
drawn from a sample of 50 homes from which house nitrogen dioxide measurements (Dames
and Moore, 1986) were available. This is the only study reported where field measurements
were made on gas cooking ranges actually in use. Five of the 10 homes were resampled after
routine service adjustments. Emissions were measured for top burners and ovens (without a
cooking load) by two different research groups using similar protocols but different air-
sampling equipment. Emissions measurements were made for two top burners and for bake
and broil oven use on each range. The top-burner emissions were measured for high,
medium, and low settings.
Results of the Tikalsky et al. (1987) study showed CO-emission rates for the
preserviced top burners (across all burners, burner settings, and both measurement groups) to
range from 9.5 to 1,746 /*g/kJ. Carbon monoxide emissions for baking ranged from 6.9 to
413 #g/kJ, whereas emissions for broiling ranged from 4 to 310 /tg/kJ. Low top-burner
settings resulted in significantly higher CO emissions than the medium or high settings
(p £ 0.05). Comparison of the emission-rate measurements between the two measurement
teams indicated that one team measured higher rates. Carbon monoxide emission rates
showed a significant reduction after routine service adjustments (p > 0.05). The authors
noted that the field measurements of CO emissions in their study sometimes exceeded, those
previously measured by other investigators by a factor of 4, whereas oven emissions for both
the bake and broil were within the range of those reported by others. .,.'--
A number of studies of CO emission rates from gas cooking ranges have been
conducted in which a limited number of samples (ranges, burners, and number of
experiments) have been collected. These studies have utilized the direct and mass-balance
methods. The results of these studies for both top burners and ovens are shown in Table 7-4.
7-10
-------
TABLE 7-4. CARBON MONOXIDE EMISSIONS FROM GAS RANGES
FOR STUDIES OF SMALL SAMPLE SIZE
Study
MIT/AGA (1976)
Fortman et al. (1984)
Borrazzo et al. (1987)
Cote et al. (1974)
Traynor et al. (1982)
Goto & Tammura (1984)
Test
Burner Method3
1 top burner
4 top burners
2 ovens
4 top burners
1 oven-300 kJ/min
-150kJ/min
-160 kJ/min
2 ranges/top burner
2 ranges/top burner
2 ovens
2 top burners
1 oven
1 top burner
Db
D
D
D
D
D
D
C
C
C
C
C
C
Flame
Condition
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Yellow
Blue
Blue
Blue
Blue
Number Emission
of Tests RateO*g/kJ)
1
11
4
16
2
6
2
2
2
2
5
2
1
11.6
110 ± 40
25.8 ± 4
98 + 18
150 ± 18
33 + 1.3
33 ± 6.5
56
92.5
257
200 ± 34
., 226 ± 17
86.9
"D = direct method, C = mass-balance chamber method.
bDid not use standard pot water load.
As seen in the previous studies, the CO-emission rates for both the top burners and ovens
showed considerable variation with the yellow-tipping-flame condition resulting in higher
emissions than the blue-flame condition. Borrazzo et al. (1987) measured CO-emission rates
for the pilot lights of the gas stove in their test house as well as for fugitive emissions from
other vented combustion appliances (gas dryer, water heater, furnace, etc.). A CO-emission
rate for a pilot light flow of 7.6 kJ/min was measured at 91 ± 16 /ig/kJ, whereas emissions
from other vented sources were negligible.
Natural gas is used for domestic water heating hi approximately 55 million residences in
the United States. Cole and ZawacM (1985) summarized the available data on CO emissions
from domestic hot water heaters. They reported an average CO-emission rate for a total of
18 gas water heaters tested in three studies (Belles et al., 1979; Thrasher and DeWerth, 1977;
A.G.A.L., 1983) of 12.0 jug/kJ. Thrasher and DeWerth (1977), in comparing emissions
from 13 water heaters for blue-flame and yellow-tipping-flame conditions, found that yellow-
tipping-flame operation conditions of the heaters resulted in a fivefold increase in emissions.
7-11
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The available literature for gas appliances indicates that CO emissions are (1) highly
variable for range-top burners on a single range and between ranges and for ovens for blue-
flame conditions (properly adjusted), varying by as much as an order of magnitude or more;
(2) much higher for range top and oven burners operated under yeUow-tipping-flame
conditions (improperly adjusted) than for blue-flame conditions; (3) not different for rich or
lean fuels; (4) higher for top burners when they are operated under very low fuel
consumption rates; (5) comparable for top burners, ovens, pilot lights, and unvented gas
dryers; and (6) roughly comparable when obtained by either the direct or mass-balance
method.
The data base on CO emissions from gas cooking ranges is largely based upon
laboratory studies in which a relatively few ranges were tested. The one field study in which
CO emissions were measured, for a smaE number of gas cooking ranges used in private
residences, indicates that for top burners, the laboratory data may underestimate actual CO
emission rates. More extensive field CO emission data for cooking ranges is needed to
determine how representative the laboratory-derived data is.
Variability in use of gas appliances (e.g., number of burners used in cooking a meal,
number of pilot lights, frequency of cooMng, fuel consumption rate, length of use, and
improper use) can dramatically impact the total CO emissions into the indoor environment.
Gas appliance use data would be helpful in estimating both fuel consumption and the resultant
CO emissions into a residence, but no such data is reported in the literature.
7.2.2 Emissions from Unvented Space Heaters
Unvented kerosene and gas space heaters are used in the colder climates to supplement
cental heating systems or in more moderate climates as the primary source of heat. During
the heating season, space heaters generally will be used for a number of hours during the
day, resulting in emissions over relatively long periods of time.
Over the last several years, there has been a dramatic increase in the use of unvented
kerosene space heaters in residential and commercial establishments, primarily as a
supplemental heat source. The U.S. Consumer Product Safety Commission estimates that a
total of 16.1 million such heaters have been sold through 1986 (Womble, 1988).
A residential energy survey conducted by the U.S. Department of Housing and Urban
7-12
-------
Development (1980) estimated that three million residences use unvented gas space heaters
(fueled by natural gas or propane), with their use more prevalent in the South Census region ,
of the United States. The large number of unvented space heaters sold in the United States
and the potential for their high use, particularly during periods when energy costs rise
quickly, make them an important source of CO indoors.
Carbon monoxide emissions from unvented kerosene and gas space heaters can vary
considerably and are a function of heater design (convective, radiant, combination, etc.),
condition of heater, and manner of operation (e.g., flame setting). ,
Unvented gas space heaters (UVGSHs) range in size from 7,000 to 40.,000 Btu/h and
vary in design and operation. Design characteristics of different heaters include the;burners
(cast iron, steel, ceramic tile, catalytic surfaces, screen, etc.), ignition, heat exchanger, and
auxiliary equipment (i.e., oxygen depletion sensor). Operation characteristics,include type of
fuel (natural or liquified petroleum gas),.input modulation, primary air-shutter, flame type
(blue, yellow-tipping, infrared, etc.), and flame discharge temperature (blue flame or
convective, 2,800 °F; infrared, 1,800 °F; and catalytic, 1,200 °F). Unvented gas space
heaters often are distinguished by their flame discharge temperature and type of fuel used,
when characterizing CO emissions. Both the direct (hood over the heater from which gases
are sampled) and the mass-balance (or chamber) methods have been used to evaluate
emissions from UVGSHs. Many of the studies were parametric in nature, seeking to evaluate
the impact of some of the design and operational features on emissions. Table 7-5 presents a
general summary of the CO emission data from UVGSHs that were obtained by operating the
heaters in a well-adjusted and typically full-input mode.
The summary data in Table 7-5 indicates that there is considerable variability of CO
emissions from UVGSHs. Infrared heaters produce higher emissions than the convective or,
catalytic heaters. The mass-balance or chamber method seems to result in somewhat higher .
emissions than the direct method. The Traynor et al. (1984, 1985) data indicate that, for the
subsample of convective heaters tested for the impact of fuel (natural gas vs. propane),
natural gas use results in higher emissions. ;
In a series of tests (mass-balance methods applied in a chamber and test house) on ,
subsamples of heaters (Traynor et al., 1984, 1986), CO emissions were found to (1) be lower
for partial input heater operation, (2) increase at lower chamber oxygen concentrations,
7-13
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TABLE 7-5. CARBON MONOXIDE EMISSIONS IROM UNVENTED GAS SPACE HEATERS
Study
Traynor et al.
(1984, 1985)
Moschandreas
et al. (1985)
Thrasher and
DeWerth (1979)
Zawacki et al.
(1984)
Private
Communication11
Type of
Heater
Convective
Infrared
Convective
Infrared
Catalytic
Convective
Convective
Convective
Infrared
Number
of
Heaters
9
3
12
4
1
5
1
1
1
2
3
1
1
1
Number of
Tests/
Heaters
1
1
1
1
1
1
16
4
7
3
6
3
2
3
Fuel
Type-
NG
P
Both
NG
i P
Both
NG
NG
1
NG
NG
NG
Test
Method8
C
C
C
C
C
C
D
C
D
C
D
C
D
D
D
U
U
Fuel
Consumption
Rate (kJ/min)
177 - 784
353 - 660
277 - 368
258
186
186
260
260
207
207
131
381
263
211
ND
Flame
Blue
Blue
Infrared
Infrared
Blue
Blue
Infrared
Infrared
Blue
Blue
Blue
Blue
Blue
Suspended
Type(s) Radiating
of Burner0 Tiles
SP, DP, R
SP, DP, R
CT
CT
R
R
SP
SP
CT, R
CT, R
DP
DP
R
RS
RS
Yes
Yes
No
No
No
No
No
No
No
Yes
Yes
No
Yes
Emission Rate
Otg/kJ)
Average
33
16
29
47
45
47
9.7
16.8
69
54.6
9.0
14.2
3.1
5.2
16.3
32.7
0.22
SD
26
1.9
2.5
1.6
1.5
0.4
1.7
0.9
8.2
0.9
2.6
"NO = natural gas, P = propane.
^C = chamber mass-balance method, D = direct method, U = unknown. •
CSP = slotted port burner, DP = drilled port burner, R = pressed metal ribbon burner, CT = ceramic tile, RS = retention screen.
dData obtained and reported by Moschandreas et al. (1985).
-------
(3) be comparable between chamber and test-house studies and show some decrease in time in
test-house studies, and (4) be increased substantially for some maltuned heaters.
Moschandreas et al. (1985) found no difference in emissions for lean versus rich fuel.
Unvented kerosene space heaters fall into four basic design categories: eonvective,
radiant, two-stage, and wickless. The convective heaters operate at a relative high
combustion temperature and, depending upon burner design, can be a blue or white flame.
The radiant or infrared heaters utilize perforated ceramic or metal cylinders that become red
hot. The two-stage heaters (newer design kerosene heaters) are very similar to the radiant
heaters in design except they have a second combustion chamber above the first. The
wickless heaters have a chamber where the fuel and air are mixed and combustion occurs
with the resultant heat distributed via a fan. Carbon monoxide emissions from unvented
kerosene heaters of the convective, radiant, and two-stage design have been evaluated by both
the direct and mass-balance method for conditions of wick height (fuel consumption rate) for
well-tuned heaters. Few emission data are available for the wickless heaters.
A summary of CO-emission data for unvented kerosene space heaters is shown in
Table 7-6. There is considerable variability in emissions between and among heater types
and heater wick settings. Radiant heaters, when operated under normal wick settings,
produce considerably more CO than normal wick settings for the convective and two-stage
heaters. Two-stage heater emissions, however, jump considerably at lower wick settings.
Low-wick settings can increase CO emissions for convective heaters.
7.2.3 Emissions from Wood Stoves and Tobacco Combustion
Use of wood-burning stoves has been a popular cost savings alternative to conventional
central heating systems using gas or oil. CO and other combustion by-products enter the
indoor environment during fire start-up, fire-tending functions, or through leaks in the stove
or venting system. Hence it is difficult to evaluate indoor CO-emission rates for wood-
burning stoves. Traynor et al. (1987) evaluated indoor CO levels from four wood-burning
stoves (three airtight and one nonairtight stove) in a residence. The nonairtight stove emitted
substantial amounts of CO to the residence, particularly when operated with a large fire. The
airtight stoves contributed considerably less. The average CO source strengths during stove
7-15
-------
TABLE 7-6. CARBON MONOXIDE EMISSIONS 1ROM INVENTED KEROSENE SPACE HEATERS
Study
Leaderer (1982)
Traynor et al. (1983)
Jones et al. (1983)c
Moschandreas et al. (1985)
Type of
Heater3
C
R
C
R
2S
C
R
C
R
Number
of
Heaters
1
1
2
3
2 •
1
1
Test
Method*
C
C
C
C
C
D
D
C
C
Fuel Consumption
Rate (kJ/min)
37.3
97.9
158.0
84.4
. 113:
144
130
193
113
148
132
182
202
168d
100
129
Number
of
Tests
3
3
3
3
3
3
4
4
Emission Rate (/*g/kl)
Average
25.8
22.3
10.1
72.9 .
58.2
42.6
60
12
173
68
"54 ;
9
417
27.5
35.3 .
64.1
SD
4.7
1.5
4.1
2.6
5.0
2.5
1.1
1.1
1.4
1.5
2.5
1.2
8.2
5.2
"C = convective, R = radiant, 2S = two-stage.
kC = chamber/mass-balance method, D = direct/load method.
cAs reported by Moschandreas et al. (1985).
"^Manufacturer's rating.
-------
operation reported for the airtight stoves ranged from 10 to 140 cm3/h, whereas levels for the
nonairtight stove source strengths ranged from 220 to 1,800 cm3/h.
In 1987, 29% of the U.S. adult population, or approximately 49 million individuals,
were reported to be smokers (U.S. Department of Health and Human Services, 1989). The
combustion of tobacco represents an important source of indoor air contaminants. Carbon
monoxide is emitted indoors from tobacco combustion through the exhaled mainstream smoke
(MS) and from the smoldering end of the cigarette, sidestream smoke (SS). Mainstream
smoke and SS CO-emission rates have been evaluated extensively in small chambers (less
than a liter in volume) using a standardized smoking machine protocol. The results of these
studies have been summarized and evaluated in the Surgeon General's reports (e.g., 1986)
and the National Academy of Science Report on environmental tobacco smoke (National
Research Council, 1986). These results indicate considerable variability in total (MS+SS)
CO emissions, with a typical range of from 40 to 67 mg per cigarette. A small chamber
study of 15 brands of Canadian cigarettes (Rickert et al., 1984) found the average CO-
emission rate (MS+SS) to be 65 mg per cigarette. A more limited number of studies have
been done using large chambers with the occupants smoking or using smoking machines.
Girman et al. (1982) reported a CO-emission rate of 94.6 mg per cigarette for a large
chamber study in which one cigarette was evaluated. A CO-emission factor of 88.3 mg per
cigarette was reported by Moschandreas et al. (1985) for a large chamber study of one
reference cigarette.
On average, a smoker smokes approximately two cigarettes per hour, with an average
smoking time of approximately 10 minutes per cigarette. Using the above range of reported
CO emission rates for environmental tobacco smoke, this would roughly result in the
emission of from 80 to 190 mg of CO per smoker per hour into indoor spaces where smoking
occurs. This value compares to an approximate average CO emission rate of from 260 to
545 mg per hour for one range-top burner (without pilot light) operating with a blue flame
(estimated from Table 7-1). Two smokers in a house would produce hourly CO emissions
comparable to the hourly production rate of a single gas burner. Tobacco combustion,
therefore, represents an important indoor source of CO.
7-17
-------
7.2.4 Summary of Emission Data
Indoor sources of CO can be considered as unintentional or accidental (leaky flue pipes,
backdrafting, etc.) and intentional (emissions from unvented combustion sources). Emissions
from unintentional sources can result in indoor concentrations associated with serious acute
health effects and result in several hundred deaths per year in the United States. Carbon
monoxide emissions from these unintentional sources, despite their importance, cannot be
characterized in any standardized way. Unvented or partially vented gas cooking ranges and
ovens, gas appliances, UVGSHs, unvented kerosene space heaters, cigarette combustion, and
wood-burning stoves are all notable "intentional" indoor sources of CO emissions.
Unvented or partially vented sources of CO have been evaluated for CO emissions by
either the direct method or the mass-balance approach. The direct method samples the
emitted combustion gases as they pass through a sampling hood above the source. The mass-
balance approach measures the changes in CO over time in an environmental chamber or test
house in relation to changes in outdoor CO concentration, source emission rates, and CO
removal rates. For gas range-top burners, emissions typically are evaluated using a
standardized water load in a cooking pot.
Emissions from unvented, partially vented, or improperly vented gas cooking ranges
and ovens and gas appliances represent an important source of CO in the residential
environment in the United Steles due to the high percentage of homes (approximately 45%)
using gas to cook. CO emissions from these sources are a function of a number of variables
relating to the source type (range top or oven, burner design, pilot light, etc.), source
condition (age, maintenance, etc.), source use (number of burners used, fuel consumption
rate, etc.) and use of outside vents. The source emission studies typically have been
conducted in the laboratory setting and involved relatively few gas ranges and gas appliances.
The reported studies indicate that CO emissions are highly variable among burners on a single
gas cooking range and between gas cooking ranges and ovens, varying by as much as an
order of magnitude. Operating a gas cooking range or oven under improperly adjusted flame
conditions (yellow-tipping flame) can result in greater than a fivefold increase in emissions
when compared to properly operating flame conditions (blue flame). Use of a rich or lean
fuel appeared to have little effect on CO emissions. In general, CO emissions were roughly,
on an average, comparable for top burners, ovens, pilot lights, and unvented gas dryers when
7-18
-------
corrected for fuel consumption rate. The emissions rates gathered by either the direct or
mass-balance method were comparable. Only one study attempted to evaluate gas stove
emissions in the field for a small number (10) of residences. This study found CO emissions
to be as much as a factor of 4 higher than chamber studies. Given the prevalence of the
source, limited field measurements and poor agreement between existing laboratory and field
derived CO emission data, there is a need to establish a better CO emission data base for gas
cooking ranges in residential settings.
CO emissions from UVGSHs were found to be variable from heater to heater but were
roughly comparable to those for gas cooking ranges. Infrared gas space heaters produced
higher emissions than the convective or catalytic heaters. Emissions of CO for these heaters
were higher for maltuned heaters and for the mass-balance versus direct method of testing.
No differences for rich or lean fuel were found, but use of natural gas resulted in higher
emissions than did use of propane. Lower fuel consumption settings resulted in lower, CO
emissions. Emissions were observed to vary hi time during a heater run and increase when
room or chamber oxygen levels decreased.
Among the three principal unvented kerosene space heater designs (radiant, convective,
and two-stage burners), radiant heaters produced the highest CO emissions and convective
heaters produced the lowest emissions. Wick setting (low, normal, or high) had a major
impact on emissions, with the low-wick setting resulting in the highest CO emissions. Data
from different laboratories are in good agreement for this source.
Carbon monoxide emissions into indoor spaces from wood-burning stoves occur during
fire start-up, fire-tending, or through leaks in the stove or venting system. Few data are
available characterizing CO emissions for normal wood stove or fireplace operation. The
available data indicate that the nonairtight, wood-burning stoves can contribute substantial
amounts of CO directly to the indoor environment, whereas the airtight stoves contribute little
or none.
Tobacco combustion represents an important indoor source of CO. Emissions show
little variability among brands, with total emissions related to the number of cigarettes .
smoked. On an hourly rate, CO emissions resulting from two smokers (total of four
cigarettes per hour) may be roughly comparable to emissions from a single gas range-top
burner.
7-19
-------
The available data on CO emissions from unvented combustion sources are based
largely upon chamber or test house studies using the mass-balance or direct-measurement
method for a small sample of sources (i.e., a small number of gas cooking ranges). Given
the high variability of CO emissions observed from these sources in the available studies,
additional data are needed to better understand the factors impacting those emissions. Little
or nothing is known about CO emissions from unvented combustion sources actually in use in
residences. The few data available indicate that CO emissions from sources in the field are
considerably more variable and typically higher than those observed in the chamber or test
house studies.
7.3 CONCENTRATIONS IN INDOOR ENVIRONMENTS
Concentrations of CO in an enclosed environment are affected by a number of factors in
addition to the source factors discussed in the previous sections. These factors include
outdoor concentrations, proximity to outdoor sources (i.e., parking garages or traffic),
volume of the space, and mixing within and between indoor spaces.
Outdoor CO concentrations have been measured in a number of locations across the
United States utilizing continuous CO monitoring based upon nondispersive infrared (NDIR)
spectroscopic detection. The NDIR instruments, however, are too bulky and complicated for
either indoor or personal monitoring. Over the past decade small, lightweight, and portable
CO monitors have been developed. These monitors are based primarily on electrochemical
detection (see Chapter 5). These highly versatile CO monitors, when equipped with internal
or external data loggers, have permitted the measurement of personal exposures to CO as
well as CO concentrations in a number of indoor environments.
CO measurements in enclosed spaces have been made either in support of total personal
exposure studies or in targeted indoor studies. In the personal exposure studies, individuals
wear the monitors in the course of their daily activities, taking them through a number of
different microenvironments. In targeted studies, CO measurements are taken in indoor :
spaces independent of the activities of occupants of those spaces.
7-20
-------
7.3.1 Indoor Concentrations Recorded in Personal Exposure Studies
Three studies have reported CO concentrations in various microenvif ohments as part of
an effort to measure total human exposure to CO and to assess the accuracy of exposure
estimates calculated from fixed-site monitoring data. In each study, subjects wore personal
CO exposure monitors for one or more 24-h periods. Carbon monoxide concentrations were
recorded on data loggers at varying time intervals as a function of time spent in various
microenvironments. Participants kept an activity diary where they were asked to provide
information such as time, activity (e.g., cooking), location (microenvironrnent type), presence
and use of sources (e.g., smokers or gas stoves), and other pertinent information. Carbon
monoxide concentrations by microenvironment were extracted from the measured
concentrations by use of the activity diaries. This section will discuss the results of those
studies as they relate to the concentrations measured in different microenvifdnments.
A discussion of the results as they relate to total exposure to CO are discussed in Chapter 8. „
Two of the studies, conducted in Denver, CO, and Washington, DC, by the U.S.
Environmental Protection Agency (EPA) (Akland et'al., 1985; Whitmore et al., 1984;
Hartwell et al., 1984; Johnson, 1984), measured the frequency distribution of CO exposure in
a representative sample of the urban population. The study populations were selected using a
multistage sampling strategy. The third study, also conducted in Washington, DC (Nagda
and Koontz, 1985), utilized a convenience sample. . •• -
The first-mentioned Washington study obtained a total of 814 person-day samples for
1,161 participants, whereas the Denver study obtained 899 person-day samples for
485 participants. The Denver study obtained consecutive 24-h samples for each participant,
whereas the Washington study obtained one 24-h sample for each participant; Both studies
were conducted during the winter of 1982-1983. •
A comparison of CO concentrations measured in the Washington and Denver studies is
shown in Table 7-7 (from Akland et al., 1985). Concentrations measured in all
mieroenvironments for the Denver study were higher than those for-the Washington study.
This is consistent with the finding that daily maximum 1- and 8-h CO concentrations at
outdoor fixed monitoring sites were about a factor of 2 higher in the Denver area than in the
Washington area during the course of the studies (Akland et al., 1985). The highest
concentrations in both studies were associated with commuting, whereas the lowest levels
7-21
-------
V1
N)
N)
TABLE 7-7. SUMMARY OF CARBON MONOXIDE EXPOSURE LEVELS AND TIME SPENT
PER DAY IN SELECTED MICROENVIRONMENTS
Location
Denver, CO
Concentration (ppm)a
Microenvironment
Indoors, parking garage
In transit, car
In transit, other (bus, truck, etc.)
Outdoors, near roadway
In transit, walking
Indoors, restaurant
Indoors, office
Indoors, store/shopping mall
Indoors, residence
Indoors, total
n
31
643
107
188
171
205
283
243
776
776
X
18.8
8.0
7.9
3.9
4.2
4.2
3.0
3.0
1.7
2.1
SE
4.96
0.32
0.61
0.36
0.45
0.29
0.20
0.22
0.10
0.09
Median
Time (min)
14
71
66
33
28
58
478
50
975
1,243
Washington, DC
Concentration (ppm)a
n
59
592
130
164
226
170
349
225
705
705
X
10.4
5.0
3.6
2.6
2.4
2.1
1.9
2.5
1.2
1.4
SE
4.43
0.14
0.30
0.20
0.29
0.32
0.27
0.49
0.10
0.08
Median
Time (min)
11
79
49
20
32
45
428
36
1,048
1,332
"n = number of person-days with nonzero durations, x = mean, SE = standard error.
Source: Akland et al. (1985).
-------
were measured in indoor environments. Concentrations associated with commuting are no
doubt higher due to the proximity to and density of outside CO sources (cars, buses, and
trucks), particularly during commuting hours when traffic is heaviest. Indoor levels,
especially residential levels in the absence of indoor sources, are lower primarily due to the
time of day of sampling (noncommuting hours with lower outdoor levels). A more detailed
breakdown of CO concentrations by microenvironments for the Denver study is shown in
Table 7-8 (Johnson, 1984). Microenvironments associated with motor vehicles result in the
highest concentrations, with concentrations reaching or exceeding the National Ambient Air
Quality Standards (NAAQS) 9-ppm reference level.
TABLE 7-8. INDOOR MICROENVIRONMENTS LISTED IN DESCENDING ORDER
OF WEIGHTED MEAN CARBON MONOXIDE CONCENTRATION
Category
Public garage
Service station or motor vehicle
repair facility
Other location
Other repair shop
Shopping mall
Residential garage
Restaurant
Office
Auditorium, sports arena,
concert hall, etc.
Store
Health care facility
Other public buildings
Manufacturing facility
Residence
School
Church
Number of
Observations
116
125
427
55
58
66
524
2,287
100
734
351
115
42
21,543
426
179
CO Concentration (ppm)
Mean
13.46
9.17
7.40
5.64
4.90
4.35
3.71
3.59
3.37
3.23
2.22
2.15
2.04
2.04
1.64
1.56
' SD
18.14
9.33
17.97
7.67
6.50
7.06
4.35
4.18
4.76
5.56
4.25
3.26
2.55
4.06
2.76
3.35
Source: Johnson et al. (1984).
7-23
-------
No statistical difference (p>0.05) in CO concentrations was found for residences with
and without gas ranges in the Washington study. The results of a similar analysis on the
Denver data, according to the presence or absence of selected indoor sources, is shown in
Table 7-9 (Johnson, 1984).
TABLE 7-9. WEIGHTED MEANS OF RESIDENTIAL EXPOSURE GROUPED
ACCORDING TO THE PRESENCE OR ABSENCE OF SELECTED INDOOR
CARBON MONOXIDE SOURCES
Carbon Monoxide Concentration
CO Source
Attached garage
Operating gas
stove
Smokers
Source
Mean
2.29
4.52
3.48
Present
SD
5.34
6.10
6.58
Source
Mean
1.88
1.93
1.89
(ppm)
Absent
SD
3.00
3.92
3.69
- Difference
in Means
0.41
2.59
1.59
Significance
Level of
t test8
p< 0.0005
p< 0.0005
p< 0.0005
"Student t test was performed on logarithms of PEM values.
Source: Johnson (1984).
Attached garages, use of gas ranges, and presence of smokers were all shown to result
in higher indoor CO concentrations. Concentrations were well below the NAAQS 9-ppm
reference level, but were substantially above concentrations in residences without the sources.
In the second Washington study (Nagda and Koontz, 1985), a total of 197 person-days
of samples were collected from 58 subjects, representing three population subgroups
(housewives, office workers, and construction workers). A comparison of residential CO
concentrations from that study as a function of combustion sources and whether smoking was
reported is shown in Table 7-10. Use of gas ranges and kerosene space heaters were found
to result in higher indoor CO concentrations. The statistical significance of the differences
was not given. Concentrations were highest in microenvironments associated with
commuting. The data collected in this study were consistent with the data collected in the
EPA Washington study discussed above.
7-24
-------
TABLE 7-10. AVERAGE RESIDENTIAL CARBON MONOXIDE EXPOSURES (ppm):
IMPACT OF COMBUSTION APPLIANCE USE AND TOBACCO SMOKING*
Appliances
None
Gas stove
Kerosene space heater
Wood burning
Multiple appliances
All cases
No
1.2 (66)
2.2 (15)
5.1 (3)
0.7 (2)
1.0 (1)
1.5 (87)
Reported Tobacco Smoking
Yes
1.5 (12)
1.3 (1)
NDb
NDb
NDb
1.5 (13)
All
Cases
1.2 (78)
2.2 (16)
5.1 (3)
0.7 (2)
1.0 (1)
1.5 (100)
"Percentage of subjects' time in their own residences indicated in parentheses for each category of appliance use
and tobacco smoking.
data available.
Source: Nagda and Koontz (1985).
It is difficult for all three studies to assess the contribution to indoor CO concentrations
from either outdoor or indoor sources because concentrations outside each indoor
microenvironment were not measured.
7.3.2 Targeted Microenvironmental Studies
As demonstrated from the personal exposure studies discussed above, individuals, in the
course of their daily activities, can encounter a wide range of CO concentrations as a function
of the microenvironments in which they spend time. A number of studies have been
conducted over the last decade to investigate concentrations of CO in indoor
microenvironments. These "targeted" studies have either focused on indoor CO
concentrations as a function of the microenvironment or on sources in specific
microenvironments.
7-25-
-------
7.3.2.1 Indoor Microenvironmental Concentrations
A summary of the results of the larger studies that have investigated CO levels in
various indoor environments, independent of the existence of specific indoor sources, is
shown in Table 7-11. Major foci of these studies are microenvironments associated with
commuting. A wide range of concentrations were recorded in these studies, with the highest
CO concentrations found in the indoor commuting microenvironments. These concentrations
frequently are higher than concentrations recorded at fixed-site monitors, but are lower than
concentrations measured immediately outside the vehicles. Concentrations generally are
higher in automobiles than in public transportation microenvironments. A number of the
studies noted that CO concentrations in commuting vehicles can exceed both the 8-h, 9-ppm
level and the 1-h, 35-ppm level specified in the NAAQS (1970). Flachsbart et al. (1987) :
noted that the most important factors influencing CO concentrations inside automobiles were
such factors as link-to-link variability (a proxy for traffic density, vehicle mix, and roadway
setting), day-to-day variability (a proxy for variations in meteorological factors and ambient
CO concentrations), and time of day. This study noted that with increased automobile speed,
interior CO concentrations decreased.
Service stations, car dealerships, parking garages, and office spaces that have attached
garages can exhibit high concentrations of CO due to automobile exhaust. In one case
(Wallace, 1983), corrective measures reduced office space CO concentrations originating
from an attached parking garage from 19 ppm to approximately 4 ppm. In an investigation
of seven ice skating rinks in the Boston area, one study (Spengler et al., 1978) reported
exceptionally high average CO concentrations (53.6 ppm) with a high reading of 192 ppm.
Ice-cleaning machines and poor ventilation were found to be responsible.
Residential and commercial levels generally were found to have low concentrations, but
no information was provided on the presence of indoor sources or outdoor levels.
7.3.2.2 Concentrations Associated with Indoor Sources
As noted earlier, the major indoor sources of CO in residences are gas ranges and
unvented kerosene and gas space heaters, with properly operating wood-burning stoves and
fireplaces (nonleaky venting system) and tobacco combustion of secondary importance.
Properly used gas ranges (ranges used for cooking and not space heating) are used
7-26
-------
TABLE 7-11. CARBON MONOXIDE CONCENTRATIONS3 MEASURED IN VARIOUS
INDOOR ENVIRONMENTS AS A FUNCTION OF MICROENVIRONMENTS
Study
Cortese and
Spengler (1976)
Spengler et al.
(1978)
Colwill and
Hickman (1980)
Ziskind et al.
(1981)
Wallace (1983)
Holland (1983)
Locations
Boston, MA
Boston, MA
London,
England
Denver, CO
and
Boston, MA
Stamford, CT
Los Angeles,
CA
Microenvironment
Autos
Transit
Split
All
Outsideb
Seven skating
rinks
Autos
Outside0
Buses
Taxis
Police cars
One office
Commercial
Commuting
Residential
Commercial
Commuting
Residential
Average
Time-
Frame of
Sampling
(min)
40-70
40-70
40-70
40-70
40-70
40-160
65-90
-540
-540
-540
Hourly
10-30
10-30
10-30
10-30
10-30
10-30
Number of
Observations
248
28
70
346
1,076
17
11
75
38
19
80
659
1,341
577
1,938
96
807
Inside
Mean
1.34
7.4
8.3
11.9
53.6
25.2
4-36d
10-17d
0-46d
19.0
5.8
6.2
2.9
3.3
16.1
7.6
SD
5.4
3.7
2.8
5.5
18.0
7.0
5.9
8.0
4.7
3.9
2.5
5.8
5.0
CO
Max
(ppm)
>35
192
40
84
48
59
50
61
38
39
61
42
38
Outside
Mean SD So^Tce
Identified
Traffic
Traffic
Traffic
Traffic
6.0 4.0 Ambient
Ice
Traffic
47.0 13.1
Traffic
Traffic
Traffic
Leakage
from
garage
4.2° 3.0
5.5e 4.1 Traffic
4.3° 3.1
4.0 3.1
5.8 4.2 Traffic
3.9 2.8
Comments
66 volunteers
used— some levels
(4%) related to faulty
exhaust
Ventilation
measures —cleaning
from CO decay
11 drivers over a
35 km route
Only data gathered
by electrochemical
monitors presented
(passive dosimeter
data not included);
58% of values for
rides > 8 h were
>9 ppm
65 employees
affected; corrective
action taken
-------
TABLE 7-11 (cont'd). CARBON MONOXIDE CONCENTRATIONS8 MEASURED IN VARIOUS
INDOOR ENVIRONMENTS AS A FUNCTION OF MICROENVIRONMENTS
Average
Time-
Frame of
Inside CO Outside
g
00
Study
Flachsbart et al.
(1987)
Yocora et al.
(1987)
Peterson and
Sabersky (1975)
Chaney (1978)
Ziskind et al.
(1982)
Amendola and
Hanes (1984)
Flachsbart and
Ott (1984)
•
Locations
Phoenix, AZ
Denver, CO
Washington,
DC
Hartford, CT
Los Angeles,
CA
Several U.S.
cities
Los Angeles,
CA
New
England
5 California
cities
Microenvironment
Commercial
Commuting
Residential
Commercial
Commuting
Residential
Autos
Bus
Rail
2 Garages
Public building
Office building
Private home
Autos
Autos
Home
Work
Commute
Service station
Car dealership
Enclosed parking
Bldg. attached to
enclosed parking
Commercial
settings
Sampling
(min)
10-30
10-30
10-30
10-30
10-30
10-30
34-69
82-115
27-48
3
3
480
2-5
2-5
2-5
Number of Mean
Observations
380
839
48
1,949
3,634
528
213
35
8
47
-
564
557
461
81
10
7
202
2.2
6.8
5.8
5.9
11.0
5.6
9.1-22.3
3.7-10.2
2.2-5.2
21-94
1.8-22.7
2.1-22.9
1.8-21.9
<2.5
2-50
4-4.6
2.2-4.3
6.7-10.0
2.2-110.8
27.7
6.1
2.1
SD Max
(ppm)
2.2 17
4.9 50
3.6 17
4.3 30
7.7 54
4.4 45
2-9
1-7
0.5-5
10-56
-
45
.
-.
-
-
110.8
12.5
2.9
1.6
Mean SD
2.8 2.5
3.9 3.3
2.4 2.1
5.0 3.3
5.8 3.7
3.1 2.2
..
_
..
-
Very similar
to indoor
concentrations
Similar to
auto levels
-
-
3.0 2.6
Source
Identified Comments
Traffic
Traffic
Traffic
Traffic
Traffic
Traffic
Traffic
Traffic
Traffic
Autos
Autos
Autos
Autos
Measurements made
during commuting
hours
Two week averages day
and night over a
summer, fall, and
winter period
The slower the traffic,
the higher the CO
Higher in winter than in
summer
Indoor values have
outdoor concentrations
subtracted
-------
-J
&
VO
TABLE 7-11 (cont'd). CARBON MONOXIDE CONCENTRATIONS3 MEASURED IN VARIOUS
INDOOR ENVIRONMENTS AS A FUNCTION OF MECROENVIRONMENTS
Study
Sisovic and
Fugas (1985)
Locations
Zagreb,
Yugoslavia ,
Average
Time-
Frame of Inside CO Outside -•- •
Sampling JNumberol Mean SD Max Mean SD Source
Microenvironment (min) Observations (ppm) Identified Comments
8 Institutions Winter - 1.1-6.0 0.6- - - Traffic
'and 13.7
summer
periods
aAll measurements made with electrochemical devices.
Fixed central station sites.
Measurement made outside auto.
"95% confidence limits.
eAverage of two fixed sites.
-------
intermittently and thus would contribute to short-term peak CO levels indoors, but likely
would not result in substantial increases in longer-term average concentrations. Unvented
kerosene and gas space heaters typically are used for several hours at a time and thus are
likely to result in sustained higher levels of CO. The improper operation of gas ranges or
unvented gas or kerosene space heaters (e.g., low-wick setting for kerosene heaters or
yellow-tipping operation of gas ranges) could result in substantial increases in indoor CO
levels. Carbon monoxide levels indoors associated with tobacco combustion are, based upon
source emission data, expected to be low unless there is a very high smoking density and low
ventilation. In the absence of a leaky flue or leaky fire box, indoor CO levels from fire
places or stoves should be low, with short peaks associated with charging the fire when some
back draft might occur.
The majority of studies investigating CO concentrations in residences, as a function of
the presence or absence of a known CO source, typically have measured CO concentrations
associated with the source's use over short time periods (on the order of a few minutes to a .
few hours). These studies typically have involved fewer than 10 residences and have
reported peak CO levels (on the order of minutes). Only two studies (Research Triangle
Institute, 1990; Koontz and Nagda, 1987) have reported long-term average CO concentrations
(over several hours) as a function of the presence of a CO source for large residential sample
sizes, whereas one study (McCarthy et al., 1987) reported longer term average indoor CO
concentrations for a small sample.
Average Indoor-Source-Related Concentrations
As part of a study to determine the impact of combustion sources on indoor air quality,
a sample of 382 homes in New York State (172 in Onondaga County and 174 in Suffolk
County) were monitored for CO concentrations during the winter of 1986 (Research Triangle
Institute, 1990). In this study, four combustion sources were examined: gas cooking
appliances, unvented kerosene spa^e heaters, wood-burning stoves and fireplaces, and tobacco
products. A factorial sample that included all 16 combinations of combustion sources was
utilized. Carbon monoxide concentrations were monitored in the main living area (e.g.,
family room) and source area (e.g., in the kitchen for homes with gas ranges) for each home
over a 3-day period using an electrochemical monitor with the data stored on a data logger. •
7-30
-------
Outdoor CO levels were not recorded for these homes. Carbon monoxide concentrations
were reported as averages for the full 3-day period of measurement.
Average CO concentrations measured in the main living area as a function of county
and the presence or absence of a combustion source are shown in Table 7-12. ,Gas ranges
and kerosene heaters were found to result in small increases in average CO levels. Use of a
wood-burning stove or fireplace resulted in lower average CO levels, presumably due to
increased air-exchange rates associated with use. The study found no effect on average CO
levels with tobacco combustion and no difference by location in the residence. The data base
has not yet been analyzed for differences in short-term CO concentrations (8-h, 1-h, or less
than 1-h concentrations) as a function of sources and source use. When such an analysis is
made available, the impact of the combustion sources on residential CO levels will be much
more pronounced.
Koontz and Nagda (1987 and 1988), utilizing Census data for sample selection,
monitored 157 homes in 16 neighborhoods in north central Texas over a 9-week period
between January and March 1985. Unvented gas space heaters were used as the primary
means of heating in 82 residences (13 had one UVGSH, 36 had two UVGSHs, and 33 had
three or more UVGSHs) and as a secondary heat source in 29 residences (17 had one
UVGSH and 12 had two or more UVGSHs). There was no gas space heater present or used
in 41 of the homes and 5 of the homes were not included for various reasons (e.g., air
sample lost). A majority of all the homes in each UVGSH-use category had gas ranges and
gas water heaters (typically greater than 80%). Air samples were collected for all residences
on two separate occasions over integrating periods of approximately 15 h using Collectaire
samplers. Carbon monoxide concentrations in each sampler then were measured using a
electrochemical monitor. In 30% of the residences (46 residences), CO was monitored
continuously, consisting of sequential 15-min averages over an average monitoring period of
about 5 days with an electrochemical monitor. Measurements were made close to the
geometric center of the house.
The cumulative frequency distributions for the first integrated CO measurements by
source category are shown in Figure 7-1. Residences where UVGSHs are the primary heat
source exhibited the highest CO concentrations. Carbon monoxide concentrations were
greater than or equal to 9 ppm in 12% of the homes, with the highest concentration measured
7-31
-------
TABLE 7-12. WEIGHTED SUMMARY STATISTICS FOR CARBON MONOXIDE
CONCENTRATIONS (ppm) IN THE MAIN LIVING AREA BY USE FOR
SELECTED SOURCES BY COUNTY
Source
and
County
Source
Present
Sample Percent
Size Detected
Arith.
Mean
SE
Geo.
Mean
Geo.
SE
Kerosene Heater
Onondaga
Suffolk
Onondaga
Suffolk
Onondaga
Suffolk
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
10
198
89.3a
60.0
16 100.0a
158 72.1
Wood-Burning
39
169
33
141
Gas
90
118
86
88
3.33
1.72
3.86a
2.03
Stove/Fireplace
44.5 1.04
62.9 1.86a
82.7
72.7
Stove
77.4a
47.0
82.8
68.2
1.93
2.24
2.29a
1.33
2.55a
1.91
1.34
0.15
0.73
0.15
0.09
0.16
0.23
0.17
0.24
0.17
0.21
0.19
2.20
1.29
3.35a
1.62
0.93
1.37a
1.72
1.72
1.74a
1.04
2.04a
1.51
1.33
1.06
1.22
1.07
1.09
1.06
1.14
1.07
1.08
1.07
1.10
1.09
"Significantly different at 0.05 level.
Source: Research Triangle Institute (1990).
at 36.6 ppm. No values were measured above 9 ppm for residences where a UVGSH was not
used at all or was used as a secondary heat source. The second CO sample produced
summary statistics virtually identical to the first. Table 7-13 presents a comparison of the
CO concentrations measured in the continuously monitored residences (15-min average
concentrations summed by 1- and 8-h periods), with the number exceeding the 1-h, 35-ppm
and 8-h, 9-ppm CO standard by source category. The table also presents the mean
concentrations measured in these home over the full 5-day periods. Five of the residences
exceeded the 1-h, 35-ppm level, whereas seven of the residences exceeded the 8-h, 9-ppm
level. Higher CO levels were associated with maltuned unvented gas appliances and the use
of multiple unvented gas appliances.
7-32
-------
100 -
90 -
80 -
70 -
60 -
CO
a.
40
30 -
20 -
10-
0
I
2
Mean ± Standard Deviation:
_ Non-UVGSH - 2.2 ± 1.7
O Secondary UVGSH -- 2.9 ± 1.6
A Primary UVGSH - 5.5 ± 6.0
~
6
8 10 12
Carbon Monoxide, ppm
\
14
T
16
\
18
20
Figure 7-1. Cumulative frequency distributions and summary statistics for indoor
carbon monoxide concentrations in three groups of monitored homes.
.*
Source: Koontz and Nagda (1988).
TABLE 7-13. SUMMARY OF CONTINUOUS CARBON MONOXIDE
MONITORING RESULTS BY HEATING EQUIPMENT
Heating Equipment
Primary UVGSH
Secondary UVGSH
Non-UVGSH
Number of
Homes
26
11
9
Number Exceeding
1-h, 34-ppm
4
1
0
8-h, 9-ppm
5
0
2
CO Concentration (ppm)
Mean
6.2
2.3
2.2
SD
7.6
1.1
1.2
Source: Koontz and Nagda (1988).
7-33
-------
In a study of 14 homes with one or more unvented gas space heaters (primary source of
heat) in the Atlanta, GA, area, McCarthy et al. (1987) measured CO levels by continuous
NDIR monitors in two locations in the homes (room with the heater and a remote room in the
house) and outdoors. Measurements were taken over 5-min periods in turn from each of the
three sampling points for each house over 96-h sampling periods. The authors reported only
the summary statistics for CO (average 96-h concentrations) based on the continuously
collected data in the room with the heater and outdoors. One out of the 14 TJVGSH homes
exceeded 9 ppm during the sampling period. Mean indoor values ranged 0.26 to 9.49 ppm
and varied as a function of the use pattern of the heater. Only one of the homes used more
than one heater during the air sampling. Outdoor concentrations varied from 0.3 to 1.6 ppm.
Peak Indoor-Source-Related Concentrations
Short-term or peak CO concentrations indoors associated with specific sources were
obtained for a few field studies. The peak CO concentrations measured in these studies, by '
location in the house and presence of specific sources, are shown in Table 7-14. A wide
range of peak CO concentrations were observed in these studies between and among
residences with different indoor CO sources. The highest concentrations measured
(>600 ppm) were associated with emissions from geisers (water heaters), found in a large
study conducted in the Netherlands (Brunekreef et al., 1982). Peak levels of CO associated ;,
with gas ranges were from 1.0 to more than 100 ppra. This broad range is somewhat
consistent with the range of CO emissions observed in studies evaluating CO emissions from
gas ranges (i.e., Table 7-1). The variability is in part due to number of burners used, flanie
condition, condition of the burners, etc. As might be expected, radiant kerosene heaters
produced higher CO concentrations than convective heaters. Unvented gas space heaters
generally were associated with higher CO peaks than gas ranges or kerosene heaters. As
noted earlier, the peaks associated with gas or kerosene heaters are likely to be sustained oyer
longer periods of time because of the long source-use times. ;'•
Test houses have been used by investigators to evaluate the impact of specific sources >
modifications to sources, and variations in their use on residential peak CO concentrations.
In one of the earliest investigations of indoor air quality, Wade et al. (1975) measured
indoor and outdoor CO levels in four houses that had gas stoves. Using an NDIR analyzer,
7-34
-------
TABLE 7-14. PEAK CARBON MONOXIDE CONCENTRATIONS
BY INDOOR SOURCE MEASURED IN FIELD STUDIES
Reference
Research Triangle
Institute (1990)
Koonteetal. (1987)
Leaderer et al.
(1984)
Lebret et al. (1987)
Bnmekreef et al.
(1982)
Moschandreas and
Zabransky (1982)
Sterling and Sterling
(1979) :
Indoor
Source8
GR
K
UVGSHP, GR
UVGSHS, GR
GR
GR
CK
RK .
GA
GA •
GR
GR
Number of
Residents
12
1
26
11
9
1
8
5
12
254
• 8
3
Location6
K
LR, D, B
K
D- --
C
C
c
A
B
LR
B
LR
B
K
LR
R
K
KT •
LR
B
K,-
Averaging
Time
(min)
30
30
30
30
15
- 15
15
15
1.5
5
5
5
" 5 ...
1 •;
1
1
15
60
60
60
2
CO Concentration (ppm)
Peaks Outside
1.8- >100 0.7- 10
1.8-17 >100
5.7 - 5.0
9.7 5.0
?-69
?-69
?-26
3.5
3.0
0-3.2
0-3.4
2.1 - 21.1
4.8-8.2
4.0 - 90
3.3 - 23
3.3 - 40 • .
<10- >600
7.2-11.3
1.0 - 12.6 :\ - .
1.0-13.0 :;. -
29-120 : 3.0 -8.5
Comments
Excluding one house with range in
kitchen,
peak values were 1.8 - 15; wood stoves and
smokers were present in some houses but no
effect was seen
Houses may contain more than one
Outdoor levels subtracted
Outdoor levels subtracted
Outdoor levels subtracted
Sample of Dutch homes
Sample of Dutch homes, breathing
samples, levels related to geisefs
heater
zone
Measurements \vere taken under a variety of
gas range operating and ventilation
conditions
'GR = gas range; K = unvented kerosene space heater; UVGSHP = unvented gas space heater used as primary heat source; UVGSHS =? unvented gas space
heater as a secondary heat source; CK = unvented convective kerosene space heater; RK = radiant unvented kerosene space heater; GA = gas appliances,
includes geisers (water heaters). :
kK = kitchen, LR = living room, D = den, B = bedroom.
-------
indoor concentrations were found to range from 1.7 to 3.8 times higher than the outdoor
levels. Carbon monoxide levels in one house exceeded 9 ppm, the NAAQS reference level.
A time history of CO measured in one house is shown in Figure 7-2. For this house and for
the time averaging period used, CO was well mixed through the house. As part of a modeling
study of emissions from a gas range, Davidson et al. (1987) measured CO concentrations in
three residences. Peak CO levels in excess of 5 ppm were measured in one town house.
Indoor CO levels associated with wood-burning stoves .were measured in two test house
studies. In one study (Humphreys et al., 1986), indoor CO levels associated with the use of
both airtight (conventional and catalytic) and nonairtight wood heaters were evaluated in a
337-m3 weatherized home. Indoor CO concentrations were higher than outdoor levels for all
tests. Conventional airtight stoves produced indoor CO levels typically about 1 to 2 ppm
above background level, with a peak concentration of 9.1 ppm. Use of nonairtight stoves
resulted in average indoor CO concentrations 2 to 3 ppm above outdoors, with peak
concentrations as high as 29.6 ppm. In a 236-m3 house (Traynor et al., 1984), four wood-
burning stoves (three airtight and one nonairtight) were tested. The airtight stoves generally
resulted in small contributions to both average and peak indoor CO levels (0.1 to 1 ppm for
the average and 0.2 to 2.7 ppm for the peak). The nonairtight stove contributed as much as
9.1 ppm to the average indoor level and 43 ppm to the peak.
Indoor Concentrations Related to Environmental Tobacco Smoke
Carbon monoxide has been measured extensively in chamber studies as a surrogate for
environmental tobacco smoke (e.g., Bridge and Corn, 1972; Hoegg, 1972; Penkala and
De OHveira, 1975; Weber et al., 1976, 1979a,b; Weber, 1984; Leaderer et al., 1984;
Clausen et al., 1985). Under steady-state conditions in chamber studies, where outdoor CO
levels are monitored and the tobacco brands and smoking rates are controlled, CO can be a
reasonably good indicator of environmental tobacco smoke and is used as such. Under such
chamber conditions, CO concentrations typically range from less than 1 to greater than
10 ppm. ;
A number of field studies have monitored CO in different indoor environments with and
without smoking occupants. A summary of the results of these studies is shown in
Table 7-15 (National Research Council, 1986, Table 2-4). Although CO concentrations
7-36
-------
^ 13000 —
"fe 12000 -
g 11000 —
,g 10000 —
| 9000 —
S 8000
,§ 7000 —
^ 6000
'§ 5000 -
J 4000 —
c 3000 _
€ 2000 —
0 1000 —
0-
Kitchen over stove
Kitchen 1 m from stove
Living room
Outside
1 burner
on i
14 mln—J
1 burner on I
3mki—*l
1 bumar en I
3mln —»!
1 burner on
11
1 burner on I
7mh -*l
Oven on
65mln
1 burner on _J
Smln "*l
t burner on . i
6mln -*
1 burner on I
Smln —H
1 burner on
J
I I I I I I I I i I I I I I I I i
0400 0800 1200 1600 2000 2400 0400 0800 1200
1/31 2/01
Time, h
Figure 7-2. A time history of carbon monoxide concentrations, 2-h averages, winter of
1974.
Source: Wade et al. (1975),
generally were higher in indoor spaces when smoking occurred, the concentrations were
highly variable. The variability of CO production from tobacco combustion, number of
cigarettes smoked, and differences in ventilation and variability of outdoor concentrations
7-37
-------
TABLE 7-15. MEASURED CONCENTRATIONS OF CARBON MONOXIDE IN
ENVIRONMENTAL TOBACCO SMOKEa '
"H
00
Indoor
Location
Rooms
Tram
Submarines
(66m3)
18 Military
aircraft
8 Commercial
aircraft
Rooms
14 Public places
Ferry boat
•Theater foyer
mtercity bus
2 Conference rooms
Office
Automobile
9 Night clubs
14 Restaurants
45 Restaurants
33 Stores
3 Hospital lobbies
6 Coffee houses
Room
Hospital lobby
2 Train
compartments
Tobacco Burned
—
1-18 smokers
157 cigarettes/day
94 - 103 cigarettes/day
_
-
..
~
_
..-
23 cigarettes
3 cigarettes
-
_
—
2 smokers
(4 cigarettes)
_
—
..
—
•
Varied
18 smokers
12 - 30 smokers
2-3 smokers
Ventilation
_
Natural
Yes
Yes
, Yes
Yes
..
-
_.
,,
15 changes/h
15 changes/h
8 changes/h
236 m3/h
Natural
Natural
Mechanical
Varied
-
-
...
-
-
. .. -
--
-
*'
Mean
„
—
<40
<40
<2-5
<2
__
<10
18.4 ± 8.7
3.4 ± 0.8
32 '
18
—
__
-
—
—
13.4
9.9 ± 5.5
8.2 ± 2.2
10.0 + 4.2
—
2-23
50
5
_.
Range
4.3-9
0-40
..
—
-
_.
5-25
~
—
—
—
-
8 (peak)
< 2.5 -4.6
<2.9-9.0
42 (peak)
32 (peak)
6.5 - 41.9
—
7.1 ± 1.7
11.5 + 6.5
4.8
-
-
—
4-5
Outdoor
Mean Range References
2.2 ± 0.98 0.4 - 4.5 Coburn et al. (1965)
— — Harmsen and Effenberger
(1957)
Cano et al. (1970)
- _
— U.S. Department of
Transportation (1971)
U.S. Department of
Transportation (1971)
Portheine (1971)
Perry (1973)
3.0 ± 2.4 - Godin et al. (1972)
1.4 ± 0.8 - , -: Godin et al. (1972)
- Seiff(1973)
_
1-2 - Slavin and Hertz (1975)
Harke (1974)
_
13.5 (peak) Harke and Peters (1974)
15.0 (peak)
Sebben et al. (1977)
9.2 3.0 - 35 Sebben et al. (1977)
(outdoor)
Sebben et al. (1977)
11.5 ± 6.5 - Sebben et al. (1977)
Sebben et al. (1977)
Badre et al. (1978)
Badre et al. (1978)
Badre et al. (1978)
Badre et al. (1978)
-------
TABLE 7-15 (cont'd). MEASURED CONCENTRATIONS OF CARBON MONOXIDE IN
ENYIRONMENTAL TOBACCO SMOKEa
Indoor
Location
Automobile
10 Offices
14 Night clubs
and taverns
Tavern
Office
Restaurant
Restaurant
Bar
Cafeteria
44 Offices
25 Offices
Tavern
Tavern
Tobacco Burned Ventilation
3 smokers Natural, open
2 smokers Natural, closed
._
. —
Artifical
None
Natural, open
— Mechanical
Natural
Natural, open
11 changes/h
—
...
— 6 changes/li
— 1-2 changes/h
Mean
14
20
2.5 ± 10
13.0 ± 7.0
8.5
—
1.0 .
5.1
2.6
4.8
1.2
1.1
2.78 ± 1.42
11.5
12.0
Range
..
_
1.5 - 1.0
3.0 - 29.0
•
35 (peak)
10.0 (peak)
2.1 - 9.9
1.4 - 3.4
2.4 - 9.6
0.7 - 1.7
6.5 (max)
_
10-12
3-22
Outdoor
Mean
-
..
2.5 ± 1.0
3.0 ± 2.0
_
.. ' :
..
4.8
(outdoors)
1.5
(outdoors)
1.7
(outdoors)
0.4
(outdoors)
«•
2.59 ±
2.33
2 (outdoors).
—
Range References
Badre et al. (1978)
Badre et al. (1978)
1.5 ± 4.5 Chappell and Parker (1977)
1.0 - 5.0 ChappeU and Parker (1977)
ehappell and Parker (1977)
ChappeE and Parker (1977)
^Chappell and Parker (1977)
— Fischer et al. (1978)
Fischer et al. (1978)
Weber et al. (1976)
Weber et al. (1976)
Weber (1984)
Szadkowski et al. (1976)
Cuddebaek et al. (1976)
Cuddeback et al. (1976)
"Time-weighted average (TWA) of carbon monoxide, 50 ppm (55 mg/m3). TWA = average concentration to which worker may be exposed continuously for
8 B. without damage to health (Lundin et al., 1971).
Source: National Research Council (1986) Table 2-4.
-------
make it difficult to assess the contribution of tobacco combustion in indoor CO
concentrations. The chamber studies and field studies conducted do indicate that under
typical smoMhg conditions encountered in residences or offices, CO concentrations can be
expected to be above background outdoor levels, but lower than the levels resulting from
other unvented combustion sources. In indoor spaces where heavy smoking occurs and in
small indoor spaces, CO emissions from tobacco combustion will be an important contributor
to CO concentrations.
7.3.3 Spatial Concentration Variations
Spatial variations of CO concentrations within a space are a function of mixing within
and between spaces. Spatial variations of CO in a space are likely to be minimized if a
continuous or nearly continuous source of CO exists (i.e., unvented kerosene or gas space
heater) due to the strong convective currents, which enhance rapid mixing. Intermittent
sources (i.e., gas burner use or tobacco combustion) are likely to produce a more pronounced
spatial gradient. The within-home spatial variations are related to such variables as air-
exchange rates among rooms, air mixing within a room, volume of a house, and location and
use of the source. The question of the spatial variability of CO indoors as a function of
different indoor sources has,not been evaluated in any detail in any field study.
7.3.4 Summary of Indoor Concentrations
Indoor concentrations of CO are a function of outdoor concentrations, indoor sources ,
(source type, source condition, source use, etc.), infiltration/ventilation, and air mixing
between and within rooms. In residences without sources, average CO concentrations are
approximately equal to average outdoor levels. Proximity to outdoor sources (i.e., structures
near heavily traveled roadways or with attached garages or parking garages) can have a major
impact on indoor CO concentrations. , . .
The development of small lightweight and portable electrochemical CO monitors over,
the past decade has permitted the measurement of personal CO exposures and CO
concentrations in a number of indoor environments. The available data pn indoor CO ;;
concentrations have been, obtained from total personal exposure studies or studies.where
various indoor environments have been .targeted for measurements.
7-40
-------
The extensive total personal CO exposure studies conducted by EPA in Washington,
DC, and Denver, CO, have shown that the highest CO concentrations occur in indoor
microenvironments associated with transportation sources (parking garages, cars, buses, etc.).
Concentrations in these environments were found to frequently exceed 9 ppm. Studies
targeted toward specific indoor microenvironments also have identified the indoor commuting
microenvironment as an environment in which CO concentrations frequently exceed 9 ppm
and occasionally exceed 35 ppm. Special environments or occurrences (indoor ice skating
rinks, offices where emissions from parking garages migrate indoors, etc.) have been
reported where indoor CO levels can exceed the current ambient 1- and 8-h standards (9 and
35 ppm, respectively).
A majority of the targeted field studies monitored indoor CO levels as a function of the
presence or absence of combustion sources (gas ranges, unvented gas and kerosene space
heaters, wood burning stoves and fireplaces, and tobacco combustion). The results of these
studies indicate that the presence and use of a unvented combustion source results in indoor
CO levels above those found outdoors. The associated increase in CO concentrations can
vary considerably as a function of the source, source use, condition of the source, and
averaging time of the measurement. Intermittent sources such as gas cooking ranges can
result in high peak CO concentrations (in excess of 9 ppm), whereas long-term average
concentrations (i.e., 24 h) associated with gas ranges are considerably lower (on the order of
1 ppm). The contribution of tobacco combustion to indoor CO levels is variable. Under
conditions of high smoking and low ventilation, the contribution can be on the order of a few
parts per million. One study suggested that the contribution to residential CO concentrations
of tobacco combustion is on the order of 1 ppm, whereas another study showed no significant
increase in residential CO levels.
Unvented combustion sources that are used for substantial periods of time (i.e.,
unvented gas and kerosene space heaters) appear to be the major contributor!? to residential
CO concentrations. One extensive study of unvented gas space heaters indicated that 12% of
the homes had 15-h average CO concentrations greater than 8 ppm, with the highest
concentration at 36.6 ppm. Only very limited data are available on the contribution of
kerosene heaters to the average CO concentrations in residences, and these data indicate a
much lower contribution than gas heaters. Peak CO concentrations associated with both
7-41
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unvented gas and kerosene space heaters often exceed the current ambient 1- and 8-h
standards (9 and 35 ppm, respectively) in residences, and due to the nature of the source
(continuous) those peaks tend to be sustained for several hours, , :
Very limited data on CO levels in residences with wood-burning stoves or fireplaces is
available. Nonairtight stoves can contribute substantially to residential CO concentrations,
whereas airtight stoves can result in small increases. The available data indicate that <•
fireplaces do not contribute measurably to average indoor concentrations. No information is
available for samples of residences with leaky flues. In addition, there is no information
available on short-term indoor CO levels associated with these sources, nor are there studies
that examine the impact of attached garages on residential CO concentrations. : , •
The available data on short-term (1-h) and long-term (8-h) indoor CO concentrations as
a function of microenvironments and sources in those microenvironments are not adequate to
assess exposures in 'ffib'se environments. In addition, little- is known'about the spatial5i>!i:t
variability of CO indoors. These indoor microenvironments represent the most important CO
exposures for individuals and as such need to be characterized better-
7-42
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8. POPULATION EXPOSURE TO
CARBON MONOXIDE
8.1 INTRODUCTION
A fundamental purpose of the Clean Air Act is to protect public health. The National
Ambient Air Quality Standards (NAAQS) are set at levels that provide a margin of safety to
protect the health of the populace from adverse effects of air pollutants. In setting a pollutant
standard, population exposure is an important consideration because public health can be
affected adversely by an air pollutant only if the following two conditions coincide.
(1) Persons actually are or potentially would be exposed in daily living to levels of
the pollutant occurring in ambient air locations at or above undesirable
concentrations.
(2) The air pollutant causes adverse effects on human health in sensitive population
groups at these concentrations.
This chapter focuses on the degree to which the population actually is exposed to
outdoor, in-transit, or indoor concentrations of carbon monoxide (CO) that might produce
adverse health effects. Chapter 10 deals with the second topic, the physiological and other
health effects associated with a person's exposure to various concentrations of CO.
In evaluating population exposure to CO, it is important to understand the general
concepts of concentration, exposure, and dose. Sexton and Ryan (1988) provide the
following definitions. - .
The "concentration" of a specific air pollutant is the amount of that material per unit
volume of air. Air pollution monitors measure pollutant concentrations, which may or may
not provide accurate exposure estimates.
The term "exposure" is defined as any contact between an air contaminant of a specific
concentration and the outer (e.g., skin) or inner (e.g., respiratory tract epithelium) surface of
the human body. Exposure implies the simultaneous occurrence of two events (Ott, 1982):
8-1
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(1) A pollutant concentration, C, is present at location x,y,z at time r, and
(2) A person, z, is present at location x,y,z at time t.
A key distinction is apparent between a concentration and an exposure. The
concentration of an airborne contaminant measured in an empty room is just that, a
concentration. A concentration measured in a room with people present is a measurement of
exposure. A measured concentration is a surrogate for exposure only to the degree to which
it represents concentrations actually experienced by individuals.
A more important distinction exists between "exposure" and "dose." Whereas exposure
is the pollutant concentration at the point of contact between the body and the external
environment, dose is defined as the amount of pollutant that actually crosses one of the
body's boundaries and reaches the target tissue. Dose has been portioned into two
components: internal dose and biologically effective dose (National Research Council, 1989,
1991). Internal dose is the amount of a pollutant that is absorbed into the body over a given
time. Biologically effective dose is the amount of pollutant or its metabolites that have
interacted with the target tissue over a given period so as to alter a physiological function.
Among factors that affect the magnitude of the CO dose received are respiration rate, uptake,
and metabolism.
Carbon monoxide is emitted from incomplete combustion of carbon-based fuels.1
Consequently, ambient concentrations of CO can reach high levels close to emission sources.
The strong source-dependence of CO leads to highly variable spatial and temporal
concentrations in urban environments (see Chapter 6). Because of the variable concentration
patterns exhibited by CO, it is necessary to address the relationships between ambient
concentrations and human exposures to evaluate the potential health risk associated with
actual population exposures.
Compliance with the NAAQS currently is judged by comparing the standards to data
from fixed, ambient-air monitoring stations. The sites for such stations are chosen, however,
to monitor ambient conditions in a number of neighborhood types (Ott, 1977) rather than
'Caibon-based fuels are burned incompletely by internal combustion engines (e.g., automobiles, trucks, and
small utility engines), and by sources such as cigarettes, forest fires, and poorly adjusted gas burners.
8-2
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actual human exposure. In fact, a number of studies have shown that ambient-air monitoring
stations do not necessarily reflect the concentrations to which people are actually exposed.
This difference between fixed stations and exposures occurs because of the spatial and
temporal variability of CO. In contrast to the stationary location of an ambient monitor,
people are usually moving through a succession of microenvironinents (e.g., homes,
sidewalks, buses, automobiles, shopping malls, downtown street canyons, restaurants, offices,
factories, and garages) where they may spend time in closer proximity to CO sources and in
more enclosed spaces than the outdoors. The result is that existing ambient monitoring
stations often do not reflect individual exposure patterns, nor do they necessarily reflect the
highest concentrations to which those people are exposed. However, fixed monitors do give
some general information on the overall levels of CO and are useful for a variety of other
purposes (see Chapter 6).
Among all major air pollutants, CO has one of the clearest measures available of
biological dose (see Section 8.5). The amount of CO circulating in the blood, expressed as
the percentage of hemoglobin (Hb) bound with CO, or carboxyhemoglobin. (COHb), is a
useful measure of dose for relating this pollutant to deleterious health effects (see
Chapter 10). Blood COHb is in turn a function of inhaled CO, minute ventilation, blood
volume, and other physiological factors (see Chapter 9: Pharmacokinetic Modeling); Because
the relationship between ambient CO and blood COHb is dynamic, it is necessary to know
the timing and duration of an exposure series in order to predict resulting COHb.
Because of the spatial and temporal variability of CO as well as the loiowri functional
relationships between concentration and a measure of dose, CO is a model pollutant for '
development and evaluation of improved approaches for assessing human exposure.
A number of field studies now have been undertaken that provide a quantitative assessment of
the disparity between fixed monitoring stations and actual exposures. In addition, field
measurements of body burden (for example, blood COHb and breath CO) are available for
comparison with fixed-station monitoring data. Several personal-monitoring CO field1 studies
have employed representative statistical sampling procedures, allowing inferences to be made
about the CO exposures (or COHb levels) of an entire populatibn of a city or a region.
Finally, models of population exposure and activity patterns have been developed to bridge
the gap between ambient, fixed-station measurements, and actual personal exposures.
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Additional data need to be developed from personal monitoring field studies for use in
validating these models. The models are important for improving our understanding of
human exposure to CO and for evaluating different control strategies. The models can
indicate locations and sources of most significant exposure and therefore may suggest control
strategies to reduce human exposure and the resulting deleterious health effects.
8.2 EXPOSURE MONITORING IN THE POPULATION
In recent years, researchers have focused on the problem of determining actual
population exposures to CO. There are two alternative approaches for estimating the
exposures of a population to air pollution: the "direct approach," using field measurement of
a representative population carrying personal exposure monitors (PEMs); and the "indirect
approach," involving computation from field data of activity patterns and measured
concentration levels within microenvironments (Ott, 1982).
In the direct approach, as study participants engage in regular daily activities, they are
responsible for recording their exposures to the pollutant of interest. Subjects can record
their exposures in a diary, the method used in a study in Los Angeles (Ziskind et al., 1982),
or they can automatically store exposure data in a data logger, the method used in studies in
Denver (Johnson, 1984) and Washington, DC (Hartwell et al., 1984), which are summarized
by Akland et al. (1985). In all of these studies, subjects recorded the time and nature of their
activities while they monitored personal exposures to CO. The direct approach—sometimes
called the Total Exposure Assessment Methodology (TEAM)-is useful to obtain an exposure
inventory of a representative sample from either the general population, or from a specific
subpopulation, which can be defined by many demographic, occupational, and health factors.
The inventory can cover a range of microenvironments encountered over a period of interest
(e.g., a day), or it can focus on one particular microenvironment. With this flexibility,
policy analysts can assess the problem that emission sources pose to a particular subgroup
(e.g., commuters) active in a specific microenvironment (e.g., automobiles).
The indirect approach to estimating personal exposure is to use PEMs or
microenvironmental monitors to monitor microenvironments rather than individuals.
Combined with additional data on human activities that occur in these microenvironments,
8-4
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date from the indirect approach can be used to estimate the percentage of a subpopulation that
is at risk to pollutant concentrations that exceed national or state air quality standards.
Flachsbart and Brown (1989) conducted this type of study to estimate merchant exposure to
CO from motor vehicle exhaust at Honolulu's Ala Moana Shopping Center.
8.2.1 Personal Monitoring
The development of small PEMs, as discussed in Chapter 5, made possible the large-
scale CO human exposure field studies in Denver, CO, and Washington, DC, in the winter of
1982 to 1983 (Aldand et aL, 1985). These monitors proved effective in generating 24-h CO
exposure profiles on 450 persons in Denver and 800 persons in Washington, DC. 'Because
personal monitoring techniques are new, and few field studies have been done, the science of
measuring the exposures to chemicals in human populations is in an early stage of
development. The use of PEMs and concurrent diaries in large-scale population studies
requires rigorous quality control and introduces many new problems that are not present in
ambient monitoring studies. The PEMs must be rugged, self-powered, lightweight, and free
of drift while being carried and exposed to temperature variations; associated data loggers are
required to store the continuous PEM readings. The diary format must be clear, easy for the
subject to complete, and easy for the researcher to interpret. With good calibration practices,
the CO PEMs can provide a precision of better than +1 ppm. The Denver-Washington, DC,
study is the only large-scale population exposure field study that yet has been undertaken.
Despite the complexity of such a study, the large probability sample and high time resolution
of the PEMs yielded a rich data base for characterizing the exposures of the population to CO
in two major U.S. cities. The findings have greatly increased the understanding of the
causes, severity, and variability of the exposures of human populations to CO.
Results from the Denver-Washington, DC, study (Akland et al., 1985) show that over
10% of the Denver residents and 4% of the Washington, DC, residents v/ere exposed to, 8-h
average CO levels above 9 ppm during the winter study period. This degree of population
exposure could not accurately be deduced from simultaneous data collected by the fixed-site
monitors without taking into account other factors such as contributions from indoor sources,
elevated levels within vehicles, and individuals' activity patterns. In Denver, for example,
the fixed-site monitors exceeded the 9 ppm level only 3.1% of the time. These results
8-5
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indicate that the effects of personal activity; indoor sources; and, especially, time spent
commuting greatly contribute to a person's CO exposure.
This study emphasizes that additional strategies are required to augment data from fixed-
site monitoring networks in order to evaluate actual human CO exposures and health risks
within a community. The cumulative frequency distributions of CO data for both Denver and
Washington, DC, in Figure 8-1 show that personal monitors often measure higher
concentration than do fixed stations. As part of this study, comparisons were made of
exposure to 1-h CO concentrations as determined by personal monitors and of measured
ambient concentrations at fixed monitor sites. Correlations between personal-monitor data
and fixed-site data were consistently poor; the fixed-site data usually explained less than 10%
of the observed variation in personal exposure. For example, 1-h CO measurements taken at
the nearest fixed stations only were weakly correlated (0.14 < r < 0.27) with office or
residential measurements taken with personal monitors (Akland et al., 1985).
The conclusion that exposure of persons to ambient CO and other pollutants does not
directly correlate with concentrations determined at fixed-site monitors is supported by the
work of others (Ott and Hiassen, 1973; Cortese and Spengler, 1976; Dockery and Spengler,
1981; Wallace and Ott, 1982; Wallace and Ziegenfus, 1985).
In view of the high degree of variability of ambient CO concentrations over both space
and time, (see Chapter 6) the reported results are not surprising. A given fixed monitor is
unable to track the exposure of individuals to ambient CO as they go about their daily
activities, moving from one location to another, and seldom in the immediate vicinity of the
monitor. This does not necessarily mean, however, that fixed monitors do not give some
general information on the overall level of exposure of a population to CO. The Akland
data, although failing to show a correlation between exposures measured by individual
personal monitors and simultaneous concentrations measured by the nearest fixed-site
monitors did suggest that, in Denver, aggregate personal exposures were lower on days of
lower ambient CO levels as determined by fixed-site monitors and higher on days of higher
ambient levels. Also, both fixed-site and personal exposures were higher in Denver than in;
Washington. For example, the median ambient daily 1-h maximum CO difference was
measured by fixed monitors to be 3.2 ppm higher in Denver than in Washington, DC, and
the personal median daily 1-h maximum CO was measured by PEMs to be 3.9 ppm higher in
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Population Above Concentration Shown, %
99.9 99 90 50 10 1 0.01
Q.
CL
O
O
3
•8
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o
00 J
50 I
20 _
10 -
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1 -
~
0.5 -
—
0 P
\J,Cm
0.1 -
i | i i i ill I i i | i
/ /
/ /
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9 ppm NAAQS / //
XX ...
-/ /.'''
s^"***" s S • '
/ s^ '' ''
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Denver:
Personal Exnosure
'.* • w1! wwi •*•*! |MW/%|I/IMF w*J • *5» . '
— Fixed Stations
Washington, DC:
— Personal Exposure
Fixed Stations
i i i i i ii< i i i i i
100
I 50
_ 20 E
Q.
a.
. c
- 10 £
- 1
15 §
- 3
— \Jm£.
- 0.1
0.01 1 10 50 90 99 99.99
Population Below Concentration Shown, %
Figure 8-1. Frequency distributions of maximum 8-h carbon monoxide population
exposures and fixed-site monitor values in Denver, CO, and Washington,
DC; November 1982 - February 1983.
Source: Based on Akland et al. (1984).
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Denver. Likewise, the median ambient daily 8-h maximum CO difference was found to be
2.9 ppm higher in Denver, whereas the personal median daily 8-h maximum CO was
3.4 ppm higher in Denver.
The PEMs have shown themselves to be powerful tools for quantifying air quality levels
in in-transit, outdoor, and indoor microenvironments. A great number of microenvironments
can be compared in one study. For example, Table 8-1 shows in-transit microenvironments
in Denver, ranked from highest to lowest concentration by arithmetic mean. The in-transit
microenvironment with the highest estimated CO concentration is the motorcycle, whereas
walking and bicycling have the lowest CO concentrations. Outdoor microenvironments also
can be ranked (Table 8-2) for these data. Outdoor public garages and outdoor residential
garages and carports had the highest CO concentrations; outdoor service stations, vehicle
repair facilities, and parking lots had intermediate concentrations.. In contrast, school grounds
and residential grounds had relatively low concentrations, whereas extremely low CO
concentrations were found in outdoor sports arenas, amphitheaters, parks, and golf courses.
Finally, a wide range of concentrations was found in Denver within indoor
microenvironments (Table 8-3). The highest indoor CO concentrations occurred in service
stations, vehicle repair facilities, and public parking garages; intermediate concentrations
were found in shopping malls, residential garages, restaurants, offices, auditoriums, sports
arenas, concert halls, and stores; and the lowest concentrations were found in health care
facilities, public buildings, manufacturing facilities, homes, schools, and churches.
One activity that influences personal exposure is commuting. An estimated 1% of the
noncommuters in Washington were exposed to concentrations above 9 ppm for 8 h. By
comparison, an estimated 8% of persons reporting that they commuted more than 16 h per
week had CO exposures above the 9-ppm, 8-h level. Finally, certain occupational groups
whose work brings them in close proximity to the internal combustion engine had a potential
for elevated CO exposures. These include automobile mechanics; parking garage or gas
station attendants; crane deck operators; cooks; taxi, bus, and truck drivers; firemen;
policemen; and warehouse and construction workers. Of the 712 CO-exposure profiles
obtained in Washington, DC, 29 persons fell into this "high-exposure" category. Of these,
25 % had 8-h CO exposures above the 9-ppm level.
-------
TABLE 8-1. CARBON MONOXIDE CONCENTRATIONS IN IN-TRANSIT
MICROENVIRONMENTS - DENVER, COLORADO
(Listed in descending order of mean CO concentration)
Microenvironment
Motorcycle
Bus
Car
Truck
Walking
Bicycling
n
22
76
3,632
405
619
9
Meana
(ppm)
9.79
8.52
8.10
7.03
3.88
1,34
Standard Error
(ppm)
1.74
0.81
0.16
0>49
0.27
1.20
"An observation was recorded whenever a person changed a microenvironment, and on every clock hour; thus,
each observation had an averaging time of 60 min or less.
Source: Johnson (1984).
TABLE 8-2. CARBON MONOXIDE CONCENTRATIONS IN OUTDOOR
MICROENVIRONMENTS - DENVER, COLORADO
(Listed in descending order of mean CO concentration)
Microenvironment
Public garages
Residential garages or carports
Service stations or vehicle repair
facilities
Parking lots
Other locations
School grounds
Residential grounds
Sports arenas, amphitheaters
Parks, golf courses
n
29
22
12
61 .
126
16
74
29
21
Meana
(ppm)
8.20
7.53
3.68
3,45
3.17
1.99
1.36
0.97
0.69
Standard Error
(ppm)
0.99
1.90
1.10
0.54
0.49
0.85
0.26
0.52
0.24
"An observation was recorded whenever a person changed a microenvironment, and on every clock hour; thus,
each observation had an averaging time of 60 min or less.
Source: Johnson (1984).
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TABLE 8-3. CARBON MONOXIDE CONCENTRATIONS IN INDOOR
mCROENVmONMENTS - DENVER, COLORADO
(Listed in descending order of mean CO concentration)
Microenvironment
Public garages
Service stations or vehicle repair
facilities
Other locations
Other repair shops
Shopping malls
Residential garages
Restaurants
Offices
Auditoriums, sports arenas, concert halls
Stores
Health care facilities
Other public buildings
Manufacturing facilities
Homes
Schools
Churches
n
116
. 125
427
55
58
66
524
2,287
100
734
351
115
42
21,543
426
179
Meana
(ppm)
13.46
9.17
7.40
5.64
4.90
4.35
3.71
3.59
3.37
3.23
2.22
2.15
2.04
2.04
1.64
1.56
Standard Error
(ppm)
1.68
0.83
0.87
1.03
0.851
0.87
0.19
0.002
0.48
0.21
0.23
0.30
0.39
0.02
0.13
0.25
"An observation was recorded whenever a person changed a microenvironment, and on every clock hour; thus,
each observation had an averaging time of 60 min or less.
Source: Johnson (1984).
Several field studies also have been conducted by the U.S. Environmental Protection
Agency (EPA) to determine the feasibility and effectiveness of monitoring selected
microenvironments for use in estimating exposure profiles indirectly. One study (Flachsbart
et al., 1987) conducted in Washington in 1982 and 1983 concentrated on the commuting
microenvironment because earlier studies identified this microenvironment type as the single
most important nonoccupational microenvironment relative to total CO population exposure.
It was observed that for the typical automobile commuter the time-weighted average CO
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exposure while commuting ranged from 9 to 14 ppm. The corresponding rush-hour (7:00 to
9:00 a.m., 4:00 to 6:00 p.m.) averages at fixed-site monitors were 2.7 to 3.1 ppm.
: !'.-...' •' ' ;.
8.2.2 Carbon Monoxide Exposures Indoors
The majority of people in the United States spend a majority of their time indoors;
therefore, a comprehensive depiction of exposure to CO must include this setting. The
indoor sources, emissions, and concentrations are sufficiently diverse, however, that only a
few example studies can be cited here; a thorough discussion of CO in homes, offices, and
similar environments is presented in Chapter 7. Although a number of these studies report on
microenvironmental concentrations, they do not specifically address human exposure while
indoors.
Early studies date back to before 1970, when it was found that indoor and outdoor
levels do not necessarily agree. For example, one study determined indoor-outdoor
relationships for CO over 2-week periods during summer, winter, and fall in 1969 and 1970
in buildings in Hartford, CT (Yocom et al., 1971). With the exceptions of the private '
homes, which were essentially equal, there was a day-to-night effect iri the fall and winter
seasons; days were higher by about a factor of 2. These differences are consistent with
higher traffic-related CO levels outdoors in the daytime.
Indoor and outdoor CO concentrations were measured in four homes also in the
Hartford, CT, area in 1973 and 1974 (Wade et al., 1975); All used gas-fired"cooking stoves.
Concentrations were measured in the kitchen, living room, and bedroom. Stove use, as
determined by activity diaries, correlated directly with CO concentrations. Peak CO
concentrations in several of the kitchens exceeded 9 ppm, but average concentrations ranged
from 2 to 3 ppm to about 8 ppm. These results are in general agreement with results
i. *% -
obtained in Boston, MA (Moschandreas and Zabransky, 1982). In "this study, they found
significant differences between rooms in homes where there were gas appliances.
Effects of portable kerosene-fired space heaters on indoor air quality were measured in
an environmental chamber and a house (Traynor et al., 1982). Carbon monoxide emissions'
from white flame (WF) and blue flame (BF) heaters were compared. The WF connective
heater emitted less CO than the BF radiant heater. Concentrations in the residence were
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<2 ppm and 2 to 7 ppm, respectively. The authors conclude that high levels might occur
when kerosene heaters are used in small spaces and/or when air-exchange rates are low.
A rapid method using an electrochemical PEM to survey CO was applied in nine high-
rise buildings in the San Francisco and Los Angeles areas during 1980 and 1984 (Flachsbart
and Ott, 1986). One building had exceptionally high CO levels compared to the other
buildings; average concentrations on various floors ranged from 5 to 36 ppm. The highest
levels were in the underground parking garage, which was found to be the source of elevated
CO within the building.
The effect of residential wood combustion and specific heater type on indoor CO has
been investigated (Humphreys et al., 1986). Airtight and nonairtight heaters were compared
in a research home in Tennessee. Carbon monoxide emissions from the nonairtight heaters
were generally higher than from airtight heaters. Peak indoor CO concentration (ranging
from 1.3 to 29.6 ppm, depending on heater type) was related to fuel reloadings.
Two studies in the Netherlands have measured CO levels in homes. Carbon monoxide
levels in 254 Motherland homes with unvented gas-fired water heaters were investigated,
during the winter of 1980 (Brunekreef et al., 1982). Concentrations at breathing height were
grouped into the following categories: < 10 ppm (n=154), 11 to 50 ppm (n=50), 51 to
100 ppm (n=25), and > 100 ppm (n=17). They found that a heater vent reduced indoor CO
concentrations, and that the type of burner affected CO levels. In another study, air pollution
in Dutch homes was investigated by Lebret (1985). Carbon monoxide concentrations were
measured in the kitchen (0 to 17.5 ppm), the living room (0 to 8.7 ppm), and the bedroom
(0 to 3.5 ppm). Carbon monoxide levels were elevated in homes with gas cookers and
unvented geysers (water heaters). Kitchen CO levels were higher than those in other
locations due to peaks from the use of gas appliances. Living room CO values were slightly
higher in houses with smokers. The overall mean CO level indoors was 0 to 2.7 ppm above
outdoor levels.
In Zagreb, Yugoslavia, CO was measured in eight urban institutions housing sensitive
populations, including kindergartens, a children's hospital, and homes for the elderly (Sisovic
and Fugas, 1985). Winter CO concentrations ranged from 1.1 to 13.7 ppm, and summer
concentrations ranged from 0.6 to 6.9 ppm. The authors attributed indoor CO concentrations
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to nearby traffic density, general urban pollution, seasonal differences, and day-to-day
weather conditions. Indoor sources were not reported.
Toxic levels of CO also were found in measurements at six ice skating rinks (Johnson
et al., 1975b). This study was prompted by the reporting of symptoms of headache and
nausea among 15 children who patronized one of the rinks. Carbon monoxide concentrations
were found to be as high as 304 ppm during operation of a propane-powered, ice-resurfacing
machine. Depending on skating activity levels, the ice-resurfacing operation was performed
for 10 min every 1 to 2 h. As this machine was found to be the main source of CO, using
catalytic converters and properly tuning the engine greatly reduced emissions of CO. Similar
findings have been reported by Spengler et al. (1978).
8.2.3 Carbon Monoxide Exposures Inside Vehicles
Studies of CO concentrations inside automobiles also have been reported over the past
decade. Although the introduction of better emission control technology on new vehicles has
reduced vehicular fleet emissions of CO (see Chapter 6), the relationships identified in these
studies and factors affecting the measured CO levels would be expected to remain the same.
Newer field studies, however, will need to be conducted under typical driving conditions to
confirm the relationships found in the older studies.
Petersen and Sabersky (1975) measured pollutants inside an automobile under typical
driving conditions. Carbon monoxide concentrations were generally less than 25 ppm, with
one 3-min peak of 45 ppm. Average concentrations inside the vehicle were similar to those
outside. No in-vehicle CO sources were noted; however, a commuter's exposure is usually
determined by other high-emitting vehicles, not the driven vehicle itself (Shikiya et al., 1989;
Chanetal., 1989). '• ' • •
Drowsiness, headache, and nausea were reported by eight children who had ridden in
school buses for about 2 h while traveling on a ski trip (Johnson et al., 1975a). The students
reporting symptoms were seated in the rear of the bus, which had a rear-mounted engine and
a leaky exhaust. The exhaust system subsequently was repaired. During a. later ski outing
for students, CO concentrations also were monitored for a group of 66 school buses in the
parking lot. The investigators found 5 buses with CO concentrations of 5 to 25 ppm (mean
15 ppm), 24 buses showing concentrations in excess of 9 ppm for short periods, and 2 buses
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showing up to 3 times the 9-ppm level for short periods. Drivers were advised to park so
that exhausts from one bus would not be adjacent to the fresh air intake for another bus.
During a cross-country trip in the spring of 1977, Chaney (1978) measured in-vehicle
CO concentrations. The CO levels varied depending on traffic 'speed. On expressways in
Chicago, San Diego, and Los Angeles when traffic speed was less than 10 mph, CO
exceeded 15 ppm. Levels increased to 45 ppm when traffic stopped. In addition, it was
observed that heavily loaded vehicles (e.g., trucks) produced high CO concentrations inside
nearby vehicles, especially when the trucks were ascending a grade.
Colwill and Hickman (1980) measured CO concentrations in 11 new cars as they were
driven on a heavily trafficked route in and around London. The inside mean CO level for the
11 cars was 25.2 ppm vs. 47.0 ppm for the outside mean.
In a study mandated by Congress in the 1977 Clean Air Act Amendments, the EPA
studied CO intrusion into vehicles (Ziskind et al., 1981). The objective was to determine ,
whether CO was leaking into the passenger compartments of school buses, police cars, and
taxis, and, if so, how prevalent the situation was. The study involved 1,164 vehicles in
Boston and Denver. All vehicles were in use in a working fleet at the time of testing. The
results indicated that all three types of vehicles-often have multiple (an average of four to
five) points of CO intrusion—worn gaskets, accelerator pedals, rust spots in the trunk, and ,
such. In 58% of the rides lasting longer than 8 h, CO levels exceeded 9 ppm. Thus the
study provided evidence that maintenance and possibly design of vehicles may be an
important factor in human exposure to CO.
Petersen and Allen (1982) reported the results of CO measurements taken inside
vehicles under typical driving conditions in Los Angeles over 5 days in October 1979. They '
found that the average ratio of interior to exterior CO concentrations was 0.92. However,
the hourly average interior CO concentrations were 3.9 times higher than the fixed-site
measurements. In their analysis of. the factors that influence interior CO levels, they <•
observed that traffic flow and traffic congestion, (stop-and-go) are important, but "comfort
state" (i.e., car windows open/closed, fan on/off, etc.) and meteorological parameters (i.el,
wind speed, wind direction) have little influence on incremental exposures.
Flachsbart (1989) investigated the effectiveness of priority lanes on a Honolulu arterial
in reducing commuter travel time and exposure to CO. The CO concentrations and exposure
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of commuters in these lanes was substantially lower than in the nonpriority lanes. Carbon
monoxide exposure was reduced approximately 61% for express buses, 28% for high-
occupancy vehicles, and 18% for carpools when compared to that for regular automobiles.
The higher speed associated with priority lanes helped reduce CO exposure. These
observations demonstrate that CO concentrations have a high degree of spatial variability on
roadways.
Additional findings on CO levels inside vehicles are summarized in a literature review
by Flachsbart and Ah Yo (1989). In general, a wide variation in CO exposures has been
observed in in-transit microenvironments.
8.2.4 Carbon Monoxide Exposures Outdoors
Carbon monoxide concentrations in outdoor settings (besides those measured at fixed
monitoring stations) also show considerable variability, as is evident from the eight Denver
microenvironmental groupings listed in Table 8-2. Ott (1971) made 1,128 CO measurements
at outdoor locations in San Jose at breathing height over a 6-month period and compared
these results with the official fixed monitoring station data. This study included the
measurements of the outdoor CO exposures of pedestrians in downtown San Jose by requiring
them to carry personal monitoring pumps and sampling bags while walking standardized
routes on congested sidewalks. If an outdoor measurement was made more than 100 m away
from any major street, its CO concentration was similar, suggesting the existence of a
generalized urban background concentration in San Jose that was spatially uniform over the
city (within a 33-km2 grid) when one is sufficiently far away from mobile sources. Because
the San Jose monitoring station then was located near a street with heavy traffic, it recorded
concentrations approximately 100% higher than this background value. In contrast, outdoor
CO levels from personal monitoring studies of downtown pedestrians were 60% above the
corresponding monitoring station values and the correlation coefficient was low (r = 0.20).
By collecting the pedestrian personal exposures over 8-h periods, it was possible to compare
the levels with the NAAQS concentration level. On 2 of 7 days for which data were
available, the pedestrian concentrations were particularly high (13 and 14.2 ppm) and were
2 to 3 times the corresponding levels recorded at the same time (4.4 and 6.2 ppm) at the air
monitoring station (Ott and Eliassen, 1973; Ott and Mage, 1975). These results show that
8-15
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concentrations to which pedestrians are exposed on downtown streets can exceed a 9 ppm,
8-h average while the official air-monitoring station records values significantly less than that.
It can be argued, however, that not many pedestrians spend eight hours outdoors walking
along downtown sidewalks, and that is one of the important reasons for including realistic
human activity patterns in exposure assessments, as indicated in Section 8.3.
Godin et al. (1972) conducted similar studies in downtown Toronto using 100-mL glass
syringes in conjunction with nondispersive spectrometry. They measured CO concentrations
along streets, inside passenger vehicles, and at a variety of other locations. Like other
investigators, they found that CO concentrations were determined by very localized
phenomena, la general, CO concentrations in traffic and along streets were much higher than
those observed at conventional fixed air-monitoring stations. In a subsequent study in
Toronto, Wright et al. (1975) used Ecolyzers to measure 4 to 6 min average CO
*-•'•' , - -*• * * •
concentrations encountered by pedestrians and street workers and obtained similar results.
Levels ranged from 10 to 50 ppm, varying with wind speed and direction, atmospheric
stability, traffic density, and height of buildings. He also measured CO concentrations on the
sidewalks of a street that subsequently was closed to traffic to become a pedestrian mall.
Before the street was closed, the average concentrations at two intersections were
9.4 ± 4.0 ppm and 7.9 + 1.9 ppm (mean + standard deviation [SD]); after the street was
closed, the averages dropped to 3.7 ± 0.5 ppm and 4.0 +1.0 ppm (mean + SD),
respectively, which were equivalent to the background level.
A large-scale field investigation was undertaken of CO concentrations in indoor and
outdoor locations in five California cities using personal monitors (Ott and Flachsbart, 1982).
For outdoor commercial settings, the average CO concentration was 4 ppm. This CO level
was statistically, but not substantially, greater than the average CO concentration of 2 ppm
recorded simultaneously at nearby fixed monitoring stations. The final report of this field
study (Flachsbart and Ott, 1984) contains an extensive literature review of CO exposures
found in indoor, outdoor, and in-transit microenvironments.
8-16
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8.3 ESTIMATING POPULATION EXPOSURE TO CARBON
MtONOXIDE ' " ' ^ ' ' ; "'
Accurate estimates of human exposure to CO are a prerequisite for a realistic appraisal
of both the risks posed by the pollutant and the design and implementation of effective
control strategies. This section discusses the general concepts on which exposure assessment
is based, the limitations of using ambient fixed-site monitoring data alone for estimating
exposure, alternative approaches that have been proposed for estimating population exposure
to air pollution, and specific applications of these approaches to estimating CO. Because of
problems in estimating population exposure solely from fixed-station data, several formal
human exposure models-have been developed. Some of these models include information on
human activity patterns: the micrbenvironments people visit and the times they spend there.
These models also contain submodels depicting the sources and concentrations likely to be
found in each microenvironment, including indoor, outdoor, and in-transit settings.
8.3.1 Components of Exposure
Two aspects of exposure bear directly on the related health consequences. The first is
the magnitude of the pollutant exposure. The second is the duration of exposure. The
magnitude is an important exposure parameter because concentration typically is assumed to
be directly proportional to dose, and ultimately, to the health outcome. But exposure implies
a time component, and it is essential to specify the duration of an exposure. The health risks
of exposure to a specific concentration for five minutes are likely to be different, all other
factors being equal, than exposure to the same concentration for an hour.
The magnitude and duration of exposure can be determined by plotting an individual's
air pollution exposure over time, (Figure 8-2). The function Cz-(f) describes the air pollutant
concentration to which an individual is exposed at any point in time t. Ott (1982) defines the
quantity Ct(t) as the instantaneous exposure of an individual. The shaded area under the
graph represents the accumulation of instantaneous exposures over some period of time
(ti~t(j). This area also is equal to the integral of the air pollutant concentration function,
Cfo) between t0 and t^. Ott (1982) defines the quantity represented by this area as the
integrated exposure.
8-17
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o
1
§
I
Time (t)
Figure 8-2. Typical individual exposure as a function of time showing the instantaneous
exposure [Cf($] and the integrated exposure (shaded areas).
Source: Ott (1982).
Calculated by dividing the integrated exposure by the period of integration (^ — £0), the
average exposure represents the average air pollutant concentration that an individual was
exposed to over the defined time period of exposure. To facilitate comparison with
established air quality standards, an averaging period is chosen to equal the averaging period
of the standard. In this case, the average exposure is referred to as a standardized exposure.
As previously discussed in the introduction to this chapter, exposure represents the joint
occurrence of an individual being located at point (x,y,z) during time t, with the simultaneous
presence of an air pollutant at concentration CL,Z(?). Consequently, an individual's exposure
to an air pollutant is a function of location as well as time. If a volume at a location can be
defined such that air pollutant concentrations within it are homogeneous yet potentially
8-18
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different from other locations, the volume may be considered a "microenvironment" (Duan,
1982). Microenvironments may be aggregated by location (i.e., indoor or outdoor) or activity
performed at a location (i.e., residential, commercial) to form microenvironment types.
It is important to distinguish between individual exposures and population exposures.
Sexton and Ryan (1988) define the pollutant concentrations experienced by a specific
individual during normal daily activities as "personal" or "individual" exposures. A personal
exposure depends on the air pollutant concentrations that are present in the locations through
which the person moves, as well as on the time spent at each location. Because time-activity
patterns can vary substantially from person to person, individual exposures exhibit wide
variability (Dockery and'Spengler, 1981; Quackenboss et al., 1982; Sexton et al., 1984;
Spengler et al., 1985; Stock et al., 1985; Wallace et al., 1985). Thus, although it
is a relatively straightforward procedure to measure any one person's exposure, many such
measurements may be needed to quantify exposures for a defined group. The daily activities
of a person in time and space define his or her activity pattern. Accurate estimates of air
pollution exposure generally require that an exposure model account for the activity patterns
of the population of interest. The activity patterns may be determined through "time-budget"
studies of the population. Studies of this type have been performed by Szalai (1972), Chapin
(197% Robinson (1977), Mchelson and Reed (1975), Johnson (1987), and Schwab et al.
(1990). The earlier studies may now be dated and were not designed to investigate human
exposure questions. Ongoing exposure studies have adopted the diary methods that were
developed for sociological investigations and applied them to current exposure and
time-budget investigations. A few of these studies have been reported (e.g., Schwab et al.,
1990; Johnson, 1987).
From a public health perspective, it is important to determine the "population
exposure," which is the aggregate exposure for a specified group of people (e.g., a
community or an identified occupational cohort). Because exposures are likely to vary
substantially between individuals, specification of the distribution of personal exposures
within a population, including the average value and the associated variance, is often the
focus of exposure assessment studies. The upper tail of the distribution, which represents
those individuals exposed to the highest concentrations, is frequently of special interest
because the determination of the number of individuals who experience elevated pollutant
8-19
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levels can be critical for health risk assessments. This is especially true for pollutants for
which the relationship between dose and response is highly nonlinear.
8.3.2 Relationship to Fixed-Site Monitors
Many early attempts to estimate exposure of human population used ambient air quality
from fixed stations. An example of such an analysis can be found in the 1980 Annual Report
of the President's Council on Environmental Quality (CEQ) (1980). In this analysis, a
county's exposure to an air pollutant was estimated as the product of the number of days that
violations of the primary NAAQS were observed at county monitoring sites multiplied by the
county's population. Exposure was expressed in units of person-days. National exposure to
an air pollutant was estimated by the sum of all county exposures.
The methodology employed by the CEQ provides a relatively crude estimate of
exposure and is limited by four assumptions.
(1) The exposed populations do not travel outside areas represented by fixed-site
monitors.
(2) The air pollutant concentrations measured with the network of fixed-site monitors
are representative of the concentrations breathed by the population throughout the
area.
(3) The air quality in any one area was only as good as that at the location that had
the worst air quality.
(4) There were no violations in areas of the county that were not monitored.
Many studies cast doubt on the validity of these assumptions for CO. Reviews of these
studies are provided by Ott (1982) and by Spengler and Soczek (1984). Doubts over the
ability of fixed-site monitors alone to accurately depict air pollutant exposures are based on
two major findings on fixed-site monitor representativeness.
(1) Indoor and in-transit concentrations of CO may be significantly different from
ambient CO concentrations.
8-20
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(2) Ambient outdoor concentrations of CO that people come in contact with may
vary significantly from CO concentrations measured at fixed-site monitors.
In estimating exposure, the CEQ also assumed that each person in the population spends
24 h at home. This assumption permitted the use of readily available demographic data from
the U.S. Census Bureau. Data collected 20 years ago indicate that people spend a substantial
portion of their time away from home. In a study of metropolitan Washington, DC, residents
during 1968, Chapin (1974) found that people spent an average 6.3 h away from home on
Sunday and 10.6 h away from home on Friday. This translates to between 26.4 and 44.3%
of the day spent away from home. More recent personal-exposure and time-budget studies
(e.g., Schwab et al., 1990; Johnson, 1987) also indicate that a substantial portion of time is
spent away from home.
Fixed-site monitors measure concentrations of pollutants in ambient air. Ambient air
has been defined by EPA in the Code of Federal Regulations (1991) as air that is "external to
buildings, to which the general public has access." But the nature of modern urban lifestyles
in many countries, including the United States, indicates that people spend an average of over
20 h per day indoors (Meyer, 1983). Reviews of studies on this subject by Yocom (1982),
Meyer (1983), and Spengler and Soczek (1984) show that indoor CO concentration
measurements vary significantly from simultaneous measurements in ambient air. The
difference between indoor and outdoor air quality and the amount of time people spend
indoors reinforces the conclusion that using ambient air quality measurements alone will not
provide accurate estimates of population exposure.
8.3.3 Alternative Approaches to Exposure Estimation
In recent years, the limitations of using fixed-site monitors alone to estimate public
exposure to air pollutants have stimulated interest in using portable monitors to measure
personal exposure. These instruments, which were developed for CO in the late 1970s by
Energetics Science Incorporated and by General Electric, are called PEMs. Wallace and Ott
(1982) surveyed PEMs available then for CO and other air pollutants. (See Section 5.4 for a
more complete description of PEMs.)
8-21
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The availability of these monitors has facilitated use of the direct and indirect
approaches to assessing personal exposure (see Section 8.2). Whether the direct or indirect
approach is followed, the estimation of population exposure requires a "model"; that is, a
mathematical or computerized approach of some kind, Sexton and Ryan (1988) suggest that
most exposure models can be classified as one of three types: statistical, physical, or
physical-stochastic. . , • •
The statistical approach requires the collection of data on human exposures and the
factors thought to be determinants of exposure. These data are combined in a statistical
model, normally a regression .equation or an, analysis of variance, to investigate the,
relationship between air pollution exposure (dependent variable) and the factors contributing
to the measured exposure (independent variables). An example of a statistical model is the
regression model developed by Johnson et al. (1986) for estimating CO exposures in Denver
based on data obtained from the Denver Personal Monitoring Study. If the study group
constitutes a representative sample, the derived statistical model may be extrapolated to the
population defined by the sampling frame. It also should be noted that selection of factors
thought to influence exposure has a substantial effect on the outcome of the analysis.
Spurious conclusions can be drawn, for example, from statistical models that include
parameters that are correlated with, but not causally related to, air pollution exposure.
In the physical modeling approach, the investigator makes an a priori assumption about
the underlying physical processes that determine air pollution exposure and then attempts to
approximate these processes through a mathematical formulation. Because the model is
chosen by the investigator, it may produce biased results because of the inadvertent inclusion
of inappropriate parameters or the improper exclusion of critical components. The NAAQS
Exposure Model (NEM) as originally applied to CO by Johnson and Paul (1983) is an
example of a physical model.,
The physical-stochastic approach combines elements of both the physical and statistical
modeling approaches. The investigator begins by constructing a mathematical model that
describes the physical basis for air pollution exposure. Then a random or stochastic ; .
component mat takes into account the imperfect knowledge of the physical parameters that
determine exposure is introduced into the model. The physical-stochastic approach limits the
effect of investigator-induced bias by the inclusion of the random component, and allows for
8-22
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estimates of population distributions for air pollution exposure. Misleading results still may
be produced, however, because of poor selection of model parameters. In addition, the
required knowledge about distributional characteristics may be difficult to obtain. Examples
of models based on this approach which have been applied to CO include the Simulation of
Human Activity and Pollutant Exposure (SHAPE) model (Ott, 1984; Ott et al., 1988) and
two NEM-derived models developed by Johnson et al. (1990).
Table 8-4 provides a summary of the three model types. Table 8-5-lists exposure
models that have been applied to CO by model type. These models are described in the
following sections. General reviews of the exposure modeling literature have been provided
by Repace et al. (1980), Ott (1985), Fugas (1986), Ott et al. (1986), Sexton and Ryan
(1988), and Pandian (1987). EPA has developed a computerized BibliograpMc Literature
Information System (BUS) to facilitate access to literature concerned with total human
exposure monitoring. Included in the BLIS data base is an extensive bibliography on human
exposure modeling (Dellarco et al., 1988; Shackelford et al., 1988).
8.3.4 Statistical Models Based on Personal Monitoring Data
As discussed above in Section 8.2, fixed-site monitoring data may not provide an
accurate indication of personal exposure within an urban population, which is a function of
both geographic location (e.g., downtown vs. suburbia) and immediate physical surroundings
(e.g., indoors vs. outdoors). Better estimates of personal exposure can be developed by
equipping a large number of subjects with portable monitors and activity diaries. If the
subjects are properly selected, their exposures can be extrapolated to a larger "target"
population.
The large-scale field studies in Denver, CO, and Washington, DC, that were introduced
earlier in this chapter provide the best available data on human exposure to CO. In the
Denver study, each of 454 subjects carried a PEM and completed an activity diary for two
consecutive 24-h sampling periods and provided a breath sample at the end of each sampling
period (Johnson, 1984). Each participant also was requested to complete a detailed
background questionnaire. The questionnaire results and approximately 900 subject-days of
PEM and activity diary data collected between 1 November 1982 and 28 February 1983 were
analyzed to determine if factors such as microenvironment and the presence of indoor CO
8-23
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TABLE 8-4, COMPARISON OF DIFFERENT APPROACHES TO
AIR POLLUTION EXPOSURE MODELING
Parameter
Statistical
Physical
Physical-stochastic
Method of
formulation
Required input
Hypothesis testing Physical laws
Collected data on
human exposure
Knowledge of
important
parameters and their
values in the system
to be modeled
Physical laws and ..
statistics
Knowledge of
important parameters
and their distributions
in the systems to be
modeled
Advantages
Makes use of real
data in the model
building process
True model
developed from a
priori considerations
Model developed
from a priori
considerations;
stochastic part allows
uncertainty to
contribute, which
reduces importance of
research biases
Disadvantages
Requires data on
hand for model
builcling;
extrapolation
beyond data base
is difficult
Includes
researcher's biases;
must be validated
Requires much
knowledge of system;
must be validated
Source: Sexton and Ryan (1988).
sources significantly affect personal CO exposure. In addition, the exposure of a defined
target population was extrapolated from exposures recorded by the study participants.
Detailed descriptions of the Denver study design and data collection procedures, together with
results of initial data analyses, are available in a report by Johnson (1984).
The Washington, DC, study has been described in detail by Hartwell et al. (1984). It
differs from the Denver study in that (1) twice as many subjects were used in the Washington
study, and (2) each subject carried a PEM and a diary for a single 24-h period. Results of
8-24
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TABLE 8-5. MODELS THAT HAVE BEEN USED TO ESTIMATE
CARBON MONOXIDE EXPOSURE BY MODEL TYPEa
Model Type
Model
References
Statistical
Physical
Physical/Stochastic
Regression models based on
statistical analyses of data
obtained from Denver and
Washington Personal
Monitoring Studies
Results of ANOVA of data
obtained from Washington
Commuter Study
NAAQS Exposure Model
Ott-Willits Commuter Model
Simmon-Patterson Commuter
Model
Davidson Indoor Mass-
Balance Models
Pierce Integrated Exposure
Model
Duan Convolution Model
Duan Hybrid Model
Flachsbart Prototypical
Commuter Models
Flachsbart-Ah Yo Commuter
Model
SHAPE
Probabilistic NEM
REHEX
Johnson et at (1986)
Flachsbart et al. (1987)
Johnson and Paul (1983)
Ott and Willits (1981)
Simmon and Patterson
(1983)
Davidson et al. (1984)
Pierce et al. (1984)
Duan (1985)
Duan (1985)
Flachsbart (1985)
Flachsbart and Ah Yo
(1989)
Ott (1984)
Johnson et al. (1990)
Lurmann et al. (1989)
"Definitions: ANOVA = Analysis of variance; NAAQS = National Ambient Air Quality Standards;
SHAPE = Simulation of Human Activity and Pollutant Exposure; N1M = NAAQS Exposure-Model;
REHEX = Regional Human Exposure Model. ,
Source: Adapted from Sexton and Ryan (1988).
8-25
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analyses of the Washington data base are provided by Settergren et al. (1984), Clayton et al.
(1985), and Johnson et al. (1986).
A primary goal of the Denver and Washington personal monitoring studies was to
investigate whether personal exposures could be predicted by fixed-site ambient monitoring
data. This investigation was conducted by performing linear-regression analyses that used
PEM values grouped by microenvironment as the dependent variable and fixed-site values
recorded simultaneously as the independent variable. To perform these analyses, each PEM
value had to be paired with a value reported by a single fixed-site monitor. Because the
census tract of each nontransit PEM value was known, it was possible to use census tracts as
a means of linking PEM and fixed-site values. Whenever a PEM value was reported for a
given census tract, it was paired with the simultaneous value of the fixed-site monitor
assigned to that census tract.
This analysis suggested that a linear regression analysis that pairs each PEM value
reported for a nontransit microenvironment with the simultaneous value reported at the
nearest fixed-site might be appropriate for the Denver study data. Linear regression analyses,
weighted to reflect actual population group size, were performed with the data grouped by
selected codes related to microenvironment. Results for nontransit microenvkonments are
listed in Table 8-6. Values of R2 range from 0.00 to 0.46. As might be expected, many of
the microenvironments with small R2 values are associated with local CO sources that tend to
reduce the correlation between the PEM value and the nearest fixed-site value; however,
other microenvironments that are not associated with local CO sources have relatively larger
R2 values (e.g., park or golf course, or "other locations").
Table 8-6 does not list any in-transit microenvkonments because of the difficulty in
pairing in-transit PEM values with a "nearest" fixed-site monitor value. In the Denver data
base, each in-transit PEM value has two census tract listings, one associated with the start
address and the other with the end address. Neither was considered a good indicator of the
CO conditions encountered during the trip. An alternative procedure consisted of pairing
in-transit PEM values with simultaneous values from a composite data set created by
averaging the data from the 15 fixed-site monitors. The composite data set was found to
exhibit relatively high correlations with most of the fixed-site data sets. Consequently, the
composite site was assumed to provide an indication of the average ambient CO level in the
8-26
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j. JLVEOUJUIO V/JP if r/lVrjulliU JL>li-*JG,AJK. JtULVyiUiOa^ii ATNAJUXSJLC» WITH I>UIN 1KATSS11
PERSONAL EXPOSURE MONITOR VALUE AS DEPENDENT VARIABLE AND SIMULTANEOUS VALUE
AT NEAREST DENVER FIXED-SITE AS INDEPENDENT VARIABLE
Category
Outdoon
Outdoors
Outdoon
Indoon
Indoon
Outdoon,
Outdoon
Indoon
Outdoors
Indoon
Outdoors
Indoon
Indoon
Indoors
Indoors
Indoon
Indoors
Indoors
Outdoon
Not specified
r Outdoon ,
Indoon ,
Indoon
Indoon
- Indoon
Microenvironmenr*
Sub category
Other location
Park or golf course
School grounds
Service station or motor vehicle repair facility
Restaurant
Service station or motor vehicle repair facility
. Within 10 yards of road
Church
Parking lot
. Other repair shop
Sports arena, amphitheater, etc.
Other public building
Shopping mall ' -
Store
Health care facility
Residence , .
School ,
Office ;
Residential garage or carport
Not specified . k
Residential grounds
Public gsrsgs
Auditorium, sports arena, concert hall, etc.
Manufacturing facility
Residential garage
Other location .. '
Linear Regression
n
115
18
15
112
486
11
468
178
51
46
1«
in
^ 55
675
333 '
20,969
342
2,090
22
583
139 :
94
41
66
381
Intercept
0.35
-0.09
-0.37
4.18
1.69
1.61
1.58
. 0.09
2.26
3.69
3.05
0.74
1.24
1.67
0.97
1.00
0.97
2.53
5.67
2.071
8.44-
2.25
1.41
4.98
7.94
Slope
1.11
: 0.39
1.15
1.68
0.76
1.21
0.89
0.70
0.60
0.88
-1.76
0.42
1.43
. 0.56
0.45
0.43
0.32
,0.34
0.61
0.63
0.72
0.38
- 0.18
0.14
0.07
R2
0.46
0.44
0.27
0.27
0.25
0.23
0.21
0.21
0.21
0.18- ,
0.15
0.14
0.14
0.09
0.09-
0.07
- 0.07
. 0.05
0.05
0.05
0.04
0.04
0.03
0.00
0.00
Pb
0.000
0.003
0.049
0.000
0.000
0.134
0.000
0.000
0.000
0.003
0.128
0.000
0.005
0.000
0.000
0.000
0.000
0.000
0304
0.000
0.019
fl.060
0.246
0.662
0.791-
. * Usted in order of R2 value.
b Probability that slope = 0.
Source: Johnson et al, (1986).
-------
study area. Table 8-7 lists the results of linear regression analyses pairing in-transit PEM
values with simultaneous values from the composite data set. Values of R2 range from 0.04
(car) to 0.58 (motorcycle).
TABLE 8-7. RESULTS OF WEIGHTED LINEAR REGRESSION ANALYSES WITH
IN-TRANSIT PERSONAL EXPOSURE MONITOR VALUE AS DEPENDENT
VARIABLE AND SIMULTANEOUS VALUE FROM DENVER COMPOSITE
DATA SET AS INDEPENDENT VARIABLE
Linear Regression ,
in-Transit Subcategorya
Motorcycle
Bus
Walking
Truck
Car
All
n
22
76
619
405
3,632
4,763
Intercept
4.50
3.17
0.06
3.27
6.01
5.15
Slope
2.14
2.02
1.47
1.54
0.78
0.92
R2
0.58
0.36
0.23
0.11
0.04
0.05
Pb
: 0.000
0.010
0.000
0.000
0.000
olooo
'Listed in order of R2 value.
''Probability that slope = 0.
Source: Johnson et al. (1986).
The linear regression analyses described above suggested that the correlation between
PEM values and fixed-site CO values is weak for most microemdronments. A statistical
analysis was subsequently performed to investigate whether the 1-h CO values reported by a
particular fixed-site monitor or groups of fixed-site monitors were better correlated with PEM
values. Again, the correlations were low, with R2 values ranging from approximately 0.01
to 0.05 (Johnson et al., 1986).
Similar regression analyses were performed on the Washington, DC, CO data, and are
shown in Tables 8-8 and 8-9. Values of R2 range from 0.00 to 0.66. Several of the
microenvironments with small R2 values are associated with local CO sources that tend to
reduce the correlation between PEM value and nearest fixed-site value. Only two nontransit
microenvironments have R2 values exceeding 0.20: hospital (R2 = 0.66) and church
8-28
-------
oo
\D
TABLE 8-8. RESULTS OF WEIGHTED LINEAR REGRESSION ANALYSES WITH NONTRANSIT PERSONAL
EXPOSURE MONITOR VALUE AS DEPENDENT VARIABLE AND SIMULTANEOUS VALUE AT
NEAREST FIXED-SITE IN WASHINGTON, DC, AS INDEPENDENT VARIABLE
Category
Indoors
Indoors
Indoors
Outdoors
Indoors
Outdoors
Indoors
Outdoors
Indoors
Indoors
Outdoors
Indoors
Indoors
Indoors
Indoors
Microenvironment"
Subcategory
Hospital
Church
Garage
Park, sports arena
Laboratories
Residential area
Office
Within 10 yards of road or street
Store
Residence
Garage, parking lot
Not specified
School, school gym
Restaurant
Other indoor
Linear Regression
n
46
44
70
11
23
82
1,741
224
178
14,962
38 -
57
239
120
129
Intercept
-0.05
-0.04
4.02
0.06
0.30
0.53
0.94
1.33
1.25
1.21
5.05
3.52
1.01
2.88
5.07
Slope
0.63
0.58
3.43
.-0.01
0.26
0.52
0.45
0.50
0.33
0.18
-0.42
-0.16
0.06
-0.03
0.09
R2
0.66
0.60
0.19
0.15
0.11
0.10
0.06
0.04
0.02
0.02
0.00
0.00
0.00
0.00
0.00
Pb
0.000
0.000
0.000
0.239
0.132
0.003 :
0.003
0.002
0.047
0.000
0.709
0.751
0.555
0.848
, 0.900
"Listed in order of R2 value.
^Probability that slope = 0.
Source: Johnson et al. (1986).
-------
TABLE 8-9. RESULTS OF WEIGHTED LINEAR REGRESSION ANALYSES
WITH IN-TRANSIT PERSONAL EXPOSURE MONITOR VALUE AS
DEPENDENT VARIABLE AND SIMULTANEOUS VALUE FROM COMPOSITE
WASHINGTON, DC, DATA SET AS INDEPENDENT VARIABLE
Linear Regression
In-Transit Subcategorya
Train/subway
Jogging
Multiple response
Missing
Car
Truck
Bus
Walking
Van
Bicycle
n
38
11
20
22
2,646
85
67
510
21
16
Intercept
0.05
0.43
-0.98
-0.21
1.51
' 2.16
1.01
, 1.21
1.91
3.62
Slope
1.09
0.67
2.58
1.83
1.74
2.00
2.45
0.94
0.33
-0.08
Rz -
0.61
0.25
0.20
0.13
0.08
0.07
0.05
0.03 ,
0.03
0.01
Pb
0.000
0.118
0.050
0.100
0.000
0.014
0.06
0.000
0.478
0.721
"Listed in order of R2 value.
Probability that slope = 0.
Source: Johnson et al. (1986).
(R2 = 0.60). The R2 value for office is 0.06; the R2 value for residence is 0.02. The
in-transit microenvironments also tend to have low R2 values (e.g., the R2 value for car is
0.08).
The analyses discussed above suggest that individual PEM readings are not highly
correlated with simultaneous fixed-site readings. Also it was learned that composite fixed-site
daily maximum values are poor predictors of daily maximum exposures. However, the
magnitude of daily maximum 8-h exposures among the Denver study participants on days
when violations of the 8-h NAAQS occurred (median exposure of 5.6 ppm) versus exposures
on days when violations did not occur (median exposure of 3.2 ppm) was statistically
significant (p<0.001). . ,-•'•...-"•'•'.
8.3.5 Physical and Physical-Stochastic Models
In applying physical and physical-stochastic models, the analyst constructs a
mathematical model that describes the physical basis for air pollution exposure. As discussed
8-30
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above, physical-stochastic models differ from physical models in that the former include a
random component that reflects the analyst's imperfect knowledge concerning the physical
parameters in the model.
The Convolution and Hybrid Models—Duan (1985) evaluated two methods for
estimating CO exposures that combine activity pattern data obtained from one source with
data on CO levels measured in microenvironments obtained from another source. Duan used
the Washington Personal Monitoring Study (Hartwell et al., 1984) as the source of activity
pattern data and the Washington Commuter Study (Flachsbart et al., 1987) as the source of
the CO data. Each of 705 subjects in the former study completed a 24-h activity diary from
which the sequence of microenvironments occupied by the subject could be determined. The
latter study measured CO levels in a variety of microenvironments on each of 43 days.
In the first method—referred to as the convolution method—each of the 43 sets of
microenvironmental CO data was paired with each of the 705 person-days of activity-diary
data to yield 43 x 705 = 30,315 "convoluted" person-days of CO exposure. The CO levels
for all microenvironments occupied by a subject on a given convoluted person-day are
obtained from a single day of microenvironmental monitoring data. In the second
method—referred to as the hybrid approach—the average CO level across all 43 days was
determined for each microenvironment and was used as the estimate of CO exposure
whenever a diary-derived activity pattern indicated a subject was in the microenvironment.
This method yielded 705 person-days of CO exposure.
The exposures estimated by each of the two methods were compared to exposures
indicated by the PEMs carried by the Washington subjects. The convolution and hybrid
methods produced exposure estimates that were, on average, approximately 40% higher than
the PEM-derived exposure estimates. Despite this discrepancy, Duan (1985) found that the
two methods were powerful predictors of PEM-derived exposure estimates, in that the
correlations between model estimates and PEM-derived estimates were relatively high.
NAAQS Exposure Model—"in assessing the health risks associated with alternative forms
of NAAQS, EPA routinely uses the NEM to estimate the pollutant exposures of sensitive
population groups. The NEM itself is a general modeling framework that can be applied to
estimate the exposures of the population to individual criteria air pollutants (Biller et al.,
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1981). The general NEM framework, which continues to evolve over time, can be tailored
to reflect the characteristics of particular air pollutants. The NEM is designed to estimate
population exposures under alternative values of the NAAQS. ,
In an NEM analysis, the population of interest is divided into a set of cohorts. Each :
cohort is provided with an activity pattern that assigns the cohort to a succession of
geographic locations and microenvironments. The activity pattern specifies the duration of
each assignment and whether specific pollutant sources are present. These patterns are based
on data obtained from activity-diary studies, transportation agencies (e.g., home/work trips
and commute times), and the Bureau of Census. In some applications, a stochastic model is
used to construct activity patterns directly from activity-diary data.
A deterministic or stochastic model is used to estimate the pollutant exposure associated
with each assignment in a cohort's activity pattern. The number of persons represented by
each cohort is estimated, and the exposures of the individual cohorts are combined to yield an
estimate of exposure for the entire population. In CO NEM analyses, an algorithm is used to
estimate COHb concentrations in the exposed population.
In applications of the NEM to CO, the assumption was made that the CO concentration
reflects (1) ambient CO levels as reported by outdoor fixed-site monitors, and (2) sources and
sinks specific to a microenvironment. In the initial version of the CO NEM, the CO
exposure associated with an event occurring at time t in microenvironment m was estimated
by a first order approximation that can be stated in general terms as:
CO(m,t) = MULT(m) * MON(f) + ADD(m) , (8-1)
where MULT(ni) is a multiplicative constant specific to m, MON(f) is the CO concentration
expected to occur at a fixed-site monitor at time £,. and ADD(m) is an additive constant
specific to m (Johnson and Paul, 1983). This deterministic approximation does riot capture
the findings of PEM studies that point to relatively low correlations between
microenvironment exposure concentrations and fixed-site monitor concentrations., Further, it
captures neither the stochastic nature of any relationship that might exist between exposure
concentrations and fixed-site monitor concentrations nor the stochastic nature of source/sink
contributions within a microenvironment.
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A modified version treated the term ADD(ni) as an independent, identically distributed
stochastic variable that could be characterized by the Box-Cox distribution (Paul et al., 1988).
This change resulted in reduced levels of correlation between CO(mj) and MON(t) that were
in agreement with correlations observed in a personal monitoring study conducted in Denver
(AHand et al., 1985). A further refinement incorporates serial correlation (Johnson et al.,
1990). • : - -
Simulation of Human Activity and Pollutant Exposure—SHAPE simulates the activity
patterns and CO exposures of a sample of urban commuters during their daily routines (Ott,
1984). The simulation is over a fixed period for all individuals in the sample, usually a 24-h
period. The model uses the following equation (Duan, 1981, 1982):
/% - . ' - . -":,. (8-2)
J = l
"-" .-.._...-, \' -
where E^ is the integrated CO exposure of person i, J is the number of microenvironments
visited, c- is the concentration encountered hi microenvironment j, % is the time spent by
person i in microenvironment j, J is the number of microenvirortments visited, and
(8-3)
is the time period under consideration.
Expressed in parts per million-minutes or parts per million-hours, E^ is a product of
concentration and time. If T is an averaging time, such as 8-h. dividing £'{- by T gives the
average 8-h exposure. The SHAPE model computes hourly exposure (and 8-h running
average exposure) dynamically over 24 h for each individual in the sample. The modeling of
exposures and the various equations and definitions to be used are discussed by Duan (1982)
and Ott (1982, 1984). Applying Equation 8-2 in an exposure model requires both the
microenvironmental concentrations (the c^-'s) and the activity pattern times (the t^-'s) for each
person.
8-33
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A fundamental assumption about microenvironmental pollutant concentrations for inert
pollutants such as CO in the SHAPE model is the "superposition hypothesis." According to
this hypothesis, the total concentration c-(t) as a function of time encountered in
microenvkonmentj is treated as the sum of two concentration components:
(1) a microenvironmental component concentration cm(f) resulting from the sources of CO
within the microenvironment, and (2) an ambient (background) component concentration cu(t)
assumed to be free of any microenvironmental source influences; that is,
= lcm(t) + cumj (8-4)
The basis for this hypothesis is the interpretation of the spatial variability of CO
concentrations from field studies (Ott, 1971; Ott and Eliassen, 1973).
In the SHAPE model, the microenvironmental component depends only on the sources
of CO within the microenvironment and is independent of location in the urban area or of
conditions in the metropolitan area. An example is the CO concentration contributed by
motor vehicles inside an indoor parking garage. In contrast, the background concentration
component is the CO concentration that would be present if there were no specific sources of
CO. For example, in a house or building, the background component would be the CO in
the outdoor air entering through the ventilation system or the windows, which depends
primarily on seasonal and daily changes in meteorological conditions.
Because data on true ambient background concentrations of CO are generally
unavailable for the many microenvironments that an urban population regularly visits on a
daily basis, Ott et al. (1988) investigated the use an "overall surrogate" ambient CO
concentration thought to be associated with all the microenvironments of an urban area.
Usually, the only data available to serve as an overall surrogate measurement are CO
concentrations measured by fixed monitoring stations located in metropolitan areas. These
data may yield unrealisticaUy high estimates of ambient CO levels, as most air-monitoring
stations are placed near streets with heavy traffic. Ott et al. (1988) recommended using the
ambient component given by the hourly CO readings from fixed-site monitors located more
than 100 m from streets as a measure of the background concentration, but such data were
unavailable in Denver. Ott et al. (1988) also investigated the average of microenvironments
8-34
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without sources as a measure of the background concentration and found that the hourly
average of all fixed stations in Denver performed no better than the microenvironments
without sources. "
The original version of SHAPE (Ott, 1981, 1984) assumed that pollutant concentrations
in microenvironments behave stochastically. This assumption was based partly on a study by
Ott and Willits (1981) in which CO concentrations inside an automobile passenger
compartment were found to show considerable random fluctuation from minute to minute.
The CO data were collected on drives during a 1-year study of an urban arterial highway,
El Camino Real in California. Statistical analysis indicated that the 1-min average CO
concentration [c/0] could be treated as independent, lognormally distributed random variables
during the length of a car trip (1 h or less). Ott and Willits (1981) developed these
conclusions for the exposures incurred by the occupants of vehicles free of CO intrusion from
the vehicle's own exhaust system.
The SHAPE model (Ott, 1981, 1984) was designed with these findings in mind. All
microenvironmental CO component concentrations were represented by stationary two- ;
parameter lognormal distributions with cu(f) held constant.- Thus;, the computer treated the
microenvironmental component as the random variable [c^L whose mean and variance for
each microenvironment j were specified by the user and were held constant. The values of
the mean and variance usually were based on CO field studies in various microenvironments
reported in the literature (inside moving automobiles, buses, trucks; on bicycles in traffic; in
indoor parking garages, houses, and similar environments) and on the judgment of the user.
The SHAPE model (Ott, 1981, 1984) originally sampled microenvironmental CO
concentrations on a minute-by-minute basis. Fourteen microenvironments were defined for
this purpose. Associated with each was a lognormal distribution of l^min CO values from
which 1-min CO exposures were drawn.
The original SHAPE model simulated activity patterns for each individual by sampling
from probability distributions representing the chance of entry, the time of entry, and time
spent in specific activities or microenvironments (Ott, 1981). For example, the probability
distributions for the starting times of home-to-work trips, trip times, and travel modes (the
proportion of commuters traveling to work by car, bus, truck, and such) were based on data
8-35
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provided by Asin and Svercl (1973). Reliable data were not available for some activities; in
these cases the probability distributions were assumed by the user.
In an attempt to validate SHAPE, Ott et al. (1988) compared measured personal CO
exposures obtained from the Denver personal monitoring study to CO exposures estimated by
SHAPE. Microenvironmental CO concentrations for the model were generated by Monte
Carlo simulation based on Denver PEM data reported for 22 microenvironments. The
activity simulation portions of the model were modified to accommodate actual activity data
obtained from the diaries carried by Denver subjects.
A total of 899 24-h responses from the Denver study yielded 772 usable profiles after
invalid responses were eliminated, giving 33 paired days of observations (CO exposure
profiles from 2 successive days for the same respondent). From these data,
22 microenvironments were identified with at least 10 measurements on each of the 2 days.
Microenvironmental CO concentrations were calculated by subtracting hourly ambient
background CO concentrations. Ambient background CO concentrations were estimated by
three different approaches. All three yielded similar results, with the average value from all
fixed monitoring sites performing slightly better than the nearest fixed monitoring site. For
nearly every microenvironment, the study found negligible differences between the
microenvironmental CO frequency distributions on the 2 days, showing the statistical stability
of the microenvironmental concentrations.
In the SHAPE validation project (Ott et al., 1988), the microenvironmental CO
frequency distributions for Day 1 provided the basis for SHAPE model estimates of Day 2
exposure profiles, and the activity patterns were based on the Denver diaries for Day 2 (the
observed times at which people entered and left each microenvironment). The CO exposure
profiles were calculated using Monte Carlo sampling from the Day 1 microenvironmental CO
concentration distributions and adding the estimated ambient background components.
The arithmetic means of the predicted 1- and 8-h maximum average CO exposures
agreed well with the corresponding observed arithmetic means. The variability of the
observed values, however, exceeded the variability of the predicted values by a significant
amount (Figures 8-3 and 8-4). Ott et al. (1988) suggested that the lack of agreement may be
caused by use of a histogram rather than a continuous distribution in implementing the Monte
Carlo simulation or the model's implicit assumption that the successive exposures of a subject
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Q.
Q.
g
I
I
o
O
O
O
0.01
100
50-
10 -
5 -
0.5 -
0.1
0.01
Cumulative Frequency, %
10 50 90 99
ii i i i i i i i ii ii,
Observed
'.••' Predicted
Observed:
(n=336)
Mean: 10.2 ppm
SD: 8.9 ppm
Max: 70.7 ppm
Predicted:
Composite Mean: 10.6 ppm
(n=336) SD: 6.0 ppm
Max: 42.7 ppm
TT
1
I I I liT TT I i I
10 50 90
Cumulative Frequency, %
Ml
99
99.99
100
- 50
10 E
a.
ex
h 5 .1
1
•f-^
O
o
o
O
-i O
- 0.5
0.1
99.99
Figure 8-3. Logarithmic-probability plot of cumulative frequency distribution of
maximum 1-h average exposure of carbon monoxide (CO) predicted by
SHAPE, plus an observed frequency distribution for Day 2 in Denver.
Source: Ott et al. (1988).
8-37
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a.
a.
o
1
(D
O
O
O
CD
•o
1
O
JQ
8
0.01
100 -
50-
10
5
1 _
0.5-
0.1
i i i
0.01
Cumulative Frequency, %
10 50 90
i i i i i i i i i i i
99
99.99
Observed
Mean: 4.9 ppm
SD: 4.2 ppm
Max: 38.7 ppm
Predicted:
(n-336)
1. Composite of fixed stations
Mean: 4.8 ppm
SD: '
Max:
2. Nearest fixed station
Mean:
SD:
Max:
3. No-source microenvironment
Mean: 3.8 ppm
SD: 1.9 ppm
Max: 11.3 ppm
2.4 ppm
12.4 ppm
4.4 ppm
2.7 ppm
15.4 ppm
ill I
I i
1
I I
I I I i II
10 50 90
Cumulative Frequency, %
i i i
99
100
- 50
- 10
- 5
_ 1
- 0.5
0.1
99.99
ex
Q.
C
O
"•5
I
O
O
-------
are uncorrelated. Ott et al. (1988) suggested that better estimates would result if an
autoregressive process was used to model successive exposures.
Commuter Exposure Models-Ott and Willits (1981) conducted a study in which the CO
exposures of occupants of a motor vehicle were measured during weekly diives on an urban
artery in California. The study consisted of 93 repeated drives over exactly the same
route—5.9 miles in each direction for an 11.8 mile total distance—on El Camino Real with a
1974 VW test vehicle. Data were collected on CO levels inside the passenger compartment
of the motor vehicle, traffic counts and time spent waiting at each traffic light,
meteorological factors, and other variables. Measurements in the vehicle showed that the
passenger compartment was free of self-generated CO intrusion. Ott and Willits developed a
theoretical model for estimating diffusion of CO into a motor vehicle and then applied the
model to data collected during the study. The model incorporates a time constant that was
found to vary according to the position of the windows (closed, partially open, completely
open).
Simmon and Patterson (1983) developed a model for simulating commuter exposures
individually and collectively based on traffic flow, emissions, and atmospheric dispersion.
This model consists of two programs that are run separately on the computer. The first
program is an emissions preprocessor, which has been separated from the main model to
facilitate updating of the model package when emission factors are revised by EPA. The
second program is the main portion of the commuter exposure model, which simulates traffic
flow, computes the emission rates resulting from the traffic (using the emission factors
calculated by the preprocessor), simulates the dispersive effects of the atmosphere, and
computes statistics describing commuter exposure. Because the model treats the spatial
variation of exposure, regions of the city in which commuters experience high exposures can
be identified from model output. If a single commute pathway is of interest, that pathway
can be examined in detail. Dispersion modeling is performed by the CALINE 3 model.
In-vehicle CO concentrations are assumed to equal roadway CO concentrations. To date, the
Simmon-Patterson model has not been used in a modeling analysis.
Flachsbart (1985) developed three empirical models for predicting commuter exposure
inside a well-ventilated vehicle on a congested Honolulu artery during morning rush hour
under neutral atmospheric stability. Personal exposure monitors were used to collect
8-39
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exposure data for commuting trips on 12 days between November 1981 and April 1982.
Model A assumed that commuter CO exposure was a function of the roadway's source
strength and the ambient CO level. Model B assumed that the roadway's source strength was
diluted by windspeed. Model C assumed that commuter CO exposure was simply a function
of the emission factor and ambient CO level. This model was developed for situations for
which the analyst does not have access to traffic counts.
Plachsbart (1985) considered these models to be prototypes because they were the first
such models to link commuter exposure, inside a vehicle, directly to automotive emission
factors. Each model assumed that exposure is an additive function of a background CO level
and a roadway CO contribution, as affected by meteorological and traffic characteristics.
Flachsbart (1985) compared the observed exposure values with exposures predicted by
each of the three models. Correlations between observed and predicted values, expressed as
R2, were 0.78 for Models A and B and 0.64 for Model C.
Flachsbart's prototypical models (1985) served as model templates in subsequent efforts
by Flachsbart and Ah Yo (1989) to develop a general model of commuter exposure based on
data obtained from a study of commuter exposures in Washington, DC. Their approach
described commuter exposure on a specified commuting link with an expression that
superimposes a microenvironment component upon a background concentration:
Ei =Bi+Mi (8-5)
where E; is the commuter exposure on link /, Bi is the background concentration on link i,
and MI is the microenvironment concentration on link i.
Ideally, the background concentration should be measured near the link and should
reflect concentrations that would exist on the roadway if there were no traffic. Flachsbart
(1985) approximated this value with CO ambient air quality readings from the nearest
fixed-site station away from heavy traffic. The microenvironment component mathematically
describes the air pollutant emission and dispersion processes over the roadway. This
component also considers how the air pollutant infiltrates the vehicle's interior. An air
pollutant infiltration factor, however, was not included in Flachsbart's prototypal models
because there was a free exchange of air between the vehicle and the ambient environment.
8-40
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Using the format of the Honolulu prototypal models, Flachsbart and Ah Yo (1989)
developed 33 commuter exposure models from the Washington, DC, survey data base. Of
these models, only five were considered unsatisfactory based on the statistical significance of
the model or an illogical sign for the emission coefficient. However, the explanatory power
of the best of these models (R2 = 0.12) did not approach that of the worst Honolulu model
(R2 = 0.63).
Flachsbart and Ah Yo (1989) found use of the Honolulu prototypal models for
characterizing the Washington data to be overly simplistic. For morning trips originating in
low density suburbs, the Washington data showed that a commuter's average exposure to CO
was less than the ambient concentration measured at the fixed-site station providing the
background concentration. In addition, commuters, who began their homeward evening trips
from highly polluted parking garages, had unusually high concentrations in their cars as they
traveled along downtown streets. Tests of each vehicle at the beginning, middle, and end of
the study indicated that the high CO levels were not caused by leaks from the exhaust system
into the passenger compartment.
These observations suggested that vehicle occupants were, to some degree,
"encapsulated" from the ambient environment such that their exposure on the early links of a
trip had more to do with the concentration inside the vehicle (prior to the trip) than with any
traffic or meteorological factors on these links. Statistical analysis supported this hypothesis.
For the evening commute from downtown Washington on Route 1, the average CO exposure
on the link was significantly correlated with the pretrip interior CO concentrations. For the
morning commute into downtown Washington on Route 2, the average link exposure was
well correlated with the pretrip interior CO concentrations.
Given winter temperatures and closed windows and vents on the test vehicles,
Flachsbart and Ah Yo (1989) decided to treat the roadway setting and the vehicular passenger
compartment as separate microenvironments. Each microenvironment was modeled
separately and then combined into a two-stage model.
The data base available for development of a roadway CO empirical model was limited
to 150 measurements of roadway CO. Of 43 different models applied to this data set, the
best model was a loglinear relationship between predicted roadway CO concentrations and the
density of CO emissions. This density was the product of the CO emission factor and the ,
8-41
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average 15-min traffic count divided by the test vehicle's average link speed. This model had
an R2 value equal to 0.26; the F statistic was significant at p< 0.0001. The final step of the
regression left two independent variables in the equation: the CO emission factor and the
average 15-min traffic count.
The equation for this model was:
= (0.7906252[(Fe)(fir)/^)0-366992 (8-6)
where COgp is the predicted CO concentration within the roadway microenvironment (parts
per million); Fe is the MOBDLE3 emission factor estimated using observed traffic speeds,
ambient temperatures, percentages of five vehicle types, and default values for other required
inputs (grams per vehicle-mile); QT is the observed average 15-min traffic count (vehicles per
15 min); and Uv is the test vehicle's average link speed (miles per hour).
Flachsbart and Ah Yo (1989) assumed that commuters are exposed to CO from three
major sources within the passenger compartment: passenger smoMng, vehicle exhaust system
leaks, and emissions from traffic. Flachsbart and Ah Yo (1989) further assumed that the
in-vehicle CO concentrations created by these three sources can be described by box or cell
models. Such models are based on the principle of conservation of mass: The total mass of
an air pollutant within a volume is equal to the balance of the mass entered, exited, emitted,
and reacted within that volume. Using this principle, Flachsbart and Ah Yo (1989) derived a
theoretical commuter exposure model for the passenger compartment:
E = COR + (T/tR) (COV - COR) [1 - /R)/7] C8'7)
where E is the average CO exposure of the commuter (parts per million); COR is the
observed CO concentration within the roadway microenvironment (parts per million); T is the
time constant for the vehicle (seconds); tR is the time the vehicle spends within the roadway
microenvkonment (seconds); COvis the CO concentration within the vehicle when it enters
the microenvironment (parts per million); and e is the base of a natural logarithm
(2.71828...).
This model predicts commuter exposure to CO inside a vehicle by exponentially
diffusing observed roadway concentrations and by exponentially decaying initial
8-42
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compartmental concentrations that exist when the vehicle enters a new link on the roadway.
The plot of the observed average CO exposure with average CO exposures estimated with
Equation 8-7 suggested a linear relationship. These data had an R2 • =; 0.75 and the •'
significance of the F statistic was p<0.001. ;• '
Predicted values of COpp generated by the roadway microenvironmental model
(Equation 8-6) were substituted for the observed roadway concentrations COR in the
passenger compartment model (Equation 8-7). The values estimated by the resulting two-
stage model correlated well with the observed values (R = 0.737); the coefficient of
determination (R2) indicated that the estimates explained approximately 54% of the variation
in observed average exposures. Although the two-stage model did not have the predictive
power of the passenger compartment model that used observed roadway CO concentrations,
Flachsbart and Ah Yo (1989) considered the performance of the two-stage model to be
respectable and far better than any of the 33 models initially developed.
Other Exposure Models—Davidson et al. (1984) developed one- and two-compartment
mass-balance models for estimating indoor pollutant concentrations. They compared :
measured levels of nitric oxide (NO), nitrogen dioxide (NO^, and CO in a new townhouse'
residence with estimates provided by the one-compartment model. The townhouse was
constructed according to rigid energy-conservation guidelines. Reasonable agreement
between estimated and measured concentrations was observed, although the measured CO
levels decayed somewhat faster than predicted.
Pierce et al. (1984) presented a model for estimating integrated (i.e.; cumulative) and
average exposures based on an activity pattern listing a sequence of indoor and outdoor
locations and estimates of the pollutant concentration at each location. The model was used
to estimate CO exposures for a hypothetical 24-h activity pattern. The CO level assigned to
each location was derived from microenvironmental monitoring data obtained from other
researchers.
8.4 OCCUPATIONAL EXPOSURE TO CARBON MONOXIDE
Carbon monoxide is a ubiquitous contaminant occurring in a variety of settings.
Exposures, both acute and chronic, that occur in the occupational environment represent only
8-43
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one of several sources that may contribute to a potential body burden for GO. Two main
sources for background exposures in both occupational and nonoccupational settings appear to
be smoking and the internal combustion engine (National Academy of Sciences, 1969).
Smoking is a personal habit that must be considered in evaluating exposures in general, as
well as those occurring in work places.
In addition, work environments are often located in densely populated areas, and such
areas frequently have a higher background concentration of CO compared to less densely
populated residential areas. Thus, background exposures during work hours may be greater
than during nonwork hours. There are several sources other than smoking and the internal
combustion engine that contribute to exposure during work hours. These include
contributions to background by combustion of organic materials in the geographic area of the
work place; work in specific industrial processes that produce CO; and work in environments ;
that result in accumulations of CO, such as garages, toll booths, and confined spaces.
8.4.1 Historical Perspective
Carbon monoxide is produced from the incomplete combustion of organic substances
such as natural gas, coal, wood, petroleum, coke, vegetation, and explosives. A rich fuel
mixture favors generation of CO but it can also be produced when rapid cooling or
submersion of the flame is used to quench the combustion process. Sources of CO include
exhaust gases from internal combustion engines, gas-manufacturing plants, blast furnaces in
iron and steel manufacturing, coke ovens, coal mines, incinerators, and numerous other
processes that involve combustion of organics. Carbon monoxide is also used in specific
industrial processes, such as the manufacture of metal carbonyls, and is produced for these
purposes by the partial oxidation of hydrocarbons and natural gas, or by the gasification of
coal and coke (Lindgren, 1971). (See Chapter 6 for a more complete discussion of sources
and emissions of CO.)
Dangerous concentrations of CO can occur in numerous settings, including those at
work, at home, or in the street. Both acute and chronic CO intoxication in a variety of
occupations and settings is discussed by Grut (1949). Acute effects related to production of
anoxia from exposures to CO historically have been a basis for concern. In recent years,
8-44
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however, this concern has grown to include concerns for potential effects from chronic
exposures as well (Rosenstock and Cullen, 1986a, 1986b; Sammons and Coleman, 1974).
With regard to the occupational environment, the National Institute for Occupational
Safety and Health (NIOSH) (1972) published "Criteria for a Recommended
Standard...Occupational Exposure to Carbon Monoxide." In this report, NIOSH observed
that "... the potential for exposure to carbon monoxide for employees in the work place is
greater than for any other chemical or physical agent." Also, NIOSH recommended that
exposure to CO be limited to a concentration no greater than 35 ppm, expressed as a
time-weighted average (TWA) for a normal 8-h workday, 40 h/week. A ceiling
concentration was also recommended at a limit of 200 ppm, not to exceed an exposure time •
greater than 30 min. Occupational exposures at the proposed concentrations and conditions
underlying the basis of the standard were considered to maintain COHb in blood below 5%.
The Occupational Safety and Health Administration has recently adopted these exposure limits
in order to substantially reduce the risk of deleterious health effects among American workers
(Federal Register, 1989).
Although it was not stated; the basis of the recommended NIOSH standard (i.e.,
maintaining COHb below 5% in blood) assumes that contributions from other
nonoccupational sources would also be less than a TWA concentration of 35 ppm. It was
recognized that such a standard may not provide the same degree of protection to smokers,
for example. Although recognizing that biologic changes might occur at the low level of
exposure recommended in the proposed standard, NIOSH concluded that subtle aberrations in
the nervous system with exposures producing COHb concentrations in blood at or below 5%
did not demonstrate significant impairments that would cause concern for the health and
safety of workers. In addition, 'NIOSH observed that individuals with impairments that
interfere with normal oxygen (O^ delivery to tissues (e.g., emphysema, anemia, coronary
heart disease) may not have the same degree of protection as for less impaired individuals. It
also was recognized that work at higher altitudes (e.g., 5,000 to 8,000 ft above sea level)
would necessitate decreasing the exposure limit below 35 ppm, to compensate for a decrease
in the O2 partial pressure as a result of high altitude environments and a corresponding
decrease in oxygenation of the blood. High altitude environments of concern include airline
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cabins at a pressure altitude of 5,000 ft or greater (National Research Council, 1986) or work
in high mountain tunnels (Miranda et al., 1967).
8.4.2 Exposure Monitoring Techniques
Exposures to CO in air can be manifested in a variety of ways. At low levels,
manifestations include development and reporting of symptoms. In the work place,
environmental monitoring and inventory of sources for the presence of CO may occur.
Additionally, biologic tests, medical surveillance, diagnosis, and treatment may be conducted
on individuals who show signs and symptoms of exposure. Finally, mathematical models
may be used to predict exposures, doses, and responses to CO inhalation.
Acute and chronic CO intoxication (Grut, 1949) may be indicated by a range of signs
and symptoms from headache, dizziness, weakness, and nausea at low levels and short
durations of exposure to unconsciousness, coma, and death at high levels and durations of
exposure. Headache and nausea resulting from CO intoxication has been described in a study
of tollbooth collectors (Johnson et al., 1974) exposed at low concentrations of CO from
exhaust gases.,
A medical study of the occupational hazards of fire fighting demonstrates the signs and
symptoms of CO, as well as other associated exposures (Gordon and Rogers, 1969).
A group of 35 fire fighters Were evaluated in a medical study for heart, lung, liver, and
kidney diseases, and also were provided with neurologic examinations. Half of the study
group were smokers. Baseline tests, including enzyme tests, electrocardiogram (EKG),
COHb, and other measurements, were conducted at the start of the study. The fire fighters
were in normal ranges for COHb and the enzyme tests performed. They were followed '
through 31 fires of less than 5 min duration, 4 fires of more than 5 min duration, and
6 staged fires; they were also subjected to exercise tests. Occasionally, there were substantial
exposures to CO, and changes in blood enzyme levels were greater when fighting longer
fires. These changes were not associated with exercise, and they were reversible when not
fighting fires. The EKG tests did not reflect changes related to enzyme levels. Masks were
found to provide substantial protection.
Occupational exposure and associated signs and symptoms for fire fighters also have
been described in a study using age-matched controls (Sammons and Coleman, 1974). Blood
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samples were collected from a group of 27 fire fighters and a group of 27 control subjects
every .28 days for 5 months. Differences between the cardiac enzyme levels found in fire
fighters versus those of the matched control suggested that chronic low-level exposures to CO
have a deleterious effect on the body and myocardium. . ^ •
Environmental monitoring for CO is often carried out in studies that ate primarily
concerned with potential exposures to other substances, such as exhaust gases, environmental
tobacco smoke, and products of combustion processes. Carbon monoxide analyses also are
used to screen for the presence of other gaseous pollutants. Exposures to CO therefore are
often associated with exposures to other substances as well, including lead, paniculate matter
containing polyaromatic hydrocarbons, oxides of nitrogen (e.g., NO and NO2), and sulfur
dioxide.
Monitoring for exposures to CO has included peak and TWA sampling of ambient or
breathing zone air, collection and analysis of expired air, analysis of blood gases by gas
chromatographic methods, and use of empirical relationships to estimate CO in air from
determinations of percent COHb in blood. Measurements techniques for CO include,
infrared, volumetric, colorimetric tube, electrolytic detection, and gas chromatographic ,
methods. Samples are collected to represent the breathing zone or environmental air; these
may be grab samples or periodic or continuous samples.
Several investigators have proposed approaches to medical surveillance of workers who
are potentially exposed to CO. Medical surveillance activity is usually precipitated by
complaints that are associated with a source of potential exposure to CO. A study of
stevedores who loaded and unloaded cars and diesel trucks in a ferrying operation (Purdham
et al., 1987) assessed medical conditions by administering a questionnaire and conducting
pulmonary function tests. The questionnaire included questions on work history; smoking
history; respiratory symptoms; and nose, eye, and skin complaints. Questions on respiratory
symptoms included details on cough, sputum, wheeze, chest tightness, and shortness of
breath. Pulmonary function tests were conducted for forced vital capacity (FVC) and forced
expiratory volume at 1 min (FEVj). The subjects were seated and their noses were clipped
closed for the tests. A minimum of three and as many as six efforts were required for each
subject.
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The focus of the study was on characterizing adverse responses to exhaust fumes
primarily from diesel trucks and secondarily from gasoline-powered vehicles transported in
garages on the ferry. The medical findings were that the stevedores had significantly lower
values for all lung-function tests except for FVC, as compared to unexposed controls and to
normal values for a general population. Environmental sampling for CO and other substances
in exhaust fumes then were conducted. There was no direct correlation offered by the
authors between exposure to CO and the differences found in the medical assessments of the
stevedores versus the controls. The authors suggested use of percent COHb to assess CO
exposure, and they recommended that a larger group of longshoreman should be assessed for
chronic obstructive pulmonary disease.
Rosenstock and Cullen (1986a) have linked cardiovascular diseases,occasioned by
angina at the end of a workday with high percent COHb when this phenomenon is associated
with exposure to CO in the work place. Consequences of chronic low-level exposure are not
well established; however, in workers with underlying coronary artery heart disease, a level
of 3 to 5% COHb has been associated with increasing frequency of angina and decrease in
exercise tolerance (See Chapter 10). When levels approaching 25% COHb are reached, there
are manifestations of ischemia, dysrhythmias, and other EKG abnormalities in otherwise
healthy workers.
Miranda et al. (1967) feel that medical surveillance for high-altitude work should
include screening for cardiopulmonary abnormalities and blood dyscrasias (sickle-cell
anemia). They also recommend acclimatization before the start of work. This study
classified the onset of CO intoxication into three groups: fulminating (a decrease in O2 to
tissues within seconds), acute (a decrease in O2 occurring in minutes), and chronic
(a decrease in O2 to tissues over days, months, or years). The authors listed the concerns for
evaluation of CO exposures at high altitudes as decreased O2 in the air; percent COHb due to
smoking; and accumulation of fumes, particularly in vehicular tunnels. Altitude tolerance is
lowered by about 335 ft for each percentage point increase in COHb. The average percent
COHb for smokers who smoke 20 to 30 cigarettes per day is 5%, with a range of 3 to 10%:
To decrease from 20 to 5% COHb requires breathing fresh air at sea level for 3 to,5 hi, ..'-.-
Inhalation of CO at a concentration of 100 ppm for 2 h at 11,000 ft results in 18 ± 5%
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COHb. This level does not threaten survival, but it may impair visual threshold (see
Chapter10).
Empirical relationships have been proposed for use as diagnostic criteria for CO
intoxication (Castellino, 1984). The criteria proposed are shown in Table 8-10.
TABLE 8-10. DIAGNOSTIC CRITERIA FOR CARBON
MONOXIDE INTOXICATION8 _^__
Diagnosis COHb level, % SCN/blood, mg/L
Normal
nonsmokers . <3 <40
smokers <8 <200
Increased surveillance 8 to 12
(nonsmokers and smokers)
Increased risk 12 to 15
(nonsmokers and smokers) .
Medical treatment , >15
(nonsmokers and smokers)
"Definitions: COHb = cafboxyhemoglobin; SCN/blood = thioeyanate level in blood as a measure of tobacsco
smoke (nicotine) exposure.
Source: Castellino (1984).
Blankart et al. (1986) found hyperbarie O2 to be the best form of treatment for
decreasing the percent COHb in blood when it was administered to traffic policemen in a
clinical study. The study compared cycling ergometry, administration of pure O2 at
atmospheric pressure, and administration of. pure O2 under hyperbarie conditions (2.8 atm).
The authors recommended the hyperbarie treatment approach for both acute and chronic CO
poisoning. , .. .. . , ;
A study of toll bridge authority workers investigated normal red cell adaptation to
anemia, as a measure of CO effects on tollbooth collectors and maintenance personnel
(Goldstein et al., 1975). Diphosphoglycerides (DPGs) increase the release of oxygen to
tissues as an adaptive mechanism in anemia. Results of the studies were inconclusive in that
they considered increased DPGs to be a response to hypoxia from increased percent COHb.
However, formation of methoxyhemoglobin from exposures to NO was independent of the
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COHb reaction, and the hypoxic effects of CO and NO exposures were considered to be
additive.
Use of percent COHb in blood has been proposed for use as a biological exposure index
(BEI), as a supplement to the threshold limit value value for CO exposure recommended by
the American Conference of Governmental Industrial Hygienists (Lowry, 1986). The
proposed BEI is intended to be an index of exposure. It is not necessarily an indication of an
adverse response.
Finally, Hickey et al. (1975) expressed the need to consider genetic and other factors
resulting in differences in Hb and other individual characteristics that could influence the
extent of COHb formation on exposures to CO in air or cigarette smoke.
8.4.3 Occupational Exposures
The number of persons potentially exposed to CO in the work environment is greater
than that for any other physical or chemical agent (Hosey, 1970), with estimates as high as
975,000 occupationally exposed at high levels (National Institute for Occupational Safety and
Health, 1972).
The contribution of occupational exposures can be separated from other sources of
exposure, but there are at least two conditions to consider.
(1) When CO concentrations at work are higher than the CO equilibrium concentration
associated with the percent COHb at the start of the work shift, there will be a net
absorption of CO and an increase in percent COHb. Nonsmokers will show an
increase that is greater than that for smokers because they start from a lower
baseline COHb level. In some cases, nonsmokers may show an increase, and
smokers a decrease, in percent COHb.
(2) When CO concentrations at work are lower than the equilibrium concentration ,
necessary to produce the worker's current level of COHb, then the percent COHb
will show a decrease. There will be a net loss of CO at work.
Occupational exposures can stem from two sources: (1) through background
concentrations of CO obtained by working in a densely, populated area (as compared to the
residential environment), or (2) through work in industrial processes that produce CO as a
product or by-product. In addition, work in environments that tend to accumulate CO
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concentrations may result in occupational exposures. Rosenman (1984) lists a number of
occupations where the workers may be exposed to high CO concentrations. This list includes
acetylene workers, blast furnace workers, coke oven workers, diesel engine operators, garage
mechanics, steel workers, metal oxide reducers, miners, mond process (nickel refining)
workers, organic chemical synthesizers, petroleum refinery workers, pulp and paper workers,
and water gas workers. In addition, because methylene chloride is metabolized to CO in the
body, aerosol packagers,_ anesthetic makers, bitumen makers, degreasers, fat extractors,
flavoring makers, leather finish workers, oil processors, paint remover makers, resin makers,
solvent workers, and stain removers also can have high COHb levels.
Background sources are generally a result of combustion of organic materials. With
rich fuel mixtures, decreased amounts of O2 are available, and therefore production of CO as
a product of incomplete combustion is favored. There are numerous sources for.CO.
background exposures, and there is considerable variation and uncertainty in identifying the
CO exposure resulting from specific sources. Traffic patterns and emissions from mobile
sources, as well as an overlay of emissions from stationary sources along with wind and
weather conditions, make predictions difficult. (See Chapters 6 and 7 for a complete
discussion of the mobile, stationary, and indoor sources and emissions of CO.)
Investigations and analyses of exhaust gas in Paris (Chovin, 1967) showed that CO air
concentrations were correlated with the activity of and distribution pattern for traffic in Paris.
The average CO concentrations for the years 1965 and 1966 were 16.0 and 16.6 ppm,
respectively, based on 15,187 samples for 1965 and 15,203 samples for 1966. The maps of
pollutant distribution indicate that the areas of high and low concentrations were similar for
each year and were closely associated with the volumes and patterns of vehicular traffic.
When the measured concentration of CO in the air exceeded 100 ppm, the sample was
automatically diluted 10-fold for analysis, thereby introducing dilution and scale factors as
possible sources of error at high concentrations of CO. The variations in the measurements
of CO were closely linked to variations in the volume of traffic at each sampling location.
Carbon monoxide concentrations in the blood were determined for 331 traffic policemen
during 5 h of duty.. Blood samples were collected at the beginning and end of the 5-h shifts.
Carbon monoxide in blood was determined by heating samples and measuring the evolved gas
by an infrared method. The values obtained were compared with the average concentrations
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of CO found for the air breathed. The correlation was good between CO in blood and CO in
the air breathed for nonsmokers, but with smokers, initial concentrations of CO in blood
were high, and there was often a decrease in the CO in blood over an exposure period. This
was observed with sampling of smokers and nonsmokers at the same locations with similar
concentrations and durations of exposure. Car drivers showed increases in CO concentrations
in blood, as did traffic policemen who were nonsmokers. Carbon monoxide concentrations in
blood for smoking and nonsmoking drivers involved in traffic accidents were greater than
those for traffic policemen and others in the population considered to be accidentally exposed
to CO.
Aircraft accidents involving 113 aircraft, 184 crew members, and 207 passengers were
investigated to characterize accident toxicology and to aid in search for causation of a crash
(Blackmore, 1974). Determinations of percent COHb in blood samples obtained from victims
enabled differentiation of a variety of accident sequences involving fires. For example,
percent COHb determinations combined with passenger seating information and crew
assignments can allow differentiating between fire in flight or after the crash, survivability of
crash with death due to smoke inhalation, specific equipment malfunctions in equipment
operated by a particular crew member, or defects in space heating in the crew cabin or
passenger compartment. One accident in the series was associated with a defective space
heater in the crew compartment. Another accident also was suspicious with regard to a space
heater.
Contributions to background CO concentrations from industrial processes may be
determined by an inventory of sources and locations for the processes, the emission rates for
CO as a function of production, and the air pollution distribution pattern for the region (see
Chapter 6). The types and distributions of industrial and community activities contributing to
CO concentrations in air depend on identification of the various sources and volumes of
production involved. Production schedules are dynamic-, it is therefore difficult to model
sources and predict levels.
Carbon monoxide concentrations measured in the air were used to classify workers from
20 foundries into 3 groups: those with definite occupational exposure, those with slight
exposure, and controls (Hernberg et al., 1976). Angina pectoris, EKG findings, and blood
pressures of foundry workers were evaluated in terms of CO exposure for the 1,000 workers
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who had the longest occupational exposures for the 20 foundries. Angina showed a clear
dose response with exposure to CO either from occupational sources or from smoking, but
there was no such trend in BKG findings. The systolic and diastolic pressures of CO-exposed
workers were higher than those for other workers, when age and smoMng habits were
considered.
Carboxyhemoglobin and smoking habits were studied for a population of steelworkers
and compared to blast furnace workers, as well as to employees not exposed at work (Jones
and Walters, 1962). Carbon monoxide is produced in coke ovens, blast furnaces, and in
sintering operations. Exhaust gases from these operations are often used for heating and as
fuels for other processes. Fifty-seven volunteers working in the blast furnace area were
studied for smoking habits, symptoms of CO exposure, and estimations of COHb levels by an
expired-air technique. The main increase in COHb for blast furnace personnel was 2.0% for
both smokers and nonsmokers in the group. For smokers in the unexposed control group,
there was a decrease in percent COHb. A follow-up study found similar results (Butt et al.,
1974). Virtamo and Tossavainen (1976) report a study of CO measurements in air of
67 iron, steel, or copper alloy foundries. Blood COHb of ironworkers exceeded 6% in 26%
of the nonsmokers and 71% of the smokers studied.
Poulton (1987) found that a medical helicopter with its engine running in a narrowed or
enclosed helipad was found to be a source of potential exposure to CO, JP-4 fuel, and
possibly other combustion products for flight crews, medical personnel, bystanders, and
patients being evacuated. Measurements were made by means of a portable infrared
analyzer. Carbon monoxide concentrations were found to be greatest near the heated exhaust.
Concentrations ranged from 8 to 43 ppm.
Exhaust from seven of the most commonly used chain saws (Nilsson et al., 1987) was
analyzed under laboratory conditions to characterize emissions. The investigators conducted
field studies on exposures of loggers using chain saws in felling operations, and also in
limbing and bucking into lengths. In response to an inquiry, 34% of the loggers responded
that they often experienced discomfort from the exhaust fumes of chain saws, and another
50% complained of occasional problems. Sampling for CO exposures was earned out for
5. days during a 2-week work period in a sparse pine stand at an average wind speed of 0 to
3 m/s, a temperature range of 1 to 16 °C, and a snow depth of 50 to 90 cm. Carbon
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*2
monoxide concentrations ranged from 10 to 23 mg/m (9 to 20 ppm) with .a mean value of
*2
20.0 mg/m . Carbon monoxide concentrations measured under similar, but snow-free
conditions ranged from 24 to 44 mg/m3 with a mean value of 34.0 mg/m3. In another study,
CO exposures were monitored for nonsmoking chain saw operators with average exposures
recorded from 20 to 55;ppm with COHb levels ranging from 1.5 to 3.0% (Van Netten et al.,
1987). ,
ForMift operators, stevedores, and winch operators were monitored for CO in expired
air to calculate percent COHb, using a Mine Safety Appliances (MSA) analyzer (Breysse and
Bovee, 1969). Periodic blood samples were collected to validate the calculations. Bull
operators and stevedores work in the holds of ships; winch operators do not work in me r
holds. The ships to be evaluated were selected on the basis of their use of gasoline-powered
forklifts for operations. To evaluate seasonal variations in percent COHb, analyses were
performed for one 5-day period per month for a full year. Efforts were made to select a,
variety of ships for evaluation. A total of 689 determinations of percent COHb were made
from blood samples to compare with values from expired-air samples. The samples were
collected on 51 separate days involving 26 different ships. Two hundred men were available
before work, whereas only 147 were available at the end of the work day. Men lost to
follow-up either left before the end of shift or were transferred to other work. Smoking was
found to be a major contributing foctor to the percent COHb levels found.
Carboxyhemoglobin values for nonsmokers indicated that the use of gasoline-powered lifts in
the holds of the ships did not produce a CO concentration in excess of 50 ppm for up to 8 h
as a TWA under the work rules and operating conditions in practice during the study.
Smoking behavior confounded exposure evaluations. The exposure conditions may not , :
provide the same degree of protection for smokers as they do for nonsmokers.
Carbon monoxide concentrations have been measured in a variety of work places where
potential exists for accumulation from outside sources. Exposure conditions in work places,
however, are substantially different. There is no standard approach that apples in all
situations requiring evaluation and study. The methods to be applied, group characteristics,
jobs being performed, smoking habits, and physical characteristics of the facilities themselves
introduce considerable variety in the approaches used. Typical studies are discussed below.
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Wallace (1983) investigated CO in air and breath of employees working in an office
constructed in an underground parking garage at various times over a 1-monthi period.
Carbon monoxide levels were determined by use of a device containing a proprietary solid
polymer electrolyte to detect electrons emitted in the oxidation of CO to carbon dioxide
(CO^. The device was certified by the Mine Safety and Health Administration to be
accurate within 15%. A data logger was attached to provide readings each second, and to
provide 1-h averages from the CO monitors placed on desks. Variation in CO measurements
in ambient air showed a strong correlation with traffic activity in the parking garage.
Initially, the office CO levels were found to be at an average of 18 ppm/day, with the
average from 12:00 to 4:00 p.m.- at 22 ppm and the average from 4:00 to 5:00 p.m. at
36 ppm. Analyses of expired air collected from a group of 20 nonsmokers working in the
office showed a strong correlation with ambient air concentrations for CO and traffic activity.
For example, the average CO in expired air for one series of measurements was 23.4 ppm, as
compared to simultaneous measurements of air concentrations of CO at 22 to 26 ppm. After
a weekend, CO concentrations in breath on Monday morning were substantially decreased
(around 7 ppm) but rose again on Monday afternoon to equal the air levels of 12 ppm.
Closing fire doors and using existing garage fans decreased CO concentrations in the garage
offices to 2 ppm or less, concentrations similar to those for other offices in the complex that
were located away from the garage area.
Carboxyhemoglobin levels (Ramsey, 1967) were determined over a 3-month period
during winter months for 38 parking-garage attendants, and the values for COHb were
compared with values from a group of 27 control subjects. Blood samples were collected by
finger stick on Monday mornings at the start of the work week, at the end of the work shift
on Mondays, and at the end of the work week on Friday afternoons. Hourly analyses were
carried out on three different weekdays using potassium palado sulfite indicator tubes for the
concentrations of CO at three of the six garages in the study. Hourly values ranged from
7 to 240 ppm, and the composite mean of the 18 daily averages was 58.9 + 24.9 ppm.
Although the Monday versus Friday afternoon values for COHb were not significantly
different, there were significant differences between Monday morning and Monday afternoon
values. Smokers showed higher starting baseline values, but there was no apparent difference
in net increase in COHb body burden between smokers and nonsmokers.
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Carboxyhemoglobin values for nonsmokers ranged from a mean of 1.5 + 0.83% for the
morning samples to 7.3 ± 3.46% for the afternoon samples. For smokers, these values were
2.9 ± 1.88% for the morning and 9.3 ± 3.16% for the afternoon. The authors observed a
crude correlation between daily average for CO in air and COHb values observed for a 2-day
sampling period.
In a study of motor vehicle examiners conducted by NIOSH (Stern et al., 1981), CO
levels were recorded in six outdoor motor vehicle inspection stations with TWA levels of 4 to
21 ppm. In contrast, the semi-open and enclosed stations had levels of 10 to 40 ppm TWA. ,
The levels exceeded the recommended NIOSH standard of 35 ppm TWA on 10% of the days
sampled. In addition, all stations experienced peak short-term levels above 200 ppm, .
Carboxyhemoglobin levels were measured for 22 employees of an automobile dealership
during the winter months when garage doors were closed and ceiling exhaust fans were
turned off (Andrecs et al., 1979). Employees subjected to testing included garage mechanics,
secretaries, and sales personnel. This included 17 males aged 21 to 37 and 5 females aged
19 to 36. Blood samples were collected on a Monday morning before the start of work and ,
on Friday at the end of the work week. Analysis for COHb was by addition of sodium
dithionite and tris ammomethane, and COHb was measured in duplicate samples using a
spectrophotometer. Smokers working in the garage area showed a Monday mean value for
COHb of 4.87 ± 3.64% and a Friday mean value of 12.9 ± 0.83%. Nonsmokers in the
garage showed a corresponding increase in COHb, with a Monday mean value of.
1.50 + 1.37% and a Friday afternoon mean value of 8.71 ± 2.95%. Nonsmokers working
in areas other than the garage had a Friday mean value of 2.38 ± 2.32%, which was
significantly lower than the mean values for smokers and nonsmokers in the garage area.
Environmental concentrations or. breathing zone samples for CO were not collected. The
authors concluded that smokers have a higher baseline level of COHb than do nonsmokers,
but both groups show similar increases in COHb during the work week while working in the
garage area. The authors observed that the concentrations of COHb found in garage workers
were at levels reported to produce neurologic impairment. These results are consistent with
those reported by Amendola and Hanes (1984). They reported some of the highest indoor
levels collected at automobile service stations and dealerships. Concentrations ranged from
16.2 to 110.8 ppm in cold weather to 2.2 to 21.6 ppm in warm weather.
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A group of 34 employees, 30 men and 4 women, working in multistory garages, were
evaluated for exposures to exhaust fumes (Fristedt and Akesson, 1971). Thirteen were
service employees working at street level, and 21 were shop employees working either one
story above or one story below street level. Six facilities were included in the study. Blood
samples were collected on a Friday at four facilities, on Thursday and Friday at another, and
on a Thursday only at a sixth facility. The blood samples were evaluated for red blood cell
and white blood cell counts, COHb, lead, and delta-aminolevulinic acid. Work histories,
medical case histories, and smoking habits were recorded. Among the employees evaluated,
11 of 24 smokers and 3 of 10 nonsmokers complained of discomfort from exhaust fumes.
Smokers complaining of discomfort averaged 6.6% CQHb and nonsmokers complaining
averaged 2.2% COHb. The corresponding values for noncomplaining workers averaged
4.2% and 1.1%, respectively.
Air pollution by CO in underground garages was investigated as part of a larger study
of traffic pollutants in Paris (Chovin, 1967). Work conducted between the hours of
8:00 a.m. and 10:00 p.m. resulted in exposures in excess of 50 ppm and up to 75 ppm, on a
TWA basis.
As part of a larger study of CO concentrations and traffic patterns in Paris (Chovin,
1967), samples were taken in road tunnels. There was good correlation between the traffic
volumes combined with the lengths of the tunnels and the CO concentrations found. None of
the tunnels studied had mechanical ventilation. The average CO concentrations in the tunnels
were 27 and 30 ppm for 1965 and 1966, respectively, as compared to an average of 24 ppm
CO in the streets for both years. The "real average risk" for a man working or walking in a
street or tunnel was considered by the authors to be 3 to 4 times less than the maximal risk
indicated by values for CO from instantaneous air sample measurements. In the United
States, Evans et al. (1988) studied bridge and tunnel workers in metropolitan New York City.
The average COHb concentration over the 11 years of study averaged 1.73% for nonsmoking
bridge workers and 1.96% for tunnel workers.
In a discussion of factors to consider in CO control of high altitude highway tunnels,
Miranda et al. (1967) reviewed the histories of several tunnels. Motor vehicles were
estimated to emit about 0.1 Ib of CO/mi at sea level. At 11,000 feet and a grade of 1.64%,
emissions were estimated at 0.4 Ib/mi (for vehicles moving upgrade). Tunnels with
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ventilation are generally designed to control CO concentrations at or below 100 ppm. The
Holland Tunnel in New York was reported to average 65 ppm, with a recorded maximum of
365 ppm due to a fire. For the Sumner Tunnel in Boston, ventilation is started at CO
concentrations of 100 ppm and additional fans are turned on and an alarm is sounded at
250 ppm. The average value for CO concentration is 50 ppm. The Mont Blanc Tunnel is
7.2 mi long at an average elevation of 4,179 ft. This tunnel is designed to maintain CO
concentrations at or below 100 ppm. The Grand Saint Bernard tunnel is 3.5 mi long at an
average elevation of 6,000 ft. The tunnel is designed to maintain CO concentrations at or
below ,200 ppm. For the tunnel at 11,000 feet, the authors recommended maintaining CO
concentrations at or below 25 ppm for long-term exposures, and no greater than 50 ppm for
peaks of 1 h exposure. The recommendations are based on considerations of a combination
of hypoxia from lack of O2 due to the altitude and stress of CO exposures of workers and
motorists. The authors recommend that warning signs and notices be posted to warn
susceptible individuals to take another route.
Carbon monoxide exposures of tollbooth operators were studied along the New Jersey
Turnpike. The results reported by Heinold et al. (1987) indicated peak exposures for 1 h
ranged from 12 to 24 ppm with peak 8-h exposures of 6 to 15 ppm.
Carboxyhemoglobin levels were determined for 15 nonsmokers at the start, middle, and
end of a 40-day submarine patrol (Bondi et al., 1978). Values found were 2.1%, 1.7%, and
1.7%, respectively. The average ambient air concentration for CO was 7 ppm. The authors
observed that the levels of percent COHb found would not cause significant impairment of
the submariners.
In contrast, Iglewicz et al. (1984) found in a 1981 study that CO concentrations inside
ambulances in New Jersey were often above the EPA 8-h standard of 9 ppm. For example,
measurements made at the head of the stretcher exceeded 9 ppm on nearly 27% of the
690 vehicles tested, with 4.2% (29 vehicles) exceeding 35 ppm.
Environmental tobacco smoke (ETS) has been reviewed (National Research Council,
1986) for contributions to air contaminants in airliner cabins and to potential exposures for
passengers and flight crew members. Environmental tobacco smoke is described as a
complex mixture containing many components. Analyses of CO content and paniculate
matter in cabin air were used as surrogates for the vapor phases and solid components of
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ETS, respectively. A mathematical model was developed and used to calculate the dilution of
contaminants by outside make-up air. Total emissions for CO in mainstream smoke range
from 10 to 23 mg per cigarette. More GO is emitted in sidestream smoke; the ratio of -.,'.
sidestream smoke to mainstream smoke ranges from 2.5:1 to 4.7:1. This ratio depends on
the length of time a cigarette is held without active smoking compared to the total'inhalation
and smoking time. The amount of CO in the cabin environment depends on the rate and
number of cigarettes smoked and on the rate of dilution by outside make-up air. An
additional factor to consider is the influence of pressure altitude on the absorption of CO and
other gases. The legal limit for pressure altitude is 8,000 feet. The partial pressure of O2 is
120 mm Hg assuming 20% O2 in the cabin air, compared to 152 mm Hg at sea level. It is
possible that the absorption rate for CO would be increased under hypobaric conditions.
An examination of CO hazard in city traffic for policemen in three Swedish towns
(Gothe et al., 1969) showed that the increases observed in the percent COHb in blood for a
group of 28 policemen were associated with exposures to exhaust fumes from heavy traffic.
Conversely, results from studies of 28 traffic policemen who were smokers and had a
relatively high percent COHb in their blood at :the beginning of a work period either showed
no change or showed a decrease in percent COHb while exposed to exhaust fumes in
directing traffic. Exposures were higher in a larger, more congested city, as compared to
two smaller cities in the study. •
Carbon monoxide levels in city driving in Los Angeles were measured using a prototype
CO measuring device mounted in the passenger seat (Haagen-Smit, 1966). Carbon monoxide
concentrations were continuously monitored and were sampled by means of a glass tube
projecting through the window. Typical commuting trips were made throughout the
downtown Los Angeles area during commuting hours. The distance traveled was about
30 mi. The shortest time was 40 min and the longest time was 14i and 55 min.
Concentrations of CO averaged 37 ppm for the best trips, with an average of 54 ppm in
heavy traffic moving at 20 mph; peak CO concentrations reached as high as 120 ppm.
A study of municipal bus drivers in the San Francisco Bay area by Quinlan et al. (1985)
showed a TWA of-1 to 23 ppm, with a mean TWA of 5.5 ppm and standard deviation of
4.9 ppm. The peak exposures ranged from 7 to 47 ppm with a mean of 25.3 ppm and SD of
12.5 ppm. : . >
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Cooke (1986) reports finding no significant increases outside normal ranges, as
compared to the general population, for levels of blood lead and COHb in a group of
13 roadside workers. Samples were collected in the afternoon of a workday. Among the
subjects, 7 to 13 were smokers and showed percent COHb in blood ranging from 3.0 to
8.8 (mean of 5.5%). Each nonsmoker percent COHb ranged from 0.5 to 1.4 (mean of
/*
1.2%). Each smoker had smoked at least one cigarette in the 4 h preceding collection of
blood samples. No samples were collected before the start of work, and no measurements of
CO in air at the work sites were presented.
8.5 BIOLOGICAL MONITORING
A unique feature of CO exposure is that there is a biological marker of the dose that the
individual has received: the blood level of CO. This level may be calculated by measuring
blood COHb or by measuring CO in exhaled breath.
8*5.1 Blood Carboxyhemoglobin Measurement
Carbon monoxide in the inspired air is rapidly transferred to the blood in the alveoli at
a rate that is dependent upon several physiological variables. The blood level of CO is
conventionally represented as a percentage of the total Hb available (i.e., the percentage of
Hb that is in the form of COHb or simply percent COHb). The high affinity of CO for Hb
has the effect of retaining the bulk (90 to 95%) of the absorbed gas in the vascular space and
at the same time amplifying the exposure levels of CO. This latter phenomenon occurs
because the affinity of Hb for CO is 200 to 250 times that for O2 (Douglas et al., 1912)
resulting in a relatively high COHb level at very low partial pressures of CO in the alveolar
gas phase. The primary physical and physiological variables that determine the relationship
between ambient exposure and blood levels of CO are presented in detail in Chapter 9.
8.5.1.1 Measurement Methods
Any technique for the measurement of CO in blood must be specific for CO and have
sufficient sensitivity and accuracy for the purpose of the values obtained. The majority of
technical methods that have been published on measurement of CO in'blood have been for
8-60
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forensic purposes. These methods are less accurate than generally required for the
measurement of low levels of COHb (<5% COHb). Blood levels of CO resulting from
exposure to existing NAAQS levels of CO would not be expected to exceed 5% COHb in
nonsmoking subjects. The focus of the forensic methods has been the reliability of
measurements over the entire range of possible values: from less than 1% to 100% COHb.
These forensically oriented methods are adequate for the intended use of the values and the
nonideal storage conditions of the samples being analyzed.
In the areas of exposure assessment and low-level health effects of CO, it is more
important to know the accuracy of any method in the low level range of 0 to 5% COHb.
There is little agreement upon acceptable reference methods in this range nor are there
accurate reference standards available in this range. The use of techniques that have
unsubstantiated accuracy in the low range of COHb levels can lead to considerable differences
in estimations of exposure conditions. Measurement of low levels of CO in blood demands
careful evaluation because of the implications based upon this data for the setting of air
quality standards. Therefore, this section will focus on the methods that have been evaluated
at levels below 10% COHb and the methods that have been extensively used in assessing
exposure to CO.
The measurement of CO in blood can be accomplished by a variety of techniques that
have been divided into destructive and nondestructive methods (U.S. Environmental
Protection Agency, 1979). Carboxyhemoglobin can be determined nondestructively by
observing the change in the absorption spectrum in either the Soret or visible region brought
about the combination of CO with Hb. With present optical sensing techniques, however, all
optical methods are limited in sensitivity to approximately 1 % of the range of expected
values. If attempts are made to expand the lower range of absorbances, sensitivity is lost on
the upper end where, in the case of COHb, total Hb is measured. For example, in the
spectrophotometric method described by Small et al. (1971), a change in absorbance equal to
the limits of resolution of 0.01 units can result in a difference in 0.6% COHb. Therefore,
optical techniques can not be expected to obtain the resolution that is possible with other
means of detection of CO (Table 8-11). The more sensitive (higher resolution) techniques
require the release of the CO from the Hb into a gas phase that can be detected directly by
(1) infrared absorption (Coburn et al., 1964; Maas et al., 1970) following separation using
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TABLE 8-11. COMPARISON OF REPRESENTATIVE METHODS FOR ANALYSIS
OF CARBON MONOXIDE IN BLOOD
Source
Method
Resolution*
(mL/dL) CV%b Reference Method r°
pasometricDetection
Scholander and Roughton (1943) Syringe capillary
Hoivath and Roughton (1942) Van Slyke
' 0.02 2'to 4% Van Slyke NDd
.0.03' 6% Van Slyke-Neill
Spectrophotometric Detection
Coburn et al. (1964)
Small et al. (1971)
Maas et al. (1970)
Brown (1980)
Infared , 0.006
Spectrophotometiy 0.12
CO-Oximeter 0.21
(IL182)
CO-Oximeter 0.2
(IL-282) .
1.8% , Van Slyke-Syringe NDd
NDd Flame ionization NDd
.5% Spectrophotometric NDd
5% Flame ionization 0.999
gas Chromatographv
Ayres et al. (1966)
Goldbaum et al. (1986)
McCredie and Jose (1967)
Dahms and Horvath (1974)
Collison et al. (1968)
Kane (1985)
Vreman et al. (1984)
Thermal conductivity 0.001
Thermal conductivity NDd
Thermal conductivity 0.005
Thermal conductivity 0.006
Flame ionization 0.002
Flame ionizatioH NDd
Mercury vapor 0.002
2.0% NDd
1.35% Flame ionization
1.8% ' NDd
1.7% Van Slyke
1.8% Van Slyke
6.2% CO-Oximeter
2.2% 'NDd
NDd
0.996
NDd
•0.983
NDd'
1.00
NDd'
•The resolution is the smallest detectable amount of CO or the smallest detectable difference between
samples.
""Coefficient of variation was computed on samples containing less than 15% COHb, where possible.
The r value is .the correlation coefficient between the technique, reported and me reference method used to
verify its accuracy.
djhdicates no data were available. ' •' ' •
gas chromatography, (2) the difference in thermal conductivity between CO and the carrier
gas (Allred et al., 1989; Ayres et al., 1966; Dahms and Horvath, 1974; Goldbaum et al.,
1986; Horvath et al., 1988; McCredie and Jose, 1967), (3) the amount of ionization
following quantitative conversion of CO to methane (CH^j) and ionization of the CH4
(Clerbaux et al., 1984; Collison et al., 1968; Costantino et al., 1986; Dennis and Valeri,
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1980; Guillot et al., 1981; Kane, 1985; Katsumata et al., 1985), or (4) the release of
mercury vapor due to the combination of CO with mercuric oxide (Vreman et al., 1984).
Sample Handling
Carbon monoxide bound to Hb is a relatively stable compound that can be dissociated
by exposure to O2 or ultraviolet (UV) radiation (Chace et al., 1986; Horvath and Roughton,
1942). Ultraviolet light has not been shown by Goldstein et al. (1985) to affect COHb levels
in glass vials exposed to room lighting conditions; however, the ability of UV light to
penetrate these tubes was not demonstrated. If the blood sample is maintained in the dark
under cool, sterile conditions, the CO content will remain stable for a long period of time.
Various investigators have reported no loss of percent COHb over 10 days (Collison et al.,
1968), 3 weeks (Dahms and Horvath, 1974), 4 mo (Ocak et al., 1985), and 6 mo (Vreman
et al., 1984). The blood collection system used can influence the CO level because some
ethylenediaminetetracetic acid vacutainer tube stoppers contain CO (Vreman et al., 1984).
The increased levels of COHb due to this amount of CO have been demonstrated (Goldstein
et al., 1985; Vreman et al., 1984). The stability of the CO content in properly stored
samples does not indicate that constant values will be obtained by all techniques of analysis.
The spectrophotometric methods are particularly susceptible to changes in optical qualities of
the sample, which results in small changes in COHb with storage (Allred et al., 1989).
Carboxyhenioglobin values obtained with the EL 282 CO-Oximeter have been shown to
decrease over the first 3 days foEowing collection (Allred et al., 1989; Goldstein et al.,
1985). This decrease occurs within the first 24 h (Allred et al., 1989) and does not fall
further over the next 14 days (Goldstein et al., 1985). Storage of blood samples can result in
the formation of methernoglobin (Goldstein et al., 1985) and under some conditions
sulfhemoglobin (Rai and Minty, 1987). Both species of Hb can result in the optical methods
of COHb detection being incorrect depending upon the specific wavelengths utilized.
Therefore the care needed to make a COHb determination depends upon the technique
that is being utilized. It appears as though measurement of low levels of COHb with optical
techniques should be conducted as soon as possible following collection of the samples.
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Potential Reference Methods
Exposure to CO at equilibrium conditions results in COHb levels of between 0.1 and
0.2% COHb for each part per million of CO in the atmosphere. A reference technique for
the measurement of COHb should be able to discriminate between two blood samples with a
difference of 0.1% COHb (approximately 0.02 mL/dL). To accomplish this task, the
coefficient of variation (SD of repeated measures on any given sample divided by the mean
of the values times 100) of the method should be less than 5% so that the two values that are
0.1% COHb different can be statistically proven to be distinct. In practical terms, a
reference method should have the sensitivity to detect approximately 0.025% COHb to
provide this level of confidence in the values obtained.
The accurate measurement of CO in a blood sample requires the quantitation of the
content of CO in blood. Optically based techniques have limitations of resolution and
specificity due to the potential interference from many sources. The techniques that can be
used as reference methods involve the quantitative release of CO from the Hb followed by the
measurement of the amount of CO released. Classically this quantitation was measured
manometrically with a Van Slyke apparatus (Horvath and Roughton, 1942) or a Roughton-
Scholander syringe (Roughton and Root, 1945). These techniques have served as the ''Gold
Standard" in this field for almost 50 years. However, there are limitations of resolution with
these techniques at the lower ranges of COHb. The gasometric standard methodology has
been replaced with headspace extraction followed by the use of solid-phase gas
chromatographic separation with several different types of detection: thermal conductivity,
flame iomzation, and mercury vapor reduction. With the use of National Institute of
Standards and Technology standard gas mixtures of CO, the gas chromatographic techniques
can be standardized when proper consideration is given to potential sources of loss of
standard. The CO in the headspace can also be quantitated by infrared detection, which can
be calibrated with gas standards. However, there is no general agreement that any of the .
more sensitive methods of CO analysis are an acceptable reference method.
Flame-Ionization Detection. This technique requires the separation of CO from the
other headspace gases and the reduction of .the CO to CH4 by catalytic reduction. Collison
et al. (1968) reported that the results from their method correlated with the Van Slyke
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gasometric method at high levels of CO (8 to 13 mL/dL) where the error in the gasometric
method was minimal. The values obtained from the two independent techniques were highly
significantly correlated (p < 0.0001) with a linear regression r = 0.992. The limit of
detection was reported to be 0.01% COHb using 100 /*L of blood. The coefficient of
variation was 1.08% on a sample containing approximately 50% COHb and 1.80% on a •
sample containing approximately 0.8% COHb. The basic technique of Collison et al. (1968)
using headspace analysis and flame-ionization detection is the most sensitive method that has
been compared with the gasometric methods. Modifications of this method have been widely
used by other investigators for evaluating technically simpler methods of CO analysis
(Clerbaux et al., 1984; Coffison et al., 1968; Dennis and Valeri, 1980; Guillot et al., 1981;
Kane, 1985; Katsumata et al., 1985). This method conforms to air the requirements of a
reference method.
Thermal-Conductivity Detection. Ayres et al. (1966) reported a method for using
vacuum extraction of CO from blood in a Van Slyke apparatus for gas chromatographic
separation with thermal-conductivity analysis of the CO^ The gas phase of the reaction
chamber was eluted onto a 5 A molecular-sieve column for separation of the components.
This technique was reported to have a lower limit of detectability of 0.001 mL/dL or
approximately 0.005% COHb. The coefficient of variation was reported to be 1.95% on a
sample of unspecified percent COHb. The analysis system was calibrated using a gas sample
of known CO content injected directly into the column. No comparisons were performed
with other standard techniques. McCredie and Jose (1967) also reported results from
chromatographic separation of vacuum-extracted gas. Thermal-conductivity detection enabled
the limit of detection to be 0.005 mL/dL or approximately 0.025% COHb. This system was
also calibrated with standard gas mixtures injected directly into the column. A coefficient of
variation was not presented, but a standard deviation of 0.004 mL/dL on a series of repeat
analyses on an average blood sample indicates that this method is sufficiently reproducible.
This would represent a coefficient of variation on the blood CO content measured from the
average nonsmoker of 2.5%. Dahms and Horvath (1974) described a technique of headspace
analysis of CO using thermal-conductivity detection. The CO was released from the blood
while the mixture was stirred to produce a vortex, using Van Slyke reagents in a sealed
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reaction vial. The extraction occurred into the headspace of a sealed vial pressurized to the
head pressure on the column. The limit of detection with this technique was 0.006 mL/dL or
0.03% COHb, with a coefficient of variation of 1.7% on a sample containing 6.5% COHb.
This method used standard gases injected into the reaction vial to calibrate the system. The
results of this technique were compared to the standard Van Slyke method (Horvath and
Roughton, 1942) over the whole range of values and more specifically on 90 blood samples
containing less than 10% COHb. The correlation coefficient between the gas chromatography
and the Van Slyke method was 0.984. Linear regression analysis demonstrated essentially a
zero intercept (0.009 mL/dL) between the two techniques. This close agreement between
values obtained with these independent methods provides a basis for the use of standard gases
to calibrate gas chromatographic techniques. All of the above mentioned gas
chromatographic methods for determination of CO in blood are acceptable as reference
methods.
Infrared Detection. Coburn et al. (1964) described a method for extracting CO from
blood under normal atmospheric conditions and then injecting the headspace gas into an
infrared analyzer. This technique has a reported limit of detectability of 0.007 mL/dL or
0.035% COHb. The coefficient of variation was 1.8% on an average COHb of 1.67%. The
results of this technique were compared with the gasometric technique of Roughton and Root
(1945) on five samples; there was no difference between the two techniques. This method is
acceptable as a reference method for the measurement of CO in blood.
Hemoglobin Measurement. The conventional means of representing the quantity of CO
in a blood sample is the percent COHb: the percentage of the total CO combining capacity
that is in the form of COHb. This is conventionally determined by the use of the following
formula:
%COHb = {CO content/(hemoglobin X 1.389)] X 100 (8-8)
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where CO content is measured in cubic centimeters per deciliter blood at standard
temperature and pressure, dry (STPD); hemoglobin is measured in grams per deciliter blood;
and 1.389 is the stoichiometric combining capacity of Hb for CO in units of milliliters per
gram at STPD. • .--... •'•.-.; .. , v. . .• • ••••;. •- : •
The analytical methods that quantify the CO content in blood require the conversion of
these quantities to percent COHb. The product of the Hb and the theoretical combining
capacity (1.389 according to International Committee for Standardization in Haematplogy,
1978) yields the CO capacity. With the use of capacity and the measured content, the
percent of CO capacity (percent COHb) is calculated. To be absolutely certain of the
accuracy of the Hb measurement, the theoretical value should be routinely substantiated by
direct measurement (internal validation) of the Hb CO combining capacity. The total CO
combining capacity should be determined as accurately as the content of CO. The error of
the techniques that measure CO content are dependent on the error in Hb analysis for the
final form of the data, percent COHb. Therefore the actual CO combining capacity should
be measured and compared with the calculated value based upon the reference method for Hb
measurement. The measurement of CO combining capacity can be routinely carried out by
equilibration of a blood sample with CO (Allred et al., 1989). ,
; The standard methods for Hb determination involve the conversion of all species of Hb
to cyanmethemoglobin with the use of a mixture of potassium ferricyanide [K3Fe(CN)6],:
potassium cyanide (KCN), and sodium bicarbonate (NaHGO3). Three combinations of
similar reagents have been routinely used for the quantification of Hb. Drabkin's solution
contains 0.6 mM K3Fe(CN)6, 0.8 mM KCN, and 12 mM NaHCO3 (Drabkin and Austin,
1932). Van Kampen and Zijlstra (1961) substituted 0.7 mM potassium phosphate for the
bicarbonate in the reagent mixture. A third reagent for producing cyanmethemoglobin is that
*,
of Taylor and Miller (1965), who increased the concentration of K3Fe(CN)6 to 3 mM in
Van Kampen and Zijlstra's mixture to decrease the reaction time with COHb. The presence
of high levels of COHb slows the rate of conversion to cyanmethemoglobin so that the use of
the conventional Drabkin's reagent requires a reaction time of at least 180 min (Allred et al.,
1989; Kane, 1985), as opposed to the recommended time of 20 to 30 min. This increased
reaction time is essential for the accurate comparison of cyanmethemoglobin values with CO
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combining capacity measurements. If the reaction is not permitted to go to completion, the
spectrophotometric method will underestimate the amount of Hb present in the sample.
Other Methods of Measurement
There are a wide variety of techniques that have been described for the analysis of CO
in blood. These methods have been reviewed previously (U.S. Environmental Protection
Agency, 1979) and include UV-visible spectrophotometry (Brown, 1980; Small et al., 1971;
Zwart et al., 1984; 1986), magnetic circular dichroism spectroscopy (Wigfield et al., 1981),
photochemistry (SawicM and Gibson, 1979), gasometric methods (Horvath and Roughton, ;
1942; Roughton and Root, 1945), and a calorimetric method (Sjostrand, 1948). Not all of ••
these methods have been as well characterized for the measurement of low levels of COHb as
those listed above as potential reference methods.
Spectrophotometric Methods. The majority of the techniques are based upon optical
detection of COHb, which is more rapid than the reference techniques because these methods
do not involve extraction of the CO from the blood sample. These direct measurements also
enable the simultaneous measurement of several species of Hb, including reduced Hb,
oxyhemoglobin (O2Hb), and COHb. The limitations of the spectrophotometric techniques
have been reviewed by Kane (1985). The optical methods utilizing UV wavelengths require
dilution of the blood sample, which can lead to the loss of CO due to the competition with
the dissolved O2 in solution. Removing the dissolved O2 with dithionite can lead to the
formation of sulfhemoglobin, which interferes with the measurement of COHb (Rai and
Minty, 1987). Another limitation is that the absorption maxima (and spectral curves) are not
precisely consistent between individuals. This may be due to slight variations in types of Hb
in subjects. For these reasons, the techniques using fixed wavelength measurement points
would not be expected to be as precise, accurate, or specific as the proposed reference
methods mentioned above.
Rodkey et al. (1979) reported a modification of the spectrophotometric technique for
measuring COHb. This method converts all the Hb species in a blood sample to either
COHb or Hb by the quantitative addition of the reducing agent sodium hydrosulfite. The
absorbance at 420 nm was used for the determination of COHb and the absorbance at 432 nm
8-68
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was used for Hb. The optically based values were compared with those obtained by gas
chromatography on the same 28 samples. Twenty-five of these values were below 6% COHb
and linear regression analysis demonstrated a slope of 1.038 with an intercept of -0.154 and
an r = 0.994. The number of samples studied was relatively small and no error term was
presented for the relationship. Visual inspection of the data, however, indicates a wide
scatter of optical values for any given gas chromatograph value when the levels were at or
below 1% COHb (normal range of values for unexposed, nonsmoking individuals).
A multicomponent spectrophotometric technique for the measurement of hemoglobin
derivatives was reported by Zwart et al. (1984). This technique employs a multiwavelength
spectrophotometer that uses reversed optics to enable the rapid collection of the absorbance
spectrum from an array of photomultiplier tubes that detect transmission of light at intervals
of 2 nm. This method offers the possibility of instantaneous absorption data over the entire
spectrum rather than the collection of data at a few selected wavelengths. This optical system
offers the potential for correcting for individual variability in absorption characteristics of Hb.
The COHb data produced with this technique has not been compared with any of the
proposed reference methods, but has been compared with that obtained from the mercury
vapor detector. The correlation coefficient of the multicomponent spectrophotometric
analysis (MCA) with the gas chromatographic-mercury vapor technique (GC) was only 0.87;
linear regression analysis resulted in the following relationship: GC = 0.6:5 (MCA) + 0.24
(Vreman etal., 1987).
Mercury Vapor Detection. The most sensitive detector for the measurement of CO is
the UV-photometer that senses mercury vapor produced by the reaction of CO with mercuric
oxide (Trace Analytical). This unit has the reported ability to resolve 1 ppb. The use of
such a sensitive detector for blood determinations requires that measurements be carried out
on only 1 to 10 nL quantities of blood. Vreman et al. (1984) reported the use of this
detector following gas chromatographic separation of the CO from other gases in blood.
Mercuric oxide will react with other gases so the chromatographic separation is an essential
step in the use of this detector. Values for COHb obtained with this technique have not been
compared those obtained with any of the proposed reference methods. The COHb analysis
method of Vreman et al. (1984) was used in parallel with a gas chromatographic method
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using thermal-conductivity detection for the routine measurement of COHb in a series of
samples from subjects exposed to CO to produce levels of COHb up to 6% (Allred et al.,
1989). Paired data from samples analyzed by both techniques were obtained on 108 samples.
The values were significantly correlated (r = 0.987); however, the reduction gas analyzer
results were not corrected to STPD conditions, so an absolute comparison was not possible.
This technique needs further validation by comparison with other methods to assure that the
levels measured are accurate.
CO-Oximeter Measurements of CarboxyhemogloMn
The speed of measurement and relative accuracy of spectrophotometric measurements
over the entire range of expected values led to the development of CO-Oximeters. These
instruments utilize from two to seven wavelengths in the visible region for the determination
of proportions of O2Hb, COHb, reduced Hb and methemoglobin. The proportion of each
species of Hb is determined from the absorbance and molar extinction coefficients at present
wavelengths. All of the commercially available instruments provide rapid results for all the
species of Hb being measured. In general, the manufacturers' listed limit of accuracy for
COHb for all of the instruments is 1% COHb. However, this level of accuracy is not
suitable for measurements associated with background CO levels (<2% COHb) because it
corresponds to errors exceeding 50%. The precision of measurement for these instruments is
excellent and has misled users regarding the accuracy of the instrument. The relatively
modest level of accuracy is adequate for the design purposes of the instrument; however, at
low levels of COHb, the ability of the instrument to measure the percent COHb accurately is
limited.
The commercially available instruments for the measurement of COHb all utilize the
same basic principles: hemolysis, constant temperature, and the measurement of absorbance
at several wavelengths. These instruments have been designed to provide information
regarding COHb measurement that is +1% COHb. However, these instruments are all very
precise so that the coefficient of error between repeat measurements (standard deviation of
repetitions/mean of the repetitions) is very low. Unfortunately, very few studies have
evaluated the accuracy of the measurements made with these instruments as a routine aspect
of quality control. The concern regarding the accuracy of any optical measurement on a
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diluted blood sample should be of greatest concern due to the wide variety of substances that
can subtly alter the absorption spectrum of Hb and the optical quality of the blood sample
itself. Because of the widespread use of these instruments, the evaluations of this instrument
will be carefully reviewed. These instruments consist of the Instrumentation Laboratories
CO-Oximeters known as the IL 182 and the IL 282, the Radiometer Oximeter OSM-3, and
the Corning Oximeter 2500. There is very little information regarding the accuracy of the
OSM-3 in the low range of COHb values compared to the data obtained from paired analysis
with a reference method.
The instruments that have been used to the greatest extent in the studies on health
effects of CO have been the IL 182 and IL 282 (Instrumentation Laboratory, Inc,, Lexington,
MA). The IL 282 instrument uses absorbances at four wavelengths in the visible region and
a matrix of molar extinction coefficients to calculate each species of Hb. This method is
susceptible to interference from high concentrations of methemoglobin and jiulfhemoglobin.
The IL 282 CO-Oximeter has been shown to provide accurate data when the range of 0 to
100% COHb is considered (Brown, 1980). However, comparison of the results from this
method with the proposed reference methods indicates that, at low levels of COHb, the
results from this instrument are not sufficiently accurate to warrant their use alone for
low-level COHb investigation. Resting levels of percent COHb have been shown to be below
0.9% for nonsmokers by all the proposed reference methods (Ayres et al., 1966; Coburn
et al., 1964; Collison et al., 1968; Dahms and Horvath, 1974; McCredie and Jose, 1967).
The limit of accuracy for the IL 282 CO-Oximeter for percent COHb is 1 %, which has raised
concern over the capability of all CO-Oximeters in the low range of COHb levels.
Therefore, the accuracy of these instruments has been determined by paired observations on
blood samples with the CO-Oximeter and a reference method. The results are shown in
Table 8-12 below.
The results from the linear regression analyses of all these comparisons indicate that
there is considerable difference between instruments of the same model type. The slope of
the relationship between the optical methods are sufficiently close to unity that there is no
difference between instruments in the linearity of the measurements. Confidence intervals for
the regressions are not given, so this comparison cannot be made. The intercept values vary
widely relative to the purpose of accurately measuring low levels of COHb, These
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TABLE 8-12. EVALUATION OF THE ABILITY OF CO-OXBMETERS
CARBOXYHEMOGLOBIN AS COMPARED TO PROPOSED
TO MEASURE LOW LEVELS OF
CE METHODS
Instrument
EL 182
EL 182
EL 182
IL282
EL 282
IL282
3 EL 282
IL282
Coming
2500
Corning
2500
Reference
Method"
GC-FED
GC-FID
Infrared
GC-FED
GC-FED
GC-TCD
GC-FID
CG-TCD
GC-FED
GC-FID
Slope
0.690*GC
1.049*GC
0.977*ER
0.990*GC
1.122*GC
0.919*GC
0.895*GC
1.0069*GC
1.05*GC
1.05*GC
1.05*GC
0,92*GC
1.013*GC
Intercept
+3.59
-0.54
+3.33
+0.45
-0.907
-0.068
+0.66
-0.01
+0.79
+0.55
+0.47
+ 1.17
-1,279
R
0.59
NDb
NDb
0.997
0.993
0.961
0.856
0.99
0.99
0.979
0.989
n
16
275
12
39
13
20
16
NDb
203
192
162
50
286
COHb
Range Reference
< 15% Costantino et al. (1986)
<15% Guillot et al. (1981)
<100% Maas et al. (1970)
< 100% Dennis and Valeri
(1980)
< 17% Dennis and Valeri
(1980)
<8% Goldbaum et al. (1986)
< 15% Costantino et al. (1986)
<9% Horvath et al. (1988)
<6% Allred et al. (1989)
<6% Allred et al. (1989)
<6% Allred et al. (1989)
<20% Kane (1985)
<15% Tikuisis et al: (1987)
" :: :' •- - •
"Abbreviations: GC-FID is gas chromatography with flame-ioni2ation detection; GC-TCD is gas chromatography with thermal-conductivity detection.
""Indicates no data were available.
-------
differences probably reflect the difference between instruments. In order to use these
instruments for the measurement of low levels of COHb, they must be individually and
routinely calibrated with a reference method. The linearity of the response of the instruments
implies that a standard correction can be applied to the value for COHb with the result that
the average value of COHb obtained with these instruments will be correct.
The interaction of Hb species with the measurement of COHb below 10% has been
evaluated by Allred et al. (1989). In freshly drawn blood samples, levels of COHb were
maintained constant, as measured by gas chromatography, while levels of methemoglobin,
total Hb, and O2Hb were varied. Only the level of O2Hb interacted significantly with the
COHb value. In a series of 46 subjects, the effect of O2Hb was measured to determine its
role in routine measurements of COHb. The effect of O2Hb varied considerably between
individuals, with the average change being approximately 0.1% COHb for every 10% change
in O2Hb. Almost all COHb measurements were made on venous blood, which can vary
considerably in O2Hb concentration and consequently affect the measurement of low levels of
COHb.
Hydrogen ion concentration was shown to have an effect on the measured percent
COHb in blood stored in acid citrate dextrose solution for two days. However the effect of
pH on percent COHb in freshly drawn samples has not been clearly demonstrated (Allred
et al., 1989). Hydrogen ion concentration has been demonstrated to change the absorbance
spectrum of O2Hb and therefore may be expected to have an effect on the ability of
CO-Oximeters to measure COHb. Plasma lipid, triglyceride and cholesterol levels were
found to not have any effect on the ability of the IL 282 CO-Oximeter to measure COHb as
determined by the difference between in instrument value and the reference value obtained by
gas chromatography.
The content of CO in blood stored in a tightly capped syringe at 4 °C in the dark has
been shown to remain stable for up to 4 months. Measurement of COHb by IL 282
CO-Oximeter on blood samples (COHb range of 4.3 to 1.3%) within 15 rnih of collection,
followed by storage for 24 and 48 h as described above, .resulted in a decrease in the detected
percent COHb. The apparent loss of COHb occurred in the first 24 h and averaged 16%
(Allred et al., 1989). There was no change in percent COHb as determined by gas
chromatography. It is not clear when in the first 24-h period this change occurred.
8-73
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The use of CO-Oximeters to measure low levels of COHb can provide useful
information regarding mean values, provided a reference technique is used to properly
calibrate the instrument. It has been shown, however, that the range of values obtained with
the optical method will be greater than that obtained with a reference method. In a group of
subjects with cardiovascular disease, the SD of the percent COHb values for nonsmoking,
resting subjects was 2 to 2.5 times greater for the CO-Oximeter values than for the gas
chromatograph values on paired samples (Allred et al., 1989). Therefore, the potential exists
with the CO-Oximeter for having an incorrect absolute value for COHb, as well as an*
incorrectly broadened range of values. .
In addition, it is not clear exactly how sensitive the CO-Oximeter techniques are to
small changes in COHb at the low end of the CO dissociation curve. Allred et al. (1989) ...
have noted that the interference from changing O2 saturation can have a very significant
influence on the apparent COHb reading in a sample. The interaction between Hb species
was also reported by Dennis and Valeri (1980). This suggests nonlinearity or a
disproportionality in the absorption spectrum of these two species of Hb. It is also a potential
source of considerable error in the estimation of COHb by optical methods.
8.5.1.2 Carboxyhempglobin Measurements in Populations
Numerous studies have used the above described methodologies to characterize the
levels of COHb for the general population. These studies have been designed to determine
frequency distributions of COHb levels in the populations being studied. In general, the
higher the frequency of COHb levels above baseline in nonsmoking subjects, the greater the
incidence of significant CO exposure. ,
Carboxyhemoglobin levels in blood donors have been studied for various urban
populations in the United States. Included have been studies of blood donors and sources of
CO in the metropolitan St. Louis population (Kahn et al., 1974); evaluation of smoking and
COHb in the St. Louis metropolitan population (Wallace et al., 1974); analyses of
16,649 blood samples for COHb provided by the Red Cross Missouri-Illinois blood donor
program (Davis and Gantner, 1974); a survey of blood donors for percent COHb in Chicago,
Milwaukee, New York, and Los Angeles (Stewart et al., 1976); a national survey for COHb
in American blood donors from urban, suburban, and rural communities across the
8-74
-------
United States (Stewart et al., 1974); and the trend for percent GOHb associated with
vehicular traffic in Chicago blood donors (Stewart et al., 1976). These extensive studies of
volunteer blood donor populations show three main sources of exposure to CO in urban
environments. These are smoking, general activities (usually associated' witii internal
combustion engines), and occupational exposures. For comparisons of sources^ the
populations are divided into two main groups—smokers and nonsmokers. The main groups
often are divided further into subgroups consisting of industrial workers, drivers, pedestrians,
and others, for example. Among the two main groups, smokers show an average of 4%
COHb with a usual range of 3 to 8%; nonsmokers average about 1 % COHb (Radfofd and
Drizd, 1982). Smoking behavior generally occurs as an'intermittent diurnal pattern, but in
some individuals who chain-smoke, COHb levels can rise to a maximum of about .15%.
In addition to tobacco smoke, the most significant sources of other potential exposure to
CO in the population are community air pollution, occupational exposures, and household
exposures (Goldsmith, 1970). Community air pollution comes mainly from auto exhaust and
has a typical intermittent diurnal pattern (see Chapter 6). Occupational exposures occur for
up to 8 h for 5 days a week, producing COHb levels generally less than 10%. However,
exposures to high concentrations of CO in occupational settings have caused death from CO
intoxication. Household exposures usually 'result in less than 2% COHb, but Mgh
concentrations, occurring particularly during nighttime hours, have been known to cause
death. For example, during the winter, a number of people die as a result of using a variety
of space-heating devices in poorly ventilated spaces (Goldsmith, 1970). Poorly-vented floor
heaters are also a source of CO intoxications, with many such exposures occurring at night
More recent studies characterizing COHb levels in the population have appeared in the
literature. Turner et al. (1986) used an IL 182 CO-Oximeter to determine percent COHb in
venous blood of a study group consisting of both smoking and nonsmoking hospital staff,
inpatients, and outpatients. Blood samples were collected for 3,487 subjects
(1,255 nonsmokers) during morning hours over a 5-year period. A detailed smoking history
was obtained at the time of blood collection. Secondary pipe or secondary cigar smokers
were considered to be those who were initially cigarette.smokers but subsequently Switched to
cigars or pipes. Primary cigar or pipe smokers were those who had never smoked cigarettes
and were not in the habit of inhaling large amounts of tobacco smoke,-as is the observed
8-75
-------
custom with cigarette smoMng. Using 1.7% COHb as a normal cutoff value, the distribution
for the population studied showed above normal results for 94.7% of cigarette smokers,
10.3% of primary cigar smokers, 97.4% of secondary cigar smokers, and 94.7% of
secondary pipe smokers.
Zwart and van Kampen (1985) tested a blood supply using a routine spectrophotometric
method for total Hb and for COHb in 3,022 samples of blood for transfusion in hospital
patients in the Netherlands, For surg%ry patients over a 1-year period, the distribution of
percent COHb in samples collected as a part of the surgical protocol showed 65% below
1.596 COHb, 26.5% between 1.5 and 5% COHb, 6.7% between 5 and 10% COHb, and
0.3% in excess of 10% COHb. This distribution of percent COHb was homogeneous across
the entire blood supply, resulting in 1 in 12 patients having blood transfusions at 75%
available Hb capacity.
Radford and Drizd (1982) have analyzed blood COHb in approximately 8,400 samples
obtained from respondents in the 65 geographic areas of the nationwide Health and Nutrition
Examination Survey (HANES) during the period 1976 to 1980. When the frequency
distributions of blood COHb levels are plotted on logarithmic-probability paper (Figure 8-5)
to facilitate comparison of the results for different age groups and smoking habits, it is
evident that adult smokers in the United States have COHb levels considerably higher than
those of nonsmokers, with 79% of the smokers' blood samples above 2% COHb and 27% of
the observations above 5% COHb. The nationwide distributions of persons aged 12 to 74
who have never smoked and those who are ex-smokers were similar, with 5.8% of the ,
ex-smokers and 6.4% of the never-smokers above 2% COHb. It is evident that a significant
proportion of the nonsmoking U.S. population had blood levels above 2% COHb. For these
two nonsmoking groups, blood levels above 5% were found in 0.7% of the never-smokers
and 1.5% of the ex-smokers. It is possible that these high blood levels could be due, in part,
to misclassification of some smokers as either ex- or nonsmokers. Children aged 2 to 11 had
lower COHb levels than the other groups, with only 2.3% of the children's samples above
2% COHb and 0.2% above 5% COHb.
Wallace and Ziegenfus (1985) utilized available data from the second National Health
and Nutrition Examination Survey (NHANES n) to analyze the relationship between the
measured COHb levels and the associated 8-h CO concentration at nearby fixed monitors.
8-76
-------
99.99 99.9 99 98 95 90 80
SO
20 10 5 2 1 0.5 0.1 0.01
10.0
5.0
1.0
0.5
0.2
0.1
0.01 0.1 12 510 20 SO 40 50 90 95
Cumulative Frequency, %
j
J
/
IZj
Srnok
/
e
f
fS
!!!!!!!! 111-!! HUM
lilllil! Illil HUH
Current Smokei
Age 12-74
" : n-2384
L.
\ ,•
,'
f
•
t
*
• ',"' •
' ',"' j
Nonsmokers
Illl III!! !!!!!!! II
mi inn iiiiiii i i
•s Ex-Smokers
Age 12-74
: ::::::n«i289
v
,/
I''
• :': ' .''"
.' '
,'' ,'J
':• ~f , • '
''
[
\
/.
/
(
C'
/ -'
/ •'
/
.'
/
(III ililll I I
- N
....S
A
,-T _ n
S^Hh
'? T-
' T
1
r
v u
>».A(
n
T
|
aver
•ncka
je 12
-814
I
Mldre
je2-1
-15S
r)
-74
•j
n
1
1
10.0
5.0
1.0
0.5
0.2
99
99.9 99.99
o>
o
o
Figure 8-5. Frequency distributions of carboxyhemoglofoin levels in the U.S. population,
by smoking habits.
Source: Adapted from Radford and Drizd (1982); data for NHANES H.
Carboxyhemoglobin data were available for a total of 1,658 nonsmokers in 20 cities. The
day and hour the blood samples were drawn for each individual were obtained from the
NHANES II data, and the preceding 1-h and 8-h running average ambient CO levels at each
fixed station in the city were calculated using the U.S. EPA centralized data base
(SAROAD). For each of the 20 cities, the station with the highest Spearman correlation
between COHb concentrations and the preceding 8-h CO averages was selected for a linear
regression. The results (Table 8-13) show that 17 of the 20 stations had R2 values ranging
from 0.00 (6 cities) to 0.10.
8-77
-------
TABLE 8-13. REGRESSION PARAMETERS FOR THE RELATIONSHIP BETWEEN
CARBOXYHEMOGLOBIN AND EIGHT-HOUR CARBON MONOXIDE AVERAGES
FOR 20 CITIES*
City
Atlanta
Bronx
Cincinnati
Chicago
Dayton
Des Moines
Washington
Hampton
Honolulu
Houston
Indianapolis
Los Angeles
Manhattan
Pittsburgh
Racine
Rock Hill
San Diego
San Jose
Tacoma
Washington
Wichita
All cities
n
63
65
93
78
91
90
73
89
65
71
93
66
71
55
91
85
' 67
59
82
73
81
1,528
Slopeb
0.12(+0.03)
0.18(±0.10)
-0.02(±0.21)
-0.02(±0.06)
-0.03(+0.08)
O.Q03(±0.03)
0.06(±0.04)
0.16(+0.10)
0.39(±0.14)
0.24(±0.12)
0.0005(±0.019)
0.12(+0.03)
0.09(±0.03)
0.03(+0.02)
-0.12(±0.13)
'0.23(+0.11)
0.01(+0.08)
0.08(+0.04)
0.04(±0.06)
0.06(+0.04)
-0.11 (±0.28)
0.066(±0.009)
Intercept0
0.41(±0.09)
0.60(±0.29)
0.94(±0.22)
1.21(±0,18)
0.93(±0.15)
0.52(±0.12)
1.38(±0;18)
0.50(±0.09)
0.44(±0.18)
0.68(±0.15)
. 0.79(±0.07)
0.99(±0.18)
0.84(±0.08)
0.77(±0.13)
0.75(+0.14)
0.61(±0.24)
0.84(+0.13)
0.87(±0.11)
0.76(±0.14)
1.38(±0.18)
0.84(±0.35)
0.77(±0.03)
R2
0.27
0.05
0.00
0.00
0.00
0.00
0.03
0.03
0.11
0.06
0.00
0.16
0.10
0.05
0.01
0.05 .
0.00
0.06
0.01
0.03
0.00 ,
0.03
"For cities with multiple CO stations, the station with the strongest Spearman correlation was chosen for the'1
regression.
bPereent COHb per mg/m3 (±SD).
Tercent COHb <±SD).
Source: Wallace and Ziegenfas (1985).
8-78
-------
Finally, because the participants were part of a nationwide probability sample, all
COHb data were merged with the CO data from the station within each city that showed the
strongest correlation with the COHb values and a linear regression was run. The R2 value
for the 1,528 paired measurements was 0.031 (i.e., only 3% of the variance in the COHb
concentrations was explained by the ambient CO data). The authors concluded that fixed
outdoor CO monitors alone are, in general, not providing useful estimates of CO exposure of
urban residents.
8.5.2 Carbon Monoxide in Expired Breath
Carbon monoxide levels in expired breath can be used to estimate the levels of CO in
the subject's blood. The basic determinants of CO levels in the alveolar air have been
described by Douglas et al. (1912), indicating that there are predictable equilibrium
conditions that exist between CO bound to the Hb and the partial pressure of the CO in the
blood. The equilibrium relationship for CO between blood and the gas phase to which the
blood is exposed can be described as follows:
PCO/P0 = M (%COHb/%O2Hb) (8-9)
£i
where Pco is the partial pressure of CO in the blood, Po is the partial pressure of O2 in the
blood, M is the Haldane coefficient (reflecting the relative affinity of Hb for O2 and CO),
%COHb is the percent of total Hb combining capacity bound with CO, and %O2Hb is the
percent of total Hb combining capacity bound with O2.
The partial pressure of CO in the arterial blood will reach a steady state value relative
to the partial pressure of CO in the alveolar gas. Therefore, by measuring the end-expired
breath from a subject's lungs, one can measure the end-expired CO partial pressure and, with
the use of the Haldane relationship, estimate the blood level of COHb. This measurement
will always be an estimate because the Haldane relationship is based upon attainment of an
equilibrium, which does not occur under physiological conditions.
The measurement of CO levels in expired breath to estimate blood levels is based upon
application of the Haldane relationship to gas transfer in the lung (Equation 8-9). For
example, when the O2 partial pressure is increased in the alveolar gas, it is possible to predict
8-79
-------
the extent to which the partial pressure of CO will increase in the alveolar gas. This
approach is limited, however, because of the uncertainty associated with variables that are
known to influence gas transfer in the lung and that mediate the direct relationship between
liquid-phase gas partial pressures and air-phase partial pressures.
The basic mechanisms that are known to influence CO transfer in the lung have been
identified through the establishment of the techniques to measure pulmonary diffusion
capacity for CO (Forster, 1964). Some of the factors that can result in decreased diffusion
capacity for CO (altering the relationship between expired CO pressures and COHb levels)
are increased membrane resistance, intravascular resistance, age, alveolar volume, pulmonary
vascular blood volume, pulmonary blood flow, and ventilation/perfusion inequality (Forster,
1964). The extent to which each of these variables actually contributes to the variability in
the relationship has not been experimentally demonstrated. There are very few experiments
that focus on the factors leading to variability in the relationship between alveolar CO and
percent COHb at the levels of COHb currently deemed to be of regulatory importance. This
may be due in part to the difficulties in working with analytical techniques, particularly the
blood techniques, that are very close to their limits of reproducibility. For example, a
change of approximately 6 ppm of CO in the alveolar gas occurs for every change of 1 %
COHb (Jones et al., 1958). Therefore, in order to reliably measure COHb levels to better
than 0.1% COHb, the analytical method must be able to resolve at least 0.5 ppm CO. This
is well within the range of precision of the electrochemical methods (Lambert et al., 1988;
Wallace et al., 1988). Without the use of a well-established method for the measurement of
CO levels in blood, the influence of all the physiological variables on the accuracy of this
method remain undetermined.
The expired breath method for obtaining estimates of blood levels of CO has a distinct
advantage for monitoring large numbers of subjects because of the noninvasive nature of the
method. Other advantages include the ability to obtain an instantaneous reading and the
ability to take an immediate replicate sample for internal standardization. The breath-holding
technique for enhancing the normal CO concentration in exhaled breath has been widely used;
however, it should be noted that the absolute relationship between breath-hold CO pressures
and blood CO pressures has not been thoroughly established for percent COHb levels below
8-80
-------
5 % . The breath-holding method allows time (20 s) for diffusion of CO into the alveolar air
so that CO levels are higher than following normal tidal breathing.
Partial pressures of CO in expired breath are highly correlated with percent COHb
levels over a wide range of COHb levels (Table 8-14). The accuracy of the breath-hold
method is unknown due to the lack of paired sample analyses of CO partial pressures in
exhaled breath and concurrent COHb levels in blood utilizing a sensitive reference method
(see Section 8.5. 1). No one has attempted to determine the error of estimate involved in
applying group average regression relationships to the accurate determination of COHb.
Therefore, the extrapolation of breath-hold CO partial pressures to actual COHb levels must
be made with reservation until the accuracy of this method is better understood.
8.5.2.1 Measurement Methods
Ventilation in healthy individuals involves air movement through areas in the pulmonary
system that are either primarily involved in conduction of gas or in gas exchange in the
alveoli. In a normal breath (tidal volume), the proportion of the volume in the non-gas
exchanging area is termed the dead space. In the measurement of CO in the exhaled air, the
dead-space gas volume serves to dilute the alveolar CO concentration. Several methods have
been developed to account for the dead-space dilution.
Mixed Expired Gas Using the Bohr Equation
This technique involves the measurement of the mixed expired CO concentration from
which the alveolar CO concentration is calculated. The Bohr equation used to determine the
physiological dead space is:
(8-10)
where F^ is the fractional concentration of a gas in the mixed expired air, V'E is the total
volume of expired gas, F^ is the fractional concentration of the gas in the alveolar space,
VA is the volume of alveolar gas, F^ is the fractional concentration of gas in the inspired air,
VD is the volume of dead-space gas.
8-81
-------
TABLE 844. SUMMARY OF STUDIES COMPARING END-EXPIRED BREATH CARBON MONOXIDE
WITH CARBOXYHEMOGLOBM LEVELS2
Thesis
Methods
Expired
% COHb CO Range
Sample Population (n) Range (ppm)
Blood-Breath Relationship
Reference
Developed rebreathing method to Rebreathing into Douglas bag
estimate COHb from alveolar air
CO concentration
23 (sex not reported) 5-35
M
rco _ com
P0 02Hb
Sjostrand (1948)
Relationship between alveolar
breath CO and blood COHb
levels
Rebreathing method of
SjSstrand (1948)
Blood: venous, van Slyke
55 (men and women; 0-6
smokers and nonsmokers)
No regression equation reported; line of fit Carlsten et al.
as predicted by Haldane equation (1954)
00
00
(si
Using lungs as aerotonoraeters,
sampling of alveolar air allows
estimation of COHb
Verify method of Jones et al.
(1958); apply to community
exposure survey
20-s breath-hold; save end
expired sample
Breath: NDIR corrected
Blood: venous, NDIR
20-s breath-hold; first few
hundred mL volume discarded;
save end-expired sample
Breath: IR (COj scrubbed by
Ascarite)
Blood: venous, NDIR
13 (men and women)
0.7-26.0
4 (men; 2 smokers,
2 nonsmokers)
End-expired breath measurements Not described
can be used as an indicator of
exposure to cigarette smoking and
community air pollution
209 (men, long shoremen, 0.2-19.0
smokers and nonsmokers)
Experimental exposure study
correlating alveolar breath CO
with venous blood COHb
20-s breath-hold; discard first
half expired; save end-expired
Breath: GC and long path IR
Blood: venous, GC
14 (men, white, ages
24 to 42 year)
0-32
2-185 Line of fit as predicted
by Haldane equation:
1+0.00206 [C0ppm]
1.2-20.0 3-100 %COHb = 0.2[CO ] + 0.5
0-82 For respondents (N=130) with
oardiorespiratory conditions:
%COW) = 1.09 + 0.14[C0nnm]
r2 = 0.56
"ppm1
Jones et al.
(1958)
Ringold et al.
(1962)
Goldsmith (1965)
4-250 %COHb = 109.08 + 7.60[CO']-!!.89 Peterson (1970)
SB =1.06% COHb
r = 0.976
-------
TABLE 8-14 (cont'd). SUMMARY OF STUDIES COMPARING END-EXPIRED BREATH CARBON MONOXIDE
WITH CARBOXYHEMOGLOBIN LEVELS*
Thesis
Methods
Sample Population (n)
%COHb
Range
Expired
CO Range
Blood-Breath Relationship
Reference
OO
OO
Bpidemiologio research
investigating tobacco smoking
behavior and blood COHb levels
Developed practical method to
rapidly estimate COHb from
breath samples in field
fire-fighting situation
End-expired air analysis may
be used to distinguish between
populations of smokers and
nonsmokers
Ambient CO levels during time
of breath-holding maneuver bias
%COHb estimate
59 (men and women,
smokers and nonsmokers)
20-s breath-hold; discard first 300
mL; save next 500 mL expired air
Breath: JR (CO2 scrubbed by soda
lime)
Blood: venous, spectrophotometric
20-s breath-hold; discard first portion; 56 (men, fire fighters)
save remainder expired breath
Breath: electrochemical (Ecolyzer
2100) and GC
Blood: not described
Breath: IR (COj scrubbed by soda
lime)
Blood: venous, spectrophotometric
(Tietz and Kereek, 1973)
20-s breath-hold; discard first
portion; save end-expired air
Breath: electrochemical (Ecolyzer
2000)
Blood: venous, IL 192 (verified by
unspecified spectrophotometric
technique)
14 (sex not reported)
46 (sex not reported)
0.3-8.1
0.8-33
0.3-8.0
0.4-11.5
2-41 No regression equation reported; Rea et al. (1973)
estimated regression from bivariate plot:
%COH3) = 0.21 [CO]
1-239 Line of fit as predicted by Haldane Stewart et al. (1976)
equation (without correction for water
vapor pressure):
4-46 %COHb = 0.18[CO ]-0.26 Rawbons etal. (1976)
r2 = 0.92; 95% confidence limits =
±l%COHb
2-64 For constant, low ambient CO
environment:
%com = o.i8[co]
£• = 0.94
For fluctuating, high ambient CO
environment:
%com = o.i4[co ]
r2 = 0.48 -
Smith (1977)
Mixed-expired air samples are 30-s breath-hold and rebreathing
equivalent to 30-s end-expired
air sample collection method
End-expired breath analysis is
useful for estimating %COHb
in traffic control personnel
methods
Breath: IR (CO2 scrubbed by soda
lime)
Blood: venous; IL.282, verified by
spectrophotometric method of Tietz
and Fiereck (1973)
Breath: electrochemical, Ecolyzer
2000
Blood: venous, IL 282
29 (sex not reported)
(4 nonsmokers,
25 smokers)
0.8-10.4
1.1-12.5
8-62
5-60
%COHb = 0.395|
-------
TABLE 8-14 (eont'd). SUMMARY OF STUDIES COMPARING END-EXPIRED BREATH CARBON MONOXIDE
WITH CARBOXYHEMOGLOBIN LEVELS3 '
Thesis
Methods
SSCOHb
Sample Population (n) Range
Expired
CO Range
(ppm) Blood-Breath Relationship
Reference
In subjects with emphysema,
decreased end-expired [CO] is
attributed to impaired diffusion
End-expired breath anilysis may
be used to distinguish between
smokers and noosmokers
To most accurately estimate
%COHb, end-expired breath
samples requite a correction for
Inspired ambient CO at time of
sampling
The correction for inspired air
may vary between persons
20-s breath-hold; expire to bag
Breath: electrochemical, Ecolyzer
2000
Blood: venous, EL 282
182 smokers
35 emphysema patients
(sex not repotted)
0.3-14.5
187 (men; 162 smokers, 0.4-13
25 nonsmokers)
20-s breath-hold; expire to
collection tube
Breath: electrochemical, Ecolyzer
2000
Blood: venous, IL 182
20-s breath-hold; discard first
portion; save end-expired
Breath: electrochemical, COED-1
(GE)
Blood: not sampled
20-s breath-hold at room air CO 7 (sex not reported)
level and at 10, 30, and 50 ppm CO
1 (male, nonsmoker)
Cigarette smoking interferes with 20-s breath-hold
alveolar sampling Breath: E. (CO2 scrubbed before
analysis)
Blood: venous, OSM2
spectrophotometer
101 smokers (42 men,
59 women)
0-12
4-90 For normal smokers: Jarvis et si, (1980)
%COHb = -0.28+0.175[CO_ J
r2 = 0.98;SE = 0.76%COHb
For emphysema patients: r^ = 0.92
Slopes of two regression lines were
significantly different
3-65 %COHb = 0.18[0? ]-0.14 Wald et al. (1981)
r = 0.97
— I "ppnvmeasured
Wallace (1983)
10-50 I«>Wi««««rf" Wallace etal. (1988)
"' P«yv+o-i7(±o-n)
4-71 %COBb = 0.034 + 0.179 lCOppmI Guyatt et al. (1988)
r = 0.938
aNotes: ND = No data are available. See glossary of terms and symbols for abbreviations and acronyms.
Source: Adapted from Lambert and Colome (1988).
-------
Solving this equation for CO concentration in the alveolar gas results in:
-V) (8-11)
CO "" "CO
This equation has been used by Rawbone et al. (1976)* to describe the relationship
between alveolar CO concentrations and COHb levels. These investigators measured inspired
ventilatory volume, inspired CO concentration, and estimated dead space from anatomical
correlations. Carbon monoxide concentration must be converted to partial pressure in order
to relate alveolar gas tension to percent COHb. However, the transfer of CO from blood to
the alveolar gas phase is not in equilibrium, so the alveolar gas is a reflection of the partial
pressure of CO in the capillary blood. This is demonstrated by the increase in alveolar CO
with breath holding. The relationship between alveolar levels determined from mixed expired
CO concentrations and percent COHb is comparable to that of other methods (Table 8-14).
Breath-hold
Early methods of measurement of CO concentration in air samples by
nonchromatographic techniques required a relatively large sample of gas, usually larger than
1 L. Therefore, end-tidal (alveolar) gas samples from normal respiration would not provide a
sample of sufficient volume for analysis. Jones et al. (1958) developed a method of
inspiration to total lung capacity followed by a breath-hold period of various durations.
A breath-hold time of 20 s was found to provide near maximal values for CO pressures. The
breath-hold period allows more time for diffusion of CO from the blood into Hie alveolar
space.,
The precision of the method has been found to be of the order of 0.1 to 0.2 ppm by
several investigators (Hartwell et al., 1984; Wallace et al., 1988; Lambert et al., 1988). This
is the theoretical equivalent of 0,02 to 0.04% COHb. Physiologically, however, the breath-
hold gas is not normal alveolar gas because this breath-hold maneuver results in the CO2
*
concentration being below normal, with presumably an elevated O2 tension (Jones et al.,
1958; Guyattetal., 1988).
The blood breath-hold alveolar air/CO relationship is influenced by the inspired pressure
level of CO. Several investigators (Smith, 1977; Wallace, 1983; Wallace et al., 1988) have
8-85
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found that a correction is required in the CO pressure found in the breath-hold sample. This
is an important consideration, when this method is used to assess the exposure of subjects in
their normal environment (see Section 8.5.2.2).
Rebreathing
The earliest approach to obtaining a sufficient volume of exhaled air was rebreathing
5 L of O2 for 2 to 3 min while removing the CO2 (Hackney et al,, 1962; Carlsten et al.,
1954). Hackney et al. (1962) reported that the O2 content in the rebreathing system fell due
to dilution over the first minute, after which the decline in O2 was related to the
O2 consumption of the subject. The CO concentration in the system reached its peak value at
1 min of rebreathing in healthy subjects. Hackney et al. also reported that the CO r
concentration in the system was related to the O2 tension in the system. The advantage to
using a rebreathing system is that the ratio of change in percent COHb to change in expired
CO is between 27 (Hackney et al,, 1962) and 3.0 pprn/percent COHb (Carlsten et al., 1954),
This a gain of fivefold over the breath-hold method of Jones et al. (1958). The disadvantages
are the time required for the measurement and the need to measure O2 in the system.
Summary of the Methods • .-• .
Kirkham et al. (1988) compared all three techniques for measuring expired CO to
predict percent COHb. The rebreathing and breath-hold methods both yield approximately
20% higher levels of "alveolar" CO than does the Bohr computation from mixed expired gas.
Subjects rebreathed from a system that contained 20% O2 for the 3 min of the rebreathing.
Kirkham et al. (1988) also carried out an experiment to determine if these techniques had
reached a steady state between alveolar gas and blood levels. If a steady state existed, then
changes in ventilation/perfusion and capillary blood volume would not effect the relationship.
Ventilation/perfusion was altered by changing body position from lying to standing. Both the
mixed-expired and breath-holding techniques showed a significant decline in the alveolar CO
tension when standing. Therefore, measurements of expired CO must be made in the same
body position relative to control measurements or reference measurements.
The conventional relationship between blood and expired CO is assumed to be linear
(Table 8-14). Data collected by Rees et al. (1980), however, indicates that the relationship is
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not linear. A second order polynomial equation proved to be the best fit of the data where
percent COHb = 3.95 (CO) - 0.32 (CO)2 - 2.4. Guyatt et al. (1988) also reported a
nonlinear relationship where: %COHb = -0.47 + 0.217 (CO) - 0.0006 (CO)2. Peterson
(1970) also found that a quadratic equation described the relationship between
percent COHb over the range of 0 to 30% COHb. Without more precise data, the
relationship between FA(COj and COHb for under 5% COHb appears to be sufficiently linear
to justify the use of a linear expression to predict percent COHb from Fco\ measurements.
8.5.2.2 Breath Measurements in Populations
There are numerous approaches described in the literature utilizing the above methods
for the collection and analysis of CO in expired air. In addition, many of the investigators
have also provided data demonstrating a relationship between the concentration of CO in
ambient or expired air samples and the percent COHb in blood. All of these approaches
show internally consistent results and are based on the assumption that the air collection
methodology represents expired alveolar air. In making comparisons, differences in
collection methods, analytical techniques, smoking history, and types of subjects being
studied must be considered. For example, possible subjects include hospital patients with
certain types of medical histories, joggers, and the general population. Sampling locations
vary as well, ranging from outdoors to indoors and from clinics to living rooms.
A study by Wallace (1983) in which breath measurements of CO were used to detect an
indoor air problem has been cited previously in this chapter (see Section 8.4.3). Sixty-five
workers in an office had been complaining for some months of late-afternoon sleepiness and
other symptoms, which they attributed to the new carpet. About 40 of the workers had their
breath tested for CO on a Friday afternoon and again on a Monday morning. The average
breath CO levels decreased from 23 ppm on Friday to 7 ppm on Monday morning
(Figure 8-6), indicating a work-related condition. Nonworkmg fans in the parking garage
and broken fire doors were identified as the cause of the problem. In this case, the ease with
which the breath measurements were taken contributed to the swiftness with which the
problem was identified and rectified (Figure 8-7). All measurements were taken in a period
of less than 2 h, without the necessity for drawing blood, sterilizing needles, or using a
trained phlebotomist.
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Figure 8-7. Eight-hour average carbon monoxide concentrations in basement office
before and after corrective action.
Source: Wallace (1983).
alveolar air were collected at 2-min intervals within 5 min of collecting venous blood for
COHb estimation. Alveolar air was collected by having the subject hold his breath for 20 s
and then exhale through a 1-m glass tube with an internal diameter of 17 mm and fitted with
a 3-L anesthetic bag at the distal end. Air at the proximal end of the tube was considered to
be alveolar air, and a sample was removed by a small side tube located at 5 mm from the
mouthpiece. CO content was measured using an Ecolyzer. The instrumental measurement is
based on detection of the oxidation of GO to CO2 by a catalytically active electrode in an
aqueous electrolyte. The mean of the last two readings to the nearest 0.25 ppm was recorded
as the alveolar CO. Subjects reporting recent alcohol consumption were excluded because
ethanol in the breath affects the response of the Ecolyzer. A linear regression equation of
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percent COHb on alveolar CO (see Table 8-14) had a correlation coefficient of 0.97,
indicating that a COHb level could be estimated reliably from an alveolar CO level.
Honigman et al. (1982) determined alveolar CO concentrations by end-expired breath
analysis for athletes (joggers). The group included 36 nonsmoking males and 7 nonsmoking
females, all conditioned joggers, covering at least 21 mi/week for the previous 6 months in
the Denver area. The participants exercised for a 40-min period each day over one of three
defined courses in the Denver urban environment (elevation 1,610 m). Expired air samples
were collected and analyzed before start of exercise, after 20 min, and again at the end of the
40-min exercise period. Heart rate measurements at 20 min and 40 min were 84 and 82% of
mean age-predicted maxima, respectively, indicating exercise in the aerobic range. Relative
changes in expired air CO concentrations were plotted and compared to ambient air
concentrations for CO measured at the time of collecting breath samples. Air and breath
samples were analyzed using an MSA model 70. Relative changes in expired end-air CO
based on the concentration of CO in breath before the start of exercise were plotted in terms
of the ambient air concentrations measured during the exercise period, at both 20 and 40 min
of exercise. For ambient concentrations of CO below 6 ppm, the aerobic exercise served to
decrease the relative amount of end-air-expired CO as compared to the concentration
measured before the start of exercise. For ambient concentrations in the range of 6 to
7 ppm, there was no net change in the CO concentrations in the expired air. For ambient air
concentrations in excess of 7 ppm, the aerobic exercise resulted in relative increases of
expired CO, with the increases after 40 min being greater than similar increases observed at
the 20 min measurements. Sedentary controls at the measurement stations showed no relative
changes. Thus, aerobic exercise, as predicted by the physiologic models of uptake and
elimination, is shown to enhance transport of CO, thereby decreasing the time to reach
equilibrium conditions.
Verhoeff et al. (1983) surveyed 15 identical residences that used natural gas for cooking
and geyser units for water heating. Carbon Monoxide concentrations in the flue gases were
measured using an Ecolyzer (2000 series). The flue gases were diluted to the dynamic range
of the instrument for CO (determined by Draeger tube analyses for CO2 dilution to 2 to
2.5%). The theoretical concentration for CO2 in the flue gases is 11.70% under conditions
of zero excess air for the natural gas to air mixture used. Breath samples were collected
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from 29 inhabitants by having each participant hold a deep breath for 20 s and exhale
completely through a glass sampling tube (225-mL volume). The sampling tube was
stoppered and taken to a laboratory for analysis of CO content using a gas-liquid
chromatograph (Hewlett Packard, 5880A). The overall coefficient of variation for sampling
and analysis was 7%, based on results of previous measurements. No significant differences
were observed for nonsmokers as a result of their cooking or dishwashing activities using the
natural gas fixtures. There was a slight increase in expired air CO for smokers, but this may
be due to the possibility of increased smoking during the dinner hour.
Wallace et-al. (1984) report data on measurements of end-expired air CO and
comparisons with predicted values based on personal CO measurements:for populations in
Denver and Washington, DC. Correlations between breath CO and preceding 8-h average
CO exposures were high (0.6 to 0.7) in both cities. Correlation coefficients were calculated •
for 1-h to" 10-h average personal CO exposures in 1-h increments; the highest correlations
occurred at 7, to 9 h, providing support for the EPA choice of 8 h as an-averaging time for
the NAAQSi However, breath CO levels showed no relationship with ambient, CO
measurements at the nearest fixed-station monitor. «
The major large-scale study employing breath measurements of CO was carried out by
EPA in Washington and Denver in the winter of 1982 to 1983 (Johnson, 1984; Hartwell
et al.» 1984; Akland et al., 1985; Wallace et al., 1984, 1988), In Washington, '870 breath ,
samples were collected from 812,participants; 895 breath samples were collected from .
454 Denver participants (two breath samples on two consecutive days in Denver). All
participants also carried personal monitors to measure their exposures over a 24-h period in
Washington or a 48-h period in Denver. The subjects in each city formed a probability
sample representing 1.2 million adult nonsmokers in Washington and 500,000 adult
nonsmokers in Denver. The distribution of breath levels in the two cities is shown for the
subjects themselves ("unweighted" curves) and the larger populations they represented
("weighted" curves) in Figure 8-8. •
These distributions appear to be roughly lognornial, with geometric means of 5.2 ppm
CO for Denver and 4.4 ppm CO for Washington. Geometric standard deviations were about
1.6 for each city. Arithmetic means were 7.1. ppm for Denver and 5.2 ppm for Washington.
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99.99 99.9 99 98 95 90 80
50
20 10 5 2 1 0.5 0.1 0.01
Carbon Monoxide Concentrate, ppm
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Cumulative Frequency, %
Figure 8-9. Percent of Washington sample population with 8-h average carbon
monoxide exposures exceeding the concentrations shown. The 8-h period
ended at the time the breath sample was taken. The curve marked
"Observed" contains the actual readings of the personal monitors; these
readings were corrected using the measured breath values.
Source: Wallace et al. (1988).
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1982 to 1983. Models based on fixed-station readings would have predicted that an
exceedingly tiny proportion of the Washington population received exposures exceeding the
standard. Therefore, the results from the breath measurements indicated that a much larger
portion of both Denver and Washington residents were exceeding 2% COHb than was
predicted by models based on fixed-station measurements.
It also should be noted that the number of people with measured maximum 8-h
exposures exceeding the EPA outdoor standard of 9 ppm was only about 3.5% of the
Washington subjects. This value appears to disagree with the value of 10% obtained from
the corrected breath samples. However>, the personal monitors used in the study were shown
to experience several different problems, including a loss of response associated with battery •
discharge toward the end of the 24-h monitoring period, which caused them to read low.
Therefore, Wallace et al. (1988) concluded that the breath measurements were correct and the
personal air measurements were biased low. The importance of including breath
measurements in future exposure and epidemiology studies is indicated by this study.
Hwang et al. (1984) describe the use of expired air analysis for CO in an emergency
clinical setting to diagnose the presence and extent of CO intoxication. The subjects were
47 Korean patients brought for emergency treatment showing various levels of consciousness
ranging from alertness (11), drowsiness (21), stupor (7), semicoma (5), coma (1), and
unknown (2). The study group included 16 males, ages 16 to 57, and 31 females, ages
11 to 62. Exposure durations ranged from 2 to 10 h, with all exposures occurring in the
evening and nighttime hours. The source of CO Was mainly from use of charcoal fires for
cooking and heating. In order to estimate expired-air CO concentrations, a detector tube
(Gastec ILa containing potassium paUadosulfite as both a reactant and color-change indicator
for the presence of CO on silica gel) was fitted to a Gastec manual sampling pump. One
stoke of the sampling plunger represents 100 cc of air. A 100-cc expired-air sample was
collected by inserting a detector tube at a nostril and slowly pulling back the plunger for one
full stroke for expired air. A 10-cc sample of venous blood also was collected at this time
for determination of percent COHb using a CO-Oximeter. The subjects showed signs of
acute intoxication and significant relationships were found between expired air CO and
percent COHb for low (< 100 ppm) and high (•> 100 ppm) CO concentrations.
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Cox and Whichelow (1985) analyzed aid-exhaled air (collected over approximately the
last half of the exhalation cycle) for CO concentrations for a random population of
168 adults—69 smokers and 99 nonsmokers. The results were used to evaluate the influence
of home heating systems on exposures to and adsorption of CO. Ambient indoor
concentrations of CO were measured in the homes of study subjects. The subjects included
86 men and 82 women, ranging in age from 18 to 74. Interviews usually were conducted in
the living room of the subject's home. The type of heating system in use was noted and the
indoor air concentration of CO was measured using an Ecolyzer. After the ambient indoor
CO was determined, a breath sample was collected from the subject. The subject was asked
to hold a deep breath for 20 s, and then to exhale completely into a trilaminate plastic bag.
The bag was fitted to the port of the Ecolyzer and the CO content of the exhaled air was
measured. For smokers, the time since smoking their last cigarette and the number of
cigarettes per day were noted. For nonsmokers, there was a strong correlation between
ambient CO and expired air CO. With smokers, the correlation was strongest with the
number of cigarettes per day. The data also supported the supposition that smokers are a
further source of ambient CO in the indoor environment.
Lambert et al. (1988) compared breath CO levels to blood COHb levels in 28 subjects
(including two smokers). Breath CO was collected using the standard technique developed by
Jones et al. (1958): maximal inspiration was followed by a 20-s breath-hold and the first
portion of the expired breath was discarded. One-liter bags were used to collect the breath
samples, which were measured on an Ecolyzer 2000 monitor equipped with Purafil® and
activated charcoal filters to scrub interferences such as alcohol. Excellent precision
(+0.2 ppm),was obtained in 35 duplicate samples. Blood samples were collected within
15 min of the breath samples using a gas-tight plastic syringe rinsed with sodium heparin.
Carboxyhemoglobin was measured using an IL 282 CO-Oximeter. Some samples also were
measured using a gas chromatograph. The CO-Oximeter appeared to be reading high,
particularly in the <2% COHb range of interest. A reading of 0.5 %COHb on the particular
CO-Oximeter used in this study would be only 0.3% using the gas chromatograph and a
reading of 1% COHb on the CO-Oximeter would be only 0.7% on the gas chromatograph.
The results showed poor correlation between the pooled nonsmokers' breath-CO and ,
blood COHb levels (n = 104 measurements, r2 = 0.19). However, better correlation was
8-95
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observed for three individual nonsmoking subjects, who appeared to have roughly parallel
slopes (0.13 to 0.27) but widely differing blood COHb intercepts (0.1, 0.4, and
1.0% COHb). The authors interpreted these findings as suggesting that the CO-Oximeter
may be sensitive to an unidentified factor in the blood of individuals. Possible factors
suggested by the authors include triglycerides and hemochromagens (a group of compounds
formed when heme combines with organic nitrogen species), which are known to absorb light
in the 550 to 555 nm wavelength used by the CO-Oximeter. Another concern regarding the
CO-Oximeter is the calibration method, which uses saturated (98% COHb) bovine serum a,s
the only span calibration point. This is far above the 0.5 to 3% COHb range of interest for
nonsmoking subjects.
In view of the great dependence in laboratory studies on the CO-Oximeter, the authors
concluded that there was "an important and immediate need to further investigate the
instrument's performance at COHb levels resulting from typical ambient exposures." Such
4
studies should include a comprehensive side-by-side study with other reference methods, ;
including gas chromatography, manometry, and other spectrophotometric methods. Full .
spectral scans should be performed to quantify light absorbance and scattering effects on
COHb measurement. Also, an improved calibration method should be developed, including
whole blood and dye standards and the use of multiple calibration points in the 0-to-
3% COHb range of interest.
8.5.3 Potential Limitations
8.5.3.1 Pulmonary Disease
A major potential influence on the relationship between blood and alveolar partial
pressures of CO is the presence of significant lung disease. Hackney etal. (1962)
demonstrated the slow increase in exhaled CO concentration in a rebreathing system peaked
after 1.5 min in healthy subjects but required 4 min in a subject with lung disease. These
findings have been substantiated by Guyatt et al. (1988), who reported that patients with
pulmonary disease did not have the same relationship between percent COHb and breath-hold
CO concentrations. The group with pulmonary disease had a FEVj/FVC percentage of
<71.5% compared to the healthy subjects with a FEVj/FVC percentage of >86%. The
linear regression for the healthy group was COHb =,0,629 + 0.15S(ppm CO); for the
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pulmonary disease group the linear regression was COHb = 0.369 + Q.l%5(ppm CO). This
means that at low CO levels, individuals with obstructive pulmonary disease would have a
lower "alveolar" CO level for any given percent COHb level than would the healthy subjects.
8.5.3.2 Subject Age
The relationship between age and COHb level is not well established. Kahn et al.
(1974) reported that nonsmoking subjects under the age of 19 years had a significantly lower
percent COHb than older subjects, but there was no difference in COHb between the ages of
20 and 59 years. Kahn et al. (1974) also reported that there was a slight decrease in the
COHb levels in nonsmoking subjects over the age of 60 years. Radford and Drizd (1982)
also reported that younger subjects, 3 to 11 years old, had lower levels of COHb than did the
older age group of 12 to 74 years. Goldsmith (1970) reported that expired CO levels were
unchanged with age in nonsmokers; however, there was a steady decline in the expired CO
levels with age in smokers. The decrease in expired CO is disproportionately large for the
decrease in COHb levels measured by Kahn et al. (1974) in older subjects. Therefore, by
comparison of the data from these two studies, it would appear that older subjects have
higher levels of COHb than predicted from the expired CO levels. It is not known how
much of this effect is due to aging of the pulmonary system, resulting in a condition similar
to the subjects with obstructive pulmonary disease.
8.5.3.3 Effects of Smoking
Studies evaluating the effect of cigarette smoking on end-expired CO have found a
phasic response that depends on smoking behavior (Woodman et al., 1987; Henningfield
et al., 1980). There is an initial rapid increase in the CO concentration of expired air as a
result of smoking. This is followed by a rapid (5-min) decrease after cessation of smoking
and a slow decrease over the 5- to 60-min period after smoking. A comparison of the results
from one study (Tsukamoto and Matsuda, 1985) showed that the CO concentration in expired
air increases by approximately 5 ppm after smoking one cigarette. This corresponds to an
increase of 0.67% COHb based on blood-breath relationships developed by the authors. Use
of cigarettes with different tar and nicotine yields or the use of filter tip cigarettes showed no
apparent effect on end-expired CO concentrations (Castelli et al., 1982). However,
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knowledge of the breath sample results does. King et al. (1983) were able to show that
immediate feedback on CO concentrations promoted behavioral changes in cigarette smokers
that subsequently resulted hi lower CO concentrations in expired air for return visits.
Furthermore, reported rates of smoking were lower for the second visit than those reported
for the first visit.
The relationship between breath-hold CO and blood CO is apparently altered due to
smoking, making the detection of small changes difficult. Guyatt et al. (1988) have shown
that smoking one cigarette results in a variable response in the relationship between breath-
hold alveolar CO \FACO(Bhy\ and COHb levels. The range of FACO(Bh) values for a 1 %
increase in COHb was from -5 ppm to +5 ppm. The correlation between the change in
FACO(Bh) and the change in COHb in 500 subjects was only 0.705. This r value indicates
that only 50% of the change in FACO(Bh) was due to changes in COHb. It is not known
how much of this residual error is due to subject compliance or to error in the method.
Therefore, the results obtained with breath-holding in smoking subjects should be viewed
with caution unless large differences in FACO(BK) are reported (i.e., considerable cigarette
consumption is being evaluated).
In summary, the measurement of exhaled breath has the advantages of ease, speed,
precision, and greater subject acceptance than measurement of blood COHb. However, the
accuracy of the breath measurement procedure and the validity of the Haldane relationship
between breath and blood at low environmental CO concentrations remains in question.
There appears to be a clear research need to validate the breath method at low CO exposures.
In view of the possible problems with the CO-Oximeter, such validation should be done using
gas ehromatography for the blood COHb measurements.
8.6 SUMMARY AND CONCLUSIONS
The current NAAQS for CO (9 ppm for 8 h, 35 ppm for 1 h) are designed to protect
against actual and potential human exposures in outdoor air that would cause adverse health
effects. Compliance with the NAAQS is determined by measurements taken at fixed-site
ambient monitors, the use of which is intended to provide some measure of the general level
of exposure of the population represented by the CO monitors. Results of both exposure
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monitoring in the field and modeling studies, summarized in this chapter, indicate that
individual personal exposure does not directly correlate with CO concentrations determined
by using fixed-site monitors alone. This observation is due to the mobility of people and to
the spatial and temporal variability of CO concentrations. Although they fail to show a
correlation between individual personal monitor exposures and simultaneous nearest fixed-site
monitor concentrations, studies do suggest that aggregate personal exposures are lower on
days of lower ambient CO levels as determined,by the fixed-site monitors and higher on days
of higher ambient levels. .
Cigarette consumption represents a special case of CO exposure; for the smoker, it
almost always dominates over personal exposure from other sources. Studies by Radford and
Dridz (1982) show that COHb levels of cigarette smokers average 4% whereas those of
nonsmokers average 1 %. Therefore, this summary focuses on environmental exposure of
nonsmokers to CO*
•People encounter CO in a variety of environments that include traveling in motor
vehicles, working at their jobs, visiting urban locations associated with combustion sources,
or cooking over a gas range. Studies of human exposure have shown that among these
settings, the motor vehicle is the most important for regularly encountered elevations of CO.
Studies by Flachsbart et al. (1987) indicated that CO exposures while commuting in> •
Washington, DC, average 9 to 14 ppm at the same time that fixed-station monitors record
concentrations of 2.7 to 3.1 ppm. Similar studies conducted by EPA in Denver and
Washington have demonstrated that the motor vehicle interior has the highest average CO
concentrations (averaging 7 to 10 ppm) of all microenvironments (Johnson, 1984). In these
studies, 8% of all commuters experienced 8-h exposures greater than 9 ppm, whereas only
1% of noncommuters received exposures over that level. Furthermore, commuting exposures
have been shown to be highly variable, with some commuters breathing CO in excess of
25 ppm. . •....:'.•,•' ": •>.;.-.• \:\< '.-.-. ;;/
Another important setting for CO exposure is the workplace. In general, exposures at
work exceed CO exposures during nonwork periods, apart from commuting to and from,
work;. Average concentrations may be elevated during this period because workplaces t are
often located in congested areas that have higher background CO concentrations than do many
residential neighborhoods. Occupational and nonoccupational exposures may overlay one
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another and result in a higher concentration of CO in the blood. Certain occupations also
increase the risk of high CO exposure (e.g., those occupations involved directly with vehicle
driving, maintenance, and parking). Occupational groups exposed to CO by vehicle exhaust
include auto mechanics; parking garage.and gas station attendants; bus, truck, or taxi drivers;
police; and warehouse workers. Other industrial processes produce CO directly or as a
by-product, including steel production, coke ovens, carbon black production, and petroleum
refining. Firefighters, cooks, and construction workers also may be exposed at work to:
higher CO levels. Occupational exposure in industries or settings with CO production also
represent some of the highest individual exposures observed in field monitoring studies. For
example, in EPA's CO exposure study in Washington, of the approximately 4% (29 of 712)
of subjects working in jobs classified as having a high potential for CO exposure, 7 subjects
(or approximately 25%) experienced 8-h CO exposures in excess of 9 ppm.
The highest indoor nonoccupational CO exposures are associated with combustion
sources and include enclosed parking garages, service stations, restaurants, and stores. The
lowest indoor CO concentrations are found in homes, churches, and health care facilities.
EPA's Denver Study showed that passive cigarette smoke is associated with increasing a
nonsmoker's exposure by an average of about 1.5 ppm and that use of a gas range is
associated with an increase of about 2.5 ppm at home. Other sources that may contribute to
CO in the home include combustion space heaters and wood-burning stoves.
As noted above, people encounter different and often higher exposures than predicted
from fixed-site monitoring data because of the highly localized nature of CO sources. For
example, during the winter sampling period, 10% of Denver volunteers and 4% of
Washington volunteers recorded personal exposures in excess of 9 ppm for 8 h. Breath
measurements from the Washington volunteers indicated that as much as 9% of the
population could have experienced a 9-ppm, 8-h average. In contrast, during the entire
winter period of 1982 to 1983, the two ambient CO monitors in Washington reported only
one exceedance of the 9-ppm level. In another study, using data from analyses of COHb in
blood, Wallace and Ziegenfus (1985) report that CO in blood is uncorrelated with CO
measured by ambient monitors. These findings point out the necessity of having personal CO
measurements augment fixed-site ambient monitoring data when total human exposure is to be
evaluated. Data from these field studies can be used to construct and test models of human
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exposure that account for time and activity patterns known to affect exposure to CO. Models
developed to date tend to underpredict the variability of CO exposures observed in field
studies and have not been able to successfully predict individual exposures. The models may
be modified and adjusted using information from field monitoring studies in order to capture
the observed distribution of CO exposures, including the higher exposures found in the tail of
the exposure distribution. The models also are useful for evaluating alternative pollutant
control strategies.
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REFERENCES
Akland, G. G.; Ott, W. R.; Wallace, L. A. (1984) Human exposure assessment: background concepts, purpose,
and overview of the Washington, DC - Denver, Colorado field studies. Presented at: 77th annual meeting
of the Air Pollution Control Association; June; San Francisco, CA. Pittsburgh, PA: Air Pollution
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9. PHARMACOKUSfETICS AND MECHANISMS OF
ACTION OF CARBON MONOXIDE
Pharmacokinetics in the classical sense has been concerned primarily with the
determination of blood levels for various dosage regimens of pharmacological agents. More
modern approaches tend to extend the definition to include other aspects of substance
kinetics. For example, it may include membrane diffusion, substance binding and release
characteristics, modeling, metabolic pathways, and other processes. The general tendency is
to depart from anatomically or physiologically defined region(s) to a more encompassing and
unifying concept of compartment(s) comprised of real as well as abstract constructs (Bischoff,
1986), It will be in this sense that the carbon monoxide (CO) pharmacoMnetics will be
approached and presented in this chapter.
9.1 ABSORPTION, DISTRIBUTION, AND PULMONARY
ELIMINATION
9.1.1 Introduction
>
The scope of this chapter and generally of this criteria document does not allow for an
extensive review of the mechanisms and factors involved in CO uptake and elimination. The
review will concentrate on fundamental processes and the key factors affecting CO
metabolism and resultant effects. For a more in-depth explanation of certain facets of CO
toxicity, the reader is referred to other chapters of this document and to other review material
(FishmanetaL, 1987).
9.1.2 Pulmonary Uptake
9.1.2.1 Mass Transfer of Carbon Monoxide
Although CO is not one of the respiratory gases, the similarity of the physicochemical
properties of CO and oxygen (O2) permit an extension of the findings of studies on the
kinetics of transport of O2 to those of CO.
The rate of formation and elimination of carboxyhemoglobin (COHb), its concentration
in blood, as well as its catabolism are controlled by numerous physical and physiological
9-1
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mechanisms. The relative contribution of these mechanisms to the overall COHb kinetics
will depend on the environmental conditions (ambient CO concentration, altitude, etc.);
physical activity of an individual; and many other physiological processes, some of which are
complex and still poorly understood.
The mass transport of CO between the airway opening (mouth and nose) and red blood
cell (KBC) hemoglobin (Hb) is predominantly controlled by physical processes. The CO
transfer to the Hb-binding sites is accomplished in two sequential steps: (1) transfer of CO in
a gas phase, between the airway opening and the alveoli; and (2) transfer in a "liquid" phase,
across air-blood interface including the KBC. Although the mechanical action of the
respiratory system and the molecular diffusion within the alveoli are the key mechanisms of
transport in the gas phase, the diffusion of CO across the alveolp-eapillary barrier, plasma, ,
and KBC is the virtual mechanism of the liquid phase.
9,1.2.2 Effects of Dead Space and Uneven Distribution of Ventilation and Perfusion
Ideally, the optimal transfer of gases across alveole-capillary membrane can be achieved
only if regional distribution of ventilation is uniform and matches regional blood flow.
Numerous studies have shown that in the upright subject, ventilation is preferentially ,
distributed to the lower lung zones (Milic-Emili et al.,. 1966). Besides posture (Clarke et al.,
1969), changes in resting lung volume (Sutherland et al., 1968), airway resistance (Hughes ,
et al., 1972), and lung compliance (Glaister et al., 1973) by either exogenous factors or
pathophysiological conditions will aggravate maldistribution of ventilation. The unevenness is
further affected by inspiratory (Anthonisen et al., 1970) and expiratory flow rates (Millette ;
et al., 1969), which influence sequential filling and emptying of the lung regions.
Even in perfectly healthy subjects, the homogeneity of ventilation, perfusion, and
consequent ventilation to perfusion ratio (VA/Q ratio) of unity is unattainable because of a
right-to-left shunt. Normally, only a small amount of mixed venous blood (2 to 4%)
bypasses the alveoli and reaches systemic circulation without oxygenation. Any increase in
the alveolar-arterial O2 gradient will contribute to hypoxemia, thus enhancing CO loading
(Riley and Permutt, 1973). It follows that any imbalance in the distribution patterns of these
two compartments must result in a decrease in the efficiency of gas exchange (Scrimshire,
1977), including CO exchange. The average VA/Q ratio of about 0.9 reported in the.. •
9-2
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upright subjects indicates that overall perfusion exceeds ventilation; regional nommiformity,
however, is considerably greater (the VA/Q ratios range from 0.6 to 3.0; Inkley and
Maclntyre, 1973). Consequently, in the underventilated but overperfused regions of the lung,
the amount of CO available for diffusion will be less than if the ventilation and perfusion
were matched, whereas in the overventilated but underperfused regions, the amount of CO
that could diffuse would be the same as if the distributions were matched. On exercise, when
the distribution of both ventilation and perfusion becomes more uniform, the ratios increase
above resting levels and the rate of COHb formation will accelerate (Harf et al., 1978).
Besides regional inhomogeneity of distribution, the bulk movement of inhaled air will
be influenced by factors related to inspiratory flow and subsequent mixing with residual air.
At rest, mixing of gases is almost complete and no discernible stratification of concentration
between the large airways and the alveoli occurs. However, any changes in ventilation or
pattern of breathing (e.g., during exercise) will aggravate stratified inhomogeneity and
increase a concentration gradient between central and peripheral airways. The relative effects
of ventilation and perfusion inhomogeneities on convectional and diffusional transport of CO
will very much depend on the rate of change and concentration of CO in inspired air. The
higher the concentration and the shorter the rise time of CO in the inspired air, the greater
the effects these factors will have on the CO uptake and ultimately COHb concentration in
blood. ,
The ventilation-perfusion unevenness will not only contribute to hypoxemia, but the
mismatch will influence the size of the physiological dead space (VD) (Standfuss, 1970) and
ultimately alveolar ventilation, which is one of the principal, but seldom-measured
determinants of the rate of uptake of CO (see Section 9.3 on Coburn-Forster-Kane [CFK]
modeling). Any increase in a dead space to tidal volume ratio will decrease alveolar
ventilation and vice versa. In normal healthy subjects at rest, VD comprises about 25 to 45%
of tidal volume; in older subjects or in patients with pulmonary disease, the percentage might
be as high as 70% (Martin et al., 1979).
9.1.2.3 Alveolo-Capillary Membrane and Blood-Phase Diffusion
Although the above mechanisms controlling the rate of formation of blood COHb are
predominantly active processes, the second key mechanism, a diffusion of gases across the
9-3
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alveolar air-Hb barrier, is an entirely passive process. In order to reach the Hb-binding sites,
CO and other gas molecules have to pass across the alveolo-capillary membrane, diffuse
through the plasma, pass across the RBC membrane, and finally enter the RBC stroma before
reaction between CO and Hb can take place. The molecular transfer across the membrane
and the blood phase is governed by general physicochemical laws, particularly by Pick's first ,
law of diffusion. The exchange and equilibration of gases between the two compartments (air
and blood) is very rapid. The dominant driving force is a partial pressure differential of CO
across this membrane. For example, inhalation of a bolus of air containing high levels of CO
will rapidly increase blood COHb; by immediate and tight binding of CO to Hb, the partial
pressure of CO within the RBC is kept low, thus maintaining a high pressure differential ,
between air and blood, and consequent diffusion of CO into blood. Subsequent inhalation of
CO-free air progressively decreases the gradient to the point of its reversal (higher CO
pressure on the blood side than alveolar air) and CO will be released into alveolar air. The
air-blood pressure gradient for CO is usually much higher than the blood-air gradient;
therefore, the CO uptake will be a proportionally faster process than CO elimination. The
rate of CO release will be further affected by the products of tissue metabolism. Under
pathologic conditions, where one or several components of the air-blood interface might be
severely affected, as in emphysema, fibrosis, or edema, both the uptake and elimination of.
CO will be affected.
The rate of diffusion of gases might be altered considerably by many physiological
factors acting concomitantly. Diurnal variations in CO diffusion related to variations in Hb
have been reported'in normal, healthy subjects (Frey et al., 1987). Others found the changes
to be related also to physiological factors such as oxyhemoglobin (O2Hb), COHb, partial
pressure of alveolar carbon dioxide (CO^, ventilatory pattern, O2 consumption, blood flow,
functional residual capacity, etc. (Forster, 1987). It has been confirmed repeatedly that
diffusion is body-position and ventilation dependent. In a supine position at rest, CO
diffusion has been significantly higher than that at rest in a sitting position. In both positions,
CO diffusion during exercise has been greater than at rest (McClean et al., 1981). Carbon
monoxide diffusion will increase with exercise, and at maximum work rates the diffusion will
be maximal regardless of position. This increase is attained by increases in both the
membrane-diffusing component and the pulmonary capillary blood flow (Stokes et al., 1981).
9-4
-------
Diffusion seems to be relatively independent of lung volume within the midrange of vital
capacity. However, at extreme volumes, the differences in diffusion rates could be
significant; at total lung capacity, the diffusion is higher, whereas at residual volume it is
lower than the average (McClean et al., 1981). Smokers showed on the average lower
diffusion rates than nonsmokers (Rnudsonet al., 1989).
The above physiological processes will minimally affect COHb formation in.healthy
individuals exposed to low and relatively uniform levels of CO. Under such ambient
conditions, these factors will be the most influential during the initial period of CO
distribution and exchange. If sufficient time is allowed for equilibration, the sole determinant
of COHb concentration in blood will be the ratio of the partial pressures of CO (PCO) and
O2 (PO2J. However, the shorter the half-time for equilibration (e.g./due to hyperventilation,
high concentration of CO, increased cardiac output, etc.), the more involved these
mechanisms will become in modulating the rate of CO uptake (Pace et al., 1950; Coburn
et al., 1965). At high transient CO exposures of resting individuals, both the caurdiac and the
lung function mechanisms will control the rate of CO uptake. Incomplete mixing of blood
might result in a substantial difference between the arterial and venous COHb concentrations
(Godin and Shephard, 1972). In chronic bronchitics, asthmatics, and other subpopulations at
risk (pregnant women, the elderly, etc.), the kinetics of COHb formation will be even more
complex because any abnormalities of ventilation and perfusion and gas diffusion will
aggravate CO exchange (see Chapter 12 for details on subpopulations at risk).
9.1.3 Tissue Uptake
Distribution of CO within the tissue(s) will be determined primarily by exchange and
chemical reaction kinetics. In order to facilitate understanding of these well-integrated
processes, it would be helpful to consider CO uptake by the most involved physiological
compartments/organs.
9.1.3.1 The Blood
Although the rate of CO binding with Hb is about 1/5 slower and the rate of
dissociation from Hb is an order of magnitude slower than the respective rates for O2, the
CO chemical affinity (represented by the Haldane coefficient, M) for Hb is about 245 (240 to
9-5
-------
250) times greater than that of O2 (Roughton, 1970). One part of CO and 245 parts of
O2 would form equal parts of O2Hb and COHb (50% of each), which would be achieved by
breathing air containing 21 % oxygen and 570 ppm CO. Moreover, under steady-state
conditions (gas exchange between blood and atmosphere remains constant), the ratio of COHb
to O2Hb is proportional to the ratio of their respective partial pressures. The relationship
between the affinity constant M and PO2 and PCO first expressed by Haldane (1898), has the
following form.
COHb/O2Hb = M* (PCO/PO£ (9-1)
At equilibrium, when Hb is maximally saturated by O2 and CO at their respective gas
tensions, the M value for all practical purposes is independent of pH and
2,3-diphosphoglycerate over a wide range of PCO/PO2 ratios. The M, however, is
temperature dependent (Wyman et al., 1982).
Under dynamic conditions, competitive binding of O2 and CO to Hb is complex; simply
said, the greater the number of hemes bound to CO, the greater is the affinity of free hemes
for O2. Any decrease in the amount of available Hb for O2 transport (CO poisoning,
bleeding, anemia, blood diseases, etc.) will reduce the quantity of O2 carried by blood to the
tissue. However, CO not only occupies O2-binding sites, molecule for molecule, thus
reducing the amount of available O2, but also alters the characteristic relationship between
O2Hb and PO2, which in normal blood is S-shaped. With increasing concentration of COHb
in blood, the dissociation curve is shifted gradually to the left and its shape is transformed
into that of a rectangular hyperbola (Figure 9-1). Because the shift occurs over a critical
saturation range for release of O2 to tissues, a reduction in O2Hb by CO poisoning will have
more severe effects on the release of O2 than the equivalent reduction in Hb due to anemia.
Thus, in an anemic patient (50%) at the tissue PO2 of 26 torr (v^), 5 vol % of O2 (50%
desaturation) might be extracted from blood, the amount sufficient to sustain tissue
metabolism. In contrast, in a person poisoned with CO (50% COHb), the tissue PO2 will
have to drop to 16 torr (v'2 ; severe hypoxia) to release the same, 5 vol % O2 (Figure 9-1).
Any higher demand on oxygen under these conditions (e.g., by exercise) might result in
coma of the CO-poisoned individual.
9-6
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100
o
o
E
s
0
Q.
0
5mL/100mL Nbrmal
i
50% Anemia
'v, (O2 Hb Capacity = 10mL /100 mL)
40 60
PO2, mm Hg
100
Figure 9-1. Oxyhemoglobin dissociation curves of normal human blood, of blood
containing 50% carboxyhemoglobin (COHb), and of blood with a 50%
normal hemoglobin (Hb) concentration due to anemia.
Source: Adapted from National Research Council (1977); Rahn and Fenn (1955); Roughton and Darling
(1944),, - .,- , .•.'-...- • ; -v : , •
9-7
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9.1.3.2 The Lung
Although the lung in its function as a transport system for gases is exposed continuously
to CO, very little CO actually diffuses and is stored in the lung tissue itself, except for the
alveolar region. The epithelium of the conductive zone (nasopharynx and large airways)
presents a significant barrier to diffusion of CO (Guyatt et al., 1981). Therefore, diffusion
and gas uptake by the tissue, even at very high CO concentrations, will be very slow; most of
this small amount of CO will be dissolved in the mucosa of the airways. Diffusion into the
submucosal layers and interstitium will depend very much on the concentration of CO and
duration of exposure. Experimental exposures of the oronasal cavity of monkeys to very high
concentrations of CO for a very short period of time increased their blood COHb level to
only 1.5%. Comparative exposures of the whole lung, however, elevated COHb to almost
60% (Schoenfisch et al., 1980). Thus diffusion of CO across the airway mucosa will
contribute very little if at all to overall COHb concentration. In the transitional zone
(^ 20th generation) where both conductive and diffusive transport take place, diffusion of
CO into lung interstitium will be much easier, and at times more complete. In the respiratory
zone (alveoli), which is the most effective interface for CO transfer, diffusion into the lung
interstitium will be complete. Because the total lung tissue mass is rather small compared to
other CO compartments, a relatively small amount of CO (primarily as dissolved CO) will be
distributed within the lung structures.
9.1.3.3 Heart and Skeletal Muscles
The role of myoglobin (Mb) in O2 transport is not yet. fully understood. Myoglobin as
a respiratory hemoprotein of muscular tissue will undergo a reversible reaction with CO in a
manner similar to O2. The greater affinity of O2 for Mb than for Hb (hyperbolic versus
S-shaped dissociation curve) is in this instance physiologically beneficial because a small drop
in tissue PO2 will release a large amount of O2 from oxymyoglobin. The main function of
Mb is thought to serve as a temporary store of O2 and act as a diffusion .facilitator between
Hb and the tissues (for details, see Section 9.4.2).
Myoglobin has an affinity constant approximately eight times lower than Hb (M=20 to
40 vs. 245, respectively). As with Hb, the combination velocity constant between CO and
Mb is only slightly lower than for O2, but the dissociation velocity constant is much lower
9-8
-------
than for O2. The combination of greater affinity (Mb is 90% saturated at PO2 of 20 mmHg)
and lower dissociation velocity constant for CO favors retention of CO in the muscular tissue.
Thus, a considerable amount of CO potentially can be stored in the skeletal muscle. The
ratio of carboxymyoglobin (COMb) to COHb saturation for skeletal muscle of a resting dog
and cat has been determined to be 0.4 to 0.9; for cardiac muscle, the ratio is slightly higher
(0.8 to 1.2) (Coburn et al., 1973; Sokal et al., 1986). Prolonged exposures did not change
this ratio in either muscle (Sokal et al., 1984). During exercise, the relative rate of CO
binding increases more for Mb than for Hb, and CO will diffuse from blood to skeletal
muscle (Werner and Lindahl, 1980); consequently, the COMb/COHb will increase for both
skeletal and cardiac muscles (Sokal et al., 1986). A similar shift in CO has been observed
under hypoxic conditions because a fall in intracellular PO2 below a critical level will
increase the relative affinity of Mb to CO (Coburn et al., 1971). Consequent .reduction in
O2-carrying capacity of Mb might have a profound effect on the supply of O2 to the tissue
(see Section 11.1).
9.1.3.4 Brain and Other Tissues
Apart from Hb and Mb, which are the largest stores of CO, other hemoproteins will
react with CO. However, the exact role of such compounds on O2-CO kinetics still needs to
be ascertained (see Section 9.4). Concentration of CO in brain tissue has been found to be
about 30 to 50 times lower than that in blood. During the elimination of CO from brain, the
above ratio of concentrations was still maintained (Sokal et al., 1984). (For a more in-depth
discussion, see Section 10.4.)
9.1.4 Pulmonary and Tissue Elimination
An extensive amount of data available on the rate of CO uptake and the formation of
COHb contrast sharply with the limited information available on the dynamics of CO washout
from body stores and blood. Although the same factors that govern CO uptake will affect
CO elimination, the relative importance of these factors might not be the same (Landaw,
1973; Peterson and Stewart, 1970). Both the formation as well as the decline of COHb fit a
second-order function best, increasing during the uptake period and decreasing during the
elimination period. Hence, an initial rapid decay will gradually slow down (Landaw, 1973;
9-9
-------
Wagner et al., 1975; Stewart et at., 1970). The elimination rate of CO from an equilibrium
state will follow a monotonically decreasing second-order (logarithmic or exponential)
function (Pace et al., 1950). The rate, however, might not be constant following transient
exposures to CO, whereas at the end of exposure, the steady-state conditions were not
reached yet. In this situation, particularly after very short and high CO exposures, it is
possible that COHb decline could be biphasic and it can be approximated best by a double-
exponential function: The initial rate of decline or "distribution" might be considerably
faster than the later "elimination" phase (Wagner et al., 1975). The reported divergence of
the COHb decline rate in blood and in exhaled air suggests that the CO elimination rate(s)
from extravascular pool(s) is (are) slower than that reported for blood (Landaw, 1973).
Although the absolute elimination rates are associated positively with the initial concentration
of COHb, the relative elimination rates appear to be independent of the initial concentration
of COHb (Wagner et al., 1975).
The half-time of CO disappearance from blood under normal recovery conditions while
breathing air showed considerable between-individual variance. For COHb concentrations of
2 to 10%, the half-time ranged from 3 to 5 h (Landaw, 1973); others reported the range to
be 2 to 6.5 h for slightly higher initial concentrations of COHb (Peterson and Stewart, 1970).
Increased inhaled concentrations of oxygen accelerated elimination of CO; by breathing 100%
O2, the half-time was shortened by almost 75% (Peterson and Stewart, 1970). The elevation
of PO2 to 3 atm reduced the half-time to about 20 min, which is approximately a 14-fold
decrease over that seen when breathing room air (Britten and Myers, 1985; Landaw, '1973).
Although the washout of CO can be somewhat accelerated by an admixture of 5% CO2 in
O2, hyperbaric O2 treatment is more effective in facilitating displacement of CO.
9.2 TISSUE PRODUCTION AND METABOLISM OF CARBON
MONOXIDE
In the process of natural degradation of hemoglobin to bile pigments, a carbon
atom (a-bridge C) is separated from the porphyrin nucleus and subsequently is
catabolized by microsomal heme oxygenase into CO. The major site of heme breakdown,
and therefore the major production organ of endogenous CO, is the liver (Berk et al., 1976).
9-10
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The spleen and the erythropoietic system are other important catabolic generators of CO.
Because the amount of porphyrin breakdown is stoichiometrically related to the amount of
endogenously formed CO, the blood level of COHb or the concentration of CO in the
alveolar air have been used with mixed success as quantitative indices of the rate of heme
catabolism (Landaw et al., 1970; SolanH et.al., 1988). Not all of endogenous CO comes
from RBC degradation. Other hemoproteins, such as Mb, cytochromes, peroxidases, and
catalase, contribute approximately 20 to 25% to the total amount of generated CO (Berk
et.al., 1976). Approximately 0.4 mL/h of CO is formed by Hb catabolism and about
0.1 mL/h originates from non-Hb sources (Coburn et al., 1964). Metabolic processes other
than heme catabolism contribute only a very small amount of CO (Miyahara and Takahashi,
1971). In both males and females, week-to-week variations of CO production are greater
than day-to-day or within-day variations. Moreover, in females, COHb levels fluctuated with
the menstrual cycle; the mean rate of CO production in the premenstrual, progesterone phase
almost doubled (Lynch and Moede, 1972; Delivoria-Papadopoulos et al., 1970). Neonates
and pregnant women also showed a significant increase in endogenous CO production related
to increased breakdown of RBCs.
Any disturbance leading to increased destruction of RBCs and accelerated breakdown of
other hemoproteins would lead to increased production of CO. Hematomas, intravascular
hemolysis of RBCs, blood transfusion, and ineffective erythropoiesis all will elevate CO
concentration in blood. Degradation of RBCs under pathologic conditions such as anemias
(hemolytic, sideroblastic, sickle, cell), thalassemia, Gilbert's syndrome with hemolysis, and
other hematological diseases also will accelerate CO production (Berk et al., 1974; Solanki
et al., 1988). In patients with hemolytic anemia, the CO production rate was 2 to 8 times
higher, and blood COHb concentration was 2 to 3 times higher than hi normals (Coburn
et al., 1966). Increased CO-production rates have been reported after administration of
phenobarbital, diphenylhydantoin (Coburn, 1970), and progesterone (Delivoria-Papadopoulos
etal., 1970).
9-11
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9.3 MODELING CARBOXYHEMOGLOBIN FORMATION
9.3.1 Introduction
The National Ambient Air Quality Standards (NAAQS) for CO were designed to
establish ambient levels of CO that would protect sensitive individuals from experiencing
adverse health effects. In retaining the current CO primary standards, both the U.S.
Environmental Protection Agency (EPA) and the Clean Air Scientific Advisory Committee
concluded that the critical effects-level for NAAQS-setting purposes was approximately 3%
COHb without including a margin of safety (Federal Register, 1985). Using exposure
modeling and available monitoring data, EPA estimated that the current 9-ppm, 8-h average
standard would keep more than 99.9% of the adult population with cardiovascular disease
below 2.1% COHb. Because of the variability of ambient CO concentration profiles, and
other exogenous and endogenous factors affecting formation of COHb in an individual, it is
obvious that the only practical approach to evaluate the protection provided by these standards
is to continue to use mathematical models. The COHb formation modeling, however, has
much wider application because the quantification of the relationship between exogenous CO
and blood COHb is also of clinical and occupational interest.
9.3.2 Regression Models
The most direct approach to establishing a prediction equation for COHb is to regress
observed COHb values against the level and duration of exogenous CO exposure. Inclusion
of other predictor variables such as initial COHb level and alveolar ventilation generally will
improve the precision of the predictions. All regression models are purely empirical and
have no physiological basis. Their applicability therefore is limited to the exact conditions
that were used to collect the data on which they are based. So far, the most viable models ,
have been tested and used to estimate COHb levels for healthy subjects only. No validation
studies have been reported on potentially at-risk subpopulations (see Chapter 12), such as
patients with cardiovascular or hematologic dysfunction.
Peterson and Stewart (1970) developed regression Equation 9-2 for percent COHb after
exposure to moderate CO levels,
Log10 %COHb = 0.85753 Log10 CO + 0.62995 Log10 t - 2.29519 -0.00094r' (9-2)
9-12
-------
where CO refers to the concentration of CO in inhaled ambient air in parts per million, t is
the exposure duration in minutes, and,?' is the postexposure time in minutes. The final term
(-0.00094?') reflects CO elimination and was computed using the average COHb half-life
found in the study. The percent COHb in the blood samples was determined twice, using an
IL CO-Oximeter and a gas chromatograph. The percent COHb values that were used to
estimate the equation were themselves averages over observations on 2 to 10 subjects
(r = 0.985). The range of CO concentrations used was 25 to 523 ppm CO, and the
exposures lasted from 15 min to 8 h. The subjects were 18 healthy males that did not smoke
during the duration of the study. More recently, Equation 9-2, without its final term, was
modified by Zanld (1981) to correct the time, t, in the equation for altitude and subject
activity level. However, no justification or reference was cited for these changes.
Another regression equation (Equation 9-3) developed by Stewart et al. (1973) applies
to briefer exposures of considerably higher levels of CO.
LoglQ[%COHb(fi\ = Loglo[%COHb(i)] + Loglo\_%COHb(t0)] (9-3)
+ 1.036 Logw CO -4.4793 •
+ Log IQ (liters inhaled)
In this study, the exposures ranged from 1,000 ppm (for 10 min) to 35,600 ppm (for 45 sec).
The regression equation was based on 13 experimental exposures but only on six different
subjects (r = 0.995). The subjects remained sedentary throughout the study. Possible
correlations between readings on the same subject were not taken into account. The predicted
quantity is the logarithm of the "increase in percent COHb saturation in venous blood per
liter of CO mixture inhaled." The percent COHb in the blood samples was determined twice,
using an automated blood analyzing system and a gas chromatograph. The increase in COHb
saturation was computed using the peak COHb concentration occurring approximately 2 min
after CO exposure stopped. However, the immediate postexposure inhalation of pure
O2 almost certainly lowered the peak COHb values and influenced subsequent estimates.
9-13
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9.3.3 The Coburn-Forster-Kane Differential Equations
Li 1965, Coburn, Forster, and Kane developed a differential equation to describe the
major physiological variables that determine the concentration of COHb in blood ([COHb])
for the examination of the endogenous production of CO. The equation, referred to as the
CFK model, is still much in use today for the prediction of [COHb] consequent to inhalation
of CO, for two reasons. First, the model is quite robust to challenges to the original
assumptions. Second, the model can be relatively easily adapted to more specialized
applications.
9.3.3.1 Linear and Nonlinear CFK Differential Equations
Equation 9-4 represents the CFK model.
- [COHb} PcO2/MB[O^lb\ + PjCO/B (9-4)
where
B = 1/DLCO + PL/VA
and VB is the blood volume in milliliters (5,500 mL), [COHb] represents milliliters of CO
per milliliter of blood, Vco is the endogenous CO production in milliliters per minute
(0.007 mL/min), PCO2 is the average partial pressure of O2 in the lung capillaries in
millimeters of mercury (100 mm Hg), M is the Haldane affinity ratio (218), [OjBb]
represents milliliters of O2 per milliliter of blood (the maximum O2 capacity of blood is 0.2),
PjCO is the partial pressure of CO in inhaled air in millimeters of mercury, DLCO is the
pulmonary diffusing capacity for CO in milliliters per minute per millimeter of mercury
(30 mL/min/mm Hg), PL is the pressure of dry gases in the lungs in millimeters of mercury
(713 mm Hg), and VA is the alveolar ventilation rate in milliliters per minute
(6,000 mL/min).
Under the assumption that O2Hb is constant, Equation 9-4 is linear. In this case, the
equation is restricted to relatively low COHb levels. For higher levels, the reduction in
O2Hb with increasing COHb must be taken into account, thus making Equation 9-4
9-14
-------
nonlinear. The values in parentheses indicated for the variables of Equation 9-4 are the
values given in Peterson and Stewart (1970), although it is not clear whether a consistent set
of conditions (i.e., body temperature and pressure, saturated with water vapor [BTPS] or
standard temperature and pressure, dry [STPD]) was used. In addition, Peterson and Stewart
(1970) assumed a constant value of [O2Hb], thus making Equation 9-4 linear. Restricting the
conditions to low CO exposures allows the mathematical assumption of instant equilibration
of (1) the gases in the lungs, (2) COHb concentrations between venous .and arterial blood,
and (3) COHb concentrations between the blood and CO stores in nonvascular tissues.
The advantage to using the linear differential equation (where applicable) is that the
solution can be written explicitly as ^ -.
[COHb] (f) = \COHb\QeAt + CIA (1 - eAt) (9-5)
where .
A = Pc O2/VB MB [O2 Hb]
C= VCO/VB
From this solution, we see that for small t, the formation of COHb proceeds linearly, as
A [COHb] * tfj CO /VB B (9-6)
Because O2 and CO combine with Hb from the same pool, higher C0Hb values do
affect the amount of Hb available for bonding with O2. Such interdependence can be .
modeled by substituting (1.38 Hb - [COHb]) for [O^Hb], where Hb refers, to the number of
grams of hemoglobin per milliliter of blood (e.g., see Tikuisis et al., 1987b). The CFK
differential equation then becomes nonlinear, and iterative methods or numerical integration
must be used to solve the equation (Muller and Barton, 1987). Solutions of either CFK
equation require that the volumes of all gases be adjusted to the same conditions. Coburn,,
Forster, and Kane (1965) use STPD conditions, but the equation can be solved under any
conditions if consistently used (Tikuisis et al., 1987a,b).
The equilibrium value predicted by the nonlinear differential equation will always be
less than 100% COHb, and is given by the following expression.
9-15
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[COHb] = 1.38 Hb 1(1 + Pc O2/M / (B Vco + Pj CO)) (9-7)
A sensitivity analysis has been done on the parameters of both the linear and nonlinear
CFK equation at five different work levels (McCartney, 1990). The author shows that a 1 %
error in any one of the parameters produces no more than a 1 % error in COHb prediction by
the nonlinear model. .
The nonlinear CFK model is more accurate physiologically, but has no explicit solution.
It is reasonable, therefore, to ask under what conditions the solutions to the linear and
nonlinear equations are "close" together. Because both solutions are generated by known
differential equations, the question is a purely mathematical one. The precise answer is
complex and depends on several factors (e.g., ambient CO, level of activity, etc.) In
general, the linear CFK differential equation is a better approximation to the nonlinear
equation during the uptake of CO than during the elimination of CO. The approximation also
is better for COHb levels further from the equilibrium value predicted by the nonlinear:
model. In particular, it can be shown that as long as the linear CFK equation predicts COHb
levels at or below 6% COHb, the solution to the nonlinear CFK model will be no more than
0.5% COHb away (Smith, 1990).
9.3.3.2 Confirmation Studies of the CFK Model
Since the publication of the original paper (Coburn et al., 1965), other investigators
have tested the fit of the CFK model to experimental data by using different exposure profiles
and different approaches to evaluating the parameters of the model. Stewart et al. (1970) and
Peterson and Stewart (1970) tested the CFK linear differential equation on 18 resting subjects
exposed to 25 CO exposure profiles for periods of 0.5 to 24 h and to CO concentrations
ranging from 1 to 1,000 ppm. All physiological coefficients were assumed (see p. 9-14).
The percent COHb in the blood samples was determined twice, using an IL CO-Oximeter and
a gas chromatograph. It is important to note that in this experiment the predictions were
compared to individual observations instead of averages. The predicted values yielded GOHb
values quite close to the measured values. The greatest discrepancy (4.9%) was observed in
the experiment with steadily rising inhaled CO concentration over a 2-h period, which isr not
9-16
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surprising because the authors assumed a constant inhaled concentration of CO in solving the
CFK equation.
In 1975, Peterson and Stewart presented a second series of experiments testing the
nonlinear CFK model. Three women were included among the 22 subjects, and three
different levels of exercise were used. The values of Pc O2, DLCO, VB, and V^ were
estimated for each subject. The percent COHb in the blood samples was determined by a
CQ-Oximeter that was continually compared to a gas chromatograph. Based on summary
data, they concluded that the predicted and measured values were very close for both males
and females under conditions at rest and during exercise.
In 1981, Joumard et al. tested both the linear and nonlinear CFK models for CO uptake
and elimination in pedestrians and car passengers exposed to ambient CO levels in the city of
Lyon, France. The cohort, consisting of 37 male and 36 female nonsmoking subjects who
were 18 to 60 years old, was divided into two groups. One group was driven around the city
in cars while the second group walked on the street at a nearly uniform pace. Each journey
lasted about 2 h. Blood COHb readings were taken at the beginning and end of each
journey. The percent COHb in the blood samples was determined by infrared spectroscopy.
All other physiological parameters were estimated. As might be expected at these COHb
levels (-2.3%), the authors found no significant difference between the linear and nonlinear
CFK equations. No significant difference (a. = 0.05) was found between the final predicted
and observed COHb values except for male pedestrians. The unspecified difference for that
group was attributed to an underestimate of the alveolar ventilation.
In 1984, Hauck and Neuberger ran a series of experiments testing the predictive ability
of the CFK model on four subjects exposed to a total of 10 different CO exposure profiles
combined with a variety of exercise (bicycle ergometer) patterns so that each exposure was a
unique combination of GO concentration and exercise pattern. The group, all nonsmokers,
included three adult males and one ten-year-old female. The COHb values were calculated at
1-min intervals using a numerical solution of the CFK model; all parameters were kept
constant, with the exception of ventilation-derived parameters, which were updated every
minute. The percent COHb in the blood was determined by an improved van Slyke method.
The maximal differences within each experimental run (expressed as percent of a maximal
predicted value) ranged from 4.2 to 11.1%.
9-17
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The most recent validation of the nonlinear CFK model was reported by Tikuisis et al.
(1987a,b). Experiments were completed on 6 to 11 nonsmoking middle-aged males. All of
the CFK parameters but DLCO and VA were estimated; DLCO and VA were measured for
each subject. The percent COHb in the blood samples was determined by gas
chromatography. Several transient intermittent CO exposure profiles were tested: 1,500 ppm
for 5 min and 7,500 ppm for 1 min at rest, along with stepwise symmetric profiles of 500 to
4,000 ppm for 4.5 min and 4,000 ppm for 75 s during rest and intermittent exercise (V^ =
30 L/min; Figure 9-2). On an average, the predicted and measured values at rest were very
close, with the CFK model slightly overpredictive (<0.5% COHb). This overprediction was
greater during exercise, reaching almost 3% COHb in one of the subjects (Figure 9-2). It is
of interest to note that predicted values based on the current National Institute for
Occupational Safety and Health (NIOSH) solution of the CFK model are even higher,
overpredicting by as much as 6% COHb (National Institute for Occupational Safety and
Health, 1972). The model appeared to be most sensitive to VA; thus errors in conversion of
gas volumes (e.g., from ambient temperature and pressure, saturated with water vapor and
BTPS to STPD) will affect the predicted values.
9.3.3.3 Modified OK Models
Bernard and Duker (1981) simplified the linear form of the CFK model in a unique
way. Using regression equations from the literature, they were able to relate physiological
parameters to the O2 uptake by the body, which in turn related to an activity level. A linear
relationship was assumed between the rate of O2 uptake and the maximum COHb level under
which that rate could be sustained. A summary of predictive relationships between pairs of
variables were developed, but none were experimentally tested.
A more fundamental modification of the CFK model was made by Hill et al. (1977) to,
study the effect of CO inspired by the mother on the level of fetal COHb. The Hill
equation (Equation 9-8) combines the CFK equation (for maternal COHb), with a term
denoting COHb transfer from the placenta into the fetus (the subscripts m and/denote
maternal and fetal quantities, respectively).
9-18
-------
.Q
I
20 -
15 -
10 _
5 _
0
20 -
15 _
10 _
5
0
20 _
15 „
10
5
0
Subject RV
4946'..
I29 5019
n n
Subject DH
509a'.->
Subject JG
n
Subject RP
4487-'-
/4935 4459
n n
Subject MB
5035 4956
Subject RE
4945 4923
- 4000
- 51000
n 2000
_ 1000
0
iiiiiT
0 10 20 30 40 500 10 20 30 40 50
Time, min
- '4000
- 3000
_ 2000
_ 1.000
0
- 4000
- 3000
E
U 2000 §:
L 1000
0
Figure 9-2. Measured and predicted carboxyhemoglobiu (COHb) concentrations from
six intermittently exercising subjects. The bars represent the time when the
subject was given carbon monoxide (CO), and the numbers above these
bars indicate the CO dose in ppm»min. The solid lines represent the
measured percent COHb; the short-dashed lines are the solutions to the
nonlinear Coburn-Forster-Kane (CFK) equation; and the long-dashed lines
are predicted values based on the CFK model adapted by NIOSH.
Source: Tikuisis et al. (1987b).
9-19
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VBm d\COHbmVdt = VCOm - LCOHbm] PC02 l(Mm\02Hb\B) (9-8)
+ PjCO/B - DpCO (PmCO - Pf CO)
Thus, Equation 9-8 is the same as Equation 9-4, except for the final term on the right. In
Equation 9-8, D-CO is the CO diffusion coefficient across the placenta; PmCO and P* CO are
the partial pressures of CO in the maternal and fetal placenta! capillaries, respectively. The
latter two quantities are estimated using the Haldane relationship and separate models for the
lungs and placenta. The level of fetal COHb is predicted from a similar equation.
Comparative evaluation of predicted and measured fetal COHb concentrations under time-
varying and steady-state conditions in both men and animals showed acceptable agreement
s- _-
only under steady-state conditions (Hill et al., 1977; Longo and Hill, 1977).
9.3.3.4 Application of the CFK Model
Ott and Mage (1978), using a linear differential equation model that was patterned after
the linear CFK differential equation, examined the dynamics of blood COHb concentration
fluctuation as a function of ambient CO concentration observed for a 1-year period. Other
parameters of the model were estimated and kept constant. The calculated COHb levels
exceeded 2% on 25 occasions; twice without violating the 8-h NAAQS. The 8-h standard
was violated six times without causing the calculated COHb level to exceed 2%. The 1-h
standard was not violated. Besides evaluation of the averaged CO concentrations, the authors
examined the effects of peak, transient CO concentrations on the target COHb. They showed
that the presence of such spikes in CO data averaged over hourly intervals may lead to
underestimating the COHb level (due to exogenous CO) by as much as 21%. Consequently,
they recommended that monitored CO be averaged over shorter periods, such as 10 to
15 min. (See Chapter 8 for a more complete description of population exposure to CO.)
Venkatram and Louch (1979) extended the above application to more dynamic
conditions by fitting interpolated values of the ambient 1-h CO averages from Toronto,
Canada into the CFK model. In addition, they reexpressed the solution of the model from
units of percent COHb to parts per million of CO. Such a transformation allows the
examination of a variety of CO concentration profiles, while keeping a simple preselected
target COHb as a constant. They calculated that a 2% COHb level in blood very likely
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would be exceeded on numerous occasions without ever violating the standard. By including
transients, their approach appears to predict COHb more accurately, particularly in response
to 8-h running averages.
Biller and Richmond (1982) investigated the effects of inhaling various patterns of
hourly-averaged CO concentrations that just attained alternative 1-h and 8-h CO NAAQS
using the CFK equation. Their analysis also estimated the distributions of various
physiological parameters that are inputs to the CFK equation for individuals with
cardiovascular disease. The authors found that depending on which air quality pattern was
used, the percentage of the population exceeding 2.1% COHb ranged from less than 0.01%
to 10%.
More recently, Saltzman and Fox (1986) investigated the effect of inhaling oscillating
levels of CO on the COHb level of rabbits using the linear CFK equation simplified by
combining the original parameters. They concluded that ambient CO values could be
averaged safely over any time period less than or equal to the half-life of COHb.
9.3.4 Summary
The best all around model for COHb prediction is still the equation developed by
Coburn, Forster, and Kane (1965). The linear solution is useful for examining air pollution
data leading to relatively low COHb levels, whereas the nonlinear solution shows good
predictive power even for high CO exposures. The two regression models might be useful
only when the conditions of application closely approximate those under which the parameters
were estimated.
It is important to remember that almost all of the above studies assumed a constant rate
of CO uptake and elimination, which is rarely true. A number of physiological factors,
particularly changes in ventilation, will affect both rates. The predicted COHb values also
will differ from individual to individual due to smoking, age, or lung disease. There does
not appear to be a single optimal averaging time period for ambient CO; however, the shorter
the period, the greater the precision. In general, the averaging time period should be well
within the COHb half-life, which decreases with increased activity.
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9.4 EXTRACELLULAR EFFECTS OF CARBON MONOXIDE
9.4.1 Introduction
The principal cause of CO toxicity is tissue hypoxia due to CO binding to Hb, yet
certain physiological aspects of CO exposure are not explained well by decreases in
intracellular PO2 related to the presence of COHb. For many years, it has been known that
CO is distributed to extravascular sites such as skeletal muscle (Cobuni et al., 1971; Coburn
et al., 1973) and that 10 to 50% of the total body store of CO may be extravascular
(LuomanmaM and Coburn, 1969). Furthermore, extravascular CO is metabolized slowly to
CO2 in vivo (Fenn, 1970). Consequently, secondary mechanisms of CO toxicity related to
intracellular uptake of CO have been the focus of a great deal of research interest. Carbon
monoxide binding to many intracellular compounds has been well documented both in vitro
and in vivo; however, it is still uncertain whether or not intracellular uptake of CO in the
presence of Hb is sufficient to cause either acute organ system dysfunction or long-term
health effects. The virtual absence of sensitive techniques capable of assessing intracellular
CO binding under physiological conditions has resulted in a variety of indirect approaches to
the problem as well as many negative studies. The purposes of this section of the document
are to summarize current knowledge pertaining to intracellular CO-binding proteins and to
evaluate the potential contribution of intracellular CO uptake to the overall physiological
effects of CO exposure. Selected aspects of this topic have been reviewed previously
(Forster, 1970; National Research Council, 1977; Coburn, 1979; Piantadosi, 1987; Coburn
and Forman, 1987).
Carbon monoxide is known to react with a variety of metal-containing proteins found in
nature. Carbon monoxide-binding metalloproteins present in mammalian tissues include
O2-carrier proteins such as Hb (Douglas et al., 1912) and Mb (Antonini and Brunori, 1971)
and metalloenzymes (oxidoreductases) such as cytochrome c oxidase (Keilin and Hartree,
1939), cytochromes of the P-450 type (Omura and Sato, 1964), tryptophan oxygenase
(Tanaka and Knox, 1959), and dopamine hydroxylase (Kaufman, 1966). These
metalloproteins contain iron and/or copper centers at their active sites that form metal-ligand
complexes with CO in competition with molecular oxygen. Carbon monoxide and O2 form
complexes with metalloenzymes only when the iron and copper are in their reduced forms '
(Fe n, Cu I). Caughey (1970) has reviewed the similarities and differences in the
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physicochemical characteristics of CO and O2 binding to these transition metal ions. The
competitive relationship between CO and O2 for the active site of mtracellular hemoproteins
usually is described by the Warburg partition coefficient (K), which is the CO/O2 ratio that
produces 50% inhibition of the O2 uptake of the enzyme or, in the .case of Mb, a 50%
decrease in the number of available O2-binding sites. ,
The measured Warburg coefficients of various mammalian CO-binding proteins have
been tabulated recently by Coburn and Forman (1987) (see Table 9-1). These K values range
from approximately 0.025 for Mb to 0.1 to 12 for cytochromes P-450. Warburg
coefficient (K) values of 2 to 28 have been reported for cytochrome c oxidase (Keilin and
Hartree, 1939; Wohlrab and Ogunmola, 1971; Wharton and Gibson, 1976), By comparison,
the K value for human Hb of 0.005 is some three orders of magnitude less than that of.
cytochrome c oxidase. This means, for example, that CO would bind to cytochrome oxidase
in vivo only if O2 gradients from RBCs in the capillary to the mitochondria were quite steep.
Application of K values for intracellular hemoproteins in this way, however, merits caution
because most measurements of CO binding have not been made at physiological temperatures
or at relevant rates of electron transport.
Apart from questions about the relevance of extrapolating in vitro partition coefficients
to physiological conditions, experimental problems arise that are related to determining actual
CO/O2 in intact tissues. Reasonably good estimates of tissue PCO may be obtained by
calculating the value in mean capillary blood from the Haldane.relationship (National
Research Council, 1977), neglecting the low rate of CO metabolism by the tissue.
Experimental estimates of the PCO in animal tissues have been found to be in close
agreement with these calculations and average slightly less than alveolar PCO (Goethert
et al., 1970; Goethert, 1972). In general, steady state estimates for tissue PCO,range from,
0.02 to 0.5 torr at COHb concentrations of 5 to 50%. Therefore, at 50% COHb, a CO/O2
of 5 may be achieved at sites of intracellular O2 uptake only if tissue PO2 in the vicinity of
the CO-binding proteins is approximately 0.1 torr.
Whether such low intracellular PO2 values exist in target tissues such as brain and heart
during CO exposure is difficult to determine from the existing scientific literature.
Experimental measurements of tissue PO2 using polarographic microelectrodes indicate a
significant range of PO2 values in different tissues and regional differences in PO2 within a
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TABLE 9-1. IN VITRO INHIBITION RATIOS FOR HEMOPROTEINS THAT BIND CARBON MONOXIDE
Hemoprotein
Hemoglobin
Myoglobin
Cytochrome c oxidase
Cytochrome P-450
Dopamine p
hydroxylase
Tryptophan oxygenase
Source
Human RBC
Sperm whale
Bovine heart
Rat liver
Bovine adrenal
Pseudomonas
Ra
0.0045
0.025 - 0.040
5-15
0.1 - 12
2
0.55
Mb
218
25-40
0.1-0.2
10-0.1
0.5
1.8
Temperature (°C)
37
25
25
30-37
—
25
aR = 1O/O2 at 50% inhibition
bM = 1/R
Source: Adapted from Coburn and Forman (1987).
-------
given tissue. This normal variability in tissue PO2 is related to differences in capillary
perfusion, RBC spacing, velocity and path length, and local requirements for O2. Normal
PO2 values obtained from such recordings are generally in the range of 0 to 30 torr (Leniger-
Follert et al., 1975). These PO2 values usually represent average interstitial values, although
it is often difficult to determine the exact location of the electrode and the effect of
O2 consumption by the electrode on the PO2 measurement. Furthermore, the gradient
between the capillary and the intracellular sites of O2 utilization are thought to be quite steep
(Sies, 1977). A major component of the gradient arises between the RBC and interstitium
(Heliums, 1977), but the PO2 gradient between the cell membrane and respiring mitochondria
and other O2-requiring organelles remains undetermined in intact normal tissues. Even less
is known about intracellular PO2 in the presence of COHb. It has been determined,
however, that both PO2 in brain tissue (Zorn, 1972) and cerebrovenous PO2 (Koehler et al.,
1984) decrease linearly as a function of COHb concentration. Presumably then, iritracellular
PO2 declines with increasing COHb concentration, and at certain locations, CO forms ligands
with the O2-dependent, intracellular hemoproteins. As the intracellular PO2 decreases,1 the
CO/O2 ratio in the tissue increases at constant PCO and an increasing fraction of the
available intracellular O2-binding sites become occupied by CO.
The intracellular uptake of CO behaves generally according to the preceding principles;
most of the experimental evidence for this line of reasoning was derived from in vivo studies
of COHb formation by Coburn and colleagues (1965) at the University of Pennsylvania. For
all intracellular hemoproteins, however, two crucial quantitative unknowns remain. These are.
(1) the fraction of intracellular-binding sites in discrete tissues inhibited by CO at any level of
COHb saturation, and (2) the critical fraction of inhibited sites necessary to amplify or initiate
a deleterious physiological effect, or trigger biochemical responses with long-term health
effects. In general then, the activities of certain intracellular hemoproteins may be altered at
physiologically tolerable levels of COHb. The problem is in determining what level of
intracellular reserve is available during CO hypoxia. In view of this general conclusion,
recent literature for the candidate hemoproteins has been evaluated to obtain positive evidence
for intracellular CO binding and corroboration of functional consequences of the intracellular
CO effects at specific COHb levels.
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9.4.2 Carbon Monoxide Binding to Myoglobin
The red protein Mb is involved in the transport of O2 from capillaries to mitochondria
in red muscles. The binding of CO to Mb in heart and skeletal muscle in vivo has been
demonstrated at levels of COHb below 2% in heart and 1% in skeletal muscle (Coburn and
Mayers, 1971; Coburn et al., 1973). The ratio of COMb/COHb saturation has been found to
be approximately one in cardiac muscle and less than one in skeletal muscle. These ratios did
not increase with increases in COHb up to 50% saturation. In the presence of hypoxemia
and hypoperfusion, the amount of CO uptake by Mb has been, measured and was shown to
increase (Coburn et al., 1973; Coburn et al., 1971). A similar conclusion has been reached
during maximal exercise in humans, where CO shifts from Hb to the intracellular
compartment (i.e., Mb, at COHb levels of 2 to 2.5%) (Clark and Coburn, 1975). The
significance of CO uptake by Mb is uncertain because our understanding of the functional
role of Mb in working muscle is incomplete. Myoglobin undoubtedly enhances the uptake of
O2 by muscle cells so that the continuous O2 demand of working muscle is satisfied .,
(Wittenberg et al., 1975). Myoglobin may contribute to muscle function by serving as an
O2 store, by enhancing intracellular diffusion of O2, or by acting as an O2 buffer to maintain
a constant mitochondrial PO2 during changes in O2 supply. Functional Mb has been found to
be necessary for maintenance of maximum O2 uptake and mechanical tension in exercising
skeletal muscle (Cole, 1982). The binding of CO to Mb would therefore be expected to limit
O2 availability to mitochondria in working muscle. This possibility has been verified
theoretically by computer simulations of Hoofd and Kreuzer (1978) and Agostoni et al.
(1980). The three-compartment (arterial and venous capillary blood, and Mb) computer
model of Agostoni et al. (1980) predicted that COMb formation in low PO2 regions of the
heart (e.g., subendocardium) could be sufficient to impair intracellular O2 transport to
mitochondria at COHb saturations of 5 to 10%. The concentration of COMb ([COMb]) also
was predicted to increase during conditions of hypoxia, ischemia, and increased O2 demand.
The direct effects of CO on cardiac function also have been evaluated in the absence of
Hb in fluorocarbon-perfused.rabbits (Takano et al., 1981). Exposure of these animals to high
concentrations of CO (CO/O2 = 0.05 to 0.25) significantly decreased the heart rate-systolic
pressure product in the absence of COHb formation. Cardiac output and [COMb], however,
were not determined. Increases in cardiac [COMb] have been measured after heavy work;
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loads in CO-exposed rats, independent of changes in [COHb] (Sokal et al., 1986). These
investigators reported that exercise significantly increased cardiac [COMb] at COHb
saturations of approximately 10, 20, and 50%, although metabolic acidosis worsened only at
50% COHb. It remains unknown, however, whether or not low [COMb] could be
responsible for decreases in maximal O2 uptake during exercise reported at COHb levels of
4 to 5% (see Chapter 10, Section 10.3).
9.4.3 Carbon Monoxide Uptake by Cytochrome P-450
Mixed-function oxidases (cytochrome P-450) are involved in the detoxification of a
number of drugs and steroids by "oxidation." These enzymes are distributed widely
throughout mammalian tissues; the highest concentrations are found in the microsomes of
liver, adrenal gland, and the lungs of some species (Estabrook et al., 1970). These oxidases
also are present in low concentrations in kidney and brain tissues. Mixed-function oxidases
catalyze a variety of reactions (e.g., hydroxylation) involving the uptake of a pair of electrons
from reduced nicotinamide adenine dinucleotide phosphate with reduction of one atom of
O2 to water and incorporation of the other into substrates (White and Coon, 1980); These
enzymes bind CO, and their K values range from 0.1 to 12 in vitro (see Cobum and Forman,
1987). The sensitivity of cytochrome P-450 to CO is increased under conditions of rapid
electron transport (Estabrook et al., 1970); however, previous calculations have indicated that
tissue PCO is too low to inhibit the function of these hemoproteins hi vivo at less than 15 to
20% COHb (Coburn and Forman, 1987). There have been few attempts to measure
CO-binding coefficients for these enzymes in intact tissues. In isolated rabbit lung, the
effects of CO on mixed-function oxidase are consistent with a K of approximately 0.5 (Fisher
et al., 1979). Carbon monoxide exposure decreases the rate of hepatic metabolism of
hexobarbital and other drugs in experimental animals (Montgomery and Rubin, 1973; Roth
and Rubin, 1976a,b). These effects of CO on xenobiotic metabolism appear to be
attributable entirely to COHb-related tissue hypoxia because they are no greatesr than the
effects of "equivalent" levels of hypoxic hypoxia. Three optical studies of rat liver perfused
in situ with Hb-free buffers have demonstrated uptake of CO by cytochrome P-450 at CO/O2
ratios of 0.03 to 0.10 (Sies and Brauser, 1970; lyanagi et al., 1981; Takano et al., 1985). In
the study by Takano et al. (1985), significant inhibition of hexobarbital metabolism was
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found at a CO/O2 ratio of about 0.1. This CO/O2 ratio, if translated directly to [COHb],
would produce a [COHb] that is incompatible with survival (—95%). At present, there is no
scientific evidence that CO significantly inhibits the activity of mixed-function oxidases at
COHb saturations below 15 to 20%. Although most studies do not indicate effects of CO on
cytochrome P-450 activity at physiologically relevant CO concentrations, specific P-450
isoenzymes may have higher affinities for CO. Also, the rate of substrate metabolism and
substrate type may increase CO binding by P-450 enzymes. More basic research is needed in
this area because of the important role of these enzymes in living organisms.
9.4.4 Carbon Monoxide and Cytochrome c Oxidase
Cytochrome c oxidase, also known as cytochrome a a3, is the terminal enzyme in the
mitochondrial electron transport chain that catalyzes the reduction of molecular O2 to water.
Although the enzyme complex binds CO, three reasons are often cited for why this should
occur only under conditions of severe hypoxia. First, the Warburg binding constant for
cytochrome oxidase is unfavorable for CO uptake relative to the other candidate
heraoproteins. Second, the enzyme has an in vitro Michaelis-Menten constant (K^) for O2 of
less than 1 torr (Chance and Williams, 1955). Because intracellular PO2 is probably higher
than this, the oxidase should remain oxidized until severe tissue hypoxia is present. The
above arguments, however rational, are not supported well by in vivo observations and may .
not be valid for the conditions encountered in living systems. The reasons for this difficulty
center around differences in the redox behavior of cytochrome oxidase in vivo relative to its ,
in vitro behavior. The enzyme has a high resting reduction level at normal PO2 in brain
(Jobsis et al., 1977) and other tissues, and its oxidation state varies directly with PO2 in vitro
(Kreisman et al., 1981). These findings may indicate that the oxidase operates near its :
effective K^ in vivo or that the availability of O2 to each mitochondrion or respiratory chain
is not continuous under most physiological circumstances. There also may be differences in
or regulation of the K^ for O2 of the enzyme according to regional metabolic conditions.
For example, the apparent K^ for O2 of cytochrome oxidase increases several times during
rapid respiration (Oshino et al., 1974), and in isolated cells it varies as a function of the
cytosottc phosphorylation potential (Erecinska and Wilson, 1982). Conditions of high a -
respiration and/or high eytosolic phosphorylation potential in vitro increase the concentration
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of CO-cytochrome oxidase at any CO/O2 value. This concept is particularly relevant for
tissues like the heart and brain.
Enhanced sensitivity of cytochrome oxidase to CO has been demonstrated in uncoupled
mitochondria, where CO/O2 as low as 0.2 delay the oxidation of reduced cytocfarome oxidase
in transit from anoxia to normoxia (Chance et al., 1970). Several studies of respiring tissues,
however, have found CO/O2 of 12 to 20 to be necessary for 50% inhibition of O2 uptake
(Coburn et al., 1979; Fisher and Dodia, 1981; Kidder, 1980). In this context, it is important
to note that in a given tissue, the CO/O2 necessary to inhibit one half of the O2 uptake does
not necessarily correspond to CO binding to one half of the oxidase molecules. This is
because unblocked cytochrome oxidase molecules may oxidize respiratory complexes of
blocked chains, thus causing the O2 consumption to fall more slowly than predicted for
strictly linear systems. The capacity of tissues to compensate for electron transport inhibition
by branching has not been investigated systematically as a function of PO2, CO/O2, cytosolic
phosphorylation potential, or rate of electron transport in vivo.
The contention that intracellular CO uptake by cytochrome oxidase occurs is supported
by a few experiments. It has been known for many years, primarily through the work of
FennXFehn and Cobb, 1932; Perm, 1970), that CO is slowly oxidized in the body to CO2.
This oxidation occurs normally at a much lower rate than the endogenous rate of CO
production; however, the rate of oxidation of CO increases in proportion to the CO body
store (LuomanmaM and Coburn, 1969). The oxidation of CO to CO2 was shown in 1965 by
Tzagoloff and Wharton to be catalyzed by reduced cytochrome oxidase. More recently,
Young et al. (1979) demonstrated that oxidized cytochrome oxidase promotes CO oxidation,
and subsequently, that cytochrome oxidase in intact heart and brain mitochondria was capable
of catalyzing the reaction at a CO/O2 of approximately 4 (Young and Caughey, 1986). The
physiological significance of this reaction is unknown.
Other studies indicating possible direct effects of CO on cytochrome oxidase include a
photoreversible effect of 500 to 1,000 ppm CO on spontaneous electrical activity of cerebellar
Purkinje cells in tissue culture (Raybourn et al., 1978). These CO concentrations would be
expected to produce [COHb] in the range of 33 to 50%. At 7.5% COHb, inhibition of the
b-wave of the electroretinogram has been reported in the cat (Ingenito and Durlacher, 1979).
Persistent changes in the retinogram were reminiscent of the "remnant effect" of CO on
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visual thresholds in humans reported by Halperin et al. (1959). Other optical evidence
suggesting that cytochrome oxidase is sensitive to CO in vivo comes from studies of the
effects of CO on cerebrocortical cytochromes in fluorocarbon-perfused rats (Piantadosi et al.,
1985, 1987). In these studies, CO/O2 of 0.006 to 0.06 were associated with spectral
evidence of CO binding to reduced cytochrome oxidase. The spectral data also indicated that
the intracellular uptake of CO produced increases in the reduction level of b-type
cytochromes in the brain cortex. At CO/O2 of 0.06, most (> 80%) of the cytochrome b
became reduced in the cerebral cortex. The cytochrome b response is not understood well; it
is thought to represent an indirect (e.g., energy-dependent) response of mitochondrial
£-cytochromes to CO because these cytochromes are not known to bind CO in situ. The
CO/O2 used in the studies of Piantadosi et al. (1985, 1987) would produce [COHb] in the
range of 50 to 90%. The venous PO2 in those experiments, however, was about 100 torr;
thus at tissue PO2s that are significantly lower, this effect should occur at lower COHb
saturations. It is unlikely, however, that cerebral uptake of CO is significant at COHb below
5% because tissue PCO is so low in the presence of Hb. The physiological significance of
these effects of CO have not yet been determined.
Direct effects of CO on mitochondrial function have been suggested by several recent
studies that indicate decreases in cytochrome oxidase activity by histochemistry in brain and
heart after severe CO intoxication in experimental animals (Pankow and Ponsold, 1984;
Savolainen et al., 1980; Somogyi et al., 1981). The magnitude of the decrease in
cytochrome oxidase activity may exceed that associated with severe hypoxia, although
problems of determining "equivalent" levels of CO hypoxia and hypoxic hypoxia have not
been addressed adequately by these studies. The effects of passive cigarette smoking on
oxidative phosphorylation in myocardial mitochondria have been studied in rabbits
(Gvozdjakova et al., 1984). Mitochondrial respiratory rate (State 3 and State 4) and rates of
oxidative phosphorylation were found to be decreased significantly by [COHb] of 6 to 7%.
These data, however, are not definitive with respect to CO because they include effects of
nicotine, which reached concentrations of 5.7 /*g/L in blood. A recent study by Snow et al.
(1988) in dogs with prior experimental myocardial infarction indicated that a COHb of 9.4%
increased the resting reduction level of cytochrome oxidase in the heart. The CO exposures
also were accompanied by more rapid cytochrome oxidase reductions after coronary artery
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occlusion and less rapid reoxidation of the enzyme after release of the occlusion. The authors
concluded that CO trapped the oxidase in the reduced state during transient cardiac ischemia.
There is also evidence that formation of the CO-cytochrome oxidase ligand occurs in the
brain of the rat at COHb saturations of 40 to 50% (Brown and Piantadosi, 1990). This
binding appears to be related to hypotension and probable cerebral hypoperfusion during CO
exposure. This effect is in concert with experimental evidence that CO produces direct
vasorelaxation of smooth muscle. This vasodilation occurs in rabbit aorta (Coburn et al.,
1979), in the coronary circulation of isolated perfused rat heart (McFaul and McGrath,
1987), and in the cerebral circulation of the fluorocarbon-perfused rat (Piantadosi et al.,
1987). The mechanism of this vasodilator effect is unclear, although it appears to be related
to decreased calcium concentrations in vascular smooth muscle (Lin and McGrath, 1988) and
elevation of cellular cyclic guanosine monophosphate levels (Ramos et al., 1989). The
stimulus does not require hypoxia, adenosine or prostaglandins and it is possible that it
represents a direct effect of CO on the guanylate cyclase system in vascular smooth muscle
(Graeser et al., 1990). The physiological significance of this phenomenon is undetermined.
In summary, there is evidence to suggest that CO binds to cytochrome oxidase in
mammalian heart and brain tissues at a range of systemic PO2 values. The only experimental
evidence at present that this effect occurs at COHb levels less than 10% is the slow oxidation
of CO to CO2, which has been shown to occur in vivo and in isolated mitochondria in vitro.
Experimental evidence indicates that CO binding to cytochrome oxidase does occur during
tissue hypoxia produced by overtly toxic COHb concentrations. The physiological
significance of these effects beyond those of tissue hypoxia remains unknown. Once CO -
binding to cytochrome oxidase occurs, however, the small rate constant for CO dissociation
from the enzyme yields an apparent rate-dependent inhibition constant for CO under
nonequilibrium conditions. This means that at high rates of respiration and low
O2 concentrations, recovery of enzymatic function by the oxidase is relatively slow in
comparison to simple O2 deprivation.
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10. HEALTH EFFECTS OF CARBON MONOXIDE
10.1 INTRODUCTION
Concerns about the potential health effects of exposure to carbon monoxide (CO) have
been addressed in extensive studies with various animal species as subjects. Under varied
experimental protocols, considerable information has been obtained on the toxicity of CO, its
direct effects on the blood and other tissues, and the manifestations of these effects in the
form of changes in organ function. Many of these studiqs, however, have been conducted at
extremely high levels of CO (i.e., levels not found in ambient air). Although severe effects
from exposure to these high levels of CO are not directly germane to the problems from
exposure to current ambient levels of CO, they can provide valuable information about
potential effects of accidental exposure to CO, particularly those exposures occurring indoors.
These higher level studies, therefore, are being considered in this chapter only if they extend
dose-response information or if they provide clues to other potential health effects of CO that
have not been identified already. In this document, emphasis has been placed on studies
conducted at ambient or near-ambient concentrations of CO that have been published in the
more recent peer-reviewed literature since completion of the previous criteria document (U.S.
Environmental Protection Agency, 1979) and an addendum to that document (U.S.
Environmental Protection Agency, 1984). Where appropriate, information available from
older studies either has been summarized in the text or placed in tables.
The effects observed from nonhuman experimental studies have provided some insight
into the role CO plays in cellular metabolism. Caution must be exercised, however, in
extrapolating the results obtained from these data to humans. Not only are there questions
related to species differences, but exposure conditions differ markedly in the studies
conducted by different investigators. Although these studies must be interpreted with caution,
they do serve the valuable ends of (1) suggesting studies to be verified in humans;
(2) exploring the properties and principles of an effect much more thoroughly and extensively
than is possible in humans; (3) protecting human subjects from unwarranted exposure;
(4) permitting a compression of exposure duration in relation to aging as a result of .the
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shorter life expectancies of laboratory animals; and (5) providing tissues, organs, and cellular
material more readily, allowing more precise observation of specific functions.
Fortunately, our knowledge of the influence of CO on biological systems is n6t limited
to studies on nonhuman animals. Many direct experiments on humans have been conducted
during the last century. Although many reports describe inadvertent exposures to various
levels of CO, there are a considerable number of precise and delineated studies utilizing
human subjects. Most of these have been conducted by exposing young adult males to
concentrations of CO equivalent to those frequently or occasionally detected during anibient
monitoring. Research on human subjects, however, also can be limited by methodological
problems. As with the literature on experimental laboratory animals, many methodological
and reporting problems make the data difficult to interpret. These problems include
(1) failure to measure blood carboxyhemoglobin (COHb) levels; (2) failure to distinguish
between the physiological effects from a CO dose of high concentration (i.e., bolus effect)
and the slow, insidious increment in COHb over time from lower inhaled CO concentrations;
(3) failure to distinguish between normal blood flow and blood flow increased in response to
hypoxia (compensatory responses); and (4) the use of small numbers of experimental subjects.
Other factors involve failure to provide control measures (e.g., double-blind conditions) for
experimenter bias and experimenter effects; control periods so that task-learning effects do
not mask negative results; homogeneity in the subject pool, particularly in groups labeled
"smokers;" control of possible boredom and fatigue effects; arid poor or inadequate statistical
treatment of the data. In this chapter, an effort will be made to account for such
methodological and reporting problems whenever possible by making appropriate comments
in the text. Contributors to this chapter are limited, however, by the data provided in the
reports published in the peer-reviewed literature. For example, information on the COHb
levels achieved and the duration of exposure utilized in the studies will be provided in the
text or tables if they were available in the original manuscript. Where this information is
lacking, only the CO levels (parts per million) will be reported.
One problem that emerges when reviewing research on both humans and laboratory
animals is the use of inappropriate statistical techniques for data analysis. Some
experimenters use tests designed for simple two-group designs when analysis of variance
(ANOVA) is required, or use several univariate tests when more than one dependent variable
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is measured and multivariate tests are inappropriate. Such statistical problems usually yield
results in which the p-value is too small, so that possibility exists that too many results were
falsely declared to be statistically significant. If criticisms of statistical evaluation are valid,
the possible consequences of such errors will be discussed in the text or appropriate
corrections will be made. Unless actual p values are given, all general statements of effects
reported in the text or tables are statistically significant at p < 0.05.
Another problem that is particularly unique to human research is that only low levels of
CO exposure are commonly used. In such instances of low-level exposure, research findings
necessarily deal with near-threshold effects. When research, by necessity, is restricted to
such barely noticeable effects it may be expected that (1) results will be more variable
because of statistical sampling fluctuations, and (2) other uncontrolled variables that also
affect the dependent variable in question will be of major importance and will increase the
variability of results. For these reasons, data on human subjects, although being of prime
interest, also will be of highest variability. Such high variability must be resolved with
(1) large groups of subjects, (2) theoretical interpretation of results relying on knowledge
gained from experimental laboratory animal data, and (3) consideration of consistency of the
data within and across experiments.
This chapter is intended to review available data from published studies in which both
humans and laboratory animals have been exposed to low levels of CO. The chapter is
divided according to specific health effects, starting with pulmonary and cardiovascular
effects. The neurobehavioral effects of CO are described next, followed by developmental
toxicity and other systemic effects of CO. Finally, adaptation to CO exposure is discussed.
An introduction and summary is provided for each major section of the chapter in order to set
the tone for a clearer understanding of the health effects of CO. Although human and
laboratory animal data may be presented separately under each effect category, the summary
and conclusion of these sections makes an attempt to integrate the relevant material from each
of these types of studies.
10-3
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10.2 ACUTE PULMONARY EFFECTS OF CARBON MONOXIDE
10.2.1 Introduction
The binding of CO to hemoglobin (Hb), producing COHb, decreases the oxygen
(O^-carrying capacity of blood and interferes with O2 release at the tissue level; these two
main mechanisms of action underlay the potentially toxic effects of low-level CO exposure
(see Chapter 9). Impaired delivery of O2 can interfere with cellular respiration and result in
tissue hypoxia. Hypoxia of sensitive tissues, in turn, can affect the function of many organs,
including the lungs. The effects would be expected to be more pronounced under conditions
of stress, as with exercise, for example. Although the physiological mechanism by which
adverse effects of COHb formation are well known, CO-induced toxicity at the cellular level
and its related biochemical effects still are not fully understood. Other mechanisms of
CO-induced toxicity have been hypothesized, but none have been demonstrated to operate at
relatively low (near-ambient) CO exposure levels. The effect of CO on cytochromes
involved in cellular oxidative pathways is just one of the possible mechanisms of action of
CO. Mitochrondia, the principal site of O2 utilization, are present in parenchyma! lung cells
and the highest concentrations are found in the Type 2 epithelial cell. Prolonged exposure to
low levels of CO, therefore, may potentially interfere with cell function and cause loss of
alveolar epithelial integrity.
This section will review the available literature on morphological effects of CO and
determine if it is likely that CO can cause direct toxicity to cells lining the respiratory tract
through an effect on O2 transport or cellular metabolism. In addition, this section will
review a predominately newer data base on the effects of CO on pulmonary function.
10.2.2 Effects on Lung Morphology
Reports appearing in the literature have investigated the histotoxic effects Of CO on lung
parenchyma and vasculature, an area not reviewed in the previous criteria document (U.S.
Environmental Protection Agency, 1979). Results from human autopsies have indicated that
severe pulmonary congestion and edema were produced in the lungs of individuals who died
from acute smoke inhalation resulting from fires (Burns etal., 1986; Fein et al., 1980).
These individuals, however, were exposed to relatively high concentrations of CO as well as
other combustion components of smoke, such as carbon dioxide (CO^, hydrogen cyanide,
10-4
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various aldehydes (e.g., acrolein), hydrochloric acid, phosgene, and ammonia (see
Section 11.3.2). If CO, contained in relatively high concentrations in the inhaled smoke, was
responsible for the pathological sequelae described in fire victims, then to what extent can
edema be attributed to the primary injury of capillary endothelial or alveolar epithelial cells?
10.2.2.1 Studies in Laboratory Animals
Laboratory animal studies by Niden and Schulz (1965) and Fein et al. (1980) found that
very high levels of CO (5,000 to 10,000 ppm) for 15 to 45 min were capable of producing
capillary endothelial and alveolar epithelial edema in rats and rabbits, respectively. Evidence
of increased capillary permeability to protein also was reported in early studies on human
subjects by Siggaard-Andersen et al. (1968) and Parving (1972) following acute, high-level
CO exposure. These effects of CO have not been reported, however, at lower levels of CO
exposure. ,
In a small number (n = 5) of New Zealand white rabbits, Fein et al. (1980) reported a
significant increase in the permeability of chromiume-51 emylenediaminetetraacetic acid
(51Cr-EDTA) from alveoli to arterial blood within 15 min after the start of exposure to 0.8%
(8,000 ppm) CO. Passage of this labeled marker persisted and increased throughout the
remaining 30 min of the study. The mean COHb level after exposure was 63+4% (mean
+ standard error). Although morphometric examination was not performed, transmission
electron microscopy showed evidence of capillary endothelial and alveolar epithelial swelling
and edema along with detachment of the endothelium from the basement membrane.
Mitochondria were disintegrated and alveolar Type 2 cells were depleted of lamellar bodies.
None of these effects were found in four control animals exposed to air.
Despite an increase in gross lung weight, Penney et al. (1988a) were unable to "
demonstrate any evidence of edema in the lungs of male albino rats after 7.5 weeks of
exposure to incrementally increasing concentrations of CO ranging from 250 to 1,300 ppm.
The authors also .reported that this effect was not due to increased blood volume in the lung
nor due to fibrosis, as measured by lung hydroxyproline content. There was, therefore, no
obvious explanation for the lung hypertrophy reported in this study after chronic exposure to
high concentrations of CO. , "
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Fisher et al. (1969) failed to find any histologic changes in the lungs of mongrel dogs
exposed to CO concentrations of 8,000 to 14,000 ppm for 14 to 20 min (up to 18% COHb).
Similarly, no morphological changes were found by Hugod (1980) in the lungs of adult
rabbits continuously exposed to 200 ppm CO for up to 6 weeks (range of 11.9 to 19%
COHb) or to 1,900 ppm CO for 5 h (range of 31 to 39% COHb).
Niden (1971) speculated about possible effects of low levels of CO on cellular oxidative
pathways when he reported that exposure of mice to concentrations of CO from 50 to 90 ppm
for 1 to 5 days, resulting in COHb levels of < 10%, produced increased cristae in the
mitochondria and dilation of the smooth endoplasmic reticulum in the nonciliated bronchiolar
(Clara) cell. Minimal changes, consisting of fragmentation of lamellar bodies, were found in
the Type 2 epithelial cell. The morphological appearance of the remaining cells of the
terminal airways was normal. The results of this study were not presented in detail,
however, and have not been confirmed at low concentrations of CO. Thus, the significance,
if any, of changes in the structure of cells lining the terminal airways is unknown.
Weissbecker et al. (1969) found no significant changes in the viability of alveolar
macrophages exposed in vitro to high concentrations of CO (up to 190,000 ppm). These
results were later confirmed in more extensive in vivo exposure studies by Chen et al.
(1982). They obtained alveolar macrophages by bronchoalveolar lavage from rats exposed to
500 ppm (41 to 42% COHb) from birth through 33 days of age. Morphological and
functional changes in the exposed cells were minimal. There were no statistically significant
differences in cell number, viability, maximal diameter, surface area, or acid phosphatase
activity. The phagocytic ability of alveolar macrophages was enhanced by CO exposure, as
determined by a statistically significant (p<0.05) increase in the percentage of spread forms
and cells containing increased numbers of retained latex particles. The biological
significance of this finding is questionable, however, because very few (n = 5) animals were,
evaluated and no follow-up studies have been performed.
10.2.2.2 Studies in Humans
In a study by Parving (1972) on 16 human subjects, transcapillary permeability to
iodine-131 (13*I)— labeled human serum albumin increased from an average 5.6% per hour in
controls to 7.5% per hour following exposure to CO. The subjects were exposed for 3 to 5 h
10-6
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to 0.43% (4,300 ppm) CO, resulting in approximately 23% COHb. There were no
associated changes in plasma volume, hematocrit, or total protein concentration.
The only other relevant permeability studies were conducted with cigarette smoke.
Mason et al. (1983) showed rapidly reversible alterations in pulmonary epithelial permeability
induced by smoking using radiolabeled diethylene triamine pentacetic acid (99mTcDTPA) as a
marker. This increased permeability reverted to normal fairly rapidly when subjects stopped
smoking (Minty et al., 1981). Using a rat model, the permeability changes associated with
cigarette smoke were demonstrated later by Minty and Royston (1985) to be due to the
particulate matter contained in the smoke. The increase in 99mTcDTPA clearance observed
'after exposure to dilute whole smoke did not occur when the particles were removed,
suggesting that the CO contained in the gaseous phase does not alter permeability of the
alveolar-capillary membrane.
10.2.3 Effects on Lung Function
10.2.3.1 Lung Function in Laboratory Animals
Laboratory animal studies of lung function changes associated with CO exposure
parallel the morphology studies previously described (see Section 10.2.2) because high
concentrations (1,500 to 10,000 ppm) of CO were utilized.
Fisher et al. (1969) ventilated the left lung of seven dogs with 8 to 14% CO for 14 to
20 min. Femoral artery blood COHb levels ranged from 8 to 18% at the end of CO
breathing. No changes in the diffusing capacity or pressure-volume characteristics of the
lung were found.
Fein et al. (1980) measured lung function in the same study discussed in Section 10.2.2.
Nine New Zealand white rabbits were exposed for 45 min to either 0.8% CO or air. After
CO exposure, COHb levels reached 63%. The dynamic lung compliance significantly
decreased and the airway resistance significantly increased at 15 and 30 min after the start of
CO exposure, respectively. The mean blood pressure fell to 62% of the baseline value by the
end of exposure; the heart rate was not changed. The arterial pH decreased progressively
throughout exposure, although there were no changes in the alveolar-arterial partial pressure
of oxygen (PO^ difference.
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Robinson et al. (1985), also interested in the effects of acute CO poisoning in humans,
used mongrel dogs to examine ventilation (VA) and perfusion (Q) distribution during and
following CO exposure. A small number (n = 5) of mongrel dogs were exposed to 1 % CO
(10,000 ppm) for 10 min, resulting in peak COHb levels of 59 ± 5.4%. Inert gas
distributions were measured at peak exposure and 2, 4, and 24 h after exposure. No changes
in VA/Q were found. Previous studies were unable to show accumulation of lung water in
the same model (Halebian et al., 1984a,b). The authors concluded that other constituents of
smoke, besides CO, were responsible for the pulmonary edema and VA/Q mismatching
found in victims exposed to smoke in closed-space fires.
Very little is known about the effects of CO on ventilation in laboratory animals and the
few studies available are contradictory. No effects of CO on ventilation were found in
unanesthetized rabbits (Korner, 1965) or cats (Neubauer et al., 1981), whereas large increases
were reported in conscious goats (Chapman et al., 1980; Doblar et al., 1977; Santiago and
Edelman, 1976). In anesthetized cats, high concentrations of CO (10,000 ppm) increased
ventilation (Lahiri and Delaney, 1976). Gautier and Bonora (1983) used cats to compare the
central effects of hypoxia on control of ventilation under conscious and anesthetized
conditions. The cats were exposed for 60 min to either low inspired O2 fraction (where the
fraction of inspired O2 [FjOJ = 0.115) or CO diluted in air. In conscious cats, 1,500 ppm
CO caused a decreased ventilation, whereas higher concentrations (2,000 ppm) induced first a
small decrease, followed by tachypnea that is typical of hypoxic hypoxia in carotid-
denervated conscious animals. In anesthetized cats, however, CO caused only mild changes
in ventilation.
Other respiratory effects of CO hypoxia, such as the increased total pulmonary
resistance estimated by trachea! pressure, have been reported in anesthetized laboratory rats
and guinea pigs (Mordelet-Dambrine et al., 1978; Mordelet-Dambrine and Stupfel, 1979).
The significance of this effect is unknown, however, particularly under the extremely high
CO exposure conditions utilized in these studies (4 min inhalation of 2.84% CO) that
produced COHb concentrations >60% (Stupfel et al., 1981). Similar increases in trachea!
pressure also were seen with hypoxic hypoxia (FjO2 = 0.89), suggesting a possible general
mechanism associated with severe tissue hypoxia.
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10.2.3.2 Lung Function in Humans
Human studies of pulmonary function mostly are devoted to the identification of effects
occurring in the lungs of individuals exposed to relatively high concentrations of CO. Older
studies in the literature describe the effects of brief, controlled experiments with high CO-air
mixtures. Chevalier et al. (1966) exposed 10 subjects to 5,000 ppm CO for 2 to 3 min until
COHb levels reached 4%. Measurements of pulmonary function and exercise studies were
performed before and after exposure. Inspiratory capacity and total lung capacity decreased
7.5 (p<0.05) and 2.1% (p<0.02), respectively, whereas maximum breathing capacity
increased 5.7% (p<0.05) following exposure. Mean resting diffusing capacity of the lungs
decreased 7.6% (p<0.05) compared to air-exposed controls. Fisher et al. (1.969) exposed a
small number (n = 4) of male subjects, aged 23 to 36 years, to 6% (60,000 ppm) CO for
18 s, resulting in estimated COHb concentrations of 17 to 19%. There were no significant
changes in lung volume, mechanics, or diffusing capacity. Neither of these studies was
definitive, however, and no follow-up studies were reported.
More recent studies in the literature describing effects of CO on pulmonary function
have been concerned with exposure to the products of combustion and pyrolysis from such
sources as tobacco, fires, or gas- and kerosene-fueled appliances and engines,, One group of
individuals, representing the largest proportion of the population exposed to (HO, is tobacco
smokers. The reader is referred to Section 11.4 for a discussion on environmental tobacco
smoke and to other reviews on the direct effects of smoking.
A second group evaluated for potential changes in acute ventilatory function includes
occupations where individuals are exposed to variable, and often unknown, concentrations of
CO in both indoor and outdoor environments (see Section 8.4 for a more complete discussion
of occupational exposure to CO). Firefighters, tunnel workers, and loggers are typical
examples of individuals at possible risk. Unfortunately, as described in Section 10.2.2, these
individuals also are exposed to high concentrations of other combustion components of smoke
and exhaust. It is very difficult to separate the potential effects of CO from those due to
other respiratory irritants (see Section 11.3.2 for more complete discussion of exposure to
combustion products).
Firefighters previously have been shown to have a greater loss of lung function
associated with acute and chronic exposure to smoke inhalation (as reviewed by Sparrow
10-9
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et al., 1982). None of these earlier studies, however, characterized the exposure variables,
particularly the concentrations of CO found in smoke, nor did they report the COHb levels
( -
found in firefighters after exposure. Most reports of lung function loss associated with other
occupational exposures also fail to characterize exposure to CO. The following studies have
attempted to monitor, or at least estimate, the CO and COHb levels found in occupational
settings where lung function also was measured.
Sheppard et al. (1986) reported that acute decrements in lung function were associated
with routine firefighting. Baseline airway responsiveness to methacholine was measured in
29 firefighters from one fire station in San Francisco, CA, who were monitored over an
8-week period. Spirometry measurements were taken before and after each 24-h workshift
and after each fire. Exhaled gas was sampled 55 times from 21 firefighters immediately after
each fire and was analyzed for CO. Despite the use of personal respiratory protection,
exhaled CO levels exceeded 100 ppm on four occasions, with a maximum of 132 ppm,
corresponding to predicted COHb values of 17 to 22%. Of the 76 spirometry measurements
obtained within 2 h after a fire, 18 showed a greater fall in forced expiratory volume (FEVj)
and/or forced vital capacity (FVC) compared to routine workshifts without fires. Decrements
in lung function persisted for as long as 18 h in some of the individuals, but they did hot
appear to occur selectively in those individuals with preexisting airway hyperresponsiveness.
Evans et al. (1988) reported on changes in lung function and respiratory symptoms
associated with exposure to automobile exhaust among bridge and tunnel officers.
Spirometry measurements were obtained and symptom questionnaires were administered on a
voluntary basis to 944 officers of the Triborough Bridge and Tunnel Authority in New York
City over an 11-year period between 1970 and 1981. Regression analyses were performed on
466 individuals (49%) who had been tested at least three times during that period.
Carboxyhemoglobin levels were calculated from expired-air breath samples. Small, but
significant differences were found between the bridge and tunnel officers. Estimated levels of
COHb were consistently higher in tunnel workers compared to bridge workers for both
nonsmoking individuals (1.96 and 1.73%, respectively) and smoking individuals (4.47 and
4.25%, respectively). Lung function measures of FEVj and FVC were reduced, on an
average, in tunnel versus bridge workers. There were no reported differences in respiratory
symptoms except for a slightly higher symptom prevalence in tunnel workers who smoked.
10-10
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Because differences in lung function between the two groups were small, it is questionable if
the results are clinically significant or if they were even related to CO exposure.
Hagberg et al. (1985) evaluated the complaints of 211 loggers reporting dyspnea and
irritative symptoms in their eyes, nose, and throat after chain-saw use. Measurements of
lung spirometry, COHb, and exposure to CO, hydrocarbons (HCs), and aldehydes were
conducted on 23 loggers over 36 work periods lasting 2 h each. Ventilation levels during
tree felling averaged 41 L/min. Carboxyhemoglobin levels increased after chain-saw use
(p<0.05) but were weakly correlated (r = 0.63) with mean CO concentrations of 17 ppm
(4 to 73 ppm range) in nonsmokers. Corresponding COHb levels were apparently <2%;
unfortunately, the absolute values before and after exposure were not reported.. 'Peripheral
bronchoconstriction, measured by a decreased FEVj/FVC (p<0.03) and forcisd expiratory
flow measured at 25 to 75% of FVC (p< 0.005), was found after the work periods but no
correlations were obtained between lung function, COHb levels, and exposure variables.
There were no reported changes in FEVj or FVC.
High CO concentrations also can be found indoors near unvented space heaters (see
Section 7.2). The potential effects on lung function by indoor combustion products of
kerosene space heaters was evaluated by Cooper and Alberti (1984). Carbon monoxide and
sulfur dioxide (SO2) concentrations were monitored in 14 suburban homes in Richmond, VA,
during January and February of 1983 while modern kerosene heaters were in operation.
Spirometry measurements were obtained in 29 subjects over a 2-day period, .randomizing
exposures between days with and without the heater on. During heater operation, the CO
concentration was 6.8 + 5.9 ppm (0 to 14 ppm range), and the SO2 concentration was
0.4 + 0.4 ppm (0 to 1 ppm range). On control days, the indoor CO cpncentration was
0.14 + 0.53 ppm, whereas SO2 was undetectable. Six of the homes had CO concentrations
exceeding the primary 8-h National Ambient Air Quality Standard of 9 ppm., Corresponding
outdoor CO concentrations were 0 to 3 ppm. Carboxyhemoglobin levels significantly
increased from 0.82 + 0.43% on control days to 1.11 + 0.52% on days when kerosene
heaters were used. Exposure to heater emissions, however, had no effect on FVC, FEVl5 or
maximum mid-expiratory flow rate.
Most of the published community population studies on CO have investigated the
relationship between ambient CO levels and hospital admissions, deaths, or symptoms
10-11
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attributed to cardiovascular diseases (see Section 10.3). Little epidemiological information is
available on the relationship between CO and pulmonary function, symptomatology, and
disease.
One study by Lutz (1983) attempted to relate levels of ambient pollution to pulmonary
diseases seen in a family practice clinic in Salt Lake City, UT, during the winter of 1980 and
1981, when heavy smog conditions prevailed. Data on patient diagnoses; local climatblogical
conditions; and levels of CO, ozone (O3), and participate matter were obtained over a
13-week period. Pollutant levels were measured daily and then averaged for each week of
the study; absolute values were not reported. For each week, weighted simple linear
regression and correlation analyses were performed. Significant correlations (p = 0.01)
between pollution-related diseases and the environmental variables were found for paniculate
matter (r = 0.79), O3 (r = —0.67), and percent of smoke and fog (r = 0.79), but not for
CO (r = 0.43) or percent of cloud cover (r = 0.33). The lack of a significant correlation
with CO was explained by a small fraction (2%) of diagnoses for ischemic heart disease
compared to a predominance of respiratory tract diseases such as asthma, bronchitis,
bronchiolitis, and emphysema.
Daily lung function in a large community population exposed to indoor and outdoor air
pollution was measured in Tucson, AZ, by Lebowitz et al. (1983a,b, 1984, 1985, 1987),
Lebowitz (1984), and Robertson and Lebowitz (1984). Subsets of both healthy subjects and
subjects with asthma, allergies, and airway obstructive disease were drawn from a symptom-
stratified, geographic sample of 117 middle-class households. Symptoms, medication use,
and peak-flow measurements were recorded daily over a 2-year period. Indoor and outdoor
monitoring was conducted in a random sample of 41 representative houses. Maximum 1-h
concentrations of O3, CO, and nitrogen dioxide (NO^ and daily levels of total suspended'
particulates, allergens, and meteorological variables were monitored at central stations within
0.5 mi of each population subset. Because gas stoves and tobacco smoking were the '
predominant indoor sources, indoor pollutant measurements were made for particles and CO.
Levels of CO were low, averaging less than 2.4 ppm indoors and 3.8 to 4.9 ppm outdoors.
Spectral time series analysis was used to evaluate relationships between environmental
exposure and pulmonary effects over time (Lebowitz et al., 1987; Robertson and Lebowitz,
1984). Asthmatics were the most responsive, whereas healthy subjects showed no significant'
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responses. Outdoor O3, NO2, allergens, meteorology, and indoor gas stoves were
significantly related to symptoms and peak flow.
10.2.4 Summary
, Currently available studies on the effects of CO exposures producing GOHb
*
concentrations of up to 39% fail to find any consistent effects on lung parenchyma and
vasculature (Hugod, 1980; Fisher et al., 1969) or on alveolar macrophages (Chen et al.,
1982; Weissbecker et al., 1969). The lack of significant changes in lung tissue is consistent
with the lack of histologic changes in the pulmonary and coronary arteries (see
Section 10.3.4). Alveolar epithelial permeability to 51Cr-EDTA increased in rabbits (Fein
et al., 1980) exposed to high concentrations of CO (63% COHb), and increased capillary
endothelial permeability to 131I-labeled human serum albumin was reported in early human
studies, (Parving, 1972) following acute, high-level CO exposure (23% COHb); however, no
accumulation of lung water was found in dogs with COHb levels of 59% (Halebian et al.,
1984a,b) and no edema was found,in the lungs of rats chronically exposed to CO
concentrations as high as 1,300 ppm (Penney et al., 1988a). In addition, no changes in
diffusing capacity of the lung were found in dogs with COHb levels up to 18% (Fisher et al.,
1969). It is unlikely, therefore, that CO has any direct effect on lung tissue except at
extremely high concentrations. The capillary endothelial and alveolar epithelial edema found;
with high levels of CO exposure in victims of CO poisoning may be secondary to cardiac
failure produced by myocardial hypoxia (Fisher et al., 1969) or may be due to acute cerebral
anoxia (Naeije et al., 1980).
Ventilatory responses to CO are related to the CO concentration as well as to the
experimental conditions and the animal species being studied. In conscious goats (Chapman
et al., 1980; Doblar et al., 1977; Santiago and Edelman, 1976) and cats (Gautier and Bonora,
1983), after an initial depression, ventilation suddenly increases, particularly at high CO
concentrations (>2,000 ppm). This response may result from the direct effects of hypoxia
and/or a specific central nervous system (CNS) effect of CO (see Section 10.3). .No effects
on ventilation and perfusion distribution were found, however, in dogs exposed to 1 % CO for
10 min, resulting in COHb levels of ,59% (Robinson et al., 1985). At very high
concentrations .of CO (COHb >60%), total pulmonary resistance, measured, indirectly by
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traeheal pressure, was reported to increase (Mordelet-Pambrine et al., 1978; Mordelet-
Dambrine and Stupfel, 1979).
Human studies on the pulmonary function effects of CO are complicated by the lack of
adequate exposure information, the small number of subjects studied, and the short exposures
explored. Occupational or accidental exposure to the products of combustion and pyrolysis,
A
particularly indoors, may lead to acute decrements in lung function if the COHb levels are
greater than 17% (Sheppard et al., 1986) but not at concentrations less than 2% (Evans et al.,
1988; Hagberg et al., 1985; Cooper and Alberti, 1984). It is difficult, however, to separate
the potential effects of CO from those due to other respiratory irritants in the smoke and
exhaust. Community population studies on CO in ambient air have not found any
relationships with pulmonary function, symptomatology, and disease (Lebowitz et al., 1987;
Robertson and Lebowitz, 1984; Lutz, 1983).
10.3 CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE
10.3.1 Introduction
The maintenance of adequate blood flow to the tissues during exercise stress is critical.
As discussed in Chapter 9, CO exposure has the potential to exert deleterious effects in
humans by several mechanisms. Carbon monoxide combines with Hb to form COHb, which
directly decreases the O2 content of blood. In addition, CO shifts the oxyhemoglobin (O2Hb)
dissociation curve to the left, providing less O2 to the tissues at a given tissue PO2., The net
result is a reduction of O2 availability and possible hypoxia in the affected tissues.
Fortunately, mechanisms exist in normal, healthy individuals to compensate for this reduction
in tissue O2. Cardiac output increases, blood vessels dilate to carry more blood, and the
tissue extracts greater amounts of O2 from the blood. There are several medical conditions,
however, that can make an individual more susceptible to the potential adverse effects of CO
during exercise. Occlusive vascular disease prevents an increase in blood flow to the tissues;
chronic obstructive lung disease causes gas-exchange abnormalities that limit the amount of
O2 that diffuses into the blood; and anemia reduces the O2-carrying capacity of the blood.
Under any of these conditions, exposure to CO could further reduce the amount of
O2 available to the affected tissues.
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This section will discuss studies in huinans dealing with the effects of CO in healthy
individuals, in patients with heart disease, and in other susceptible population groups, in
addition, this section will discuss the relationship between CO exposure and the risk of
developing cardiovascular diseases in humans, either through studies on the exposed
population or through experimental studies in laboratory animals. ;"
* ,.-•, . -". ......
10.3.2 Experimental Studies in Humans
10.3.2.1 Cardiorespiratory Response to Exercise
Effects in Healthy Individuals
The most extensive human studies on the cardiorespiratory effects of CO are those
involving the measurement of O2 uptake during exercise. These studies were discussed in the
previous CO criteria document (U.S. Environmental Protection Agency, 1979), an addendum
to that document (U.S. Environmental Protection Agency, 1984), and in other published
reviews (Horvath, 1981; Shephard, 1983, 1984).
Healthy young individuals were used in most of the studies evaluating the effects of CO
on exercise performance (see Table 10-1); healthy older individuals were used in only two
studies (Raven et al., 1974a; Aronow and Cassidy, 1975). In these studies, O2 uptake during
submaximal exercise for short durations (5 to 60 min) was not affected by COHb levels as '
high as 15 to 20% (Table 10-1). Under conditions of short-term'maximal exercise, however,
statistically significant decreases (3 to 23%) in maximal O2 uptake (VO2 nuix) were found at
COHb levels ranging from 5 to 20% (Klein et al., 1980; Stewart et al., 1978; Weiser et al.,
1978; Ekblom and Huot,'1972; Vogel:and Gleser, 1972; Pirnay et al., 1971). In another
study by Horvath et al. (1975), the critical level at which COHb marginally influenced
VO2 max (p<0.10) was approximately 4.3%. The data obtained by Horvath's group and
others are summarized in Figure 10-1. There is a linear relationship between", decline ih -
VO2 max and increase in COHb that can be expressed as Percent Decrease in
VO2 max = 0.91 (% COHb) + 2.2 (U.S. Environmental Protection Agency, 1979;
Horvath, 1981). Short-term maximal exercise duration also has been shown to be reduced
(3 to 38%) at COHb levels ranging from 2.3 to 7% (Horvath et al.- 1975; Drihkwater et al.,
1974; Raven et al., 1974 a,b; Weiser etal.y 1978; Ekblom and;Huot, 1972). (See '
Table 10-1.) ' >: v ": •" • • ' - -•'•
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o
TABLE 10-1. SUMMARY OF EFFECTS OF CARBON MONOXIDE ON MAXIMAL AND
SUBMAXIMAL EXERCISE PERFORMANCE
Exposure"'''
50 and 100 ppm CO
4h
treadmill exercise at
85% maximal heart
rate(HR)
50 ppm CO, 25 and
35 °C
5-min treadmill
exercise to exhaustion
50 ppm CO, 35 °C
20-min treadmill
exercise to exhaustion
50 ppm CO, 25 °C
5-min treadmill
exercise to exhaustion
COHb(56)c
2.17 (50 ppm)
4.15 (lOOTpra)
2.3 (nonsmokers)
5.1 (smokers)
2.5 (nonsmokers)
4.1 (smokers)
2.7 (nonsmokers)
4.5 (smokers)
Subject®
23 males
,20-38 years
(8 smokers)
16 males
40-57 years
(7 smokers) ,
20 young males equally
divided by smoking
history
20 males
21-30 years equally
divided by smoking
history
Observed Effects'1
Mean exercise duration was
19 s shorter on CO days;
coagulation variables,
cholesterol, and triglyceridcs
were not significantly
changed
No change in VO2 max; total
work time decreased at 25 °C
in older nonsmokers
No change in "v*02 max;
exercise duration decreased hi
nonsmokers; change in
respiratory pattern in both
smokers and nonsmokers
No change in VO2 max or
work time; no smoking effect
Conclusions
Submaximal exercise duration
decreased significantly at 4%
COHb
No significant decrease in
VO2 max in older men exposed
to CO, but work time to
exhaustion decreased in
nonsmokers at 2.3 % COHb
Work time decreased in
nonsmokers at 2.5% COHb
No significant decrease in
maximal exercise performance
Reference6
Brinkhous (1977)
TJaven et al. (1974a)
Drinfcwateretal. (1974)
Raven et al. (I974b)
75 and 100 ppm CO
15-min treadmill
exercise to exhaustion
3.3-4.3
4 males
24-33 years (1 smoker)
max decreased
(p<0.10)at4.3%COHb;
lower work times and
ventilatory volumes at all
COHb levels (p<0.05)
Maximal exercise performance
decreased at COHb >4%
Horvath et al. (1975)
100 ppm CO ..'. 3.95
1 h '
treadmill exercise to
exhaustion
0.5% CO 3.95
2.5-3.5 min
5-min submaximal
exercise at
1.84 L/min VO2
9 male
1 female nonsmokers
44-55 years
10 nonsmokers
Xii= 30 years
Mean exercise time until
exhaustion decreased 5%
(p<0.001)
No change in mean VO2; 02
debt per ^02 increased 14%
Exercise time decreased in older
nonsmokers at 3.95% COHb
Work at 4% COHb was
performed with "greater metabolic
cost
. . •
Aronow and Cassidy (1975)
Chevalier et al. (1966)
-------
TABLE 10-1 (cont'd). SUMMARY OF EFFECTS OF CARBON MONOXIDE ON MAXIMAL AND
SUBMAXIMAL EXERCISE PERFORMANCE
. . . . . Exposure8'15 COHb(%)°
50 ppjm CO, 25 and 4.6-6.8
35 "C
4-h exercise at 35%
^2 max
15-min rebreathing to 4.8-21 .2
achieve target COHb;
exercise at 30, 70,
100% ^02 max
SOppmCO 5.0
5-h
treadmill exercise until
exhaustion
20-min rebreathing to 5.1
achieve target COHb;
treadmill exercise until
exhaustion
20,000 ppm CO for 5.5
45 s followed by
30 ppm for 4 h;
treadmill exercise
100 ppm CO 7.3 (nonsmokers)
1-h bicycle exercise at 9.5 (smokers)
50% V max
10,000 ppm CO bolus 7.8
followed by 60-70 ppm
for 5 min
Subjeot(s)
19 males
18-55 years
10 subjects
22-34 years
6 male nonsmokers
25-39 years
9 male nonsmokers
24.7 ± 1.4 years
residents of Denver, CO
6 male nonsmokers
25-39 years
12 males
12 females equally
divided by smoking
history
9 male nonsmokers
Observed Effects'1
Stroke volume decreased with
higher ambient temperature;
HR increased with CO
exposure but no change in
cardiac output or stroke
volume
During maximal exercise,
work time and VO2 max
significantly decreased at
7-20%" COHb; no change in
VC>2 with submaximal
exercise ' •
V02 max decreased, Vg and
HR both increased
Total exercise time decreased
3.8%, total work performed
decreased 10%, and'VO2
max decreased-2.8%
Maximal exercise time and
V(>2 decreased, HR and Vg
increased
No change in FEVi ,
™P25-75%>VC' VO2, %
TV, or fg.
'frig and fg increased, VO2
max and (A-a) O2 difference
decreased with exercise
Conclusions
No major change in cardio-
; respiratory response to
submaximal work with COHb
levels <1%
Maximal exercise performance
and Vc>2 max decreased with
increasing COHb
Maximal 02 uptake decreased at
5% COHb
Maximal exercise performance in
Denver, CO, (1610 m) decreased
at 5% COHb
Maximal exercise performance
decreased at 5.5% COHb
CO did not affect pulmonary
function, subjective symptoms, or
exercise metabolism
Maximal 02 uptake decreased at
8% COHb
Reference8
Gliner et al. (1975)
Ekblom and Huot (1972)
Klein et al. (1980)
Weiser et al. (1978)
Stewart et al. (1978)
DeLucia et al. (1983)
Collier et al. (1972)
-------
9
H1*
oo
TABLE 10-1 (cont'd). SUMMARY OF EFFECTS OF CARBON MONOXIDE ON MAXIMAL AND
SUBMAXIMAL EXERCISE PERFORMANCE
Exposure"'11 COHb(%)c
15-min febreathing to 12.8-15.8
achieve target COHb;
exercise at 30, 70, and
0.05% CO 15.4
5 min -
moderate exercise
for 15 min at
4 km/h
0.15-0.35% CO ' 16-52
>70 min
Subject(s)
9 males
23-34 years
5 males
24-35 years
4 males ."
", 21-33 years
Observed Effects'1
Vmax decreased 14.256 with
maximal exercise; no change
in ventilation or V02 with
submaximal exercise
Increased HR but no change •
in V 02 or ventilation with
submaximal exercise; "vX^
max decreased 15.1%
No hyperpnea at rest; arterial
PCO2 increased and pH
Conclusions
Maximal exercise performance
decreased after CO exposure
Maxima] O2 uptake decreased at
15% COHb
CO has a depressive action on
the respiratory center
Reference8
Efcblora et al. (1975)
Pirnay et al. (1971)
Chiodi et al. (1941)
225.ppmCO , 18-20-
1-h bicycle exercise at
50, 75, and 100%
v"O2max - ..
225 ppm CO 20.3
1-h bicycle exercise at
45, 75, and :
VO2 max
8 males
20-23 years (3 smokers)
16 males "(6 smokers)
decreased; cardiac output
increased with.increasing
COHb
VO2 max decreased 23 %
(p<0.001); with submaximal
exercise HR increased
(p<0.05)and VO2 was ,
unchanged
VO2 max decreased 24%
(p <0.001); no change in
work efficiency or with
submaximaj exercise
Maximal 02 uptake decreased at
> 18% COHb •
Maximal O2 uptake decreased at
>20% COHb
Vogel and Gleser (1972)
Vogel et al. (1972)
aExposure concentration, duration, and activity level.
blppm = 1.145 mg/m3 and lmg/m3 = 0.873-"ppm at 25 ''C, 760mmHg; 1%
°EstImated or measured blood carboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and acronyms.
eCited in U.S. Environmental Protection Agency (1979, 1984).
10,000 ppm.
-------
40
8 35-
o 3°-
.E 25 -
CO __
I 20-
I 15-
4-1
| 10-
0)
O
0
i
5
10
i
15
20 25
Percent COHb
30 35 40
Figure 10-1. Relationship between carboxyhemoglobin (COHb) level and decrement in
maximal oxygen uptake (VO2 max) for healthy nonsmokers.
Source: Adapted from U.S. Environmental Protection Agency (1979) and Horvatti (1981).
Acute effects of cigarette smoke on maximal exercise performance are apparently
similar to those described above in subjects exposed to CO. Hirsch et al. (1985) studied the
acute effect of smoking on the cardiorespiratory function during exercise in nine healthy male
subjects who were current smokers. They were tested twice—once after smoking three
cigarettes per hour for 5 h and once after not having smoked. The exercise tests were done
on a bicycle ergometer with analysis of gas exchange and intra-arterial blood gases and
pressures. On the smoking day, VO2 max was significantly decreased by 4% and the
anaerobic threshold was decreased by 14%. The rate-pressure product was a significant 12%
higher at comparable work loads of 100 W on the smoking day compared to the nonsmoking
day. There were no changes due to smoking, however, on the duration of exercise or on the
mean work rate during maximal exercise testing. The blood COHb level before exercise was
1.8% on the nonsmoking day and 6.6% on the smoking day. At peak exercise, the COHb
was 0.9% and 4.8% on the nonsmoking and smoking day, respectively. The authors
10-19
-------
concluded that the main adverse effect of smoking was due to CO, although the increase in
rate-pressure product also might be the result of the simultaneous inhalation of nicotine.
They felt that the magnitude of change in performance indicators corresponded well with
earlier reports.
It would be interesting, therefore, to determine if smokers and nonsmokers had different
responses to CO exposure. Unfortunately, smokers and nonsmokers were not always
identified in many of the studies on exercise performance, making it difficult to interpret the
available data. Information derived from studies on cigarette smoke is also sparse. As a
result, attempts to sort out the acute effects of CO from those due to other components of
cigarette smoke have been equivocal. Seppanen (1977) reported that the physical work
capacities of cigarette smokers decreased at 9.1% COHb levels after breathing either boluses
of 1,100 ppm CO or after smoking cigarettes. The greatest decrease in maximal work,
however, was observed after CO inhalation.
JQausen et al. (1983) compared the acute effects of cigarette smoking and inhalation of
CO on maximal exercise performance. They studied 16 male smokers under three different
conditions: after 8 h without smoking (control), after inhalation of the smoke of three
•_ - > •• -
cigarettes, and after CO inhalation. Just before maximal exercise testing, the arterial COHb
level reached 4.51 and 5.26% after cigarette smoke and CO inhalation, respectively,
compared to 1.51% for controls. Average VO2 max decreased by about 7% with both
smoke and CO. Exercise time, however, decreased 20% with smoke but only 10% with CO,
suggesting that nicotine, smoke particles, or other components of tobacco smoke may
1 I - ...
contribute to the observed effects. The authors, therefore, concluded that a specified COHb
level induced by either smoke or CO decreased maximal work performance to the same
degree. Of note is the more marked decrease in work time compared to VO2 max induced
by CO, a finding that agrees with the Ekblom and Huot (1972) results (see Table 10-1).
If the magnitude of the effect of CO exposure is due only to a decrease in O2-earryihg
capacity proportional to the COHb concentration, the magnitude should be roughly the same
as if the O2 capacity is decreased by anemia. Celsing et al. (1987) found in a series of very
carefully performed studies in normal subjects that VO2 max decreased by 19 mL/min/kg per
. fc. • . - . 1 - ->'*-. J
gram per liter change in Hb over a range of Hb concentrations from 13.7 to 17.0 g/dL. This'
change represents a 2% decrease in VO2 max for every 3% decrease in Hb concentration in
10-20
-------
a well-trained subject. The decrease also corresponds to the decrease in VO2 max reported
by Ekblom and Huot (1972) and Horvath et al. (1975). However, Ekblom and Huot found a
much more marked effect on maximal work time (i.e., work on a constant load until
exhaustion with a duration of about 6 min). An explanation for the marked decrease in
maximal work time could be that CO has a negative effect on the oxidative enzymatic
system, whereas the decrease in work time is due to a combination of a decrease in
O2 capacity and a less efficient oxidative enzymatic system. If the data are extrapolated to
lower COHb values, a 3% level of COHb should decrease the maximal work time by about
20%. However, this decrease is more than the 10% average decrease reported by Klausen
et'al. (1983), where they also found more marked effects in less well-trained stibjects
compared to well-trained subjects.
Effects in Individuals with Heart Disease
The previous criteria document (U.S. Environmental Protection Agency, 1979)
concluded that patients with heart disease are especially at risk to CO exposure sufficient to
produce 2.5 to 3% COHb. This statement was based primarily on studies initiated by
Aronow et al. (1972) and Aronew and Isbell (1973) demonstrating that patients with angina
pectoris, when exposed to low levels of CO, experienced reduced time to onset of exercise-
induced chest pain as a result of insufficient O2 supply to the heart muscle. A study by
Anderson et al. (1973) reported similar results at mean COHb levels of 2.9 and 4.5% (see
Table 10-2).
In 1981, Aronow reported an effect of 2% COHb on time to onset of angina levels in
! 1A : ' • ' . • ' ' '
15 patients. The protocol was similar to previously reported studies, with patients exercising
until onset of angina. Only 8 of the 15 subjects developed 1 mm or greater ischemic ST
segment depression at the onset of angina during the control periods. This was not
significantly affected by CO. One millimeter or greater ST segment depression is the
commonly accepted criterion for exercise-induced ischemia. It is questionable, therefore, as
to whether the remaining patients truly met adequate criteria for ischemia despite
angiographically documented cardiac disease. After breathing 50 ppm of CO for 1 h, the
patients' times to. onset of angina significantly decreased from a mean of 321.7 ± 96 s to
289.2 + 88s. ......
10-21
-------
TABLE 10-2. SUMMARY OF EFFECTS OF CARBON MONOXIDE EXPOSURE IN
PATIENTS WITH ANGINA3
Exposure
;b,c
COHb(%)c ACOHb(«)f
Subjects)
Observed Effects
Reference
50 or 100 ppm CO for 50 min 2.9 (SP) ND 1.6
of each hour X 4 h; 4.5 (SP) 3.2
postcxposure exercise on a
treadmill
100 ppm CO for 60 min; 3.0 (CO-Ox) 2.8 (CO-Ox) 1.5
postexposurc incremental
exercise at 48.6 L/min on a
cycle ergometer
117 or 253 ppm CO for 50-70 3.2 (CO-Ox) 2.7 (CO-Ox) 2.0
min; pre- and postexposure 5.6 (CO-Ox) 4.7 (CO-Ox) 4.4
incremental exercise at ~6
METS on a treadmill 2.4 (GC) 2.0 (GC) 1.8
(modified Naughton protocol) 4.7 (GC) 3.9 (GC) 4.0
10 males, 5 smokers
and 5 nonsmokers, with
reproducible exercise-induced
angina; 49.9 years
24 male nonsmokers with
reproducible exercise-induced
angina; 59 ± 1 years (49-66
years)
63 male nonsmokers with
reproducible exercise-induced
angina; 62 ± 8 years (41-75
years)
Duration of exercise before onset
of angina was significantly
shortened at 2.9 and 4.5% COHb
(p<0.005); duration of angina
was significantly prolonged at
4.5% COHb.
Time to onset of angina decreased
5.9% (p = 0.046); no significant
effect on the duration of angina.
02 uptake at angina was reduced
about 3% (p = 0.04). There were
no significant changes in heart
rate or systolic blood pressure at
angina.
Earlier onset of myocardial
ischemia was found with CO
exposure: time to ST end point
decreased 5.1 (p = 0.01) and
12.1% (p < 0.001) and time to
angina onset decreased 4.2
(p = 0.027) and 7.1%
(p = 0.002) at 2.0 and 3.9%
COHb (GC), respectively; mean
duration of exercise was
significantly shorter at 3.9%
COHb (p < 0.0001). A significant
linear dose-response relationship
was found for time to ST change
for the range of COHb levels
from 0.2 to 5.1% (GC). Changes
in performance are clinically
significant.
Anderson et al. (1973)S
Weinman et al. (1989)
Allred et al. (1989a,b;
1991)
-------
PATIENTS WITH ANGINAa
Exposure >c
COHb(%)d
COHb(%)e ACOHb(%)f
Subject(s)
Observed Effects
Reference
100-200 ppm CO for 60 min;
postexposure incremental
exercise at 317 KPM on a
cycle ergometer
4.1 (CO-Ox)
3.6 (CO-Ox)
2.2
25 male and 5 female
nonsmokers with evidence of
exercise-induced angina on at
least one day; 58 + 11 years
(36-75 years)
100-200 ppm CO for 60 min;
postexposure incremental
exercise at 300 KPM on a
cycle ergometer
5.9 (CO-Ox)
5.1 (CO-Ox)
4.2
11 male and 8 female
nonsmokers with evidence of
exercise-induced angina on at
least one day; 58 ± 11 years
(36-75 years)
No significant difference in time
to onset or duration of angina. No
significant difference in maximal
exercise time, maximal ST
segment depression, or time to
significant ST segment depression
during exercise. No significant
difference in maximal ejection
fraction; small decreases in blood
pressure (p = 0.031) and change
in ejection fraction (p = 0.049)
during CO exposure requires
further evaluation. Actuarial
analysis (Bissette et al., 1986)
including 3/30 subjects
experiencing angina only on the
CO-exposure day showed a
significant decrease in time to
onset of angina after CO
exposure.
Earlier onset of ventricular
dysfunction, angina, and poorer
exercise performance was found
with CO exposure; mean duration
of exercise was shorter (p <0.05);
subjects were likely to experience
angina earlier during exercise
with CO (p<0.05) using actuarial
analysis. Both the level
(p = 0.05) and change in left
ventricular ejection fraction at
submaximal exercise (p = 0.05)
were less on the CO-exposure day
compared to the air-exposure day.
There was no significant
difference in the peak exercise left
ventricular ejection fraction.
Shops et al. (1987)
Adams et al. (1988)
aSee glossary of terms and symbols for abbreviations and acronyms.
Exposure concentration, duration, and peak activity level. NOTE: Because oxygen consumption was not measured, it is not possible to determine the actual level of exercise at which angina
occurred. , .
= 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 °C, 760 mm Hg; 1 % ,= 10,000 ppm.
Measured blood carboxyhemoglobin (COHb),level after CO exposure;. GC = gas chromatograph, CO-Ox = CO-Oximeter, SP = spectrophotometric method of Buchwald (1969).
Measured blood carboxyhemoglobin (COHb) level after exercise stress test; GC = gas chromatograph, CO-Ox = CO-Oximeter, ND = not determined.
Postexposure increase in COHb over baseline.
in U.S. Environmental Protection Agency (1979, 1984).
-------
In 1983, the studies by Aronow and his colleagues were reevaluated by an ad hoc
committee to the EPA (especially the 1981 study). The committee concluded that the results
of Aronow's studies did not meet a reasonable standard of scientific quality and, therefore,
should not be used by the Agency in defining the critical COHb level at which adverse health
effects of CO are occurring. A summary of the committee findings and a revaluation of the
key health effects information reported to be associated with relatively low-level CO exposure
can be found in an addendum to the 1979 criteria document for CO (U.S. Environmental
Protection Agency, 1984).
The experimental design used in the Aronow studies on CO exposure effects in patients
with angina set the stage for subsequent, more precisely designed studies. Aronow and his
colleagues used the subjective measure of time to onset of angina as their only significant
variable of CO effect. In an attempt to improve upon these earlier preliminary studies, the
more recent studies placed greater emphasis on electrocardiogram (EGG) changes as objective
measures of ischemia. Another consideration in the conduct of the newer studies on angina
was to better establish the dose response relationships for low levels of CO exposure.
Although the COHb level is accepted as the best measure of the effective dose of CO, the
reporting of low-level effects is problematic because of inconsistencies in the rigor with
which the devices for measuring COHb have been validated. The most frequently used
technique for measuring COHb has been the optical method found in the IL series of
CO-Oximeters (CO-Ox). Not only is there a lot of individual variability in these machines,
but recent comparisons with the gas chromatographic (GC) technique of measuring COHb
have suggested that the optical method may not be a suitable reference technique for
measuring low levels of COHb. (See Section 8.5 for more details.) Several additional
studies have appeared in the literature to help define the precise COHb levels at which
cardiovascular effects occur in angina patients (see Table 10-2). The rest of this section
describes the results from these newer studies in their order of appearance in the published
literature. Supportive study reports containing more detailed information are also referenced
if they were made available by the research sponsor. Since, as noted above, the range of
COHb values obtained with the optical method of analysis may be different than that obtained
by GC, the method used to measure COHb will be indicated in parentheses for each of these
studies.
10-24
-------
Sheps et al. (1987) studied 30 patients with ischemic heart disease age 38 to 75 years
and assessed not only symptoms during exercise, but radionuclide evidence of ischemia (left
ventricular ejection fraction changes). Patients were nonsmokers with ischemia, defined
either by exercise-induced ST segment depression, angina, or abnormal ejection fraction
response (i.e., all patients had documented evidence of ischemia).
Patients were exposed to CO (100 ppm) or air during a 3-day, randomized double-blind
protocol to achieve a postexposure level of 4% COHb (CO-Ox measurement). Resting
preexposure levels were 1.7%, postexposure levels were 4.1%, and postexercise levels were
3.6% on the CO exposure day; thus the study examined acute elevation of COHb levels from
1.7% to an average of 3.8%, or an average increase of 2.2% from resting values.
Comparing exposure to CO to exposure to air, there was no significant difference in time to
onset of angina, maximal exercise time, maximal ST segment depression (1.5 mm for both),
or time to significant ST segment depression. The conclusion of this study was that 3.8%
COHb produces no clinically significant effects on this patient population.
Interestingly, further analysis of the time to onset of angina data in this paper
demonstrated that 3 of the 30 patients experienced angina on the CO exposure day but not on
the air control day. These patients had to be deleted from the classical analysis of differences
between time to onset of angina that was reported in the publication. However, actuarial
analysis of time to onset of angina including these patients revealed a statistically significant
(p<0.05) difference in time to onset of angina favoring an earlier time under the
CO-exposure conditions (Bissette et al., 1986). None of the patients had angina only on the
air exposure day.
Subsequent work from these same investigators (Adams et al., 1988) focused on
repeating the study at 6% COHb (CO-Ox measurement). Thirty subjects with obstructive
coronary artery disease and evidence of exercise-induced ischemia were exposed to air or CO
on successive days in.a randomized double-blind crossover fashion. Postexposure COHb
levels averaged 5.9 ± 0.1% compared to 1.6 ± 0.1% after air exposure, representing an
increase of 4.3%. The mean duration of exercise was significantly longer after air compared
to CO exposure (626 + 50 s for air vs. 585 + 49 s for CO, p<0.05). Actuarial methods
suggested that subjects experienced angina earlier during exercise on the day of CO exposure
10-25
-------
(p<0.05). In addition this study showed that, at a slightly higher level of CO exposure, both
the level and change in ejection fraction at submaximal exercise were greater on the air day
than on the CO day. The peak exercise left ventricular ejection fraction, however, was not
different for the two exposures.
These results demonstrated earlier onset of ventricular dysfunction and angina and
poorer exercise performance in patients with ischemic heart disease after acute CO exposure
sufficient to increase COHb to 6%. It is of interest that in both the 4% study and the 6%
study reported by this group, seven of the patients experienced angina on the CO day, but not
on the air exposure day. There were no patients who experienced angina in the reverse
sequence, providing further support for a significant effect of CO exposure on angina
occurrence.
Kleinman and Whittenberger (1985) and Kleinman etal. (1989) studied nonsmoking
male subjects with a history of stable angina pectoris and positive exercise tests. All but two
of the 26 subjects had additional confirmation of ischemic heart disease, such as previous
myocardial infarction (MI), positive angiogram, positive thallium scan, prior angioplasty, or
prior bypass surgery. Subjects were exposed for 1 h in a randomized double-blind crossover
fashion to either 100 ppm CO or to clean air on 2 separate days. Subjects performed an
incremental exercise test on a cycle ergometer to the point at which they noticed the onset of
angina. For the study group, the 1-h exposure to 100 ppm CO resulted in an increase of
COHb from 1.4% after clean air to 3% (CO-Ox measurement) after CO. For the entire
study group (n = 26), the 1-h exposure to 100 ppm resulted in a decrease of the time to
onset of angina by 6.9% from 6.5 to 6.05 min (Kleinman and Whittenberger, 1985). This
difference was significant in a one-tailed paired t-test (p = 0.03). When using a two-tailed
test, the difference loses statistical significance at the p = 0.05 level.
In the published version of results from this study (Kleinman et al., 1989), the two
subjects with inconsistencies in their medical records and histories were dropped from the
analysis. For this study group (n = 24), the 1-h exposure to 100 ppm CO (3% COHb by
CO-Ox measurement) resulted in a significant decrease of time to onset of angina by 5.9%
using a one-tailed, 2-factor ANOVA (p = 0.046). There was no significant effect on the
duration of angina, but O2 uptake at angina point was reduced 2.7% (p = 0.04). Only eight
of the subjects exhibited depression in the ST segment of their ECG traces during exercise.
10-26
-------
For this subgroup, there was a 10% reduction (p<0.036) in time to onset of angina and a
19% reduction (p< 0.044) in the time to onset of 0.1 mV ST segment depression.
A multicenter study of effects of low levels of COHb has been conducted in three cities
on a relatively large sample (n = 63) of individuals with coronary artery diseases (Allred
et al., 1989a,b, 1991). The purpose of this study was to determine the effects of GO
exposures producing 2.0% and 3.9% COHb (GC measurement) on time of onset of
significant ischemia during a standard treadmill exercise test. Significant ischemia was
measured subjectively by the time of exercise required for the development of angina (time of
onset of angina) and objectively by the time required to demonstrate a 1-mm change in the
ST segment of the EGG (time to ST). The time to onset of ST segment changes was
measured to the nearest second, rather than to the nearest minute as in the other studies on
angina, a strength of this study. Male subjects, ages 41 to 75 (mean = 62.1 years) with
stable exertional angina pectoris and a positive stress test, as measured by a greater than
1-mm ST segment change, were studied. Further evidence that these subjects had coronary
artery disease was provided by the presence of at least one of the following criteria:
angiographic evidence of narrowing (> 70%) of at least one coronary artery, documented
prior MI, or a positive stress thallium test demonstrating an unequivocal perfusion defect.
Thus, as opposed to some previous studies reported, this study critically identified patients
with documented coronary artery disease.
The protocol for this study was similar to that used in the Aronow studies because two
exercise tests were performed on the same day. The two tests were separated by a recovery
period and a double-blind exposure period. On each of the 3 exposure days, the subject
performed a symptom-limited exercise test on a treadmill, then was exposed for 50 to 70 min
to CO concentrations that were experimentally determined to produce end-exposure COHb
levels of 2% and 4%. The mean exposure levels and ranges for the test environment were
clean air, 0 ppm CO, 117 ppm CO (42 to 202 ppm), and 253 ppm CO (143 to 357 ppm).
The subject then performed a second symptom-limited exercise test. The time to the onset of
angina and the time to 1-mm ST change was determined for each test. The percent change
following exposure at both 2.0 and 3.9% COHb (GC measurement) then were compared to
the same subject's response to the randomized exposure to room air (less than 2 ppm CO).
10-27
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When potential exacerbation of the exercise-induced ischemia by exposure to CO was
tested using the objective measure of time to 1-mm ST segment change, exposure to CO
levels producing 2.0% COHb resulted in a 5.1% decrease (p = 0.01) in the time to attain
this level of ischemia. At 3.9% COHb, the decrease in time to the ST criterion was 12.1%
(p £ 0.0001) relative to the air-day results. At the 3,9% COHb level, this reduction in time
to ST depression was accompanied by a significant (p = 0.03) reduction in the heart rate-
blood pressure product (double product), an index of myocardial work. The maximal
amplitude of the ST segment change also was significantly affected by the CO exposures: At
2% COHb, the increase was 11% (p = 0.002) and at 3.9% COHb, the increase was 17%
relative to the air day (p< 0.0001).
When the individual center data in the Allred et al. (1989a,b, 1991) study were
analyzed for covariates that may have influenced the results of this study, only the absolute
level of COHb was found to have had a significant effect. This finding is not surprising
given the dose-response relationship between CO and time to ST (see Figure 10-2). This
analysis compared the slopes for each individual subject: The three times to ST were plotted
against the three actual COHb levels. The 62 individual slopes then were combined to yield
a significant (p<0.005) regression: Change in Time to ST = (-3.85 + 0.63) (%COHb) +
(8.01% ± 2.48%). This dose-response relationship indicates that there is a 3.9% decrease in
the time to ST criterion for every 1% increase in COHb.
The time to the onset of angina also was significantly reduced in these subjects. At
2.0% COHb, the time to angina was reduced by 4.2% (p = 0.027) and at 3.9% COHb, the
time was reduced by 7.1% (p = 0.002). There were no significant changes in the double
products at the time of the onset of angina in either exposure condition. The regression
analysis for the time to angina data also resulted in a significant relationship (p<0.025.) The
average regression was Time to Angina = (-1.89% ± 0.81%) (%COHb) + (1.00%
± 2.11 %). The lower level of significance and the larger error terms for the angina
regression relative to the ST analysis indicate that the angina end point is more variable,
This may be due to the subjective nature of this end point and the variability in the ability of
subjects to clearly recognize the onset of the pain.
The two end points (time to angina and time to ST change) in the Allred study also
were correlated, with a Spearman rank correlation coefficient of 0.49 (p < 0.0001). The
10-28
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s
F
70
60—
50—
40—
30—
20—
10—
0—
-10 —
-20
-30 —
^0 —
-50
0 1 23 4.5 6
Percent COHb after Exercise
Figure 10-2. Regression of the percent change in time to threshold isehemic ST segment
change (ST End Point) between the pre- and postexposure exercise tests
and the carboxyhemoglobin (COHb) levels measured after exercise. Each
subject is represented by three data points. The line represents the
average of individual regressions for each subject
Source: Allied et al. (1989b; 1991).
conclusion of all of the analyses from this multicenter study.is that the response of the
myocardium in these patients with coronary artery disease is consistent, although the effects
are relatively small. :
The analysis of the covariates in this multicenter study also provides answers to
ancillary questions that have been raised elsewhere in this document. The medication being
used by these subjects did not significantly influence the results (i.e., there does not appear to
be any drug interaction with the effects of CO). The major medications being used in this
group were betablockers (used by 38 of the 63 subjects), nitrates (used by 36 of the
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63 subjects), and calcium-channel blockers (used by 40 of the 63 subjects). The other major
concern was the influence of the severity of the disease. The simplest approach to this was to
evaluate the influence of the duration of the exercise because the subjects with more severe
disease were limited in their exercise performance. No significant correlation was found
between duration of exercise and the percentage change in the time to angina or ST criterion.
There also was no relationship between the average time of exercise until the onset of angina
and either of the end points. There also was no relationship between the presence of a
previous MI and the study end points.
The duration of exercise was significantly shortened at 3.9% COHb but not at
2.0% level. This finding must be used cautiously because these subjects were not exercised
to their maximum capacity in the usual sense. The major reason for termination of the
exercise was the progression of the angina (306 of 376 exercise tests.) The subjects were to
grade their angina on a four-point scale, and when the exercise progressed beyond level two,
they were stopped. Therefore this significant decrease in exercise time of 40 s at the 3.9%
COHb level is undoubtedly due to the earlier onset of angina followed by the normal rate of
progression of the severity of the angina.
The individual center data provides insight into the interpretation of other studies that
have been conducted in this area. Each of the centers enrolled the numbers of subjects that
have been reported by other investigators. The findings reported above were not
substantiated in all instances at each center. When one considers the responses of the group
to even the 3.9% COHb, it is clear as to why one might not find significance in one
parameter or another. For the decrease in ST segment at 3.9%, only 49 of 62 subjects
demonstrated this effect on the day tested. The potential for finding significance at this effect
rate with a smaller sample size is reduced. Random sampling of this population with a
smaller sample easily could provide subjects that would not show significant effects of these
low levels of CO on the test day.
The recent reports (Allred et al., 1989b, 1991) of the multicenter study, organized and
supported by the Health Effects Institute, discuss some reasons for differences between the
results of the studies cited above (also see Table 10-2 and Table 10-3). The studies have
different designs, types of exercise tests, inclusion criteria (and, therefore, patient
populations), exposure conditions, and means of measuring COHb. All of the studies have
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TABLE 10-3. COMPARISON OF SUBJECTS IN STUDIES OF THE EFFECT OF CARBON MONOXIDE
EXPOSURE ON OCCURRENCE OF ANGINA DURING EXERCISEa
Subject Characteristics
Study
Number of Subjects Gender
Medication
Smoking History
Description of Disease
Age (years)
Anderson et al. (1973)
Kleinman et al. (1989)
Allred et al. (1989a,b;
1991)
Sheps et al. (1987)
Adams et al. (1988)
10
24
63
male
male
male
30 (23 with angina) 25 male
5 female
30 (25 with angina) 22 male
•8 female
1 subject took digitalis;
drug therapy basis for
exclusion
14 on betablockers; 19 on
nitrates; 8 on Ca-channel
blockers
38 on betablookers; 36 on
nitrates; 40 on Ca
antagonists
26.subjects on medication;
19 on beta blockers; 11 on
Ca-channel blookera; 1 on
long-acting nitrates
25 subjects on medication;
13 on beta blockers +
Ca-ohannel blockers; 6 on
beta blockers; 5 on
Ca-channel blockers; 1 on
long-acting nitrates
5 smokers (refrained
for 12 h prior to
exposure)
No current smokers
No current smokers
No current smokers
No current smokers
Stable angina pectoris,
positive exercise.test (ST
changes); reproducible
angina on treadmill
Ischemic heart disease,
stable exertional angina
pectoris
Stable exertional angina
and positive exercise test
(ST changes) plus one or
more of the following:
(1)S70% lesion by
angipgraphy in one or
more major vessels,
(2) prior MI, (3) positive
exercise thallium test
Ischemia during exercise
(ST changes or abnormal
ejection fraction response)
and one or more of the
following: (1) angio-
graphically proven CAD,
(2) prior MI, (3) typical
angina
Ischemia during exercise
(ST changes or abnormal
.ejection fraction response)
and one or more of the
following: (1) angio-
graphically proven CAD,
(2) prior MI, (3) typical
angina
(mean = 49.9)
49-66 (mean = 59)
41-75 (mean = 62.1)
36-75 (mean = 58.2)
36-75 (mean = 58)
aSee glossary of terms and symbols for abbreviations and acronyms.
Source: Adapted from Allred et al. (1989b, 1991).
-------
shown an effect of COHb elevation on the time to onset of angina (see Figure 10-3). Results
from the Kleinman et al. (1989) study showed a 6% decrease in exercise time to angina at
3.0% COHb (CO-Ox measurement) measured at the end of exposure. Allred *et al. (1989a,b)
reported a 5 and 7% decrease in time to onset of angina after increasing COHb levels to
3.2 and 5.6% (CO-Ox measurement), respectively, at the end of exposure. Although the
Sheps et al. (1987) and Adams et al. (1988) studies did not observe statistically significant
changes in time to onset of angina using conventional statistical procedures, the results of
these studies are not incompatible with the rest of the studies reporting an effect of CO. Both
studies reported a significant decrease in the time to onset of angina on days when COHb
levels at the end of exposure were 4.1 and 5.9% (CO-Ox measurement), respectively, if the
data analysis by actuarial method included subjects who experienced angina on the CO day ,
but not the air day. In addition, the Adams et al. (1988) study reported that left ventricular
performance, assessed by radionuclide measurement of the ejection fraction, was reduced
during submaximal exercise after CO exposure when compared to air exposure.
Of particular importance in this group of studies was the fact that the multicenter study
(Allred et al., 1989a,b, 1991) demonstrated a dose-response effect of COHb on time to onset
of angina. The only other single study that investigated more than a single target level of
COHb was Anderson et al. (1973) and their results, based on a smaller number of subjects,
did not show a dose response relationship for angina.
The time to onset of significant ECG ST-segment changes, which are, indicative of
myocardial ischemia in patients with documented coronary artery disease (CAD), is a more
objective indicator of ischemia than angina is. Allred et al. (1989a,b, 1991) reported a
5.1 and 12.1 % decrease in time to ST depression at .COHb levels of 2.0 and 3.9% :
(GC measurement), respectively, measured at the end of exercise. An additional , ,,
measurement of the ST change was made by Allred et al. (1989b) to confirm this response-
all the leads showing ST segment changes were summed. This summed ST score also was
significantly affected by both levels of COHb. The significant finding for the summed ST
score indicates that the effect reported for time to ST was not dependent upon changes ;,
observed in a single ECG lead. , ,, ...
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rt
<
o
0)
1
w —
25-
20-
15-
10-
5-
0-,
-5-
-10
1
1 Anderson 1
l
-p .. . •
Kleinman j
1 i .Allred
..-•.' - . '
- . • (
r * '
1 Shepsa
1 Adams
-L
i • . .1 i .
2 4 6
Percent COHb by Optical Methods
Figure 10-3. The effect of carbon monoxide (CO) exposure on time to onset of angina.
For comparison across studies, data are presented as mean percent
differences between air- and CO-expos,ure days for individual subjects
calculated from each study. Bars indicate calculated standard errors of
the mean. Carboxyhemoglobin (COHb) levels were measured at the end
of exposure; however, because of protocol differences among studies and
lack of precision in optical measurements of COHb, comparisons must be
interpreted with caution. (See text and Table 10-2 and Table 10-3 for
more details.)
aAlternative statistical analyses of the Sheps data (Bissette et al., 1986) indicate a significant decrease in time to
onset of angina at 4.1% COHb if subjects that did not experience exercise-induced angina during air exposure
are also included in the analyses.
Source: 'Adapted from Allred etal. (19 89b, 1991).
The differences between the results of these five studies on exercise-induced angina can
largely be explained by differences in experimental methodology and analysis of data and, to
some extent, by differences in subject populations and sample size. For example, the
Kleinman study and the Allred study used one-tailed p values, whereas the Sheps and Adams
studies used two-tailed p values. The Allred study also used trimmed means (with the two
highest and two lowest values deleted) to guard against outliers. If a two-sided p value was
utilized on the time to onset of angina variable observed at the lowest COHb level in the
Allred study, it would become 0.054 rather than 0.027, a result that would be considered
borderline significant. If a two-sided p value were used in the Kleinman study, the difference
in time to onset of angina would lose significance at the p = 0.05 level.
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The entry criteria in the Allred study were more rigorous than in the other studies. All
subjects were required to have stable exertional angina and reproducible exercise-induced ST
depression and angina. Besides these criteria, all subjects were required to have either a
previous MI, angiographic disease, or a positive thallium stress test. In addition, only men
were studied. These strict entry criteria were helpful in allowing the investigators to more
precisely measure an adverse effect of CO exposure. The protocol for the multicenter study,
however, was slightly different from some of the protocols previously reported. On each test
day, the subject performed a symptom-limited exercise test on a treadmill, then was exposed
for approximately 1 h to air or one of two levels of CO in air, and then underwent a second
exercise test. Time to the onset of ischemic ECG changes and time to the onset of angina
were determined for each exercise test. The percent difference for these end points from the
pre- and postexposure test then was determined. The results on the 2% target day and then
the 4% target day were compared to those on the control day.
The statistical significance reported at the low-level CO exposure is only present when,
the differences between pre- and postexposure exercise tests are analyzed. Analysis of only
the postexposure test results in a loss of statistical significance for the 2% COHb level.
Some of the differences between the results of this multicenter study and previous studies
may be related to the fact that the exposure was conducted shortly after patients exercised to
angina. The length of time, required for resolution of exercise-induced ischemia is not
known. However, exercise treadmill testing'of patients with CAD has been shown to induce
regional wall motion abnormalities of .the left ventricle that persist for over 30 to 45 min after
exercise when chest pain and ECG abnormalities are usually resolved (Kloner et al., 1991).
In addition, radionuclide studies in these patients have shown metabolic effects of ischemia to
last for more than 1 h after exercise (Camici et al., 1986). Because the effects of ischemia
may have a variable duration, differences between pre- and postexposure tests may have been
due to effects of CO exposure on recovery from a previous episode of exercise-induced
ischemia rather than detrimental effects only during exercise. ,
In conclusion, five key studies have investigated the potential for CO exposure to ,
enhance the development of myocardial ischemia during progressive exercise tests. Despite .
differences between them, it is impressive that all of the studies identified in Figure 10-3
show a decrease .in the time to onset of angina at postexposure COHb levels ranging from
10-34
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2.9 to 5.9%. This represents incremental increases of 1.5 to 4.4% COHb from preexposure
baseline levels. Therefore, there are clearly demonstrable effects of low-level GO exposure
in patients with ischemic heart disease. The adverse health consequences of these types of
effects, however, are very difficult to predict in the at-risk population of individuals with
heart disease. There exists a distribution of professional judgments on the clinical
significance of small performance decrements occurring with the levels of exertion and CO
exposure defined in these five studies. The decrements in performance that have been
described at the lowest levels (< 3% COHb) are in the range of reproducibility of the test and
may not be alarming to some physicians. On the other hand, the consistency of the responses
in time to onset of angina across the studies and the dose-response relationship described by
Allred et al. (1989a,b, 1991) between COHb and time to ST segment changes would
strengthen the argument in the minds of other physicians that, although small, the effects
could limit the activity of these individuals and affect the quality of their life. In addition, it
has been argued by Bassan (1990) that 58% of cardiologists believe that recurrent episodes of
exertional angina are associated with a substantial risk of precipitating an MI, a fatal
arrhythmia, or slight but cumulative myocardial damage.
Effects in Individuals with Chrome Obstructive Lung Disease
Aronow et al. (1977) studied the effects of a 1-h exposure to 100 ppm CO on exercise
performance in 10 men, aged 53 to 67 years, with chronic obstructive lung disease. The
resting mean COHb levels increased from 1.4% baseline levels to 4.1% after breathing CO.
The mean exercise time until marked dyspnea significantly decreased (33%) from 218 s in the
air-control period to 147 s after breathing CO. The authors speculated that the reduction in
exercise performance was due to a cardiovascular limitation rather than respiratory
impairment.
Only one other study in the literature, by Calverley et al. (1981), looked at the effects
of CO on exercise performance in older subjects with chronic lung disease. They evaluated
15 patients with severe reversible airway obstruction due to chronic bronchitis'and
emphysema. Six of the patients were current smokers but they were asked to stop smoking
for 12 h before each study. The distance walked within 12 min was measured before and
after each subject breathed 0.02% CO in air from a mouthpiece for 20 to 30 min until COHb
10-35
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levels were 8 to 12% above their initial levels. A significant decrease in walking distance
was reported when the mean COHb concentration reached 12.3%, a level much higher than
most of those reported in the studies on healthy subjects.
Thus, although it is possible that individuals with hypoxia due to chronic lung diseases
such as bronchitis and emphysema may be susceptible to CO during submaximal exercise
typically found during normal daily exercise, these effects have not been studied adequately at
relevant COHb concentrations of <5%. ,
Effects in Individuals with Chronic Anemia
An additional study by Aronow et al. (1984) on the effect of CO on exercise
performance in anemic subjects found a highly significant decrease in work time (16%)
induced by a 1.24% increase in COHb. The magnitude of change seems to be very unlikely,
however, even considering the report by Ekblom and Huot (1972). The study was double-
blind and randomized, but with only 10 subjects. The exercise tests were done on a bicycle
in the upright position with an increase in workload of 25 W every 3 min. However, no
measure of maximal performance such as blood laetate was used. The mean maximal heart
rate was only 139 to 146 beats/min compared to a predicted maximal heart rate of ,
170 beats/min for the mean age of the subjects. A subject repeating a test within the same
day, which was the case in the Aronow et al. (1984) study, often will remember the time and
work load and try to do the same in the second test. Normally, however, some subjects will
increase while others will decrease the time. This situation was apparent on the air-control
day, with an increase demonstrated in 6 out of 10 subjects, despite the high reproducibility
for such a soft, subjective end point. Also, comparing the control tests on the air day with
the CO day, 7 out of 10 subjects increased their work time. After CO exposure, however,
every subject decreased their time between 29 and 65 s. These data appear to be implausible
given the soft end point used, when two to three of the subjects would be expected to
increase their time even if there was a true effect of CO.
10.3.2.2 Arrhytfamogenie Effects .......
The literature until recent years has been confusing with regard to potential
arrhythmogenic effects of CO.
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Davies and Smith (1980) studied the effects of moderate CO exposure on healthy
individuals. Six matched groups of human subjects lived in a closed, environmental-exposure
chamber for 18 days and were exposed to varying levels of CO. Standard 12-lead ECGs
were recorded during 5 control, 8 exposure, and 5 recovery days. P-wave changes of at least
0.1 mV were seen in the ECGs during the CO exposure period in 3 of 15 subjects at 2.4%
COHb and in 6 of 15 at 7.1% COHb compared to none of 14 at 0.5% COHb. The authors
felt that CO had a specific toxic effect on the myocardium in addition to producing a
generalized decrease in O2 transport to tissue.
Several methodological problems create difficulties of interpretation for this study. The
study design did not use each subject as his own control. Thus, only one exposure was
conducted for each subject. Half of the subjects were tobacco smokers who were required to
stop smoking and certainly some of the ECG changes could have been due to tiie effects of
nicotine withdrawal. Although the subjects were deemed to be normal, no screening stress
tests were performed to uncover latent ischemic heart disease or propensity to arrhythmia.
Most importantly, no sustained arrhythmias or measurable effects on the conduction system
were noted by the authors. If p-wave changes of clinical significance are representative of a
toxic effect of CO on the atrium, then an effect on conduction of arrhythmias should be
demonstrated. . , >
Knelson (1972) reported that 7 of 26 individuals, aged 41 to 60 years, had abnormal
ECGs after exposure to 100 ppm CO for 4 h (COHb levels of 5 to 9%). Two of them
developed arrhythmias. No further details were given regarding specifics of these
abnormalities; Among 12 younger subjects aged 25 to 36 years, all ECGs were normal.
Hinderliter et al. (1989) reported on effects of low-level CO exposure on resting and
exercise-induced ventricular arrhythmias in patients with CAD and no baseline ectopy. They
studied 10 patients with ischemic heart disease and no ectopy according to baseline
monitoring. After an initial training session, patients were exposed to air, 100 ppm CO, or
200 ppm CO on successive days in a randomized, double-blinded crossover fashion. Venous
COHb levels after exposure to 100 and 200 ppm CO averaged 4 and 6%, respectively.
Symptom-limited supine exercise was performed after exposure. Eight of the 10 patients had
evidence of exercise-induced ischemia—either angina, ST segment depression, or abnormal
left ventricular ejection fraction response—during one or more exposure days. Ambulatory
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ECGs were obtained for each day and were analyzed for arrhythmia frequency and severity.
On air- and CO-exposure days, each patient had only zero to one ventricular premature beat
per hour in the 2 h prior to exposure, during the exposure period, during the subsequent
exercise test, and in the 5 h following exercise. The authors concluded that low-level CO
exposure is not arrhythmogenie in patients with CAD and no ventricular ectopy at baseline.
The results of low-level CO exposure on patients with higher levels of ectopy were
reported by the same investigators (Sheps et al., 1990, 1991). They studied 41 nonsmokers
with documented coronary artery disease over 4 consecutive days. On the first day, a
training session was conducted without exposure. Baseline COHb was measured by CO-Ox
and a supine bicycle test was done. On the second through fourth days, patients were
exposed to room air, 100 ppm CO, or 200 ppm CO followed by supine bicycle exercise with
radionuclide ventriculography. Venous COHb levels after exposure to 100 and 200 ppm CO
averaged 4 and 6%, respectively. Ambulatory ECG recordings were made during the four
consecutive days to determine the frequency of ventricular premature depolarization (VPD).
Subjects were categorized by arrhythmia frequency on the training day before, during, and
6 h after exercise; 10 had no arrhythmias (0 to 2 VPD/h), 11 had low-level arrhythmia (3 to
50 VPD/h), 11 had intermediate-level arrhythmias (51 to 200 VPD/h), and 9 had high-level
arrhythmia (>200 VPD/h). The mean of the maximal and submaximal VPDs per hour was
greater than 175. The frequency of a single VPD per hour was significantly greater after CO
exposure producing 6% COHb (167.72 + 37.99) compared with exposure to room air
(127.32 ± 28.22, p=0.03) and remained significant when adjusted for baseline VPD levels
for all subjects regardless of VPD frequency category. During exercise, the mean number of
multiple VPDs per hour was greater after CO exposure producing 6% COHb (9.59 ± 3,70)
compared with exposure to room air (3.18 + 1.67, p=0.02) and remained significant after
adjustment for baseline multiple VPD levels and when all subjects were included regardless
of VPD frequency category. The authors concluded that the number and complexity of
ventricular arrhythmias increases significantly during exercise after CO exposures producing
6% COHb compared with room air exposures but not after CO exposures producing 4%
COHb. Because statistically significant effects were only shown during the exercise period,
however, these reported changes are likely occurring at a lower COHb level. In fact, the
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COHb levels during exercise were 1.4% on the air-exposure day, 3.7% on the 4% COHb
target-exposure day, and 5.3% on the 6% COHb target-exposure day, reflecting the mean
values of the pre- and postexercise levels. Analysis of dose-response relationships could not
be carried out in this study, making it more difficult to determine the strength of the evidence
for the effects of CO on arrhythmia. In this study, the amount of arrhythmia produced by
CO exposure was not correlated with measured variables of angina (e.g., time to STrsegment
depression and time to angina) or with the clinical descriptors of disease status or medication
usage. It is not known, therefore, if the increased arrhythmia is mediated by the known
effect of CO on myocardial ischemia. ;
Although no definite evidence exists to date relating effects of CO exposure and lethal
arrhythmias, the recent epidemiologic study of Stern and colleagues (Stern et ill.,, 1988)
indicates that an excess of cardiovascular mortality in tunnel workers could be due to
exposure to high levels of CO (see Section 10.3.3). Their findings that risk decreased after
job cessation and that risk was not related to length of exposure suggest an acute effect of CO
exposure maybe the causative factor (perhaps due to arrhythmia production). These findings
are consistent with the general lack of effect of CO exposure on the development or
progression of atherosclerosis.
10.3.2.3 Effects on Coronary Blood Flow
The effects of breathing CO on myocardial function in patients with and. without
coronary heart disease have been examined by Ayres et al. (1969, 1970, 1979). Acute
elevation of COHb from 0.98 to 8.96% by a bolus exposure using either 1,000 ppm CO for
8 to 15 min or 50,000 ppm for 30 to 45 s caused a 20% average decrease in coronary sinus
O2 tension without a concomitant increase in coronary blood flow in the patients with
coronary artery disease. Observations in patients with coronary disease revealed that acute
elevation of COHb to approximately 9% decreased the extraction of O2 by the myocardium.
However, overall myocardial O2 consumption did not change significantly because an
increase in coronary blood flow served as a mechanism to compensate for a lower overall .
myocardial O2 extraction. In contrast, patients with noncoronary disease increased their
coronary blood flow with an insignificant decrease in coronary sinus O2 tension as a response
to increased COHb. The coronary patients also switched from lactate extraction to lactate
10-39
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production. Thus, because of their inability to increase coronary blood flow to compensate
for the effects of increased COHb, a potential threat exists for patients with coronary heart
disease who inhale CO.
Although in this study the coronary sinus P02 dropped only slightly (reflecting average
coronary venous O2 tension), it is certainly possible that, in areas beyond a significant
coronary arterial stenosis, tissue hypoxia might be precipitated by very low tissue PO2 values.
Tissue hypoxia might be further exacerbated by a coronary-steal phenomena whereby
increased overall coronary flow diverts flow from areas beyond a stenosis to other normal
areas. Therefore the substrate for the worsening of ischemia and consequent precipitation of
arrhythmias is present with CO exposure.
10.3.3 Relationship Between Carbon Monoxide Exposure and Risk of
Cardiovascular Disease in Humans ,
Epidemiologic studies on the relation between CO exposure and ischemic heart disease
are scarce. In the United States, a population study by Cohen et.al. (1969) suggested an. .
association between atmospheric levels of CO and increased mortality from MI in
Los Angeles, but potential confounders were not effectively controlled. In contrast, a similar
study in Baltimore (Kuller et al., 1975) showed no association between ambient CO levels
and MI or sudden death. A study of emergency room visits for cardiovascular complaints in
Denver (Kurt et al., 1978), showed a relationship with CO exposure levels, but the
correlations were relatively weak and other environmental factors were not evaluated. These
early epidemiological date were summarized by Kuller and Radford (1983). They concluded
that mortality and morbidity studies have been negative or equivocal in relating CO levels to
health effects, but studies in human subjects with compromised coronary circulation support
an effect of acute exposure to CO at blood levels equivalent to about 20 ppm over several
hours. They calculate that based on health surveys, probably over 10 million subjects in the
United States are exposed to potentially deleterious levels of CO and that perhaps 1,250
excess deaths related to,low-dose environmental CO exposure occur each year.
Early studies of occupational exposure to CO (Redmond, 1975; Redmond et al., 1979;
Jones and Sinclair, 1975) failed to identify any increased risk of cardiovascular disease
associated with CO exposure. In a Finnish study (Hernberg et al., 1976; Koskela et al.,
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1976), the prevalence of angina among foundry workers showed an exposure-response
relationship with regard to CO exposure, but no such result was found for ischemic EGG
findings during exercise.
Stern et al. (1981) reported a study performed by the National Institute for Occupational
Safety and Health. They investigated the health effects of chronic exposure to low
concentrations of CO by conducting a historical prospective cohort study of mortality patterns
among 1,558 white, male motor vehicle examiners in New Jersey. The examiners were
exposed to 10 to 24 ppm CO. The COHb levels were determined in 27 volunteers. The
average COHb level before a work shift was 3.3% and the postshift level was 4.7% in the
whole group and 2.1 and 3.7%, respectively, in nonsmokers only. The death rates were
compared to the rates in the U.S. population based on vital statistics. The cohort
demonstrated a slight overall increase in cardiovascular deaths but a more pronounced excess
was observed within the first 10 years following employment. The study has several
important limitations, however, including the use of historical controls. A second limitation
is the lack of knowledge about smoking habits. A third is that the individuals' values of
COHb were not known.
Stern et al. (1988) published coronary heart disease mortality data among bridge and
tunnel officers exposed to CO. They investigated the effect of occupational exposure to CO
on mortality from arteriosclerotic heart disease in a retrospective study of 5,529 New York
City bridge and tunnel officers. There were 4,317 bridge officers and 1,212 tunnel officers.
Among former tunnel officers, the standardized mortality ratio was 1.35 (90% confidence
interval [CI] was 1.09 to 1.68) compared to the New York City population. Using the
proportional hazards model, the authors compared the risk of mortality from arteriosclerotic
heart disease among tunnel workers with that of the less-exposed bridge officers. They found
an elevated risk in the tunnel workers that declined within as little as 5 years after cessation
of exposure. The 24-h average CO level in the tunnel was around 50 ppm in 1961 and
around 40 ppm in 1968. However, higher values were recorded during rush hours. In 1971,
the ventilation was further improved and the officers were allowed clean-air breaks.
Although the authors concluded that CO exposure may play an important role in the
pathophysiology of cardiovascular mortality, other factors must be taken into consideration.
Mortality from arteriosclerotic heart disease has a complex multifactor etiology. The
10-41
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presence of other risk factors, such as cigarette smoke, hypertension, hyperlipidemia, family
history of heart disease, obesity, socioeconomic status, and sedentary living all can increase
the risk of developing coronary heart disease. In addition, detailed exposure monitoring was
not done in this study. The bridge and tunnel workers were not only exposed to CO but also
were exposed to other compounds emitted from motor vehicle exhaust and to the noise and
stress of their environment. These other factors could have contributed to the findings.
Hansen (1989) reported the results of a 10-year follow-up study on mortality among
583 Danish men between 15 and 74 years of age that were occupationally active as
automobile mechanics. The number of deaths expected for the automobile mechanics was
compared to a similar group of Danish men employed as carpenters, electricians, and as other
skilled workers free from occupational exposure to automobile exhaust, petrochemical
products, asbestos, and paint pigments. The number of deaths observed among the
automobile mechanics exceeded the expected number by 21%. Although the increased
mortality was not confined to any single cause of death, the author reported a remarkable
excess of deaths attributed to ischemic heart disease where the standardized mortality ratio
(SMR) was 121 and the 95% CI was 102 to 145. The only other significant category of
death was that due to external causes (SMR = 131, 95% CI = 113-153). No significant ,
differences were found among the automobile mechanics for other diseases except, for an . ;
increase in pancreatic cancer (SMR = 219, 95% CI = 128-351). Exposure to CO and
polycyclic aromatic hydrocarbons through the inhalation of automobile exhaust and the
handling of solvents and oils may have accounted for the difference in ischemic heart disease
deaths between the automobile mechanics and the comparison group; however, other
occupational exposures or other life-style factors, as indicated above, may also have
contributed to the findings. >
Intoxication with CO that induces COHb levels around 50 to 60% is often lethal;
however, even levels around 20% COHb have been associated with death, mainly coronary
events, in patients with severe coronary artery disease. Balraj (1984) reported on 38 cases of
individuals dying immediately or within a few days following CO exposures producing 10 to
50% COHb, usually nonlethal levels of CO. All of the subjects had coronary artery disease,
and 29 of them had severe cases. The author concluded that the CO exposure, between 10 to
30% COHb in 24 cases, triggered the lethal event in subjects with a restricted coronary flow
10-42
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reserve. Similar associations between CO exposure and death or MI have been reported by
several other authors. Atkins and Baker (1985) reported two cases with 23 and 30%' COHb,
McMeekin and Finegan (1987) reported one case with 45% COHb, Minor and Seidler (1986)
reported one case with 19% COHb, and Ebisuno et al. (1986) reported one case with
21% COHb.
Forycki et al. (1980) described electrocardiographic changes in 880 patients treated for
acute poisoningi Effects were observed in 279 cases, with the most marked changes in cases
with CO poisoning. In those, the most common change was a T-wave abnormality and in
six cases a pattern of acute MI was present. Conduction disturbances also were common in
CO poisoning, but arrhythmias were less common.
The association between smoking and cardiovascular disease (CVD) is fully established
(Surgeon General of the United States, 1983). Although little is known about the relative
importance of CO compared to nicotine, most researchers consider them to be equally
important. The nicotine component clearly aggravates the decrease in O2 capacity induced by
CO through an increase in the O2 demand of the heart. This is exemplified in the study by
Deanfield et al. (1986) using positron emission tomography. They found that smoking one
cigarette induced perfiision abnormalities in six out of eight patients with CAD and exercise-
induced angina. However, the smoke-induced ischemia was without angina or silent ischemia
in all of the patients and without ST depression in seven of the patients. This raises an
important question regarding analyses of the effect of CO. Electrocardiographic evidence of
horizontal or downslope ST segment displacement of 1 mm or greater, which is characteristic
of myocardial ischemia, may be reported during an episode of exercise-induced angina in
some patients. Yet, ischemia may not always be associated with angina and/or ST segment
displacement (Haiat et al., 1983). Most of the reports used to develop the guidelines for CO
exposure have used angina and/or ST depression as a sign of ischemia. Only the two studies
by Sheps et al. (1987) and Adams et al. (1988) used additional techniques to diagnose
ischemia (see Section 10.3.2). Both used gated radionuclide angiography to measure changes
in ejection fraction and wall motion induced by exercise, allowing the detection for signs of
ischemia in the absence of angina and/or ST depression. Positron emission tomography is
even more sensitive, however. Future studies on the effects of CO in patients with CVD,
10-43
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therefore, will need to include more sensitive measures of ischemia than angina and/or ST
depression.
Passive smoMng exposes an individual to all components in the cigarette smoke, but the
CO component dominates heavily because only 1 % or less of the nicotine is absorbed from
sidestream smoke compared to 100% in an active smoker (Wall et al., 1988; Jarvis, 1987).
Therefore, exposure to sidestream smoke will be the closest to pure CO exposure even if the
resultant levels of COHb are low (about 1 to 2%) (Jarvis, 1987). The relationship between
passive smoking and increased risk of coronary heart disease (CHD) is controversial. Early"
studies on this relationship were reviewed in the 1986 report of the Surgeon General (Surgeon
General of the United States, 1986) and by the National Research Council (1986). Since that
time, the epidemiological evidence linking passive smoking exposure to heart disease has
rapidly expanded. Glantz and Parmley (1991) reviewed the available literature to "date on the
relationship between passive exposure to environmental tobacco smoke in the home and the
risk of heart disease death in the nonsmoking spouse of a smoker (Butler, 1990; Garland
et al., 1985; Gillis et al., 1984; He, 1989; Helsing et al., 1988; Hirayama, 1984; Hole
et al., 1989; Humble et al., 1990; Lee et al., 1986; Svendsen et al., 1987). All but one of
the studies yielded relative risks greater than 1.0; however, three studies in men and five
studies in women had 95% CI that included 1.0, indicating that the risk of passive smoking -t(
for heart disease was not statistically significant. By combining the studies to improve the ;
power to detect an effect, Glantz and Parmley (1991) reported a combined relative risk of 1.3
(95% CI = 1.2 to 1.4). Even though it is impossible to rule out an effect of the other
components in sidestream smoke, the data suggest an increase in risk of CHD associated with
a prolonged exposure to low levels of CO.
In a cross-sectional study of 625 smokers, age 30 to 69, Wald et al. (1973) reported
that the incidence of CVD was higher in subjects with COHb greater than 5% compared to
subjects below 3%, a relative risk of 21.2 (95% CI = 3.3 to 734.3). Even if all of the
subjects were smokers, the association between COHb and CVD might be due to the fact that
percent COHb is a measure of smoke exposure. '
Low to intermediate levels of COHb might interfere with the early course of an acute
MI. The increase in COHb can be due to recent smoking or environmental exposure. Mall
et al. (1985) reported on a prospective study in smoking and nonsmoking patients with an:
10-44
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acute MI who were separated by their baseline COHb levels. A total of 66 patients were
studied. Thirty-one patients were found to have a COHb level of 1.5% and 35 were found to
have a level of 4.5%. In the group with elevated COHb, more patients developed transmural
infarction, but the difference was not significant. Patients with transmural infarction had
higher maximum creatine phosphokinase values when COHb was over 2%. During the first
6 h after admission to the hospital, these patients needed an antiarrhythmic treatment
significantly more frequently. Differences in rhythm disorders were still present at a time
when nicotine, due to its short half-life, was already eliminated. The authors concluded that
moderately elevated levels of COHb may aggravate the course of an acute ML
10.3.4 Studies in Laboratory Animals
10.3.4.1 Introduction
The cardiovascular system is sensitive to alterations in O2 supply, and because inhaled
CO limits O2 supply, it might be expected to adversely affect the cardiovascular system; the
degree of hypoxia and the extent of tissue injury will be determined by the dose of CO. The
effect of CO on the cardiovascular system has been the subject of several recent reviews
(Turino, 1981; McGrath, 1982; Penney, 1988). This section will discuss studies in animals
that have evaluated the effects of CO on ventricular fibrillation, hemodynamics,
cardiomegaly, hematology, and atherosclerosis. In this review, CO concentrations, times of
exposure, and COHb levels are provided whenever they were mentioned in the original
manuscript. An attempt has been made to focus, where possible, on those studies that have
used the most relevant concentrations of CO, For a more detailed treatment of the effects of
higher concentrations of CO, the reader is referred to the review by Penney (1988).
10.3.4.2 Ventricular Fibrillation Studies
Data obtained from animal studies suggest that CO can disturb cardiac conduction and
cause cardiac arrhythmias (see Table 10-4). In dogs exposed intermittently or continuously to
CO (50 and 100 ppm, 2.6 to 12.0% COHb) for 6 weeks in environmental chambers, Preziosi
et al. (1970) reported abnormal ECGs; the changes appeared during the second week and
continued throughout the exposure. The blood cytology, Hb, and hematocrit values were
unchanged from control values. DeBias et al. (1973) studied the effects of breathing CO
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TABLE 10-4. VENTRICULAR FIBRILLATION AND HEMODYNAMIC
STUDIES IN LABORATORY ANIMALS
1— '
2
ON
Exposure"'1" COHb(»)°
CO = 50 ppm —
continuously for 3 mo
CO = 50-100 ppra for 2.6-12
6 weeks intermittently
or continuously
CO = 100 ppm for 24 wk, 12.4
23 h/day; CO = 100 ppm 9.3
for 6 h
CO = 500 ppm, pulsed 21.6
12 h/day for 14 mo
CO = 100 ppm, 2 h; 6.3
coronary artery ligated;
normal
CO = 5,000 ppm, 4.9-17.0
5 sequential exposures to
produce desired COHb;
coronary artery ligated
CO = 160-200 ppm for 20
6 weeks; chronieally
instrumented
CO = 100 ppm; 6.8-14.6
coronary artery
occluded briefly
Animal
Dog (n = 4)
Rabbit (n = 4)
Rat (n = 100)
Dog (n = 28)
Cynomolgus monkey
(n = 52; 20)
Cynomolgus monkey
(n = 26)
Dog (n = 21, 20)
Dog (n = 11)
Goat (n = 6)
Dog (n = 14)
Dependent Variable**
EGG, heart rate
ECG and pathology
ECG and susceptibility
to induced fibrillation
ECG, arterial pressure,
left ventricular pressure,
dP/dt, V^
Ventricular fibrillation
threshold (VFT)
ECG, coronary blood
flow
Cardiac index, stroke
volume, heart rate
contractility
Arrhythmia; conduction
slowing in ischemic
myocardium
Results*1
No effects
Abnormal ECG, heart
dilation, myoeardial
thinning, some subjects
showed scarring and
degeneration in heart
muscle
Abnormal ECG and
increased sensitivity to
fibrillation voltage
No effects
Reduced VFT to
normal and ligated dogs
Elevated ST segment;
increased flow to
nonischemic
myocardium
No changes
No changes
Comments
Infarcted animals
showed greatest eifect
of COHb on both
dependent variables
Subjects on normal and
high cholesterol diets
Studies were conducted
blind
CO can augment
ischemia in acute MI
Concluded CO is not
arrhythmogenic during
early minutes of
infarction
Reference
Mussulman et al. (1959)
Preziosi et al. (1970)
DeBias et al. (1973)
Malinow et al. (1976)
Aronow et al. (1978,
1979)
Becker and Haak (1979)
James et al. (1979)
Foster (1981)
-------
TABLE 10-4 (cont'd). VENTRICULAR FIBRILLATION AND
HEMODYNAMIC STUDIES IN LABORATORY ANIMALS
Exposure3'15 COHb(%)° Animal Dependent Variable4 Results'1
CO = 200 ppm for 60 and 1,6.4-6.30 Dog (n = ?) Threshold for ventricular No effects
Comments Reference
Hutcheon et al. (1983)
90 min; Paced hearts and
introduced premature
stimulus
CO = 3,000 ppm for 13-15
15 min followed by 130 ppm
for 1 h; coronary artery
ligated .."..•
CO = 500 ppm for 5-20
90-120 min; : "
Normal dogs, ischemic heart
dogs .
CO = 500 ppm for 5-20
60-120 min;
coronary artery obstructed
60-80% "for 2 min
arrhythmias and
refractory period
Dog (n = 10) ST-ssgment elevation
Dogs (n = 7; 11) Heart rate, arterial
pressure, effective
refractory period,
vulnerable period timing,
ventricular fibrillation
threshold
Dogs (n = 7) • Cycle period of'coronary No effects
blood flow, platelet
aggregability.
Increased ST-segment
elevation
No effects
CO increases
ST-segment elevation
and ischemia more than
ligation alone
Sekiya et al. (1983)
Verrier et al. (1990)
Verrier et al, (1990)
CO = 25-50 ppm for 24 h; 9.7± 1 .6
conscious dogs
CO-= 1,500 ppm for 5-15
varying times;
susceptible and resistant dogs
with health myocardial
infarcts
Dogs (n = 7) Repetitive extrasystole
threshold
Dogs (n = 16; 17) heart rate, ECG,
''""' ' ventricular arrhythmias
No effects
• • - ..
Significant increase in
heart'fate at 15% "'
CQHb,
-•• . -:. ,' ..-'••
... . Verrier et al. (1990)
Vanoli et al. (1989)
Farber et al. (199*0)
aExposure concentration and duration.
bippm"= 1.145-mg/m3. and 1 mg/m? = 0.873 ppm at 25 *C, 760 mm Hg; 1% = 10,000 ppm.
cMeasured blood carboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and- acronyms.
-------
(96 to 102 ppm, 12.4% COHb) continuously (23 h/day for 24 weeks) on the ECGs of healthy
monkeys and monkeys with myoeardial infarcts induced by injecting microspheres into the
coronary circulation. The authors observed higher P-wave amplitudes in both the infarcted
and noninfarcted monkeys and a higher incidence of T-wave inversion in the infarcted
monkeys. The authors concluded there was a greater degree of ischemia in the infarcted
animals breathing CO. Although there was a greater incidence of T-wave inversion in the
infarcted monkeys, the effects were transient and of such low magnitude that accurate- , ,
measurements of amplitude were not possible.
In other long-term studies, however, several groups have reported no effects of CO
either on the ECG or on cardiac arrhythmias. Musselman et al. (1959) observed no .changes
in the ECG of dogs exposed continuously to CO (50 ppm, 7.3% COHb) for 3 months.
These observations were confirmed by Malinow et al. (1976), who reported no effects on the
ECG in cynomolgus monkeys exposed to CO (500 ppm, pulsed; 21.6% COHb) for
14 months.
Several research groups have investigated the effects of CO on the vulnerability of the
heart to induced ventricular fibrillation. DeBias et al. (1976) reported that CO (100 ppm
inhaled for 16 h, 9.3% COHb) reduced the threshold for ventricular fibrillation induced by
an electrical stimulus applied to the myocardium of monkeys during the final stage of
ventricular repolarization. The voltage required to induce fibrillation was highest in normal
animals breathing air and lowest in infarcted animals breathing CO. Infarction alone and CO
alone each required significantly less voltage for fibrillation; when the two were combined,,
the effects on the myocardium were additive. These observation^ were confirmed in both
anesthetized, open-chested dogs with acute myoeardial injury (Aronow et al., 1978) .and in
normal dogs*(Aronow et al., 1979) breathing CO (100 ppm, 6.3 to 6.5% COHb) for 2 h.
However, Kaul et al. (1974) reported that anesthetized dogs inhaling 500 ppm CO (20 to
35% COHb) for 90 min were resistant to direct electrocardiographic changes. At 20%
COHb, there was evidence of enhanced sensitivity to digitalis-induced ventricular tachycardia,
but there was no increase in vulnerability of the ventricles to hydrocarbon/epinephrine or to
digitalis-induced fibrillation following exposure to 35% COHb.
Several workers have investigated the effect of breathing CO shortly after cardiac injury
on the electrical activity of the heart. Becker and Haak (1979) evaluated the effects of CO
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(five sequential exposures to 5,000 ppm, producing 4,9 to 17.0% COHb) on the ECGs of
anesthetized dogs 1 h after coronary artery ligation. Myocardial ischemia, as judged by the
amount of ST-segment elevation in epicardial ECGs, increased significantly at the lowest
COHb levels (4.9%) and increased further with increasing CO exposure; there were no
changes in heart rate, blood pressure, left atrial pressure, cardiac output, or blood flow to the
ischemic myocardium. Similar results were noted by Sekiya et al. (1983), who investigated
the influence of CO (3,000 ppm for 15 min followed by 130 ppm for 1 h, 13 to 15% COHb)
on the extent and severity of myocardial ischemia in dogs. This dose of CO inhaled prior to
coronary artery ligation increased the severity and extent of ischemic injury, and the
magnitude of ST-segment elevation, more than did ligation alone. There were no changes in
heart rate or arterial pressure.
On the other hand, several groups have reported no effects of CO on the ECG or on
cardiac arrhythmias. Musselman et al. (1959) observed no changes in the ECG of dogs
exposed continuously to CO (500 ppm) for 3 months. Their observations were confirmed by
Malinow et al. (1976), who reported no effects on the ECG in cynomolgus monkeys exposed
to CO for 14 months (500 ppm, pulsed; 21.6% COHb). Foster (1981) concludes that CO
(100 ppm for 6 to 9 min, 10.4% COHb) is not arrhythmogenic in dogs during the early
minutes of acute MI following occlusion of the left anterior descending coronary artery. This
level of CO did not effect either slowing of conduction through the ischemic myocardium or
the incidence of spontaneous ventricular tachycardia. These results were confirmed by
Hutcheon et al. (1983) in their investigation of the effects of CO on the electrical threshold
for ventricular arrhythmias and the effective refractory period of the heart. They conclude
that.CO (200 ppm for 60 and 90 min, 5.1 to 6.3% COHb) does not alter the effective
refractory period or the electrical threshold for ventricular arrhythmias in dogs. These results
are consistent with those of Mills et al. (1987), who studied the effects of 0 to 20% COHb
on the electrical stability of the heart in ehloralose-anesthetized dogs during coronary
occlusion. There were no major effects on heart rate, mean arterial blood pressure, effective
refractory period, vulnerable period, or ventricular fibrillation threshold.
The effects of acute CO exposure on cardiac electrical stability • were studied in several
canine heart models (Vanoli et al., 1989; Verrier et al., 1990). These workers examined the
direct effects of CO on the normal and ischemic heart in the anesthetized dog as well as
10-49
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possible indirect effects mediated by changes in platelet aggregability or CNS activity in.the
conscious dog. In anesthetized dogs, exposure to COHb levels of up to 20% (500 ppm CO
for 90 to 120 min) had no effect on ventricular electrical stability in the normal or acutely
ischemic heart. In a second study using anesthetized dogs, these workers evaluated the
effects of CO on platelet aggregability and its effect on coronary flow during partial coronary
artery stenosis. Concentrations of COHb up to 20% (500 ppm for 60 to 120 min) did not
alter platelet aggregability or its effect on coronary blood flow during stenosis. In a third
model using conscious dogs, these workers studied the effects on the heart of CO-elicited
changes in central nervous system activity. They observed no adverse effects on cardiac
excitability in response to COHb levels of up to 20% (200 to 500 ppm CO for 90 to
120 min) or to 9.7 ± 1.6% COHb (25 to 50 ppm CO) for 24. h. .
Father et al. (1990) studied the effects of acute exposure to CO on ventricular
arrhythmias in a dog model of sudden cardiac death. In this model, 60% of dogs with a -'•'
healed anterior ME will experience ventricular fibrillation during acute myocardial ischemia
with mild exercise. Dogs that develop ventricular fibrillation during acute myocardial
ischemia with exercise are considered at high risk for sudden death and are defined as -;:
"susceptible." Dogs that survive the test without a fetal arrhythmia are considered at low risk
for sudden death and are defined as "resistant." Using this model; Farber et al. (1990) tested
the effects of COHb levels ranging from 5 to 15% (1,500 ppm CO for varying times) in
resistant and susceptible dogs. Heart rates increased with increasing COHb ;levels but the '
increase did not become significant until COHb levels reached 15%. This trend was
observable at rest as well as during exercise in both resistant and susceptible.dogs. In
resistant animals, in which, acute myocardial ischemia is typically associated with bradycardia,
this reflex response occurred earlier and was augmented by exposure to CO. In both resistant
and susceptible dogs, CO induced a worsening of ventricular arrhythmias in a minority of,'
cases. The ventricular arrhythmias were not reprodueable in subsequent trials. The authors
concluded that acute exposure to CO is seldom arrhythmogenic in dogs that have survived
MI. , .. , • .-,- • ••...' -• .: ..:-.-
Thus, there are mixed results from animal studies, suggesting that inhaled CO may \
cause disturbances in cardiac rhythm in both healthy and compromised hearts. Depending on
the exposure regime and species tested, the threshold for this response in studies showing
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effects varies between 50 and 100 ppm CO (2.6 to 12% COHb) in dogs and 100 ppm
(12.4% COHb) in monkeys inhaling CO for 6 to 24 weeks, and 500 ppm CO (4.9 to
17.0% COHb) in dogs and 100 ppm (9.3% COHb) in monkeys inhaling CO for 0.6 to 16 h.
10.3.4.3 Hemodynamic Studies
The effects of CO on coronary flow, heart rate, blood pressure, cardiac output,
myocardial O2 consumption, and blood flow to various organs have been investigated in
laboratory animals. The results are somewhat contradictory (partly because exposure regimes
differed); however, most workers agree that CO in sufficiently high doses can affect many
hemodynamic- variables. •-.'•••
Adams et al. (1973) described increased coronary flow and heart fate and decreased
myocardial O2 consumption in anesthetized dogs breathing 1,500 ppm CO for 30 min
(23.1 % COHb). The decreased O2 consumption indicates that the coronary flow response
was not great enough to compensate for the decreased O2 availability. The authors noted that
although there was a positive chronotropic response, there was no positive inotropic response.
The authors speculated that (1) the CO may have caused an increase in the endogenous
rhythm or blocked the positive inotropic response or (2) the response to CO was mediated
reflexly through the cardiac afferent receptors to give a chronotropic response without the
concomitant inotropic response. When they used /J-adrenergic blocking agents., the heart-rate
response to CO disappeared, suggesting possible reflex mediation by the sympathetic nervous
system.
In a later study in chronically instrumented, awake dogs exposed to 1,000 ppm CO
producing COHb levels of 30%, Young and Stone (1976) reported an increase in coronary
flow with no change in myocardial O2 consumption. The increased coronary flow occurred
hi animals with hearts paced at 150 beats/min, as well as in nonpaced animals., and in animals
with propranolol and atropine blockade. Because the changes in coronary flow with arterial
O2 saturation were similar whether the animals were paced of not, these workers conclude
that the increase in coronary flow is independent of changes in heart rate. Furthermore, the
authors reasoned that if the coronary vasodilation was caused entirely by the release of a
metabolic vasodilator, associated with decreased arterial O2 saturation, the clrange in coronary
10-51
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flow in animals with both /J-adrenergic and parasympathetic blockade should be the same as
in control dogs. Young and Stone conclude that coronary vasodilation observed with an
arterial O2 saturation reduced by CO is mediated partially through an active neurogenic
process.
Increased myocardial blood flow after CO inhalation in dogs was confirmed by Einzig
et al. (1980), who also demonstrated the regional nature of the blood flow response. Using
labeled microspheres, these workers demonstrated that whereas both right and left ventricular
beds were dilated maximally at COHb levels of 41% (15,000 to 20,000 ppm CO for 10 min),
subendocardial/subepicardial blood flow ratios were reduced. The authors conclude that in
addition to the global hypoxia associated with CO poisoning, there is also an underperfusion
of the subendocardial layer, which is most pronounced in the left ventricle.
The results on the endocardium were confirmed by Kleinert et al. (1980) who reported
the effects of lowering O2 content by about 30% with low O2 or CO gas mixtures
(10,000 ppm CO for 3 min, 21 to 28% COHb). Regional myocardial relative tissue PO2,
perfusion, and small vessel blood content were evaluated in anesthetized, thoracotomized
rabbits. Both CO and hypoxic hypoxia increased regional blood flow to the myocardium, but
to a lesser extent in the endocardium. Relative endocardia! PO2 fell more markedly than
epicardial PO2 in both conditions. Small vessel blood content increased more with CO than
with low PO2, whereas regional O2 consumption increased under both conditions. The
authors conclude that the response to lowered O2 content (whether by inhaling low 62 or CO
gas mixtures) is an increase in flow, metabolic rate, and the number of open capillaries, and
the effects of both types of hypoxia appear more severe in, the endocardium.
A decrease in tissue PO2 with CO exposure also has been reported by Weiss and Cohen
(1974). These workers exposed anesthetized rats to 80 and 160 ppm CO for 20-min periods
and measured tissue O2 tension as well as heart rate. A statistically significant decrease in
brain PO2 occurred with inhalation of 160 ppm CO, but there was no change in heart rate.
Horvath (1975) investigated the coronary flow response in dogs with COHb levels of
6.2 to 35.6% produced by continuous administration of precisely measured volumes of CO.
Coronary flow increased progressively as blood COHb increased and was maintained for the
duration of the experiment. However, when animals with complete atrioventricular block
; , j
were maintained by cardiac pacemakers and were exposed to COHb levels of 6 to 7%, there
10-52
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was no longer an increase in coronary blood flow. These results are provocative, because
they suggest an increased danger from low COHb levels in cardiac-disabled individuals.
Petajan et al. (1976) exposed unanesthetized rats to 1,500 ppm CO for 80 min to
achieve COHb levels of 60 to 70%. After a slight transient increase, heart rate as well as
blood pressure decreased throughout the exposure. The authors interpret their data as
indicating that the lowering of blood pressure was more important than the degree of hypoxia
to the neurological impairment seen in their studies.
The effects of CO hypoxia and hypoxic hypoxia on arterial blood pressure and other
vascular parameters also were studied in carotid baroreceptor and chemoreceptor-denervated
dogs (Traystman and Fitzgerald, 1977). Arterial blood pressure was unchanged by CO
hypoxia, but increased with hypoxic hypoxia. Similar results were seen in carotid
baroreceptor-denervated animals with intact chemoreceptors. Following carotid
chemodenervation, arterial blood pressure decreased equally with both types of hypoxia.
In a subsequent report from the same laboratory (Sylvester et al., 1979), the effects of
CO hypoxia (10,000 ppm CO followed by 1,000 ppm CO for 15 to 20 min; 61 to
67% COHb) and hypoxic hypoxia, were compared in anesthetized, paralyzed dogs. Cardiac
output and stroke volume increased during both CO and hypoxic hypoxia, whereas heart rate
was variable. Mean arterial pressure decreased during CO hypoxia, but increased during
hypoxic hypoxia. Total peripheral resistance fell during both hypoxias, but the decrease was
greater during the CO hypoxia. After resection of the carotid body, the circulatory effects of
hypoxic and CO hypoxia were the same and were characterized by decreases in mean arterial
pressure and total peripheral resistance. In a second series of closed-chest dogs, hypoxic and
} - . , .
CO hypoxia caused equal catecholamine secretion before carotid body resection. After
carotid body resection, the magnitude of the catecholamine response was doubled with both
hypoxias. These workers conclude that the responses to hypoxic and CO hypoxia are
different and that the difference is dependent on intact chemo- and baroreflexes and on
differences in arterial O2 tension, but not on differences in catecholamine secretion or
ventilatory response.
In cynomolgus monkeys exposed to 500 ppm intermittently for 12 h/day for 14 months
(21.6% COHb), Malinow et al. (1976) reported no changes in arterial pressure, left
ventricular pressure, time derivative of pressure (dP/dt), and ventricular contractility. On the
10-53
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other hand, Kanten et al. (1983) studied the effects of CO (150 ppm, COHb up to 16%) for
0.5 to 2 h on hemodynamic parameters in open-chest, anesthetized rats, and reported that
heart rate, cardiac output, cardiac index, time derivative of maximal force (aortic), and stroke
volume increased significantly, whereas mean arterial pressure, total peripheral resistance,
and left ventricular systolic pressure decreased. These effects were evident at COHb levels as
low as 7.5% (0.5 h). There were no changes in stroke work, left ventricular dP/dt
maximum, and stroke power.
The effects of CO on blood flow to various vascular beds has been investigated in
several animal models, but most of the studies have been conducted at rather high CO or
COHb levels. In general, CO increases cerebral blood flow (CBF). The effects of CO on
the cerebral circulation are discussed in detail in Section 10.4.1.
In recent studies, Oremus et al. (1988) reported that in the anesthetized rat breathing
CO (500 ppm, 23% COHb) for 1 h, CO reduces mean arterial pressure through peripheral
vasodHation predominantly in the skeletal muscle vasculature. There were no differences in
heart rate or mesenteric or renal resistances between the CO-exposed and control groups.
This was confirmed by Gannon et al. (1988), who reported that in the anesthetized rat
breathing CO (500 ppm, 24% COHb) for 1 h, CO increased inside vessel diameter (36 to
40%) and flow rate (38 to 54%) and decreased mean arterial pressure to 79% of control in
the cremaster muscle. There was no change in the response of 3A vessels to topical
applications of phenylephrine as a result of CO exposure.
King et al. (1984, 1985) compared whole-body and hindlimb blood flow responses in
anesthetized dogs exposed to CO or anemic hypoxia. Arterial O2 content was reduced by
moderate (50%) or severe (65%) CO-hypoxia (produced by dialysis with 100% CO) or
anemic hypoxia (produced by hemodilution). These workers noted that cardiac output was
elevated in all groups at 30 min and in the severe CO group at 60 min. Hindlimb blood flow
remained unchanged during CO hypoxia in the animals with intact hindlimb innervation, but
was greater in animals with denervated hindlimbs. There was a decrease in mean arterial ,
pressure in all groups associated with a fall in total peripheral resistance. Hindlimb resistance
remained unchanged during moderate CO hypoxia in the intact groups, but was increased in
the denervated group. The authors concluded that the increase in cardiac output during CO
was directed to nonmuscle areas of the body and that intact sympathetic innervation was
10-54
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required to achieve this redistribution. However, aortic chemoreceptor input was not
necessary for the increase in cardiac output during severe CO hypoxia or for the diversion of
the increased flow to nonmuscle tissues.
King et al. (1987) investigated the effects of high CO (1,000 to 10,000 ppm to lower
arterial O2 content to 5 to 6 vol %) and hypoxic hypoxia on the contracting gastrocnemius
muscle of anesthetized dogs. Oxygen uptake decreased from the normoxic level in the CO
group but not in the hypoxic hypoxia group. Blood flow increased in both groups during
hypoxia but more so in the CO group. Oxygen extraction increased further during
contractions in the hypoxic group but fell in the CO group. The authors observed that the
O2 uptake limitation occurring during CO hypoxia and isometric contractions was associated
with a reduced O2 extraction and concluded that the leftward shift in the O2Hb dissociation
curve during CO hypoxia may have impeded O2 extraction.
Melinyshyn et al. (1988) investigated the role of ;8-adrenoreceptors in the circulatory
responses of anesthetized dogs to severe CO (about a 63 % decrease in arterial ()2 content
obtained by dialyzing with 100% CO). One group was ft blocked with propanolol (^ and
02 blockade), a second was /} blocked with ICI 118,551 (/J2 blockade), and a third was a time
control. Cardiac output increased in all groups during CO hypoxia with the increase being
greatest in the unblockaded group. Hindlimb blood flow rose during CO hypoxia only in the
unblockaded group. The authors conclude that 35% of the rise in cardiac output occurring
during CO hypoxia depended on peripheral vasodilation mediated through )82-adrenoreceptors.
Thus, the results from animal studies indicate that inhaled CO can adversely affect
several hemodynamic parameters. The threshold for these effects may be near 150 ppm CO
(7.5% COHb).
10.3.4.4 Cardiomegaly
The early investigations of cardiac enlargement following prolonged exposure to CO
have been confirmed in different animal models and extended to characterize the development
and regression of the cardiomegaly (see Table 10-5). Theodore et al. (1971) reported cardiac
10-55
-------
TABLE 10-5. CARDIAC HYPERTROPHY STUDIES IN LABORATORY ANIMALS
ox
Exp05urca'b
400-500 ppm for
168 days
100 ppm, 46 days
200 ppm, 30 days
500 ppm, 20-42 days
CO = 60, 125, 250,
500 ppm for 21 days
gestation
CO = 400 ppm, or
500 ppm increased to
1,100 ppm
CO = 500 ppm until
50 days of age
CO = 500 ppm for
1-42 days. Open- .
chest, anesthetized
preparation.
CO = 150 ppm
throughout gestation
COHb(%)°
32-38 (dogs
and
monkeys
only)
9.2
15.8
41.12
35-58
38-42
38-42
(15 in
adult rats)
Animal
Monkey
(n = 9)
Baboon (n = 3)
Dog (n = 16)
Rat (n = 136)
Mouse
(n = 80)
Rat (n = 32)
Fetal rats
(n = 75)
Rat (n = 30)
Rat (n > 200)
5 and 25 days
old
Rat (n = 25)
Rat (n = 88)
Dependent Variable"
Cardiovascular damage in
rat heart
Heart size; LDH
Hb, Hct, HW
Cardiomegaly (HW/BW)
and LDH
HW
Right ventricle (RV)
Left ventricle (LV)
Stoke index (SI),
Mean stroke power (SP),
Mean cardiac output (CO),
Systemic resistance (SR),
Pulmonary resistance (PR).
BW
Wet-heart weight (WHW)
Results*5
No changes except slight
hypertrophy
Hypertrophy of both left
and right ventricles, LDH
increases
Hb and Hct depressed
with 60 ppm and elevated
by 250 and 500 ppm, HW"
increased at all
concentrations
HW/BW and %M LDH
subunits increased with
low and high CO; after
removal of CO, HW/BW
and %M LDH remained
high
HW, LV, and RV
increased response greater
in younger group
SI, SP, CO increased;
SR and PR decreased
BW depressed,
WHW increased
Comments"
Threshold for cardiac
enlargement near 200 ppm
HW increase probably not due
to increased viscosity or
pulmonary hypertension
Potential for cardiac DNA
synthesis and hyperplasia ends
between 5-25 days
Concluded that increased CO
via increased stroke volume is
compensation for CO
intoxication; increased work
may cause cardiomegaly
Increased HW due to
increased water content
Reference
Theodore et al. (1971)
Penney et al. (1974a,b)
Prigge and Hochrainer (1977)
Styka and Penney (1978)
Penney and Weeks (1979)
Penney et al. (1979)
Fechter et al. (1980)
-------
o
6,
-Jl
TABLE 10-5 (cont'd). CARDIAC HYPERTROPHY STUDIES IN LABORATORY ANIMALS
Exposure3'13 COHb(%)° Animal
CO = 500 ppm for 38-42 Rat (n - 140)
32 days (1982)
CO = 157-200 ppm 21.8-33.5 Rat(n = 96)
for last 17 days
gestation
CO = 500 ppm for 38-40 Rat (n = 25)
38-47 days
CO = 200 ppm from - Rat (n > 180)
Day 7 of pregnancy
until parturition, and
for 28 days following
parturition
Dependent Variable
Cardiomegaly
RBC count, HW, placental
weight (PW), cardiac
LDH(M) subunit, Mb
Cardiac compliance and
dimensions
HW, RV, and LV weight
Results^
HW/BW higher after
70 days of exposure and
after 30 days of recovery;
both RV and LV were
affected
Depressed RBC, HW and
PW increased, LDH(M)
increased, Mb increased
No change in compliance,
LV length and outside
diameter increased
RV increased with CO
during fetal period, HW
and LV increased with
CO during postnatal
period
Comments
Cannot be explained by
changes in DNA or
hydroxyproline
Cardiomegaly not due to
elevated water content
(Disagrees with Fechter et al.,
1980)
Chronic COHb produces
eccentric cardiomegaly with
no change in wall stiffness
Hemodynamic load caused by
CO during fetal period results
in oardiomegaly due to
myocyte hyperplasia
Reference
Penney et al. (1982)
Penney et al. (1983)
Penney et al. (1984a)
Clubb et al. (1986)
aExposure concentration and duration.
1 ppm
1.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 °C, 760 mm Hg; 1% = 10,000 ppm.
°Measured blood carboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and acronyms.
-------
hypertrophy in rats breathing 500 ppm CO (32 to 38% COHb) for 168 days, but not in dogs,
baboons, or monkeys. Penney et al. (1974a) also noted cardiomegaly in rats breathing
500 ppm CO; heart weights were one-third greater than predicted within 14 days of exposure,
and 140 to 153% of controls after 42 days of exposure. The cardiomegaly was accompanied
by changes in cardiac lactate dehydrogenase (LDH) isoenzyme composition that were similar
to those reported in other conditions that cause cardiac hypertrophy (e.g., aortic and
pulmonary artery constriction, coronary artery disease, altitude acclimation, severe anemia).
To further characterize the hypertrophy and determine its threshold, Penney et al.
(1974b) measured heart weights in .rats exposed continuously to 100, 200, and 500 ppm CO,
(9.26, 15.82, and 41.14% COHb) for various times (20 to 46 days); they noted significant
increases in heart weights at 200 and 500 ppm CO, with changes occurring in the left
ventricle and septum, right ventricle, and atria especially. The authors concluded that
whereas the threshold for the Hb response is 100 ppm CO (9.26% COHb), the threshold for
cardiac enlargement is near 200 ppm CO (12.03% COHb), and unlike cardiac hypertrophy
caused by altitude, which primarily involves the right ventricle, cardiac hypertrophy caused
by CO involves the whole heart.
The regression of cardiac hypertrophy in rats exposed continuously to moderate
(400 ppm, 35% COHb) or severe (500 to 1,100 ppm, 58% COHb) CO for 6 weeks was
followed by Styka and Penney (1978). Heart weight to body weight ratio (HW/BW)
increased from 2.65 in controls to 3,52 and 4.01 with moderate and severe CO exposure,
respectively. Myocardial LDH M subunits were elevated 5 to 6% by moderate and 12 to
14% by severe CO exposure. Forty-one to 48 days after terminating the CO exposure, Hb
concentrations among groups did not differ significantly; HW/BW values were similar in the
control and moderately exposed animals, but remained significantly elevated in the severely
exposed animals.
In addition to cardiomegaly, Kjeldsen et al. (1972) has reported ultrastructural changes
in the myocardium of rabbits breathing 180 ppm CO (16.7% COHb) for 2 weeks. The
changes included focal areas of necrosis of myofibrils and degenerative changes of the
mitochondria. In addition, varying degrees of injury were noted in the blood vessels. These
included edema in the capillaries; stasis and perivascular hemorrhages on the venous side; and
10-58
-------
endothelial swelling, subendothelial edema, and degenerative changes in myocytes on the
arterial side.
The hemodynamie consequences of prolonged CO exposure have been examined in rats
breathing 500 ppm CO (38 to 42% COHb) for 1 to 42 days (Penney et al., 1979), and in
goats breathing 160 to 220 ppm CO (20% COHb) for 2 weeks (James et al., 1979). In rats,
cardiomegaly developed; stroke index, stroke power, and cardiac index increased; and total
systemic and pulmonary resistances decreased. Left and right ventricular systolic pressures,
mean aortic pressure, maximum left ventricular dP/dt, and heart rate did not change
significantly. Penney et al. (1979) concluded that enhanced cardiac output, via an increased
stroke volume, is a compensatory mechanism to provide tissue oxygenation during CO
intoxication and mat increased cardiac work is the major factor responsible for the
development of cardiomegaly. In chronically instrumented goats, James et al. noted that
cardiac index, stroke volume, left ventricular contractility, and heart rate were all unchanged
during exposure to CO, but were depressed significantly during the first week following
termination of the exposure. Discrepancies between the Penney and James studies may be
caused by differences in the CO concentrations or in the species used.
Penney et al. (1984a) studied the compliance and measured the dimensions of
hypertrophied hearts from rats breathing 500 ppm CO (38 to 40% COHb) for 38 to 47 days.
Heart weight to body weight ratios increased from 2.69 to 3.34. Although compliance of the
right and left ventricles was higher in the CO group, the differences disappeared when the
heart weight was normalized by body weight. Left ventricular apex-to-base length and left
ventricular outside diameter increased 6.4% and 7.3%, respectively; there were no changes in
left ventricle, right ventricle, or septum thickness. The authors conclude that chronic CO
exposure produces eccentric cardiomegaly with no intrinsic change in wall stiffness.
The consequences of breathing CO also have been investigated hi perinatal animals.
Prigge and Hochrainer (1977) reported elevated heart weights in fetuses from pregnant rats
exposed for 21 days to CO concentrations as low as 60 ppm. Because these animals
developed anemia rather than polycythemia, these workers discounted increased blood
viscosity as a cause of the cardiomegaly. Penney and Weeks (1979) examined the effects of
inhaling 500 ppm CO (38 to 42% COHb) until 50 days of age on cardiac growth in young
(5 days) and old (25 days) rats. They observed that the younger rats experienced the greatest
10-59
-------
change in heart weight and DMA synthesis and concluded that the potential for cardiac DNA ,
synthesis and muscle cell hyperplasia ends in rats during the 5th through 25th days of
postnatal development.
Fechter et al. (1980) reported elevated wet-heart weights at birth in neonatal rats from
dams exposed throughout gestation to 150 ppm CO (15% COHb). There were no differences ,,
in dry-heart weight, total protein, or RNA or DNA levels; the differences between groups in.
wet-heart weight disappeared after 4 days. These workers concluded that the increased heart
weight seen at birth in the CO-exposed rats is caused by cardiac edema. ......
These results were not verified by Penney et al. (1983) in offspring of pregnant rats
exposed to 157, 166, and 200 ppm CO (21.8 to 33.5% COHb) for the last 17 of 22 gestation
days. These workers observed that wet- and dry-heart weights increase proportionately and
concluded that cardiomegaly, present at birth, is not due to elevated myocardial water
content. They also determined that cardiac LDH M subunit composition and myoglobin
concentration were elevated at 200 ppm CO. They conclude that maternal CO inhalation
exerts significant effects on fetal body and placental weights, heart weight, enzyme
constituents, and composition. Moreover, in newborn rats inhaling 500 ppm CO (38 to
42% COHb) for 32 days and then developing in air, Penney et al. (1982) observed that
HW/BW increased sharply after birth, peaked at 14 days of age, and then fell progressively;
it remained higher in rats exposed prenatally to CO than in control rats for up to 107 days of
age. The persistent cardiomegaly could not be explained by changes in DNA or
hydroxyproline. . . . .
Ventricular weights (wet and dry) and myocyte size and volume were measured in
perinatal rats exposed to 200 ppm CO by Clubb et al. (1986). Pregnant rats were exposed to
air or CO, and, at birth, pups from these two groups were subdivided into four groups:
(1) control group (air/air), which were maintained in air in utero and postpartum; (2) air/CQ
group, which received CO posfpartum only; (3) CO/CO group, which received CO in utero
and postpartum; and (4) CO/air group, which received CO in utero, but were maintained in
air postpartum. Right ventricle weights were increased in animals exposed to CO during the
10-60
-------
fetal period, but left ventricular weights were increased by CO during the neonalal period.
Although HW/BW values increased to that of the CO/CO group by 12 days of age in animals
exposed to CO postnatally only (air/CO), HW/BW values decreased to that of controls
(air/air) by 28 days of age in animals exposed to air postnatally following fetal CO exposure
(CO/air). There was no difference in myocyte volume between groups at birth. Left
ventricle plus septum and right ventricle cell volumes of the CO/CO group were smaller than
the controls at 28 days of age despite the heavier wet and dry weights of the CO/CO
neonates. At birth, the CO-exposed animals had more myocytes in the right ventricle than
the air-exposed controls; CO exposure after birth resulted in left ventricular hyperplasia.
Clubb et al. (1986) concluded that the increased hemodynamic load caused by CO
during the fetal period results in cardiomegaly, characterized by myocyte hyperplasia, and
this cellular response is sustained throughout the early neonatal period in animals exposed to
CO postpartum.
Thus, results from animal studies indicate that inhaled CO can cause eardiomegaly. The
threshold for this response is high, near 200 ppm (12% COHb) in adult rats and 60 ppm in
fetal rats.
10.3.4.5 Hematology Studies v ' ;
Increase in Hb concentration, as well as hematocrit ratio, is a well-documented response
to hypoxia, which serves to increase the O2 carrying-capacity of the blood. Guyton and
Richardson (1961) and Smith and Crowell (1967) however, suggest that changes in
hematocrit ratio not only affect the O2-carrying capacity of the blood, but blood flow as well.
Therefore, when hematocrit ratios increase much above normal, O2 delivery to the tissues
may be reduced because the resultant decrease in blood flow can more than offset the
increased O2~carrymg capacity of the blood. Smith and Crowell conclude that there is an
optimum hematocrit ratio at sea level that shifts to a higher value with altitude acclimation.
Presumably a similar compensation would occur when O2 transport is reduced by CO.
Changes in Hb concentration and hematocrit ratio have been reported in numerous
animal studies (see Table 10-6). In dogs exposed to 50 ppm CO (7.3% COHb) for
3 months, Musselman et al. (1959) reported a slight increase in Hb concentration (12%),
10-61
-------
TABLE 10-6. HEMATOLOGY STUDIES IN LABORATORY ANIMALS
1— '
o
fe •
Exposure"1'1
CO - 50 ppm
continuously for 3 mo
CO = 51, 96, or 200 ppm
for 90 days
CO = 67.5 ppm
22 h/day, 7 day/week for
2 years
CO = 195 for 72 h
CO = 100 ppm, 46 days;
200 ppm, 30 days;
500 ppm, 20-42 days
CO = 200 ppm for last
18 days gestation
50 and 100 ppm for
6 weeks on various
intermittent daily schedules
CO = 50 ppm, 95 h/weefc,
whole natural life
expectancy up to 2 years
(also short-term)
COHb(%)°
7.3
3.2
1.8
3.2-6.2
4.9-12.7
9.4-20.2
depending
upon species
1.9-5.5
and
2.8-10.2
-30
9.20
15.82
41.12
27
2.6-12
Animal
Dog (n = 4)
Rabbit (n = 40)
Rat (n = 100)
Rat (n = 35)
Guinea pig (n = 35)
Monkey (n = 9)
Dog (n = 6)
Cynomolgus monkey
(n = 27)
Dog (n = 12)
Rat (n = 32)
Rat
Dog (n = 46)
Rat (n = 336)
Mouse (n = 767)
Dependent Variable"
Hb, Hct, RBC, and
ECG
Hb
Hct, Hb, RBC
counts
Hct and Kb"
Hb
Hb, Hct, and RBC
Hb
ECG, organ weights,
Hb, Hct, and RBC
Results'1
Hb, Hct, RBC increased
in dogs and rabbit; no
change in ECG in dog
Increases in rats at 96,
106, and 200 ppm;
increases in all animals
at 200 ppm
No effects
Both increased
Increased at all levels
Hb, Hct, and RBC all
lower
No effects
No effects
Comments
No toxic signs in dogs,
rabbits, or rats
Unusual variation in
COHb
Increase due to
erythropoiesis
About 30 days until Hb
approached asymptotic
values
Also showed no effects
on other variables
Reference
Mussclman et al. (1959)
Jones et al. (1971)
Eckardt et al. (1972)
Syvertsen and Harris (1973)
Penney et al. (1974b)
Penney et al. (1980)
Preziosi et al. (1970)
Stupfel and Bouley (1970)
aExposure concentration and duration.
bl ppm = 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 °C, 760 mm Hg; 1% = 10,000 ppm.
°Measured blood oarboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and acronyms.
-------
hematocrit ratio (10%), and in red blood cells (RBCs) (10%). These observations were
extended by Jones et al. (1971) to include several species of animals exposed to 51 ppm or
more CO (3.2 to 20.2% COHb), intermittently or continuously, for up to 90 days. There
were no significant increases in the Hb arid hematocrit Values observed in any of the species
at 51 ppm CO (3.2 to 6.2% COHb). At 96 ppm CO (4.9 to 12.7% COHb), significant ;
increases were noted in the hematocrit value for monkeys (from 43 to 47%) and in the Hb
(from 14.0 to 16.49%) and hematocrit values (from 46 to 52%) for rats. Hemoglobin and
hematocrit values were elevated in rats (14 and 10%, respectively), guinea pigs (8 and 10%,
respectively), and monkeys (34 and 26%, respectively) exposed to 200 ppm CO (9.4 to
12.0% COHb); they also were elevated in dogs, but there were too few animals to determine
statistical significance. However, in dogs exposed to CO (195 ppm, 30% COHb) for 72 h,
Syvertsen and Harris (1973) reported that hematocrit and Hb increased from 50.3 to 57.8%
and 15.0 to 16.2 g%, respectively. The differences m hematocrit and Hb occurred after 72-h
exposure and were attributed to increased erythropoiesis. Because no measurements were
made, however, the possibility of splenic contraction cannot be excluded. Penney et al.
(1974b) observed significant increases in Hb (from 15.6 to 16.7 g%) in rats exposed to
100 ppm CO over several weeks and conclude that the threshold for the Hb response is close
to 100 ppm (9.26% COHb). > ;
Several groups have reported no change in Hb or hematocrit following CO exposure.
Thus, Preziosi et al. (1970) observed no significant change in Hb concentration in dogs
exposed to 50 and 100 ppm CO (2.6 to 12.0% COHb) for 6 weeks. In monkeys exposed to
20 and 65 ppm CO (1.9 to 10.2% COHb)" for two years, Eckardt et al. (1972) noted no
compensatory increases in Hb concentration or hematocrit ratio. In mice exposed
5 days/week to 50 ppm CO for 1 to 3 months, Stupfel and Bouley (1970) observed no
significant increase in Hb. '
Interestingly,, in fetuses removed from pregnant rats after 21 days exposure to CO,
Prigge and Hochrainer (1977) reported a significant increase in fetal hematocrit; (from 33.3 to
34.5%) at 60 ppm and a significant decrease in: Hb and hematocrit at 250 ppm (from 9.1,to
8.0 g% and from 33.3 to 28:4%, respectively) and 500 ppm (from 9.1 to 6.5 g% and from ;
33.3 to 21.9%, respectively);; These results were confirmed by, Penney et al.:(1980), who !
reported significantly lower Hb (12.6 Vs. 15.8 g%); hematocrit (46.2 vs. 54.4%), and RBC
10^63:;
-------
counts (27.2 vs. 29.1%) in newborns from pregnant rats exposed to 200 ppm CO
(27.8% COHb) for the final 18 days of development than in controls. However, in a later
study, Penney et al. (1983) reported that although RBC counts were depressed in neonates
from pregnant rats exposed to 157, 166, and 200 ppm CO (21.8 to 33.5% COHb) for the last
17 out of 22 gestation days, mean corpuscular Hb and volume were elevated.
The results from animal studies indicate inhaled CO can increase Hb concentration and
hematocrit ratio and that the threshold for this response, at least in rats, appears to be near
100 ppm (9.26% COHb). Small increases in Hb and hematocrit probably represent a
compensation for the reduction in O2 transport caused by CO. At higher CO concentrations,
excessive increases in Hb and hematocrit may impose an additional workload on the heart and
compromise blood flow to the tissue. The O2-transport system of the fetus is especially
sensitive to CO inhaled by the mother, and it may be affected by CO concentrations as low as
60 ppm.
10.3.4.6 Atherosclerosis and Thrombosis !
The section dealing with cholesterol and atherosclerosis in the previous air quality
criteria document for CO (U.S. Environmental Protection Agency, 1979) described about
12 publications. These studies generally utilized animal models of atherosclerosis or animal ,
models describing arterial wall cholesterol uptake in response to COHb concentrations
ranging from 4.5 to 41.1% (see Table 10-7). The conclusion was that the evidence failed to
conclusively support a relationship between CO exposure and atherosclerosis in animal
models. Since completion of the 1979 air quality criteria document, a number of additional
studies have been published (Table 10-7). However, taken in aggregate, the studies still fail
to conclusively prove an atherogenic effect of exposure to low doses of CO.
Astrup et al. (1967) described atheromatosis as well as increased cholesterol
accumulation in aortas of rabbits fed cholesterol and exposed to CO (170 to 350 ppnij 17 to
33% COHb) for 10 weeks. These observations were not verified, however, by Webster et al.
(1970), who observed no changes in the aorta or carotid arteries or in serum cholesterol
levels in squirrel monkeys fed cholesterol and exposed intermittently to CO (100 to 300 ppm,
9 to 26% COHb) for 7 months; they did note enhanced atherosclerosis in the coronary ''.
10-64
-------
TABLE 10-7. ATHEROSCLEROTIC STUDIES IN LABORATORY ANIMALS
o
CT\
Exposure8'15 COHb(%)c
CO = 170 ppm for 17-33
8 weeks,, then 350 ppm for
last 2 weeks, fed
cholesterol '
CO =:iOO-300 ppm 9-26
4 h/day, 5 days/week for
7 mo, fed cholesterol
CO = 250 ppm ;: '20.6
continuously for 2 weeks
CO = 50, 100, and 4.5
180 ppm .for periods 9.0
ranging from 30 min-
24 h, and from 2-11 days
CO =' 150 ppm 6 h/day, 10
5 days/week for 52 and
84 weeks, fed cholesterol
CO = 250 ppm 4 h/day, 20
7 days/week, 10 weeks
CO = 50-500 ppm, 21.6
12 h/day for 14 mo
Animal
Rabbit (n = 24)
Squirrel monkey
Cynomolgus monkey
(n = 20)
Rabbit (n = 61)
White carneau pigeon
(n = 180)
Rabbit (n = 24)
Cynomolgus monkey
(n = 26)
Dependent Variable
Atherosclerotic
changes
Atherosclerosis
Coronary artery
pathology
Aortic damage
Severity of
atherosclerosis
Blood cholesterol)
coronary artery
atherosclerosis,
aortic cholesterol
content
Aortic and coronary
atherosclerosis
Results'1
Increased aortic ather-
omatosis and cholesterol, ,
local degenerative signs and
hemorrhages in hearts
Increased coronary athero-
sclerosis
Subendothelial edema, gaps
between endothelial cells,
infiltration cells containing
lipid droplets
Increased aortic intimal
lesions at 180 ppm CO for
4 h. or more
No effect in normocholes-
terolemic birds,- coronary
artery atherosclerosis
significantly enhanced in
hypercholesterolemic birds
at 52 weeks. .
Increased atherosclerosis-in ,
coronary arteries but no ,
differences in aortic or
plasma cholesterol
No effects
Comments
Not verified in subsequent
studies
Lipid-laden cell findings
suggest greater sensitivity
of monkeys than of rabbits
Postulates 180 ppm CO for
4 h is threshold for injury
No significant changes in
coronary arteries after
84 weeks
Study disagrees with Astrup
etal. (1967)
Subjects on High- and low-
cholesterol diets, disagrees
with Astrup et al. (1967)
Reference
Astrup et al. (1967)
Webster et al. (1970)
Thomsen (1974)
Thomson and Kjeldsen
(1975)
Armitage et al. .(1976)
Davies etal. (1976)
Malinow et al: (1976) -
-------
TABLE 10-7 (cont'd). ATHEROSCLEROTIC STUDIES IN LABORATORY ANMALS
'9
o\
O\
Exposure"'*" COHb(%)c Animal
CO « 200 ppm continuously 17 Rabbit (n - 30)
or 12 h/day for 6 weeks
CO = 200 ppm for - Rabbit (n = 150)
5-12 weeks; 2,000 ppm for
320 min; 4,000 ppm for
205 min
CO = 400 ppm for 23 Cynomolgus monkey
10 alternate half-hours of (n = 11)
Dependent Variable"
Cardiovascular
pathology
Coronary artery and
aortic damage
Cholesterol content of
vessels and plasma
Results'1
No differences in
atherosclerosis, but CO
produced higher serum
cholesterol levels
No effect
No effect on plasma-ftee
cholesterol, cholesterol ester,
Comments
Serum cholesterol was
controlled by adjusting
individual diets; apparently
coronary atherosclerosis in
Astnip et al. (1967) was
caused by increased serum
cholesterol
Inability to reproduce earlier
results may be due to lack of
blind technique and smaller
number of animals in earlier
studies
Agrees with Malinow et al.
(1976)
Reference
Slender et al. (1977)
Hugod et al. (1978)
Bing et al. (1980)
each day for 12 mo
Smoked 43 cigarettes per 0.6-1.9 Baboons (n = 36)
day for 14-19 mo, fed
cholesterol
CO = 200-300 ppm - Rabbits (n = 14)
continuously for-
1-7 weeks" " " '" ;
Smoked 43 eigarettes-per ... 0.64;2.0. Male Baboons
day for. up to33,mq, fed.,, .,, • " (n = 36)
cholesterol
•' •••• ••" •- ' - '-0.35-1.13 - Female Baboons -
Serum cholesterol
Myocardial
morphology using
electron microscopy
-Serum cholesterol ••
tri- and diglycerides, and
phospholipids; no significant
increase in cholesterol content
of aorta; no histologic
damage and no fat deposition
No significant differences in
serum total cholesterol,
VLDL + LDL cholesterol,
HDL cholesterol, or
triglyceride concentrations
No histotoxic effects
No significant differences in
serum total cholesterol,
VLDL + LDL cholesterol,
HDL'cholesterol, or
triglyceride concentrations;
slightly enhanced plaque
formation in carotid artery;
no difference in lesions or
vascular content of lipid or
prostaglandin in aorta or
coronary arteries
Rogers et al. (1980)
Hugod (1981)
Rogers et al. (1988)
-------
TABLE 10-7 (cont'd). ATHEROSCLEROTIC STUDIES IN LABORATORY ANIMALS
Exposure"'15
CO = 100 ppm
8 h/day, 5 day/week for
4 mo, fed cholesterol
COHb(%)° Animal
6.8-7.6 Pigs (n = 38)
(normal or
homozygous and
heterozygous for von
Wilebrand's disease)
with balloon-catheter
injury of coronary
arteries
Dependent Variable11 Results"
Coronary artery and No significant changes
aortic lesions
Comments Reference
Sultzer et al. (1982)
Exposure concentration and duration.
bl ppm = 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 "C, 760 mm Hg; 1% = 10,000 ppm.
"Measured blood carboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and acronyms.
-------
arteries. Davies et al. (1976) confirmed that coronary artery atherosclerosis was significantly
higher in rabbits fed cholesterol and exposed intermittently to CO for 10 weeks (250 ppm,
20% COHb), but they also reported no significant differences between groups in aortic
concentrations of triglycerides, cholesterol, phospholipids, or plasma cholesterol.
In cynomolgus monkeys fed cholesterol and exposed intermittently to CO for 14 months
(50 to 500 ppm, 21.6% COHb), Malinow et al. (1976) observed no differences in plasma
cholesterol levels or in coronary or aortic atherosclerosis. Armitage et al. (1976) confirmed
that intermittent CO (150 ppm, 10% COHb, for 52 and 84 weeks) did not enhance the .extent
or severity of atherosclerosis in the normal White Carneau pigeon. Although CO exposure
did increase the severity of coronary artery atherosclerosis in birds fed cholesterol, the
difference between groups, noted at 52 weeks, was not present after 84 weeks.
Stender et al. (1977) exposed rabbits that were fed high levels of cholesterol to CO for
6 weeks continuously and intermittently (200 ppm, 17% COHb). In the cholesterol-fed
group, CO had no effect on free- and esterified-cholesterol concentrations in the inner layer
of the aortic wall. In the normal group, CO increased the concentration of cholesterol in the
aortic arch, but there was no difference in the cholesterol content of the total aorta.
Hugod et al. (1978), using a blind technique and the same criteria to assess intimal
damage as was used in earlier studies (Kjeldsen et al., 1972; Thomsen, 1974; Thomsen and
Kjeldsen, 1975), noted no histologic changes in the coronary arteries or aorta in rabbits
exposed to CO (200, 2,000, or 4,000 ppm) for 0.5 to 12 weeks. These workers suggested
that the positive results obtained earlier were due to the nonblind evaluation techniques and
the small number of animals used in the earlier studies. Later, Hugod (1981) confirmed
these negative results using electron microscopy.
Only a few of the studies published since completion of the 1979 criteria document have
demonstrated a significant atherogenic effect of low-level CO exposure. Turner et al. (1979)
showed that CO enhanced the development of coronary artery lesions in White Carneau
pigeons that were fed a diet of 0.5 and 1%, but not 2%, cholesterol. The exposure was to
150 ppm for 6 h, 5 days/week for 52 weeks (10 to 20% COHb). Plasma cholesterol levels
may have been increased slightly by the CO, but this was significant (p<0.5) only at
Week 11. Marshall and Hess (1981) exposed minipigs to 160, 185, and 420 ppm CO for
4 h/day for 1 to 16 days (5 to 30% COHb). The higher concentrations were associated with
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adhesion of platelets to arterial endothelium and to fossae of degenerated endothelial cells.
Additional changes at the higher concentration included an increased hematocrit, an increase
in blood viscosity, and an increase in platelet aggregation.
Alcindor et al. (1984) studied rabbits with induced hypercholesterolemia. Three sets of
rabbits were studied. The first was a control group receiving a normal diet and breathing air.
The second group was given a 2% cholesterol diet. The third group was given the same diet
and was exposed to 150 ppm CO. Carboxyhemoglobin levels were not reported. Low-
density lipoprotein (LDL) particles in the CO-exposed rabbits were richer in cholesterol and
had a higher cholesterol-to-phospholipid molar ratio than did the particles from the
nonexposed rabbits after 45 days (p< 0.01).
Other animal studies have given generally negative results. Bing et al. (1980) studied
cyhomolgus monkeys (Macacafascicularis). Four animals were used as'controls. Seven
were exposed to CO at a level of 400 ppm for 10 alternate half-hours of each day during
12 months. Carboxyhemoglobin levels showed a gradual increase to a peak at 5 h of 20%.
The monkeys had no histologic evidence of atherosclerosis, vessel wall damage, or fat
deposition in the arterial wall. There was no significant change in cholesterol or in
lipoprotein levels. High density to total cholesterol ratios did not differ between the
CO-exposed and air-exposed animals. These animals were oh a normal diet with no
augmentation of cholesterol or fat content. The study demonstrated that everi high levels of
CO exposure are not invariably followed by arterial injury or abnormal lipid accumulation.
Similar negative results were reported by Sultzer et al. (1982), who studied swine. Pigs
with and without von Willebrand's disease were divided into groups that were exposed to
intermittent, low-level CO or to air. Carbon monoxide was delivered at 100 ppm for 8 h
each week day for 4 months. Carboxyhemoglobin levels averaged 7% after 5 h of exposure.
The degree of coronary and aortic atherosclerotic lesion development in response to a 2%
cholesterol diet was similar in the two exposure groups. There was no effect of the ambient
CO on the degree of hypercholesterolemia induced by the diet. The findings showed no
obvious effect of CO on atherogenesis in hypercholesterolemic pigs.
A number of studies have examined the contribution of CO in cigarette smoke to the
purported effects of smoking on atherogenesis and thrombosis. Rogers et al. (1980) fed a
high-cholesterol diet to 36 baboons for up to 81 weeks. The animals were taught to puff
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either cigarette smoke or air by operant conditioning using a water reward. Half of the
baboons smoked 43 cigarettes each day. The baboons were given a cigarette or sham every
15 min during a 12-h day, except during times of blood drawing. Average COHb levels in
smokers were about 1.9%. Only slight differences in the very-low-density lipoprotein, LDL,
and high-density lipoprotein (HDL) levels were noted between the smokers and nonsmokers.
Additionally, platelet aggregation with adenosine 5'-phosphate (ADP) and collagen was
similar in the two groups.
Rogers et al. (1988) extended their previous study of male baboons for an additional
1.2 years of diet and smoking (total diet, 3.2 years; total smoking, 2.8 years). They also
studied a separate group of 25 female baboons that received the diet for 2.6 years and were
exposed to cigarette smoke for 1.6 years. Blood levels of COHb were determined by GC and
were reported both as total concentration in milligrams per deciliter and as percent saturation
of Hb, as calculated by a validated linear regression equation. Levels of COHb in the male
baboons averaged 0.64% at baseline, whereas COHb was on an average of 0.35% in female
baboons at baseline. The weekly averages of COHb levels determined after 57 weeks were
2.01 and 1.13% in male and female baboons, respectively. The baseline cholesterol levels
were 105 mg/dL and 88 mg/dL in the two groups of baboons. Levels at 16 weeks were
226 mg/dL in males and 291 mg/dL in females. There were no significant differences in
total cholesterol, HDL cholesterol, or LDL cholesterol between smokers and controls. There
were slightly more fatty streaks and fibrous lesions in the carotid arteries of smokers than in
controls. No differences in lesion prevalence, vascular content of lipids, or prostaglandins
were seen in aorta or coronary arteries.
The results reported by Rogers et al. (1980, 1988) suggest little if any effect of cigarette
smoking on atherosclerotic lesion development in baboons. How these findings can be
extrapolated to effects of smoking in humans is difficult to know. The COHb levels attained
in the experimental animals were barely 2%. Levels in human smokers are probably 4% or
more during the waking hours of the day. On the other hand, the findings are consistent with
most studies of the effects of low levels of CO on atherogenesis.
A study of cockerels by Penn et al. (1983) has shown negative results as well. Three
groups of cockerels, each including seven animals, were used to determine if the atherogenic
effect of cigarette smoke could be separated from an effect due solely to CO. Cockerels
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develop aortic fibromuscular atherosclerotic lesions spontaneously. Various agents, including
some carcinogens, have been shown to accelerate the growth in thickness and extent of these
lesions. The authors used this model by exposing one group of animals to the smoke from
40 cigarettes each day for 5 days each week. The cockerels were exposed from about
6 weeks of age until about 22 weeks of age. A similar group of animals was exposed to CO
calibrated to give a similar COHb level to that achieved in me animals •exposed to cigarette
smoke. The third group of animals was exposed to filtered air. Carboxyhemoglobin levels
following an exposure session were measured at 6, 9, 12, and 15 weeks. The average level
in the air-exposed animals was 1.6%. Levels in the cigarette smoke and CO groups were
6.7 and 7.2%, respectively. Atherosclerosis was quantified both by the extent of the aorta
involved and by the cross-sectional area of the intimal thickening. The cigarette smoke-
exposed group had more aortic lesions and lesions with greater cross-sectional area than did
either the CO-exposed group or the air-exposed group. This difference was significant at
p<0.05 in a one-tailed chi-square test. The data suggest mat atherogenic effects of cigarette
smoke are not solely attributable to CO.
It has been postulated that a possible atherogenie effect of CO may be mediated through
an ability of CO to enhance platelet aggregation or some other component of thrombosis.
This possibility was raised in the study by Marshall and Hess (1981) noted above. Other
studies, however, have demonstrated that the effect of CO is to depress platelet aggregation.
In one study (Mansouri and Perry, 1982), platelet aggregation to epinephrine and arachidonic
acid was reduced in in vitro experiments in which CO was bubbled through platelet-rich
plasma. Similarly, platelets from smokers aggregated less well than platelets 'from
nonsmokers, although this inhibition of aggregation was not correlated with the level of
COHb. ; . , : , . ;
Madsen and Dyerberg (1984) extended these observations by studying effects of CO and
nicotine on bleeding time in humans. Smoke from high-onieotine cigarettes caused a '
significant shortening of the bleeding time. Smoke from low-nicotine cigarettes caused no
significant change in bleeding time. Carbon monoxide inhalation sufficient to raise the
COHb to 15% was followed by a shortening of the bleeding time (6.0 min to 4.8 min), but
for a short period of time (< 1.5 h). After administration of aspirin, neither nicotine nor CO
affected bleeding times or platelet aggregation. The findings suggest that the proaggregating
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effects of cigarette smoke are mediated through an inhibitory effect of nicotine on
prostacyclin (PGI^ production. Effects of CO in the smoke seem to be minor and short
lived.
These findings were corroborated by Renaud et al. (1984). The effects of smoking
cigarettes of varying nicotine content on plasma clotting times and on aggregation of platelets
with thrombin, ADP, collagen, and epinephrine were studied in 10 human subjects. Both the
clotting functions and platelet aggregation were increased with increasing nicotine content in
cigarettes. There was no correlation of these parameters, however, with COHb levels.
COHb levels, reported as percent increase from baseline, achieved about a 60% increase.
Effeney (1987) has provided convincing evidence that these effects of nicotine and GO
on platelet function are mediated through opposing effects on PGI2 production. Four rabbits
were exposed to CO in an exposure chamber at 400 ppm for 7 to 10 days. Carboxy-
hemoglobin levels averaged about 20%. Ten rabbits received an infusion of nicotine for 7 to
10 days. Full-thickness samples of atrial and ventricular myocardium were incubated with
arachidonic acid for determination of PGI2 production by radioimmunoassay of 6-keto-PGFla
(a stable metabolite of PGI^ and by inhibition of platelet aggregation. Carbon monoxide
exposure increased PGI2 production, which was significant in the ventricular myocardium.
Nicotine exposure reduced PGI2 production in all tissues examined. The combination of
nicotine and CO caused a net increase in PGI2 production. The effect of CO may be to
induce hypoxemia, a known stimulant of PGI2 production. This effect of CO would serve to
reduce aggregation.
Another explanation for the antiaggregatory effect of CO exposure recently has been
provided by Bruene and Ullrich (1987). These investigators bubbled CO through platelet-rich
plasma and then challenged the platelets with various agonists. The CO exposure was much
greater than that encountered in physiologic or even toxic states. The results, however,
indicated that inhibition of aggregation was related to enhancement of guanylate cyclase
action and associated increased cyclic guanosine monophosphate levels.
10.3.5 Summary and Conclusions
The 1984 Addendum to the 1979 Air Quality Criteria Document for Carbon Monoxide
(U.S. Environmental Protection Agency, 1984) reported what appears to be a linear
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relationship between level of COHb and decrements in human maximal exercise performance,
measured as maximal O2 uptake. Exercise performance consistently decreases at a blood
level of about 5.0% COHb in young, healthy, nonsmoking individuals (Klein et al., 1980;
Stewart et al., 1978; Weiser et al., 1978). Some studies have even observed a decrease in
short-term maximal exercise duration at levels as low as 2.3 to 4.3% COHb (Horvath et al.,
1975; Drinkwater et al., 1974; Raven et al., 1974a); however, this decrease is so small as to
be of concern mainly for competing athletes rather than for ordinary people conducting the
activities of daily life. Cigarette smoking has a similar effect on cardiorespiratory response to
exercise in nonathletic human subjects, indicating a reduced ability for sustained work (Hirsch
et al., 1985; Klausen et al., 1983).
Since the 1979 Air Quality Criteria Document (U.S. Environmental Protection Agency,
1979), several important studies appearing in the literature have expanded the cardiovascular
date base. Effects in patients with reproducible exercise-induced angina (Allred et al., . •
1989a,b, 1991) have been noted with postexposure COHb levels (CO-Ox measurement) as
low as 3.2% (corresponding to an increase of 2.0% from the baseline). Sheps et al. (1987)
also found a similar effect in a,group of patients with obstructive CAD at COHb levels of
3.8% (representing an increase of 2.2% from the baseline), Kleinman et al. (1989) studied
subjects with angina and found an effect at 3% COHb (representing an increase of 1.5% from
the baseline). Thus, the lowest observed effect level in patients with exercise-induced
ischemia is somewhere between 3 and 4% COHb (CO-Ox measurement), representing a
1.5 to 2.2% increase from the baseline. Effects on silent ischemia episodes, which represent
the majority of episodes in these patients, have not been studied (see Chapter 12).
Exposure to CO that is sufficient to achieve 6% COHb recently has been shown to
adversely affect exercise-related arrhythmia in patients with CAD (Sheps et al., 1990, 1991).
This finding combined with the epidemiologic work of Stern et al. (1988) in tunnel workers
is suggestive but not conclusive evidence that CO exposure may provide an increased risk of
sudden death from arrhythmia in patients with CAD.
There is also evidence from both theoretical considerations and experimental studies in
animals that CO can adversely affect the cardiovascular system, depending on the exposure
conditions utilized in these; studies. Tables 10-4 through 10-7 are summaries of the data
pertinent to the effects of CO on the cardiovascular systems of experimental animals.
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Although disturbances in cardiac rhythm and conduction have been noted in healthy and
cardiac-impaired animals at CO concentrations of 50 to 100 ppm (2.6 to 12% COHb), results
from these studies are not conclusive. Alterations in various hemodynamic parameters have
been observed at CO concentrations of 150 ppm (7.5% COHb), and cardiomegaly has been
reported at CO concentrations of 200 ppm (12% COHb) and 60 ppm in adult and fetal
animals, respectively. In addition, changes in Hb concentrations have been reported at CO
concentrations of 100 ppm (9.26% COHb) and 60 ppm in adult and fetal animals,
respectively. ,
There is conflicting evidence that CO exposure will enhance development of
atherosclerosis in laboratory animals, and most studies show no measurable effect. Similarly,
the possibility that CO will promote significant changes in lipid metabolism that might
accelerate atherosclerosis is suggested in only a few studies. Any such effect must be subtle
at most. Finally, CO probably inhibits rather than promotes platelet aggregation. Except for
the studies by Rogers et al. (1980, 1988) on baboons, the CO exposures used in the studies
on atherosclerosis created COHb levels of 7% or higher; sometimes much higher. Although
occupational exposures in some workplace situations might regularly lead to COHb levels of
10% or more, such high-exposure levels are almost never encountered in the /
nonoccupationally exposed general public. In this general population, exposures are rarely as
much as 25 to 50 ppm, and COHb levels typically are below 3% in nonsmokers (see
Chapter 8). When examined in this context, this review, therefore, provides little data to
indicate that an atherogenic effect of exposure would be likely to occur in human populations
at commonly encountered levels of ambient CO.
10.4 CEREBROVASCULAR AND BEHAVIORAL EFFECTS OF
CARBON MONOXIDE
10.4.1 Control of Cerebral Blood Flow and Tissue PO2 with Carbon
Monoxide and Hypoxic Hypoxia
10.4.1.1 Introduction
The effect of CO on CBF and cerebral O2 consumption (CMRO^ is complicated by the
relationship between CBF and cerebral O2 delivery or availability. Alterations in cerebral
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neurological function, as evaluated by neurological symptoms or changes in evoked potential
responses, are particularly difficult to correlate with changes in CBF or cerebral O2 delivery.
One of the most fundamental challenges to the organism is to obtain O2 from its environment
and deliver it to the tissues. However, each tissue or organ may have regulatory mechanisms
to obtain O2 that differ from other tissues or organs. Literature concerning the
cerebrovascular effects of CO is incomplete and in many cases conflicting, and, despite the
enormous literature concerning hypoxia and the cerebrovasculature, the mechanisms that
regulate the cerebral vessels during hypoxia are unclear.
Kety and Schmidt (1948) demonstrated that CMRO2 is about 3.5 mL of O2 per 100 g
of brain (cerebral hemispheres) per minute in normal adult man. This consumption of O2 is
virtually unchanged under a variety of conditions. About one-half of CMRO2 is dedicated to
synaptic transmission (Astrup, 1982; Donegan et al., 1985) and this remains relatively
constant under all conditions. Half of the remaining, vegetative O2 consumption, a quarter of
the overall value, maintains resting neuronal membrane potentials. The remaining quarter is
consumed by a variety of unidentified, but presumably irreducible, processes (Astrup, 1982).
In order for the brain to maintain its CMRO2, it has but two adaptations: (1) the brain could
extract more O2 from the blood or (2) CBF could increase. In fact, the brain generally relies
largely on increasing CBF for its major adaptability mechanism to provide more O2 to the
tissue. Thus, the following discussion concerns the regulation of CBF with hypoxia, with
little discussion of the regulation of O2 extraction.
The cerebral vasculature responds to decreases in O2 availability by increasing CBF in
order to maintain cerebral O2 delivery and/or by increasing O2 extraction in order to maintain
cerebral O2 utilization when cerebral O2 delivery is limited. Compared with other forms of
cerebral O2 deprivation, such as hypoxic hypoxia (lowered inspired O2 concentration) and
anemia, CO hypoxia may interfere with O2 delivery and cerebral O2 utilization through
effects on the Hb dissociation curve and on the cytochrome oxidase system. During
O2 deprivation (hypoxia), CBF and cerebral O2 delivery may be altered by hemodynamic
responses, specifically changes in cerebral perfusion pressure, as well as the absolute amount
of O2 limitation (arterial O2 content). Because hypoxia adversely effects cerebral
autoregulation, hypertension during hypoxia may result in an increased CBF and, hence,
cerebral O2 availability. Conversely, hypotension during hypoxia may decrease CBF and
10-75
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cerebral O2 delivery. In the following sections, the effects of hypoxia (hypoxic and CO) on
the cerebrovasculature will be demonstrated and the potential mechanisms of action of
hypoxia on cerebral blood vessels will be examined. The effects of CO on global and
regional CBF, and the effects of both high and low levels of CO on CBF and C1V1RO2 also
will be examined. An attempt will be made to demonstrate the potential mechanisms of
action of hypoxia on the cerebrovasculature, and the synergistic effects of CO and cyanide
hypoxia on the cerebral circulation will be examined.
10.4.1.2 Effects on Global Cerebral Blood Flow
At the present time, there is conflicting information concerning whether the
cerebrovascular response to CO is similar to other forms of cerebral hypoxia, such as hypoxic
hypoxia and anemic hypoxia. Few studies are available in which other types of hypoxia have
been compared to CO hypoxia, especially at similar levels of O2 deprivation. In addition,-
comparison of cerebrovascular effects of CO and other types of hypoxia from laboratories of
different investigators is difficult because of differences in anesthetic techniques, use of
different animal species, and use of different CBF techniques. An important point to
emphasize when comparing CO hypoxia to hypoxic hypoxia is that although arterial
O2 content is reduced with both hypoxic and CO hypoxia, there is no reduction in arterial
O2 tension with CO hypoxia. Comparisons of the equivalent effects of both CO and hypoxic
hypoxia on CBF and CMRO2 in the same animal preparations have been made by Traystman
and co-workers in several studies (Traystman and Fitzgerald, 1977; Traystman et al., 1978;
Fitzgerald and Traystman, 1980; Traystman and Fitzgerald, 1981; Koehler et al., 1982;
Koehler et al., 1984; Koehler et al., 1983; Koehler et al., 1985). The concept of equivalent
effects of both types of hypoxia (hypoxic and CO) has been described by Permutt and Farhi
(1969) and involves the comparison of physiologic effects of elevated COHb and low O2 at
equal reductions in Hb, arterial O2 content, arterial or venous O2 tension, or blood flow.
The focus of investigation of several laboratories, including Traystman's, concerning the
effects of hypoxia on the cerebral vasculature is not merely to describe the well-known
vasodilation that occurs, but to examine the mechanism that produces this vasodilation. This
is where much of the controversy lies. Here issues focus on the importance of local
mechanisms in controlling CBF such as tissue acidosis (Kety and Schmidt, 1948; Molnar and
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Szanto, 1964) and the direct effect of hypoxia on vascular smooth muscle (Detar and Bohr,
1968). Some years ago it also had been postulated that O2-sensitive carotid arterial
chemoreceptors might play a role in the CBF response during hypoxia (Ponte and Purves,
1974). Other groups of investigators additionally suggested that carotid baroreceptor
stimulation produces cerebral vasoconstriction (James and MacDonnell, 1975; Ponte and
Purves, 1974). This vasoconstrictor response to an elevation in blood pressure could
contribute to the autoregulatory responses of the cerebral vessels. Because the carotid and
aortic chemoreceptors are stimulated by certain forms of hypoxia, as is systemic arterial
blood pressure, the underlying mechanism of the cerebral vasodilator response to hypoxia is
complicated.
Traystman et al. (1978) previously reported that the increase in CBF in dogs during a
reduction in arterial O2 content, produced by breathing the animal with a low O2 gas mixture
(hypoxic hypoxia), was not different from the increase in CBF when O2 content was
decreased by adding CO to the breathing gas mixture (CO hypoxia) (Figure 10-4). This was
true both before and after carotid sinus chemodenervation. This study also demonstrated that,
with hypoxic hypoxia, mean arterial blood pressure increased, whereas it decreased with CO
hypoxia. Because the CBF increase with CO and hypoxic hypoxia was similar,
cerebrovascular resistance actually decreased more with CO hypoxia. This represents the
effect of the carotid chemoreceptors on systemic blood pressure during each type of hypoxia.
When the carotid chemoreceptors were denervated, cerebrovascular resistance decreased to
the same level as with CO hypoxia. They concluded that the carotid chemoreceptors do not
play an important role in the global cerebral vasodilator response to either CO or hypoxic
hypoxia.
There were two important limitations of that study, however. One involved the
possibility that the aortic chemoreceptors (aortic bodies) might have a role in controlling
CBF, and this was not considered at that time. The aortic bodies have been reported to have
a role in the control of pulmonary blood flow (Stern et al., 1964). The other involved the
fact that sectioning of the carotid sinus nerves denervated not only the carotid
chemoreceptors, but also the carotid sinus baroreceptors. Because hypoxic hypoxia and CO
hypoxia affect blood pressure, they therefore could modulate chemoreceptor input by
baroreceptor input. Traystman and Fitzgerald (1981) demonstrated that the carotid and aortic
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Kgure 10-4. Effect of hypoxic hypoxia and carbon monoxide (CO) hypoxia on cerebral
blood flow in 13 control and 9 Chemodenervated dogs. Each point
represents the mean ± SE. Analysis of variance showed that the four
slopes were not significantly different from each other. Point-by-point
analysis using Student's t-test showed that the minimum difference that
was significant was between Chemodenervated hypoxic hypoxia and
Chemodenervated CO hypoxia at 8 vol. % (p = 0.05).
Source: Traystman et al. (1978).
chemoreceptors are not necessary for the increase in CBF with hypoxia and that the increase
in CBF is not modified by the carotid and aortic baroreceptors (Figure 10-5). They also
showed that the cerebral vasodilation to hypoxia in carotid chemoreceptor-denervated animals
and in carotid sinus nerve sectioned and vagotomized animals resembles that occurring in
animals exposed to CO hypoxia with intact chemoreceptors in which both the arterial
O2 tension is high and the chemoreceptors may not be activated (Figure 10-6). Cerebral
O2 consumption remained at control values under both hypoxic hypoxia and CO hypoxia
10-78
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•—• Hypoxic Hypoxia o- - o CO Hypoxia ( ) % of Control
Figure 10-5. Effects of hypoxic and carbon monoxide Iiypoxia on cerebral blood flow,
mean arterial blood pressure, and cerebral vascular resistance in control,
carotid baroreeeptor-, and chemoreceptof-denervated^animals. Data
points and bars represent means ± SE of nine animals. Numbers in
parentheses are percent of control (* = p<0.05).
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10-79
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Figure 10-6. Effects of hypoxic and carbon monoxide hypoxia on cerebral blood flow,
mean arterial blood pressure, and cerebral vascular resistance in control
and vagotomized animals. Data points and bars represent means + SE of
five animals. Numbers in parentheses are percent of control
(* = p<0.05).
Source: Traystman and Fitzgerald (1981). , ,
10-80
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conditions and was unchanged by any denervation condition. These data support the notion
that the brain increases its blood flow in response to its O2 needs with both hypoxic and CO
hypoxia in control or baroreceptor and chemoreceptor denervated dogs in order to maintain
CMRO2 constant. The cerebral blood vessels appear to be relatively unresponsive to reflex
stimuli (Heymans and Bouekaert, 1932; Heistad and Marcus, 1978; Heistad et al., 1976), and
the CBF responses to low inspired O2 or elevated CO are not dependent on either the carotid
or aortic chemoreceptors. These responses also are not modified by either the carotid or
aortic baroreceptors. These findings would be most compatible with the idea that control of
the cerebral vasculature during hypoxia is mediated locally; however, it remains possible that
central (brainstem) mechanisms are involved. These brainstem mechanisms concerning the
CBF responses to hypoxic hypoxia have been little studied, and their possible involvement in
CBF responses to CO have not been examined at all.
The idea, however, that CBF responses to CO are always similar to those of hypoxic
hypoxia is not universal. Studies on fetal (Jones et al., 1978) and newborn lambs (Jones
et al., 1981) have demonstrated that CBF increases during hypoxic hypoxia may correlate
better with decreased arterial O2 content than with decreased arterial PO2. The description of
hypoxia in terms of arterial O2 content rather than arterial PO2 is more than simply an
arbitrary choice between two similar variables. When one considers hypoxic hypoxia as a
fall in arterial O2 content, this emphasizes the importance of cerebral O2 delivery to the
microvascular exchange site, whereas PO2 emphasizes diffusion from the exchange site to the
parenchyma. The studies previously mentioned (Jones et al., 1978; Jones et al., 1981)
demonstrated that the relationship between CBF and arterial O2 content is such that the
product of CBF and arterial O2 content, which equals cerebral O2 delivery, is essentially
constant as arterial PO2 falls. The study in newborn lambs (Jones et al., 1978) demonstrated
that arterial fractional O2 extraction (CMRO2 per amount of O2 delivered) was well
maintained in both anemic and hypoxic hypoxia conditions. The maintenance of cerebral
O2 delivery and fractional O2 extraction during anemic and hypoxic hypoxia is not unique to
the lamb and does apply to adults of other species (Jones et al., 1981).
Koehler et al. (1982), working with a newborn-lamb model, tested the hypothesis that
CBF and CMRO2 bear relationships to arterial O2 content during CO hypoxia. that are not
different from those occurring during hypoxic hypoxia. They reasoned that if these
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relationships differ between hypoxic hypoxia and CO hypoxia, then other effects of CO
exposure, such as the shift in the O2Hb dissociation curve or histotoxic effects, need to be
considered. Koehler et al. (1982) found that CO hypoxia causes a 47% greater increase in
CBF compared with hypoxic hypoxia for a similar reduction in arterial O2 content
(Figure 10-7). A greater CBF response to CO hypoxia than to anemic hypoxia also has been
reported in humans (Paulson et al., 1973). In the study of Koehler et al. (1982), CMRO2
and O2 delivery were constant during hypoxic hypoxia. Thus, fractional O2 extraction,
which equals O2 consumption divided by O2 delivery, remained constant with hypoxic
hypoxia. During CO hypoxia, although CMRO2 remained constant, O2 delivery increased
and fractional O2 extraction decreased. This decline in fractional O2 extraction was
correlated with the leftward shift of the O2Hb dissociation curve that accompanied CO
hypoxia. In this situation, the additional increase in CBF with CO hypoxia could be
explained because the shift in the curve lessens the O2 diffusion gradient into the tissue and
further lowers the arterial PO2. In other words, whereas increases in CBF maintain
O2 availability at the microvascular exchange site, overall O2 transport to the cells becomes
relatively more diffusion-dependent with CO hypoxia. Although these investigators believe
that the best explanation for the difference in the CBF response to .hypoxic hypoxia and CO
hypoxia is the leftward shift of the O2Hb dissociation curve, they cannot completely rule out
a potential histotoxic effect of CO resulting from the competition of CO and O2 for
cytochrome aa3 oxidase. This effect generally is considered to be insignificant at low CO
levels because in vitro cytochrome oxidase remains completely oxidized until very low tissue
. :. • >t ' . f't '•
O2 partial pressure levels are reached. However, Hempel et al. (1977) have shown that
cerebral cytochrome aa3 in vivo is in a substantially reduced state, raising the possibility that
CO may readily compete with O2 at relatively low CO levels. This binding relationship
between CO and the oxidase also has been demonstrated by Piantadosi et al. (1985, 1987).
On the other hand, if CO were exerting a histotoxic effect, CMRO^ would be expected to
fall, and this was not observed in Koehler's experiments. It also is possible, however, that
CO could have a direct histotoxic effect on cerebral vascular smooth muscle, independently
of brain tissue metabolism.
In a subsequent study, Koehler et al. (1984) compared the effect of hypoxic hypoxia
and CO hypoxia on CBF in adult and newborn sheep in which arterial O2 content was
10-82 .
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O)
•— Control and HH
Q-COH
Fractional Arterial 02 Saturation
Figure 10-7. Cerebral blood flow as a function of fractional arterial oxygen (O2)
saturation. Circles represent control or hypoxic hypoxia (HH) and squares
represent carbon monoxide hypoxia (COH),
Source: KoeMer et al. (1982).
reduced to 50 to 60% of control with both types of hypoxia. During hypoxic hypoxia, CBF
increased to maintain cerebral O2 delivery in both adults and newborns; however, CMRO2
did not change. Although CMRO2 was higher in newborns, the responses of CBF/CMRO2
to hypoxic hypoxia was not different in newborns and adults. In newborns and adults, CBF
increased to a greater extent with CO hypoxia than with hypoxic hypoxia for similar
reductions in arterial O2 content (Figure 10-8). This resulted in an increase in cerebral
O2 delivery with CO hypoxia. As discussed previously, the degree to which CO hypoxia
differed from hypoxic hypoxia correlated with the magnitude of the leftward shift of the
O2Hb dissociation curve that accompanies CO hypoxia. In the adult animals with CO
hypoxia, CMRO2 was reduced by 16%; however, CMRO2 was maintained in the newborns.
These data allowed for the conclusion that maintenance of cerebral O2 delivery during
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50
40H
O" 20-
CV|
o
co j f.
p 10-
4 8 12
CaO2 (vol. %)
16
Figure 10-8. Comparison of newborn and adult responses of the reciprocal of the
cerebral arteriovenous oxygen (O2)-content difference, (CaO2 — CVO2) ,
to a reduction in arterial O2 content (CaO2) during hypoxic hypoxia (HH).
Open circles represent room-air control hi newborns, solid circles
represent HH in newborns, open triangles represent room-air control in
adults, and solid triangles represent HH in adults. Regression lines were
fitted to the reciprocal of CaO2. For newborns (solid line),
(CaO2 - CVO<2) = 1.74 CaO2-1 + 0.01 (r = 0.91). For adults (dashed
line), (CaO2 - C^)"1 = 1.64 C^'1 + 0.02 (r = 0.67). Responses of
blood flow per unit O2 consumption are not significantly different between
newborns and adults. ; '' ,
Source: Koehler et al. (1984).
hypoxic hypoxia is a property of CBF regulation common to both newborn and adult sheep.
During CO hypoxia, the position of the O2Hb dissociation curve is an additional factor that;
sets the level of O2 delivery. The fetal conditions of low arterial O2 content and a
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left-shifted O2Hb dissociation curve may have provided the newborn with a mierocirculation
better suited for maintaining CMRO2 during CO hypoxia.
Some points need to be considered when comparing the cerebrovascular effects of
hypoxic hypoxia and CO hypoxia as described in the dog studies (Traystman and Fitzgerald,
1981; Traystman et at., 1978) with those described in the newborn and adult sheep. In the
studies concerning the anesthetized dogs, the CBF response to hypoxic hypoxia and CO
hypoxia was not statistically different, although the mean blood flows tended to be higher
with moderate levels of CO. This response was statistically significant in the newborn and
adult sheep experiments. One likely explanation for the different result is that arterial blood
pressure declined during CO hypoxia in the anesthetized dog, whereas it was well maintained
in the unariesthetized sheep. Because cerebral autoregulation is impaired during severe
hypoxia (Haggendal and Johannsson, 1965), a drop in perfusion pressure during CO hypoxia
may have limited the increase in CBF in the dog. A reexamination of data from the dog
study indicated that cerebral O2 delivery increased and fractional O2 extraction decreased
during CO hypoxia. Thus, the dog study is consistent with the data obtained in the sheep
study. Similar results have been reported in humans (Paulson et al., 1973) and in goats
(Doblar et al., 1977). Another possible explanation for the differences in CBF responses to
hypoxia in =the dogs versus the sheep is that the dogs were anesthetized with sodium
pentobarbital, whereas the sheep were studied in the unanesthetized state. Pentobarbital
anesthesia reduces CBF and CMRO2 so that differences in flow would be minimized in the
dog studies. Finally, the PO2 at 50% saturation of Hb (P50) of sheep Hb is considerably
higher ftian in the dog (44 mm Hg for sheep vs. 27 mm Hg for dogs) so that the leftward
shift of the O2HE> dissociation curve would be larger in sheep and therefore result in a greater
increase,in CBF with CO hypoxia versus hypoxic hypoxia. Evidence supporting a role for
P50 in the CBF response to CO was obtained by Koehler et al. (1983) in experiments hi
which lambs were first exchange transfused with high-P50 donor blood, which resulted in an
increase in cerebral fractional O2 extraction. With the induction of CO hypoxia to return
P50 to the pretransfusion level, cerebral O2 delivery and O2 extraction also returned to
pretransfusion levels. These investigators suggested that because P50 can affect capillary and
tissue O2 partial pressure independent of arterial O2 content, the position of the O2Hb
dissociation curve appears to set the level of cerebral O2 delivery about which CBF is'
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regulated when arterial O2 content is reduced. These data, taken together with the previously
mentioned work from this group, are consistent with the existence of a tissue O2 tension-
dependent mechanism controlling the cerebral vasculature in which tissue O2 tension is a
function of CMRO2, cerebral O2 delivery to the rnierocirculation, the position of the O2Hb
dissociation curve, and microcirculatory morphology.
10.4.1.3 Effects on Regional Cerebral Blood Flow
Both human and animal histopathology studies have suggested that there are regional
differences in tissue injury following severe CO exposure. One potential source of these
differences is regional differences in the CBF response to CO exposure. Two logical
comparisons of the regional CBF response to CO hypoxia are (1) anatomical (i.e., rostral to
caudal [cortex to brainstem] comparison) and (2) physiological (i.e., brain areas with a
functional blood-brain barrier versus brain areas without an intact blood-brain barrier).
Koehler et al. (1984) observed interesting regional CBF responses to hypoxic and CO
hypoxia in newborn lambs and adult sheep (Table 10-8, Figure 10-9). In adults, regions with
high normoxic blood flows such as the caudate nucleus and midbrain showed a large response
to hypoxia, whereas lower blood-flow regions with large white-matter tracts, such as the
cervical spinal cord, pons, diencephalon, and piriform lobe, showed a relatively lower
response. Other brain regions were essentially homogeneous in their responses. Carbon
monoxide hypoxia increased CBF to a greater extent than hypoxic hypoxia in all brain
regions, but the overall pattern of regional CBF was similar for the two types of hypoxia in
the adults. In Table 10-8, the regions are listed in order from highest to lowest responsivity,
and the particular groups of regions that are significantly different are separated by pairs of
vertical brackets. In the newborns, regional responses differed for each type of hypoxia.
With hypoxic hypoxia in the newborns, the brainstem regions had a significantly greater
response than all other regions except the caudate nucleus, whereas all cerebral lobes
responded significantly less than all other regions. With CO hypoxia, the difference between
brainstem responses and those of other regions was less marked. In the adults, in contrast,
there was no significant interactive effect between the type of hypoxia and the pattern of •
regional response. With both types of hypoxia, the caudate nucleus had a significantly
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TABLE 10-8. BRAIN REGIONS RANKED FROM GREATEST TO LEAST
IN RESPONSE TO HYPOXIAa
Hypoxic Hypoxia Carbon Monoxide Hypoxia
Adult sheep
Caudate nucleus_
Midbrain
Medulla
Parietal lobe
Occipital lobe
Frontal lobe
Cerebellum
Temporal lobe
Piriform lobe
Diencephalon
Pons
Spinal cord _
— 1
— i
J
-i
___
—
—
_
— "
Caudate nucleus J
Midbrain
Occipital lobe ~~
Medulla
Cerebellum
Temporal lobe
Frontal lobe
Parietal lobe
Diencephalon
Piriform lobe
Pons
Spinal cord _
_
—i
—
J
-i
1 -
J.
Newborn lambs
Medulla J
Midbrain
Pons ~
Caudate nucleus
Cerebellum
Diencephalon
Spinal cord
Frontal lobe
Occipital lobe
Temporal lobe
Parietal lobe
Piriform lobe _
—
-
Midbrain J
Caudate nucleus
Cerebellum J
Medulla
Pons
Diencephalon ~
Occipital lobe
Temporal lobe
Parietal lobe
Frontal lobe
Spinal cord
Piriform lobe _
-
_
-
^
-
"Multiple-range tests (Waller and Duncan, 1969) were performed within each type of hypoxia and each age
group. Each pair of vertical brackets encloses two groups of brain regions that have significantly different
responses.
Source: Kcehler et al. (1984).
greater response than all other regions and the cervical spinal cord responded significantly
less than all other regions.
MacMillan (1975) studied CO hypoxia in rats and did not demonstrate any gross
regional CBF differences, in contrast to the studies of Koehler et al. (1982, 1984). However,
in MacMillan's study, far fewer brain regions were studied, and the caudate nucleus and
midbrain regions, which Koehler's group found to have large responses, were not
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3000-
2000-
1000-
500-
CQ
Adults
^ COH
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I
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S S § ta-
0) C o
I I §
(L H- Q.
3000
2000-
1000-
500-
Newborns
COH
I
I
HH
Rgure 10-9. Profiles of slopes of regional blood flow responses to hypoxie hypoxia (HH,
solid lines) and carbon monoxide hypoxia (COH, dashed lines) in adults
(top) and newborns (bottom). Slopes were calculated from the change in
flow (in milliliters per minute per 100 g) per change in the reciprocal of
the arterial oxygen content (reciprocal of milliliters of oxygen per 100 mL
blood) to achieve linearity. Least significant differences for multiple
comparisons of regions within each age and type of hypoxia group are
given by the bars on the right, as calculated by the Waller and Duncan
(1969) k-ratio procedure. (Points along the profile line separated in height
by more than the height of the bars are significantly different.)
Source: KoeHer et al. (1984).
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individually reported. Okeda et al. (1987) also demonstrated CO-induced regional CBF
differences in cats. This group attempted to demonstrate that there is a selective vulnerability
of the pallidum and cerebral white matter and showed low CBF values for these brain areas.
In the newborn lambs (Koehler et al., 1984), unlike the adult sheep, the patterns of regional
CBF responses were not similar with the two types of hypoxia. Brainstem regions, especially
the medulla, had marked responses relative to the cerebrum during hypoxic hypoxia. Peeters
et al. (1979) also have made this observation in unanesthetized fetal lambs. Rosenberg et al.
(1982) found in the fetal and neonatal lamb, but not in the adult sheep, that the brainstem
also had a greater CBF response to arterial CO2 than other regions, and Cavazzuti and Duffy
(1982) observed in newborn dogs results consistent with those in the lamb in that brainstem
regions displayed a greater blood-flow response to hypoxic hypoxia and to hypercapnia. The
most likely explanation for the higher brainstem response to hypoxia and hypercapnia in the
puppy is that this region has a higher CMRO2. Normoxic glucose consumption in vivo
(Cavazzuti and Duffy, 1982) and O2 consumption in vitro (Himwich and Fazekas, 1941) are
relatively high in the brainstem of the neonatal puppy. This also may be true in the neonatal
lamb. However, if this were the only explanation, there should be a much greater CBF
response in brainstem regions relative to the rest of the brain during CO hypoxia, as well as
hypoxic hypoxia, but this has not been observed. The larger CBF response of the caudate
nucleus with hypoxia compared with the cortical lobes may be explained by the high fraction
of grey matter in the caudate nucleus. The large response of the brainstem region also may
be partly explained by a relatively high proportion of grey matter. It also is likely that
increased activation of cardiovascular and respiratory centers in the brainstem during hypoxia
produces local increases in metabolism and O2 demand, which in turn would produce an
additional increase in blood flow in this area. The capability of the CNS to increase CMRO2
during hypoxic hypoxia has been demonstrated in certain strains of rats (Berntman et al.,
1979). An alternative explanation for the regional differences in sensitivity to hypoxia is that
stimulation of the peripheral chemoreceptors by hypoxia produced sympathetic
vasoconstriction preferentially in the cerebral hemispheres. This explanation is considered
unlikely because previous studies have shown that neither carotid nor aortic chemoreceptor
denervation alters CBF from cortical regions during hypoxic hypoxia or CO hypoxia
(Traystman and Fitzgerald, 1981; Traystman et al., 1978).
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There is at least one area of the brain that does not respond to alterations in arterial
O2 content and partial pressure as do other brain areas, the neurohypophysis. The
neurohypophysis is an anatomically unique region of the brain, and the regulation of blood
flow to this area appears to be different from other areas of the brain. Hanley et al. (1986)
demonstrated that when arterial O2 content was reduced equivalently with hypoxic hypoxia
and CO hypoxia, global CBF increased by 239 and 300%, respectively. Regional CBF also
showed similar responses for all brain areas except the neurohypophysis. With hypoxic
hypoxia, neurohypophysis blood flow increased markedly (320%), but it was unchanged with
CO (Figure 10-10). These blood flow responses of the neurohypophysis occur independently
of alterations in blood pressure. .
Wilson et al. (1987) determined the role of the chemoreceptors in the neurohypophyseal
response to hypoxia atid found that chemoreceptor denervation completely inhibited the
increase in neurohypophyseal blood flow associated with hypoxia. The response to CO was
unaltered (Figure 10-11). These data (Hanley et al., 1986; Wilson et al., 1987) demonstrated
that the mechanism responsible for the increase in neurohypophyseal blood flow with hypoxia
is unique when compared to other brain regions. The only animals in which
neurohypophyseal blood flow did not respond were the denervated animals and those given
CO. Both of these conditions are ones in which the chemoreceptors have been shown to be
inactive (Traystman and Fitzgerald, 1981; Comroe, 1974). Although for most brain regions
the blood flow response to hypoxia does not involve the peripheral chemoreceptors, this is
not true for the neurohypophysis. Thus, here is an example of one regional brain area that
does not respond to CO hypoxia (i.e., a change in arterial O2 content) but does respond to a
change in arterial O2 tension. This suggests that the chemoreceptor represents the mechanism
involved in the neurohypophyseal response to hypoxic hypoxia and that local changes in
arterial O2 content are not involved in this response, because the neurohypophysis does not
respond to CO. It is unclear whether other regional brain areas have similar responses and
mechanisms to hypoxic and CO hypoxia.
10.4.1.4 Effect of Low Levels of Carbon Monoxide on Cerebral Blood Flow
Little information is available concerning the effects of low levels of CO on the cerebral
vasculature. This is particularly unfortunate because many investigators have shown
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Cerebral Caudate White Hypothatamus Ceretelum
Hemisphere
Median
Eminence
Contra! I \ I Control II
HypoxlcHypoxia
Neural
Lobe
COHypoxia
Figure 10-10. Effect of hypoxic hypoxia and carbon monoxide (CO) hypoxia on
neurohypophyseal and regional cerebral blood flow (rCBF), Each bar
represents mean + SE of five dogs. Both types of hypoxia (diagonal and
cross-hatched bars) produced significant increases (*) from control (open
and dark bars) hi blood flow to all regions except the neurohypophysis.
Both parts of the neurohypophysis, the median eminence and the neural
lobe, showed no change from control with CO hypoxia but did show
significant flow responses to hypoxic hypoxia. Note the changes in the
vertical axis at right for median eminence and neural lobe blood flow.
Source: Hanley et al. (1986).
behavioral and electrophysiological abnormalities with various levels of CO exposure
(Xintaras et al., 1966; Beard and Wertheim, 1967; Fodor and Winneke, 1972; Horvath
et al., 1971), and it is conceivable that these effects could result from abnormalities of CBF.
Carbon monoxide hypoxia results in an increase in CBF, and this has been demonstrated by a
number of investigators (Traystman and Fitzgerald, 1981; Traystman et al., 1978; Sjostrand,
1948; Haggendal and Norback, 1966; Paulson et al., 1973). However, many difficulties
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125-
I 100-
cb
s
I-
tiT
m
60-
25-
• Danervated
O Intact
- 2000
- 1600 |
I
- 1200 i
- 800
L_ 400
£
u."
Normoxla Hypoxic
Hypoxia
Cerebral Hemispheres
Normoxia
Hypoxic
Hypoxia
Neurohypophysis
Figure 10-11. Effect of complete chemoreeeptor denervation on regional cerebral blood
flow (rCBF) in the cerebral hemispheres and neurohypophysis.
Significant changes (*) in average cerebral hemispheric blood flow and
neurohypophysial blood flow are shown for intact and complete
denervation conditions during hypoxic hypoxia. Each line represents
mean ± SEM of six dogs. Note changes in y axis at right for
neurohypophyseal blood flow.
Source: Wilson et al. (1987).
have been encountered in these experiments, such as extracranial contamination of the . ,
measured CBF, surgical trauma to the cerebral vasculature, inadequate control of blood .
gases, and failure to measure COHb concentrations. , , . ..,-
Traystman (1978) examined the CBF responses to CO hypoxia in anesthetized dogs,
particularly in the range of COHb less than 20% (Figure 10-12). A COHb level as low as
2.5% resulted in a small, but significant, increase in CBF to 102% of control. With
reductions in O2-carrying capacity of 5, 10, 20, and 30% (5, 10, 20, and 30% COHb), CBF
increased to approximately 105, 110, 120, and 130% of control, respectively. At each of ...
these levels, CMRO2 remained unchanged. At COHb levels above 30%, CBF increased
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220
210-
"&. 200 -
8 190-
| 180-
170-
g 140
•8
® 130-
120-
110-
100
10 20 30
Carboxyhemoglobin, %
40
50
Figure 10-12. Effect of increasing Carboxyhemoglobin levels on cerebral blood flow,
with special reference to low-level administration (below 20%
Carboxyhemoglobin). Each point represents the mean ± SE of 10 dog
preparations. •
Source: Traystman (1978).
out of proportion to the decrease in O2-carrying capacity, but the brain could no longer
maintain CMRO2 constant. At a COHb level of 50%, CBF increased to about 200% of
control. These findings are in general agreement with those of MacMillan (1975), who
demonstrated that as COHb increased to 20, 50, and 65%, CBF increased to 200, 300, and
then 400%, respectively, in cats. These CBF increases at 20% COHb are higher than those
reported in Traystman's (1978) study but the reason for this is not known. Haggendal and
Norback (1966) demonstrated a 50 to 150% of control increase in CBF with COHbs of 30 to
70%, and Paulson et al. (1973) showed a 26% increase in CBF with a COHb of 20%, These
findings also indicate that CBF increases progressively with increasing COHb concentrations,
and that CMRO2 is maintained constant even at a COHb level of 30%. This has important
implications regarding the behavioral and electrophysiological consequences of CO exposure.
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These findings also would be consistent with those of Dyer and Annau (1978), who found
that superior colticulus-evoked potential latencies are not affected by COHb levels up to 40%.
At levels above this, the brain cannot increase blood flow enough to compensate for
decreased tissue O2 delivery. At these high COHb levels, then, behavioral and
neurophysiological abnormalities should be quite evident. At lower COHb levels, these
abnormalities should not be seen because the brain can increase its blood flow or
O2 extraction to maintain a constant CMRO2. Obviously, in a compromised cerebral
vasculature (e.g., patients with stroke, head injury, atherosclerosis, or hypertension), these
abnormalities would be evident because the brain perhaps could not increase its blood flow or
extraction enough to maintain a constant CMRO2. These data lead to the suggestion that as
long as the brain can compensate for the decrease in O2 availability by increasing its blood
flow or O2 extraction to maintain a constant CMRO2, there should be no detrimental effects
of hypoxia at these levels (i.e., up to a COHb of 30% or more). However, when these
compensatory mechanisms fail, the detrimental effects on behavioral or electrophysiological
aspects should be observed. This is a completely different hypothesis from the one that
suggests there are behavioral or neurophysiological effects at COHb levels of less than 10%,
or even 5%.
In addition, the idea of a threshold level below which changes in COHb would not
invoke increases in CBF (Otto and Reiter, 1978) was unsubstantiated by Traystman's work
(Traystman, 1978). A threshold level such as this would have nicely accounted for
behavioral and electrophysiological decrements observed by some investigators at COHb
levels of less than 5% (Xintaras et al., 1966; Beard and Wertheim, 1967). Because
Traystman (1978) showed increased CBF and stable CMRO2 up to COHb levels of 30%, this
suggests almost perfect compensation of the cerebral circulation to levels of rather severe
hypoxia. Several investigators, however, have dealt with whether there is a threshold arterial
O2 tension for alterations in CBF with hypoxic hypoxia. McDowall (1966) reported a
threshold arterial O2 tension of 50 mm Hg in anesthetized dogs. Cerebral blood flow began
to increase as arterial O2 tension approached 50 mm Hg, and at 30 mm Hg had increased to
220% of control. Kogure et al. (1970) confirmed McDowall's findings using a venous
outflow technique. However, Borgstrom et al. (1975) reported a significant increase in CBF
at arterial O2 tensions as high as 85 mm Hg. Other investigators have shown that CBF
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increases even with decreases in arterial O2 content, or O2 tension within the nonnoxic range
(Jones et al,, 1981; Traystman et al., 1978). There is little reason to think that a critical
O2 tension exists at the present time, primarily because of the experiments described above,
but also because of a better understanding of how O2 exerts itself on cellular metabolism in
intact biologic systems (Rosenthal et al., 1976; Wilson et al., 1979). A threshold response to
a decrease in arterial O2 tension or the parenchymal O2 tension (probably parenchymal
[Kontos et al., 1978]) is the major determinant of CBF. Also, because of loss of O2 from
larger arterioles (During et al., 1979) and the sigmoid shape of the O2Hb. dissociation curve,
large changes in arterial O2 tension will result in relatively small changes in O2 tension in
small arterioles and tissues. In addition, any changes in CBF that occur at high levels of
arterial O2 tension will be on the;flat portion of the hyperbolic CBF response curve (Jones
and Traystman, 1984) and will be difficult to measure. Thus, it is probably more correct to .
consider the CBF response to hypoxic hypoxia as a continuous hyperbolic function that
applies over a wide range of O2 tension values.
10.4.1.5 Synergistic Effects of Carbon Monoxide
There has been some work regarding the synergistic effects of CO with other
toxicologic substances, most of these investigating the by-products of combustion (also see
Section 11.3.2). In spite of the complex nature of fire, it is clear that CO absorption is a
major contributing factor in fire deaths (Radford et al., 1976). Cyanide also has been
demonstrated to be present as a result of combustion and the combination, Or interaction, of
this agent with CO is of specific interest in the cerebral vasculature because the combined
effects of these agents may be one of the underlying causes of mental confusion,
unconsciousness, or death in fire victims (Smith et al., 1976b).
Numerous experimental studies have shown that intoxication by cyanide compounds can
lead to damage to the brains of rats, rabbits, cats, dogs, and monkeys (for reviews see Levine
and Stypulkowski, 1959; Meyer, 1963; Brierley et al., 1976). Comatose states and deep
depression of electrical activity have been observed in a variety of species following cyanide
administration (Ward and Wheatiey, 1947; Brierley, 1975). Cyanide appeared to selectively^
damage cerebral white matter (Smith et al., 1963; Levine, 1967), but it is unclear whether
this neuropathology was due to direct effects of cyanide on the white matter, or if it was ., ,
10-95
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secondary to anoxia or ischemia. This neuropathology also may have been due to regionally
inadequate cerebral circulation during cyanide hypoxia.
The action of cyanide on the cerebral vasculature and on CMRO2 has not been studied
in any great detail under controlled conditions. Differences in methods, animal species,
dosages, failure to measure blood or tissue cyanides, lack of control in regard to other
variables such as respiration and consequently CO2, and difficulty in securing pure cerebral
venous samples have led to some inconsistencies in observations and interpretations of
cyanide and the cerebral circulation. This has been so for CO as well. McGinty (1929)
observed an increase in the outflow from the sagittal sinus of anesthetized dogs following a
small dose of sodium cyanide. Paulet (1958) observed an increase'in cerebrospinal fluid
pressure following a bolus injection of cyanide, and concluded that CBF must have increased.
Studies in cats and rabbits showed large increases in blood flow through the sagittal sinus
without any alteration in the arterio-venous O2 content difference across the blood-brain
barrier (Russek et al., 1963). Russek observed an increase in CMRO2 to 300% of control in
these experiments. He concluded that stimulation of the carotid chemoreceptors caused the
increase in CMRO2 and that the increase in ,CBF was secondary to the metabolic change.
Brierley et al. (1976) speculated that CBF decreased during cyanide administration due to
cyanide's depressive effect on the myocardium. However, he never actually measured CBF, ';•
but rather he made speculations on CBF that were based upon vascular pressure changes in
the sagittal sinus of monkeys. Aliukhin et al. (1974) also observed increases in CBF
following acute cyanide poisoning in rats.
The cerebral metabolic response to cyanide has been studied in vitro and in vivo.
McGinty (1929) observed an outpouring of lactic acid into the cerebral venous drainage
during moderate cyanide intoxication, and this was the first indication of an altered cerebral
aerobic metabolism in cyanide hypoxia. Fazekas et al. (1939) reported a decreased GMRO2
in dogs following administration of potassium cyanide, however, these workers did not
measure CBF. Doses of cyanide sufficient to decrease cerebral cytochrome oxidase activity
by 50% in rats led to increases in lactate, inorganic phosphate, and triphosphate (Albaum
et al., 1946). Olsen and Klein (1947) reported similar metabolic findings in rats and
calculated that glucose consumption must have increased to account for the rise in lactic acid.
They also discussed how the addition of cyanide to brain slices, in vitro, failed to decrease
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O2 consumption until high cyanide levels were achieved. Gasteva and Raize (1975)
demonstrated a reduction in CMRO2 with cyanide.
Early studies of the combined effects of CO and cyanide were inconclusive in describing
any interaction of these two agents (Hofer, 1926; Moss et al., 1951). Two inhalation
toxicological studies have reported no interaction between CO and cyanide with respect to
lethal-dose levels (Higgins et al.,. 1972; Yamamoto, 1976). Smith et al. (1976b), using
behavioral assessments, reported at least an additive effect of cyanide and CO on the time to
cause incapacitation and death in exercising rats. However, few studies have ever examined
the combined effects of these agents on the cerebrovasculature. Pitt et al. (1979) examined
individual and combined effects of cyanide and CO on CBF and CMRO2 because many of
the deleterious effects of the fire environment may be due to altered cerebral nervous system
function. They found that CBF increases during CO hypoxia and it also increases with
cyanide hypoxia. Cerebral O2 consumption remained unchanged until the higher levels of
either cyanide or CO were reached. These data are consistent with those previously presented
for CO. When CO and cyanide were administered simultaneously, CBF increased in an
additive manner (Figure 10-13), but significant decreases in CMRO2 occurred at the
combination of the lower concentrations (Figure 10-14). These data suggest that CO and
cyanide are physiologically additive in producing changes in CBF, but may act synergistically
onCMRO2.
Figure 10-15 (from Pitt et al., 1979) demonstrates the relationship between CBF and
CMRO2 in CO and cyanide hypoxia. Three aspects of this figure suggest that cyanide and
CO may act through similar mechanisms with respect to changes in CBF and CMRO2. First,
low doses of either agent alone produce increases in CBF that maintain CMRO2 constant.
Second, higher doses of CO or cyanide increase GBF to 200% of control while CMRO2
decreases to around 80% of control. Finally, combinations of cyanide and CO hypoxia result
in an increased CBF with a decreased CMRO2 that would be predicted on the basis of an
additive effect. Although CO binds to non-Hb proteins, including cytochrome oxidase in
vitro, it is unlikely that in vivo this binding contributes to the hypoxic effect of CO (Root,
1965). Because we demonstrated previously that the effect of CO hypoxia on the brain was
similar to an equivalent reduction in arterial Q^ content with hypoxic hypoxia, it may be that
the mechanism that mediates the increase in CBF to maintain CMRO2 relatively constant
10-97
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400.
a
•5
300 _J
200 —
O
100 —
O 1.5 /jgfmL Cyanide
01.0 /43/mL Cyanide
£ No Cyanide
10 20 30
Carboxyhemoglobin, %
40
50
Figure 10-13. Effect of cyanide (CN) and carbon monoxide (CO) hypoxia, alone and in
combination, on cerebral blood flow. Each point represents mean ± SE.
Closed circles = CO alone (19 animals), open circles = 1.0 /ig/mL blood
CN (12 animals), and open squares — 1.5 jtg/mL blood CN (7 animals).
Source: Pitt et al. (1979).
with CO and hypoxie hypoxia may be similarly affected by blocking cellular respiration with
cyanide hypoxia. The nonspeeificity of the hypoxie response suggests a common mechanism
of cerebral vasodilation with hypoxia, and it lends support to a metabolic control of cerebral
vessels although the precise mediator is unknown.
As Pitt et al. (1979) explain, there are several explanations for the loss of maintaining
CMRO2 constant when CBF increased to 200% of control, or more, for combinations of CO
and cyanide hypoxia. First, it is possible that the cortical cells themselves were damaged by
combination of cyanide and CO and were rendered incapable of utilizing the O2 and substrate
delivered. Because the observed physiological parameters returned to control when blood
cyanide and COHb levels were returned to control, the cortical cell damage was temporary
and reversible. Second, it is possible that within the brain, regional inequalities existed
10-98
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125-
100-
s
§ *M
O
50-
25 —
Q 1.5 /ug/mL Cyanide
O 1 -0 /"9/TiL Cyanide
0 No Cyanide
10 20 30 40
Carboxyhemoglobin, %
50
Figure 10-14.
Effect of cyanide (CN) and carbon monoxide (CO) hypoxia, alone and
in combination, on cerebral oxygen consumption (VO2). Each point
represents mean + SE. Closed circles = CO alone (19 animals); open
circles = 1.0 jtg/mL blood CN (12 animals); and open squares =
1.5 jtg/mL blood CN (7 animals).
Source: Pitt et al. (1979).
between the increase in CBF and the metabolic demands of the tissue. Third., it is possible
that in severe hypoxia, although the energy state of the brain may be normal and CBF
increases in an apparent adequate manner, a compensatory decrease in neuronal activity is
produced (Duffy et al., 1972). Finally, a fourth mechanism of how cyanide and CO hypoxia
could act to synergistically reduce CMRO2 is based on the characteristics of the multi-enzyme
cellular respiratory chain (Chance et al., 1970). Under normal metabolic conditions,
cerebral mitochondria! respiration is zero order with respect to O2 until mitochondria! arterial
O2 tension is less than 1 mm Hg (Chance et al., 1962). During low levels of cyanide
10-99
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Figure 10-15.
1
<5
300
250-
200-
73
8
CQ
CO Alone
O CN Alone
D CN / CO
Control
25
50 75 100
Q., , % of Control
Relationship of cerebral blood flow (CBF) to cerebral oxygen
consumption (VO2) during cyanide (CN) and carbon monoxide (CO)
hypoxia. The mean + SE of CBF (percent of control) and VO2
(percent of control) is plotted for the groups previously described.
A straight line was fitted by regression for the effects of CO or CN "
alone, and extended up to a CBF of 300% of control.
Source: Pitt et al. (1979).
hypoxia, the abundance of cytochrome oxidase (Luebbers, 1968), the ability of unblocked
respiratory chains to branch out and oxidize cyanide blocked chains, and the ability of a
multi-enzyme system to maintain a constant electron flow for a wide range of steady-state
changes in the terminal oxidase (Chance et al., 1970) enable the brain to maintain CMRO2
constant by increasing CBF. However, further reduction in O2 supply with the addition of
CO result in a further reduction in the enzyme system.
10-100
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10.4.1.6 Mechanism of Regulation of Cerebral Blood Flow in Hypoxia
Although it is clear that hypoxia produces cerebral vasodilation and an increase in CBF,
the precise mechanism by which this occurs is not clear. Hypotheses to explain this
mechanism include direct effects of O2, neurogenic mechanisms (which were referred to
earlier in this chapter), and chemical or metabolic theories. Little evidence exists concerning
the direct effects of O2 on cerebral vessels; however, there is some evidence that O2 may act
directly on the smooth muscle of cerebral vessels, with a high O2 tension leading to
vasodilation. Garry (1928) showed that spirals of carotid artery of sheep contract with high
O2 tension. This response was confirmed later by Smith and Vane (1966) and Detar and
Bohr (1968), and in addition, Detar and Bohr (1968) showed that isolated rabbit aortas
dilated when perfused with blood or saline with low O2 tension. The dependence of the
contractile response to O2 tension is explained if one assumes that O2 plays a metabolic role
within the mitochondria of smooth muscle cells. It has been documented that the mechanical
tension of some vascular smooth muscle is sensitive to altered O2 tension (in vitro); however,
Pittman and Duling (1973) have calculated that arterioles 10 /*m in diameter would be
unaffected by O2 tensions greater than 2 mm Hg. They suggested that the large-artery in
vitro experiments showing a direct relationship between smooth muscle tension and
O2 tension may be misleading because of the high 02 consumption and large diffusion
gradients of the strips. Coburn (1977) suggested the possibility that receptors sensitive to
O2 tension could exist in vascular smooth muscle but indicated that these receptors do not
appear to work through a cytochrome a3-adenosine triphosphate model. Finally, in a study
of pial vessels in vivo, Kontos et al. (1978) demonstrated that local hypoxia, administered by
application of cerebrospinal fluid containing no O2 on the surface of the brain, produced only
slight arteriolar vasodilation. This group postulated that the effects of hypoxia on cerebral
arterioles is mediated via local mechanisms because the vasodilation was 'revisrsed completely
by supplying O2 via topical application of fluorocarbons to the brain surface.
Extracellular aeidosis, secondary to cerebral lactate production, also has been suggested
to be the mechanism of cerebral vasodilation with hypoxia (Betz, 1972; SMnhoj, 1966). '
Reducing the arterial O2 tension to less than 50 mm Hg increases CBF arid the concentration
of intracellular and extracellular cerebral lactate (Siesjo and Nilsson, 1971). Wahl et al. "
(1970) suggested that cerebral metabolic acidosis affects the cerebral vascular smooth muscle
10-101
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by altering pH within the cell. Kogure et al. (1970) reported that cerebral vasodilation with
hypoxemia correlated well with cerebral cortical acidosis and concluded that hypoxia exerted
its influence secondary to the formation of parenchyma! lactate from anaerobic glycolysis.
Other results, however, have challenged this hypothesis (Borgstrom et al., 1975; Nilsson
et al., 1975; Norberg and Siesjo, 1975). These reports demonstrated that during the initial,
rapid, non-steady-state increases in CBF during hypoxia, there is only a slight increase in
lactate, or none at all. Also, this increase in CBF leads to a reduction in tissue CO2 tension
and a subsequent increase in pH. The actual measurements of cerebral parenchyma! pH show
a transient alkalotic shift of 0.02 pH units at a time when the CBF increase has reached its
maximal level. Thus, Nilsson et al. (1975) concluded that the increased blood flow must be
related to some aspect of cellular metabolism less sluggish than lactate formation.
The relationship between organ blood flow and the metabolism of that organ is an old
physiologic issue (Pfluger, 1875), and a close relationship between CBF and metabolic
by-products of the brain's interstitial fluid was proposed over a century ago (Gaskell, 1880;
Roy and Brown, 1879). One such metabolic by-product, adenosine, has been proposed to be
^
involved with metabolic increase in coronary blood flow (Rubio and Berne, 1969). Berne
et al. (1974) postulated that some aspect of adenosine metabolism may be involved in the
CBF increase with hypoxia. These investigators reported that brain adenosine levels increase
rapidly (2 to 3 s) and this results in cerebral vasodilation with cerebral ischemia. Rubio et al.
(1975) demonstrated that hypoxia increased brain adenosine levels markedly, and Winn et al.
(1981) reported a 500% increase in brain adenosine levels within 30 s of hypoxia. In
addition, Wahl and Kuschinsky (1976) showed that adenosine dilates pial arterioles when
applied to the perivascular space. These alterations in adenosine levels with hypoxia, and the
fact that adenosine causes cerebral vasodilation, support the potential role of adenosine as a
chemical link between metabolism and CBF during hypoxia; however, Wahl and Kuschinsky
(1979) point out the speculative nature of the role of this metabolite.
Other metabolic substrates, such as oxygenase, also may play a role in hypoxic
vasodilation because oxygenase inhibitors can attenuate the increase in CBF that occurs with
hypoxia (Traystman et al., 1981). Enzyme systems may play an important role in
O2 delivery to brain tissue through alterations in CBF (Harik et al., 1979; Jobsis and
Rosenthal, 1978; Sokoloff, 1978). The precise nature and location of these oxygenases is
10-102
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unclear, although Traystman et al. (1981) suggested that these receptors for hypoxia are
located close to the cerebrospinal fluid. The idea of a special O2 sensor is not new. Opitz
and Schneider (1950) proposed the existence of O2 receptors in cerebral parenchyma. Other
investigators (Bicher et al., 1973; Burgess and Bean, 1971; Mchedlishvili et al., 1976)
hypothesized that tissue O2 receptors participate in a neural feedback loop originating with
cerebral tissue to produce cerebral dilation with hypoxia. The neurogenic aspects of cerebral
circulatory control during hypoxia have been discussed earlier in this chapter, and to
summarize briefly, the prevailing opinion is that the peripheral carotid and aoitic
chemoreceptors and baroreceptors probably are not involved in the CBF response to hypoxia.
Central (brainstem) neurogenic mechanisms may be involved, however, much less is known
about these control mechanisms than for the peripheral systems. The importance of the pons
and mesencephalon in mediating the increased CBF with hypercapnia has been demonstrated
(Shalit et al., 1967). Other investigators also have demonstrated the potential involvement of
higher brain centers in the regulation of CBF (Langfitt and Kassell, 1968; Molnar and
Szanto, 1964; Stavraky, 1936), and it remains possible that these central neurogenic centers
may be involved in the CBF response to hypoxia.
Carbon monoxide can compromise tissue oxygenation in three ways: a fall in arterial
O2 content; an increase in O2Hb affinity; and theoretically, a direct cellular effect (Coburn,
1979). Arterial O2 content falls as CO occupies O2-binding sites, but when CO occupies
binding sites, the O2 affinity of the remaining sites increases (Paulson et al., 1973; Coburn,
1979; Roughton and Darling, 1944). As a result, cerebral venous O2 tension, and
presumably tissue O2 tension, decrease. Both types of hypoxia, hypoxic and CO, produce
essentially identical decreases in cerebral venous O2 tension. This reduction in cerebral
venous O2 tension could be translated into an increased CBF via some of the mechanisms
previously described (i.e., adenosine, O2 receptors, neurogenic mechanisms, etc). Because
arterial O2 tension falls only with hypoxic hypoxia, one has difficulty in ascribing changes in
CBF to alterations in arterial O2 tension. In CO hypoxia, the arterial O2 content, not
O2 tension, is reduced, thus one must consider the possibility of O2 content-type receptors,
which is unlikely. Another controversial potential effect of CO is an identifiable direct effect
of CO on cellular metabolism. If the CO/O2 tension ratio in the mitochondrion is sufficiently
high, CO can combine with cytochrome a3 (Coburn, 1979). This would prevent oxidation at
10-103
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the terminal electron transport chain and would be equivalent to a lack of molecular O2.
Whether this potential mechanism operates in vivo is unclear at the present time.
10.4.1.7 Summary
The data reviewed indicate that CO hypoxia increases CBF, even at very low exposure
levels. Cerebral O2 consumption is well maintained until levels of COHb reach upwards of
30%. The overall responses of the cerebrovasculature are similar in the fetus, newborn, and
adult animal; however, the mechanism of the increase in CBF is still unclear. In fact, several
mechanisms working simultaneously to increase CBF appear likely and these may involve
metabolic and neural aspects as well as the O2Hb dissociation curve, tissue O2 levels, and
even a histotoxic effect of CO. These potential mechanisms of CO-induced alterations in the
cerebral circulation need to be investigated further. The interaction of CO with cyanide
(additive and synergistic) on the cerebral vasculature is clear; however, the interaction of CO
with other agents and their combined effects on brain blood vessels is unknown. This also is
true for the long-term (chronic) effects of CO alone, or in combination with other agents in
low or high dose levels on the cerebral vasculature. Finally, under normal circumstances the
brain can increase its blood flow or its O2 extraction in order to compensate for a reduced
O2 environment. Whether these compensatory mechanisms continue to operate successfully
in a variety of conditions where the brain or its vasculature is compromised (i.e., stroke,'
head injury, atherosclerosis, hypertension) is unknown and requires further investigation.
10.4.2 Behavioral Effects of Carbon Monoxide
10.4.2.1 Introduction
The following is an evaluative review of the literature concerning the behavioral and
nervous system effects of elevated COHb. An effort was made to organize the findings by
subject matter, devoting a section of the review to each of several subtopics. Such an
organizational scheme is always arbitrary and is therefore occasionally strained. The
organization of the material is, however, a benefit that outweighs the disadvantages.
Extensive use is made of tables in each subtopic to help summarize the findings and
give a critique of each study. For each published report, the following information is given:
the duration of CO exposure, the range of COHb achieved, the number of subjects studied
10-104
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(n), the dependent variable studied, the authors' conclusions about effects, a comment about
the features of the study, and technical critique notes.
The technical critique notes refer to technique problems that frequently exist in studies
in the CO literature concerned with behavior. A critique code has been devised to facilitate
reference to two of the most common problems—"blinding" and multiple statistical tests
conducted on the same data base. The following paragraphs describe the problems and a
table is given to define the codes used.
One of the features of a study is the so-called blinding of subjects and experimenters to
the exposure conditions. To avoid the effects of suggestion and expectation on the part of the
subject, the subject should not be informed about his own exposure condition until after the
completion of the study (i.e., the subject should be kept "blind" regarding exposure). To
avoid unintentional bias in the handling of subjects or making unintentional suggestions to the
subjects, experimenters who deal directly with subjects also should be blind. All subjective
scoring of data should be performed blindly. An experiment in which both subjects and
experimenters were blind is called "double blind." When only subjects were blind, a single-
blind condition is said to exist. When no blinding was used, the study will be called
noriblind.
The other technical aspect of an experiment that was included in the summary, tables
involves the statistical significance test methodology that was employed. When many
individual tests are conducted on the same data set, the probability is increased that at least
one of them will be significant by chance alone. Thus, the "experiment-wise" Type I error
rate is increased (Muller et al., 1984). Studies in which data were analyzed in the above
manner will have an increased probability of reporting a significant effect even when no
effect exists in the population. This bias toward significant effect worsens with the number
of tests conducted. Statistical methods exist that can be used to test multiple hypotheses for
each data set without increased probability of false significant effects.
The two technical problems, blinding and statistical methods, are noted in the summary
tables by use of the following code letters in the column labeled "Technical Critique." If
nothing appears in the Technical Critique column, the experiment was conducted double-blind
and multiple significance testing was not done. The following list defines the code.
10-105
-------
A - No or unspecified statistical test
B - Multiple-significance tests on the same data set
C - Single-blind study
D - Nbnblind study
Examination of the summary tables reveals that many of the same references appear
repeatedly. These were instances in which the experimenters measured several variables in.
the same study. Thus, the reader should recognize that the number of experiments reported
in the literature is considerably smaller than the number of summary table entries.
10.4.2.2 Sensory Effects
Vision
Absolute Threshold. Studies of the effects of COHb on absolute visual threshold are
summarized in Table 10-9. In an experiment using four well-trained young subjects, it was
demonstrated that visual sensitivity was decreased in a dose-related manner by COHb levels
of 4.5, 9.4, 15.8, and 19.7% (McFarland et al., 1944). Various aspects of these data were
subsequently reported by Halperin et al. (1959) and McFarland (1970). Carboxyhemoglobin
elevations were accomplished by inhalation of boluses of high-concentration CO. Visual
thresholds were measured repeatedly over a 5-min period at each COHb level.
Experimenters were not blind to the exposure conditions and the subjects could have easily
deduced the conditions from the experimental design, because no air-only condition was
included to control for the effects of the testing scheme itself. Data from only one typical
subject were presented. Thresholds were measured at only one level of dark adaptation
(0.002 foot candles).
The McFarland et al. (1944) study (above) stands in disagreement with several other
studies of absolute threshold effects of COHb. An early study of dark adaptation was
reported by Abramson and Heyman (1944), in which effects were inconsistent and were not
statistically significant. Nine subjects were tested and the COHb level ranged up to 30%.
Documentation of the study was very sparse, however, so that it was difficult to consider the
study critically, but the power was apparently quite low. McFarland (1973), in a scantiy
documented article, reported that similar threshold shifts occurred at the end of a
10-106
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TABLE 10-9. EFFECTS OF CARBOXYHEMOGLOBIN ON ABSOLUTE VISUAL THRESHOLD
(— I
9
©
Exposure
Duration
(min)
7
Bolus
+ 135
18
0.5,
Elevated
COHb Range
(%) n
10.0-30.0 9
17.0 21
9.0 18
4.5-19.7 4
CO
Effect Comment
No Stimuli, methods not well specified.
No statistics given. Only one subject
at 10% COHb.
No Power for McFarland-size effect was «0.7.
Entire dark adaptation curve was
measured. Stimulus was 10.0 deg visual
angle p31 phosphor CRT with neutral
density filters.
No Measured only scotopic sensitivity.
Yes No control group for air only. Only
typical data for one subject. Tested only
at adaptation to 0.002 ft candle. Effect
was COHb-ordinal, beginning at «5%.
Technical
Critique8 Reference
A,D Abramson and Heyman
(1944)
Hudnell and Benignus
(1989)
B,C Luria and McKay (1979)
A,C McFarland et al. (1944)
Halperin et al. (1959)
McFarland (1970)
Various
Bolus
+60
6.0-17.0 27 No Smokers and nonsmokers tested, n not
given. Few methods, specifications, or
statistics, Minutes of exposure (not
given) adjusted to target COHb.
9.0-17.0 5 No Dependent variables were time to
adaptation and sensitivity after
adaptation.
A,C McFarland (1973)
von Restorff and Hebisch
(1988)
'Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-Mind conditioas and nmltiple-signiflcance tasting was not done.
-------
CO-exposure period (17% COHb) and an air-only session. Thus it is possible that the effects
reported by McFarland et al. (1944) were due to fatigue or some other time-on-task related
variable. Von Restorff and Hebisch (1988) found no dark adaptation effects on subjects with
COHb levels ranging from 9 to 17%. Luria and McKay (1979) found no effect of 9% COHb
on scotopic visual threshold.
The effect of 17% COHb (bolus administration, followed by maintenance CO level for
135 min) on the entire dark-adaptation curve was studied by Hudnell and Benignus (1989)
using 21 young men in a double-blind study. No difference between CO and air groups was
observed. A power of 0.7 was calculated for the test employed so that the conclusions are
reasonably defensible. From the above evidence, it appears that if COHb elevation to 17%
affects visual sensitivity, it remains to be demonstrated. ^
Temporal Resolution. The temporal resolution of the visual system has been studied in
the form of critical flicker frequency (CFF). In the CFF paradigm, subjects report the
frequency at which light flashes begin to appear as a continuous light. Studies of the effects
of COHb on CFF are summarized in Table 10-10. . '
Seppanen et al. (1977) reported dose-ordinal decreases of CFF for COHb values of
approximately 4.0, 6.1, 8.4, 10.7, and 12.7%. The experiment was conducted with
22 healthy subjects whose age ranged from 20 to 62 years. Carboxyhemoglobin was induced
by breathing high concentrations of CO from a Douglas bag. Subjects were blind as to the,
condition but apparently experimenters were informed. Appropriate controls for fatigue were
included and the exposure levels were randomized.
A study was reported by von Post-Lingen (1964) in which COHb levels ranged up to ,
23%. Carboxyhemoglobin was induced in 100 subjects by breathing CO-contaminated air
from a spkometer for about 7 min in a single-blind procedure. One group of subjects was
given an injection of Evipan (sodium hexobarbitone, see Reynolds and Prasad, 1982), a drug
previously shown to have produced decreases in CFF only if patients had demonstrable brain
damage. In the nondrug group, CFF was unaffected until approximately 14% COHb. In the
drug group, however, effects began at COHb levels as low as 6% and were dose proportional
up to the highest COHb value. When the drug-plus-CO study was repeated in a double-blind
10-108
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TABLE 10-10. EFFECTS OF CARBOXYHEMOGLOBED ON CRITICAL FLICKER FUSION
Exposure
Duration
(min)
Elevated
COHB Range
n
CO
Effect
Comment
Technical
Critique" Reference
60
780
65
Bolus
540
45
30
1.8-6.7 4 Yes Test specification, methods, and statistics
not.given. Effects disordinal in COHb. COHb
estimated from breath sample.
5.3b 12 - No ' Few test specifications, only brand name of
test device. .COHb estimated from exposure by
original authors.
8.9 8 No Tested with red neon lamp, 0.7" visual
angle, viewed binocularly. Luminance not
given.
12.0-17.0 5 No Tested with neon lamp, 1° visual angle,
viewed monocularly. Luminance not given.
Minutes of exposure adjusted to target COHb.
5.9-12.7 4 No Tested with red light, 1.3° visual angle,
viewed binocularly. Luminance not given.
Tested in noisy environment after CO exposure
• during sleep.
7.6-11.2 60 No No specifications for CFF test.
5.0-12.7 '22 Yes Tested with white light, 5.8° visual angle,
apparently viewed binocularly. Luminance =
50 lux. Effect was significant beginning
at 5% COHb.
7.5-17.5 17 No Tested with red neon lamp, 1° visual angle
viewed binocularly. Luminance not given.
A,D Beard and Grandstaff
(1970)
B,C Fodor and Winneke
'' (1972)
B Guest et al.
(1970)
A,D Lilienthal and Fugitt
(1946)
B O'Donnell et al.
(1971a)
B Ramsey (1973)
B,C Seppanen et al.
(1977)
B,C Vollmeretal.
(1946)
-------
TABLE 10-10 (cont'd). EFFECTS OF CARBOXYHEMOGLOBIN ON CRITICAL FLICKER FUSION
Exposure
Duration,
(min)
7
Elevated
COHB Range CO
(%) n Effect Comment
4.0-23.0 100 Yes No effects in poorly described double-blind
part of same study (n= 15). Effects of COHb
ordinal beginning at approximately 14% and at
approximately 6% with Evipan drug challenge.
Tested with green light, 2" visual angle.
Intensity of light, not frequency, was adjusted to
produce fusion.
Technical
Critique*
B,C
Reference
von Post-Lingen
(1964)
300 10.0° 18 No Few test specifications, only brand name of A,C Winneke (1974)
test device.
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
"The original authors estimated COHb from expired air.
The original authors estimated COHb from exposure using Coburn et al. (1965).
-------
replication (n=15), no effects were seen. The latter replication study was given .only one
paragraph in the report and thus it is not clear exactly what was done.
Beard and Grandstaff (1970) reported significant effects on CFF in an earlier study in;
which four subjects had been exposed to CO levels of 50, 150, or 250 ppm for 1 h. •
Carboxyhemoglobin was estimated by the authors to,have reached 3.0, 5.0, arid 7:5%, '
'• , •
respectively, by the end of the exposure. Documentation was extremely sparse and with only
four subjects, power was probably low. Even though the elevated COHb groups had ; •
decreased CFF, the results were not dose ordinal. There is a comparatively large amount of
literature published before the Seppanen et al. (1977) article, in which the effect of elevated
COHb on CFF was tested. In none of the earlier studies was CFF found to be affected, even
though much higher levels of COHb were tried. The studies and their .;maxiifeurn COHb
levels were Fodor and Winneke (1972), 7.5%; Guest et;al. <1970j; 8:9?%; Lilienthal and ,;
.* - ."•'."•-' V / I ' • , '
Fugitt (1946), 15.4%; O'DonneU et al. (1971a), 12.7%; Ramsey (1973)^11.2%; Vollmef •
et al. (1946), 17.5%; and Winneke (1974), 10.0%. To be sure, there was much variation in
size of the subject group, method, and experimental design among-the above studies, but no
pattern emerges as to why the Seppanen et al. (19,77), Beard and Grandstiaff ,(1970), and von
Post-Lingen (1964) studies found significant effects when the others did riot. It is noteworthy
that the studies reporting significant effects were all concluded in a single- or npnblind
manner. '; •".;•.?: • "; '••-.• .• ; '••• '-•
"'•'.! ' ~
Miscellaneous Visual Functions. A number of researchers reported the results of
experiments in which visual parameters other than absolute threshold or CFF were measured
as part of a battery of tests. Many of these experiments studied a large group ;'pf subjects.
Table 10-11 summarizes these studies. ; ,.
Beard and Grandstaff (1970) reported a study in which four subjects were exposed to;
CO sufficient to produce estimated (by the authors) COHb levels of 3.0, 5.0, and 7.5.%. ,The
measurements made were CFF (see above), brightness-difference thresholds, visual acuity,-
v . • .
and absolute threshold. Data for the latter variable were unreliable and were not reported.
Dose-related impairments in acuity and brightness-difference sensitivity were reported. The'
scant documentation of methods, plus the low number of subjects, make the results difficult
to evaluate. . :v- : I• '-'f - ?1 "• •<'• :;
-------
TABLE 10-11. EFFECTS OF CARBOXYHEMOGLOBIN ON MISCELLANEOUS VISUAL FUNCTIONS
Exposure
Duration
(min)
60
150
780
60
Bolus
Various
45
45
390
30
Elevated
COHb Range
(*)
3.0-7.5
7.3°
5.3°
27.0-41.0
*
17.0
6.0-17.0
5.0
7.6-11.2
5.4
4.0-12.7
n
4
42
12
5
21
27
20
60
6
22
Dependent
Variable
Brightness
difference and
OFF
Pattern
Pattern
See
comment
Acuity and
motion
Peripheral
vision
Brightness
and depth
Brightness
and depth
Brightness
discrimination
Perceptual
speed
CO
Effect
Yes
Yes
Yes
No
No
No
Yes
No
Yes
No
Technical
Comment Critique* Reference
Test specification, methods, and statistics not given.
Effects disordinal in COHb (both variables). COHb
estimated from breath sample.
Pattern displayed for unspecified short time. COHb
estimated from breath sample.
Pattern displayed for 0. 1 s. COHb estimated by
original authors from exposure.
Tested detection of dim objects in glare and
approach/recession comments of objects. No
specifications or statistics given.
Stimulus was 10' p 31 phosphor CRT. Tested both
photopic and scotopic.
Few methods, specifications, or statistics. Minutes
of exposure not given, adjusted to target COHb.
No specification for tests. Only brightness
discrimination affected.
No specifications for tests. Results did not support
previous study by Ramsey (1972).
None.
Test not well specified.
A,D
B,C
B,G
A,D
„
A,C
B,C
B
D
B,C
Beard and Grandstaff
. (1970)
Bender et al. (1972)
'
Fodor and Winneke
(1972)
Forbes et al. (1937)
Hudnell and Benignus
(1989)
McFarland (1973)
Ramsey (1972)
Ramsey (1973)
Salvatore (1974)
Seppanen et al. (1977)
-------
TABLE 10-11 (cont'd). EFFECTS OF CARBOXYHEMOGLOBIN ON MISCELLANEOUS VISUAL FUNCTIONS
Exposure
Duration
(min)
- Variable
up to
1,440
150-300
5
90-120
Bolus
Elevated
COHb Range
Continuous
distribution
Continuous
distribution
up to 20.0
7.5-17.5
2,0
5.6°
Dependent
n Variable
11 'See
comment
27 Defect
detection
17 Red field
• size .
15 Brightness
discrimination
50 See
comment
CO
Effect
No
No
No
Yes
No
Comment
Little documentation. Tested acuity, depth,
color, and phoria using clinical instruments.
Subject inspected small parts. Not well
specified.
Tested with perimeter bar and red sample patch.
Tested intensity matching with red, green, and
white. t . . ,
Poor documentation. Tested target detection in
"dim" light and during glare, recovery after
glare, and depth.
Technical
Critique,,
B
B,C
B
B
Reference
Stewart et al. (1970)
Stewart et al. (1975)
Vollmer et al. (1946)
Weir et al. (1973)
Wright et al. (1973)
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
bValues of COHb were not reported by the original authors. Values given in the table were estimated by the present author using exposure parameters and the
method of Coburn et al. (1965).
The original authors estimated COHb from expired air.
-------
Five other reports of significant visual function effects by COHb elevation are extant.
Two of the studies (Bender et al., 1972; Fodor and Winneke, 1972) reported that ;
tachistoscopic pattern detection was impaired by COHb levels of 7.3 and 5.3%, respectively.
Weir et al. (1973), Ramsey (1972), and Salvatore (1974) reported that brightness
discrimination was adversely affected by COHb levels of 6 to 20%.
Tests of visual function after COHb elevation conducted by other authors have been
uniformly nonsignificant. Table 10-11 summarizes these data. Especially noteworthy are
studies by Hudnell and Benignus (1989) and Stewart et al. (1975), both of which found no ;
acuity effects as reported by Beard and Grandstaff (1970). Brightness discrimination was
similarly not found to be affected (Ramsey, 1973), in contradiction with the reports of others.! „>
The latter study is especially interesting in that it represents a failure to replicate an earlier '
study by the same author (Ramsey, 1972). The first of the pair of studies by Ramsey was •
conducted in a single-blind manner, the second was double blind. ' ,:
The most thorough modern tests of visual function were performed by Hudnell and -
Benignus (1989), who tested absolute threshold (see,above), acuity, and motion detection
with COHb levels of 17% and found no effects due to COHb. The acuity and motion .
detection were tested at both scotopic and photopic levels.
It would appear that the results of studies of the effects of COHb elevation on .;
miscellaneous visual function are not supportive of significant effects. Results that were ;
significant in two studies (Beard and Grandstaff, 1970; Weir et al., 1973) were contradicted
by other reports using relatively large groups of subjects. . One author (Ramsey, 1972, 1973)
failed to confirm his own findings. "
Audition
Surprisingly little work has been done concerning the effects of COHb on auditory
processes. Table 10-12 is a summary of the studies. Stewart et al. (1970) reported that the ; -;:~
audiogram of subjects exposed to as high as 12.0% COHb was not affected. Haider et al. ';
(1976) exposed subjects to a 105 dB, one-octave bandwidth random noise (center frequency
of 2 kHz) for 15 min while COHb level was elevated to 13%. Under continued COHb
elevation, the temporary threshold shifts (TTSs) were measured after noise cessation. No..'- ;';
effects of COHb on TTS were observed. Guest et al. (1970) tested the effects of elevated;" •"
10-114
-------
TABLE 10-12. EFFECTS OF CARBOXYHEMOGLOBIN ON MISCELLANEOUS AUDITORY FUNCTIONS
Exposure
Duration
(min)
65
120-240
Variable up
to 480
Elevated
COHb Range
(*)
, 8.9
3.0-13.0
Continuous
distribution
up to 12.0
Dependent
n Variable
8 Flutter
fusion
20 Temporary
threshold
shift
11 Audiogram
CO
Effect
No
No
No
Comment
Auditory flutter fusion was measured
by rapid interruption of white noise,
varying frequency of interruption until
continuous sound occurred.
Measured temporary threshold shift
after exposure to 105 dB noise.
Little documentation of procedure or
results.
Technical
Critique"
B
A
B
Reference
Guest et al. (1970)
Haider et al. (1976)
Stewart et al. (1970)
o
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
-------
COHb (8.9%) on auditory flutter fusion and found no significant effect. The flutter fusion
test is analogous to CFF in vision and was tested by having the subject judge the rate at
which an interrupted white noise became apparently continuous. From these data it would
appear that the functioning of the auditory system is not particularly sensitive to COHb
elevation, but little research has been done.
10.4.2.3 Motor and Sensorimotor Performance
Fine Motor Skills
In a single-blind study, Bender et al. (1972) found that manual dexterity and precision
(Purdue pegboard) were impaired by 7% COHb. Winneke (1974) reported that hand
steadiness was affected by 10% COHb, but no supportive statistical test was presented.
Similar motor functions were evaluated by a number of other investigators and were
found not to be affected, even at higher COHb levels. Table 10-13 summarizes the
literature. Vollmer et al. (1946) reported that 20% COHb did not affect postural stability.
O'Donnell et al. (1971b) used the Pensacola Ataxia Battery to measure various aspects of
locomotion and postural stability. Subjects with 6.6% COHb were not affected. Stewart
et al. (1970, 1975) tested the ability of subjects to manipulate small parts using the Crawford
collar and pin test and screw test, the AAA hand-steadiness test and the Flanagan
coordination test. Carboxyhemoglobin levels up to 15% had no effect on any of the
measures. Two subjects were taken to 33% and 40% COHb, however, and in these subjects,
the collar and pin performance was impaired and the subjects reported hand fatigue. Manual
dexterity (Purdue pegboard), rapid precision movement (Purdue hand precision), and static
hand steadiness (pen in hole) and tapping tests were not affected by COHb levels of
approximately 5.3% (Fodor and Winneke, 1972). Wright et al. (1973) reported that hand
steadiness was not affected by COHb levels of 5.6%. Weir et al. (1973) found no effects of
14% COHb on tapping, star tracing, and rail walking. Mihevic et al. (1983) discovered no ',
effect on tapping when the task was performed alone or simultaneously with an arithmetic
task. Finally, Seppanen et al. (1977) demonstrated that tapping speed was unaffected by
12.7% COHb. Most of the above nonsignificant studies used a moderate-to-large number of.,
subjects. The overwhelming evidence hi the area of fine motor control indicates that COHb
levels below approximately 20% (the highest level tested) do not produce effects.
10-116
-------
TABLE 10-13. EFFECTS OF CARBOXYHEMOGLOBIN ON FINE MOTOR SKILLS
Exposure
Duration ."
(nan.)
150
780
150
180
30
Variable up
to 480 .
9
"-* Variable up to
-------
Reaction Tone
Table 10-14 summarizes the literature with respect to the effects of elevated COHb on
reaction time. Of the 11 experiments that studied reaction time, only one reported a
significant result (Weir et al., 1973), and that effect occurred only at 20% COHb. A number
of the nonsignificant effects were from studies using a large number of subjects. The
pervasive finding that COHb elevation does not affect reaction time is especially impressive
because of the wide range of COHb levels employed (5.0 to 41.0%).
Traddng
Tracking is a special form of fine motor behavior 'and hand-eye coordination that
requires a subject to either follow a moving target or compensate for a moving target's
motion by manipulation of a lever, for example. The literature on tracking is summarized in
Table 10-15. Of the 11 studies on the topic, 4 reported significant effects and 1 of those
found effects only at 20% COHb. The matter is more complicated, however, and the
literature in the area offers some clues to the reasons for the diversity among the reports.
O'Donnell et al. (1971a,b) used critical instability compensatory tracking in which the
task was to keep a meter needle centered. Simultaneous performance of detection tasks also
was required in one of the studies. No effects were demonstrated for COHb levels as high as
12 to 13%. The critical instability tracking task also was used by Gliner et al. (1983) in
conjunction with peripheral light detection. Carboxyhemoglobin levels up to 5.8% had no
effect on performance. Pursuit rotor tracking also was reported to be unaffected at
5.3% COHb (Fodor and Winneke, 1972). Weir et al. (1973) reported that pursuit rotor
performance was slightly affected beginning at 20% COHb. In a 1988 study, Bunnell and
Horvath used a two-dimensional tracking task in which the stimulus was presented on a
cathode ray tube and was controlled with a joystick. No effect of COHb or exercise or a
combination of the two was seen for COHb levels up to 10.2%. Schaad et al. (1983)
reported that pursuit and compensatory tracking were not affected by COHb of 20% even
during simultaneous performance of monitoring tasks.
In a pair of careful studies of different design, Putz et al. (1976, 1979) studied
compensatory tracking by having the subject try to keep a vertically moving spot in the center
of an oscilloscope screen. The tracking was performed while the subject also did a
10-118
-------
TABLE 10-14. EFFECTS OF CARBOXYHEMOGLOBIN ON REACTION TIME
o
Exposure
Duration
(rain)
,780
60
210
18
Various
45
45
20
Variable up
to 480
90-120
300
Bolus
Elevated
COHb Range
(%)
5.3 •
27.0-41.0b
5.3
9.0
6.0-17.0
5.0
4.6-11.2
7.6
Continuous
distribution '
up to 12.0
7.0-20.0
10.0°
5.6°
n
12
• 5
55'
18
27
20
60
7
11
15-25
18
50
Type
Simple and
choice
Simple
Choice
Simple and
choice
Choice
Choice
Choice
Simple
Choice
Choice
Simple and
. choice
Simple
CO
Effect
No
No
No '
No
No
No
No
No
No
Yes
No
No '
Comment
COHb estimated by original authors from exposure.
Brake-reaction time in auto simulator. No statistics
given.
Both young (n=33) and elderly (n=22) subjects.
Average age was 22.8 years for young subjects and
68,7 years for elderly subjects.
None.
Few methods or statistics. Minutes of exposure not
given, adjusted to target COHb.
None.
None.
Tested in auto simulator. Task was to press foot
pedal as quickly as possible.
None.
Effects were only seen in the 20% COHb group.
None.
None.
Technical
Critique*
B,C
A,D
B,C
A,C
B»C
B
B,C
B
B
A,C
B
Reference
Fodor and Winneke
(1972)
Forbes et al. (1937)
Harbin et al. (1988)
Lima and McKay
(1979)
McFarland (1973)
Ramsey (1972)
Ramsey (1973)
Rummo and Sarlanis
(1974)
Stewart et al. (1970)
Weiretal. (1973)
Winneke (1974)
Wright et al. (1973)
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
"The. original authors estimated COHb from expired air.
The original authors • estimated COKb from exposure using Cpburn et al. (1965). • .
-------
TABLE 10-15. EFFECTS OF CAKBOXYHEMOGLOBIN ON TRACKING
\Exposure
Duration
\ (min)
240
Bolus +
240
Bolus +
55
780
150
540
i—*
o
£ 180
O
240
240
270
90-120
Elevated
COHb Range
8.2
5.6-17.0
7.0-10.0
5.3b
5.8
5.9-12.7
3.0-12.4
3.0-5.1
3.5-4.6
20.0
7.0-20.0
n
22
74
15
12
15
4
9
30
30
10
15-25
Type
Compensatory
Compensatory
Compensatory
Pursuit rotor
Compensatory
Compensatory
Compensatory
Compensatory
Compensatory
Pursuit and
compensatory
Pursuit
CO
Effect
Yes
No
No
No
No
-
No
No
Yes
Yes
"NO
Yes
Comment
CRT display with simultaneous monitoring,
same task as Putz et al. (1976, 1979).
CRT display with simultaneous monitoring,
same task as Putz et al. (1976, 1979).
Two-dimensional tracking test performed for
9 min using CRT and joystick.
None.
Critical instability method using a line on a
CRT screen.
Task was to keep meter needle centered while
monitoring other meters and lights. Tested in
noisy environment. CO exposure during
sleep.
Critical instability method using a meter needle
centering. Noisy environment.
CRT display with simultaneous monitoring.
Significant at 5.1% COHb only.
CRT display with simultaneous monitoring.
Significant at 4.6% COHb only.
Light-monitoring and arithmetic tasks
performed simultaneously.
No consistent effects until 20% COHb.
Technical
Critique"
C
B,C
C
B
B
B,D
B
Reference
Benignus et al. (1987)
Benignus et al. (1990a)
Bunnell and Horvath
(1988)
Fodor and Winneke
(1972)
Gliner et al. (1983)
O'Donnell et al.
(1971a)
O'Donnell et al.
(1971b)
Putz et al. (1976)
Putz et al. (1979)
Schaad et al. (1983)
Weir et al. (1973)
"Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
The original authors estimated COHb from exposure using Peterson and Stewart (1970).
-------
light-brightness detection task. In both studies, tracking was significantly affected by COHb
levels of 5%. The fact that both studies demonstrated significant results despite differences in
experimental design lends credibility to the finding. Additional credibility was gained when
the Putz et al. (1976) study was replicated with similar results by Benignus et al. (1987).
The consistency of the compensatory tracking results in the Putz et al, (1976) protocol
was not continued when Benignus et al. (1990a) attempted to demonstrate a dose-effect
relationship using the same experimental design. In the latter study, independent groups were
exposed to CO sufficient to produce COHb levels of control, 5, 12, and 1.7% COHb.
Carbon monoxide was administered via Douglas bag breathing and then COHb was
maintained by low-level CO in room air. A fifth group was exposed to CO in the chamber
only and this group served as a positive control because it was treated in exactly the same
ways as the subjects in Putz et al. (1976) and in Beningus et al. (1987). No significant
effects were demonstrated on tracking in any group. The means for the tracking error were
elevated in a nearly dose-ordinal manner but not to a statistically significant extent.
At present there is no apparent reason for the lack of consistency among the reports of
tracking performance. The largest study, with the widest dose range (Benignus et al.,
1990a), appears to be the strongest indicator of no significant effects of COHb elevation.
However, it is difficult to ignore the several other studies that were controlled well and did
demonstrate significant effects. At this point the best summary seems to be that COHb
elevation produces small decrements in tracking that are sometimes significant. The possible
reasons for such high variability are unclear. Benignus et al. (1990b) discussed the issues in
a speculative manner. The latter article will be reviewed later in the present document.
10.4.2.4 VigHance
A dependent variable that is possibly affected by elevated COHb is the performance of
extended, low-demand tasks characterized as vigilance tasks. Because of the low-demand
characteristic of vigilance tasks, they are usually of a single-task type. Table 10-16 is a
summary of the literature on the subject. Of the eight reports, four reported significant
.effects. Despite the seemingly greater unanimity in this area, it is noteworthy that for each
report of significant effects, there exists a failed attempt at direct replication.
10-121
-------
TABLE 10-16. EFFECTS OF CAMBOXYHEMOGLOBIN ON VIGILANCE
1— 1
9
i— »
to
Exposure
Duration
(min)
120
780
120
210
120-240
135
Bolus
+60
300
Elevated
COHb Range
4.8
5.3b
3.0-7.6°
6.0-12.0
3.0-13.0
2.3-6.6
5.0
10. Od
n
10
12
20
20
20
15
18
18
Type
Light
White noise
Tone
Click
Tone
Light
Light
White noise
CO-
Effect
No
Yes
Yes
No
Yes
Yes
No
No'
Comment
None.
Effect disordinal in COHb.
,
Effects were significant at 3% COHb and increased^
with dose. , • ,.
None.,
Two experiments were reported, one gave effect at
approximately 7.6 % COHb and the other gave no
effect at 13%. No data presented, only
conclusions.
No effect at 2.3% COHb.
None. ; , ,
None. ' ' ; .
Technical
Critique*
B,C
A,D
B
A
C
A,C
Reference
Christensen et al.
(1977)
Fodor and Winneke
(1972)
Groll-Knapp et al.
(1972)
Groll-Knapp et al.
(1978)
Haider etal. (1976)
Horvath et al. (1971)
Roche et al. (1981)
Winneke (1974)
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
"The original authors estimated COHb from exposure using Peterson and Stewart (1970).
The original authors estimated COHb from expired air.
The original authors estimated COHb from exposure using Coburn et al. (1965).
-------
Horvath et al. (1971) reported a significant vigilance effect at 6.6% COHb. A second
study, conducted in the same laboratory (Christensen et al., 1977), failed to find significant
effects of 4.8% COHb on the same task. To be sure, the second study used slightly lower
COHb levels, but the means left no suggestion of an effect. Roche et al, (1981) from the
same laboratory reported that performance of the same task after a bolus exposure was used
to produce 5% COHb was not affected.
Fodor and Winneke (1972) reported a study in which 5.3% COHb significantly
impaired performance of a vigilance task. The same task and protocol were tried again in the
same laboratory (Winneke, 1974). In the replication attempt, no significant effects were
found, even for COHb levels up to 10%.
Groll-Knapp et al. (1972) reported dose-related significant effects of COHb ranging
from estimated values of 3 to 7.6%. Effects were large, but apparently the study was not
blind. Haider et al. (1976) reported similar effects at low COHb levels but not at higher
levels. The authors have twice mentioned failures to replicate the results (Haider et al.,
1976; Groll-Knapp et al., 1978). A similar experiment using a different stimulus failed to
produce significant effects at 12% COHb (Groll-Knapp et al., 1978).
The fact that all replication attempts for each of the reported significant effects of
COHb on vigilance have failed to verify the original reports is evidence for some unreliability
or the operation of unknown and uncontrolled variables. That the nonverifications were
conducted by the original researchers, as well as by others, makes the case for unreliability
even more convincing. If vigilance is affected by COHb elevation, a convincing
demonstration remains to be made. Perhaps a case can be made that behavioral effects of
COHb levels below 20% are present in the exposed population, but they are probably small
and, therefore, difficult to reliably demonstrate (Benignus et al., 1990b).
10.4.2.5 Miscellaneous Measures of Performance
Continuous Performance
Continuous performance is a category of behavior that is related to vigilance. The
difference is that many tasks that are performed over a long period of time are more
demanding and involve more than simple vigilance. Sometimes the continuous performance
tasks are not performed for a sufficiently long period of time to involve decrements in
10-123
-------
vigilance or are interrupted too frequently. Table 10-17 is a summary of the literature
regarding the effects of COHb on continuous performance.
Putz et al. (1976, 1979) reported that monitoring performed simultaneously with
tracking was impaired at COHb values as low as 5%. In a replication attempt of the Putz
et al. studies, Benignus et al. (1987) failed to find any effects of approximately 8% COHb.
O'Donnell et al. (1971a) also failed to find effects of COHb on a monitoring task performed
simultaneously with tracking. Schaad et al. (1983) found no effects on monitoring
simultaneously with tracking even when COHb was 20%. Gliner et al. (1983) reported that
> •• i -• .
signal detection was affected by 5.8% COHb when performed singly, but not when
performed simultaneously ,with tracking. The latter results are in conflict with Putz et al.
(1976, 1979).
Insogna and Warren (1984) reported that the total game score on the performance of a
multitask video game was reduced by COHb levels of 4.2%. Separate task scores were not
collected. Schulte (1963) reported that letter, word, and color detection tasks were dose-
ordinaUy impaired by COHb levels of as low as 5% and ranging up to 20%. Reported
COHb levels were at considerable variance with values expected from the exposure
parameters (Laties and Merigan, 1979). Benignus et al. (1977) reported that 8.2% COHb did
not effect a numeric monitoring task.
Again, there is disturbing lack of replicability in the literature. The two most credible
studies showing effects of COHb on continuous performance (Putz et al., 1976, 1979) were
not verified by Benignus et al. (1987). In the latter study, the tracking effects of the Putz
et al. work were verified. Similar studies of monitoring during tracking (O'Donnell et al.,
1971a; Schaad et al., 1983; Gliner et al., 1983) also reported no effects of COHb, even with
levels of up to 20%. It seems necessary to suspend judgment regarding the continuous
performance results until further data and understanding are-available. Perhaps the best
judgment is to hypothesize small effects.
Time Estimation
In 1967, Beard and Wertheim reported that COHb produced a dose-related decrement in
single-task time estimation accuracy beginning at 2.7%. Various versions of the same task
were tested by others (see Table 10-18) with COHb levels ranging up to 20% without effects
10-124
-------
TABLE 10-17. EFFECTS OF CARBOXYHEMOGLOBIN ON CONTINUOUS PERFORMANCE
Exposure
Duration
(min)
240
200
150
120
540
240
240
270
?
Elevated
COHb Range
(96)
8.2
4.6-12.6
5.8
2.1-4.2
5.9-12.7
3.0-5.1
3.5-4.6
20.0
0-20.0
n.
22
52
15
9
4
30
30
10
49
Type
Light
Numeric
display
Light
Complex
target
detection
Meters and
lights
Light and
tone tasks
Light and
tone tasks
Light
monitoring
Letter,
word, and
color
detection
CO
Effect
No
No
Yes
Yes
No
Yes
•Yes
No
Yes
Comment
Light monitoring simultaneously with tracking.
Task was to detect numerals of unmatched parity in
a series of three.
Same task as Putz et al. (1976, 1979) but under one
condition performed without tracking. Only the
latter condition was affected.
Video game. Targets tracked and "shot down. "
\
Monitoring meters and lights while tracking.
Light monitoring simultaneously with tracking.
Tone monitoring as separate task. Only light tasks
affected. No effect at-3.0% COHb.
Light monitoring simultaneously with tracking.
Tone monitoring as separate task. Both light and
tone task affected. No effect at 3.5% COHb.
Performed simultaneously with tracking.
COHb values larger than expected asymptotic
value. All values affected, even for low COHb.
Technical
Critique" Reference
Benignus et al. (1987)
Benignus et al. (1977)
C Gliner et al. (1983)
C Insogna and Warren
(1984)
B O'Donnell et al.
(1971a)
Putz et al. (1976)
Putzetal, (1979)
B,D Schaad et al. (1983)
B,C Schulte (1963)
Technical problems: A=no or unspecified statistical tests, B=rnultiple-significance tests on the same data, C=single-blind study, D=nonblmd study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
-------
TABLE 10-18. EFFECTS OF CARBOXYHEMOGLOBIN ON TIME ESTIMATION
o
i—i
ts>
Exposure
Duration
(min)
120
180
120
Variable up
to 1,440
150-300
90
2
Elevated
COHb Range
(*)
2.7-12.5"
3.0-12.4
3.7-7.8
Continuous
distribution
up to 12.0
Continuous
distribution
up to 20.0
20.0
2.0-8.0°
n
18
9
13
11
27
15
13
Type
Duration
discrimination
Duration and
time
Duration
discrimination
Duration
discrimination
See comment
Duration
estimation
Duration
discrimination
CO
Effect
Yes
No
No
No
No
No
No
Comment
Effects were COHb ordinal beginning at
approximately 2.7% COHb.
Tone duration discrimination and time interval
estimation. Noisy environment.
Replication of Beard and Wertheim (1967).
Tone duration compared to light duration.
Used duration discrimination, time estimation,
and Marquette test.
Various tone duration judgments were used.
Results of three experiments.
Technical
Critique*
B,C
B
B
B
D
Reference
Beard and Wertheim
(1967)
O'Donnell et al.
(1971b)
Otto et al. (1979)
Stewart et al. (1970)
Stewart et al. (1975,
1973b)
Weir et al. (1973)
Wright and Shephard
(1978b)
Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nonblind study. If no
technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
bCOHb values were not reported by the original authors. Values given in the table were estimated by the present authors using exposure parameters and the
method of Coburn et al. (1965).
The original authors estimated COHb from expired air. '
-------
being demonstrated (Stewart et al., 1970, 1975, 1973b; O'Donnell et al., 1971b; Weir et al.,
1973; Wright and Shephard, 1978b). An exact replication, which also did not find
significant results, was conducted by Otto et al. (1979). It seems safe to assume that time
estimation is remarkably impervious to elevated COHb.
Cognitive Effects
Table 10-19 is a summary of the literature concerning the effects of COHb' elevation on
the performance of cognitive tasks. Five of the 11 experiments that have been reported found
cognitive effects of COHb. Bender et al. (1972) reported effects of 7.3% COHb on a variety
of tasks. Groll-Knapp et al. (1978) reported memory to be affected after exposure to CO
during sleep (11% COHb), but a very similar study performed by the same group later found
no effects of 10% COHb (Groll-Knapp et al., 1982). Arithmetic performance was affected
slightly in a non-dose-ordinal manner when a simultaneous tapping task was performed
(Mihevic et al., 1983). Schulte (1963) reported a dose-ordinal effect on arithmetic
"performance beginning at 5% and ranging to 20% COHb. Carboxyhemoglobin levels in the
latter study were at considerable variance with expected values from the exposure parameters
(Laties and Merigan, 1979). Similar variables were tested by others, sometimes at higher
levels of COHb and with relatively large groups of subjects, without finding effects
(O'Donnell et al., 1971a; Stewart et al., 1975; Haider et al., 1976; Groll-Knapp et al., 1978;
Schaad et al., 1983). The conclusions are, at best, equivocal. ,
A recent study by Bunnell and Horvath (1988) utilized a wide range of cognitive effects
involving short-term memory, ManiHn rotation, Stroop word-color tests, visual search, and
arithmetic problems (the latter as part of a divided attention task performed simultaneously
with tracking). Carboxyhemoglobin was formed by bag breathing followed by a CO level in
room air designed to maintain a constant COHb level. Subjects were exercised at either 0,
35, or 60% of VO2 max before cognitive tests were performed. The Stroop test
performance was slightly but significantly decreased by both 7 or 10% COHb by the same
amount but exercise had no effect. The authors suggested that negative transfer effects
(difficultly in reversing instructional sets) were responsible for the decrement. Visual
-" s.
searching improved for both COHb levels at rest and at medium exercise. At the high
exercise level, however, COHb produced dose-ordinal impairments in performance. The
10-127
-------
TABLE 10-19. EFFECTS OF CARBOXYHEMOGLOBIN ON MISCELLANEOUS COGNITIVE TASKS
to
oo
Exposure
Duration
(min)
150-300
>55
210
410
480
120-240
150
540
270
?
150-300
Elevated
COHb Range
(%)
7.3"
7.0-10.0
6.0-12.0
11.0°
10.0
3.0-13.0
5.5
5.9-12.7
20.0
0.0-20.0
Continuous
distribution
up to 20.0
n
42
15
20
10
20
20
16
4
10
49
27
Task
Digit span,
nonsense syllables,
intelligence test
Memory, Stroop
test, visual search,
and arithmetic
Arithmetic,
nonsense syllables,
mood scale
Memory, mood
Verbal learning
and memory
Attention,
memory,
arithmetic
Arithmetic
Arithmetic
-Arithmetic
Arithmetic
Arithmetic
CO
Effect
Yes
Yes
No
Yes
No
No
Yes
No
No
Yes
No
Comment
Some aspect of each declared affected. COHb
estimated from breath sample.
Stroop test affected in non-dose-ordinal
manner. Visual search affected interactively
by CO and exercise.
None.
Only memory declared affected. Exposure
during sleep.
Tested before and after exposure. Exposure
during sleep.
None.
Effect was present only during multiple-task
performance and was not dose ordinal.
Tested in noisy environment.
Performed simultaneously with tracking.
COHb values larger than expected asymptotic
value. Significant effects even at low COHb.
None.
Technical
Critique*
B,C
C
B
B
B
A
C
B
B,D
B,C
Reference
Bender et al. (1972)
Bunnell and Horvath
(1988)
Groll-Knapp et al. (1978)
Groll-Knapp et al. (1978)
Groll-Knapp et al. (1982)
Haider et al. (1976)
Mihevic et al. (1983)
O'Donnell et al. (1971a)
Schaad et al. (1983)
Schulte (1963)
Stewart etal. (1975)
"Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D—nonblind study. If no
technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
"The original authors estimated COHb from expired air. ,
The original authors estimated COHb using the Coburn, Forster, and Kane equation. (Coburn et al. 1965).
-------
authors conjectured that hypoxic depression of cortical function interacted with hypoxic stress
and exercise stress to produce the effects.
Most of the data on cognitive effects of COHb elevation are not sufficiently consistent
to consider. The study by Bunnell and Horvath (1988), however, is suggestive of potentially
important effects of interactions of COHb and exercise* Before any conclusions may be
drawn about the results, the study should be replicated and expanded.
10.4.2.6 Automobile Driving
Complex behavior, in the form of automobile driving, has been tested a number of
times for effects of COHb elevation. Not only is automobile driving potentially more
sensitive to disruption because of its complexity, but it is also an inherently interesting
variable because of its direct applicability to nonlaboratory situations. The well-practiced
nature of the behavior, on the other hand, may make performances more resistant to
disruption. The complexity of the behavior also leads to methodological difficulties.
Attempting to exhaustively measure the complex behaviors usually leads investigators to
measure many dependent variables. Statistically analyzing a large number of variables in a
defensible way requires many subjects and leads to greater expense.
Table 10-20 is a summary of the studies of automobile driving as affected by COHb.
t.
In an early study by Forbes et al. (1937), using only five subjects, steering accuracy in a
simulator was investigated with COHb levels of up to 27.8%. No effects were demonstrated.
A sparsely documented experiment by Wright et al. (1973), using 50 subjects with 5.6%
COHb, tested a number of functions of simulator performance but found no effects. Weir
et al. (1973) performed an experiment with actual automobile driving on a highway in which
a great number of variables were measured and tested. None of the variables were reliably
affected until COHb exceeded approximately 20%. Wright and Shephard (1978a) failed to
find effects of 7% COHb on driving. In the latter study, the authors reported effects, but
only after misapplication of the chi-square test. The only effect on driving at a lower COHb
level (7.6%) was reported by Rummo and Sarlanis (1974), who found that the ability to
follow another car at a fixed distance was impaired.
The difference between the experiments of Rummo and Sarlanis (1974) and Weir et al.
(1973) is troubling. Both measured following distance, but only the experiment employing
10-129
-------
TABLE 10-20. EFFECTS OF CARBOXYHEMOGLOBIN ON AUTOMOBILE DRIVING TASKS
o
I
t-i
o
Exposure
Duration
(min)
60
20
90-120
Elevated
COHb Range
(«)
27.0-41.0
7.6
7.0-20.0
n
5
7
12
Task
Steering accuracy
Steering wheel
reversals and
following
distance
See comments
CO
Effect
No
Yes
Yes
Comment
In auto simulator (unspecified).
Only following distance was affected.
Tested in auto simulator.
Instrumented automobile driven on
Technical
Critique11
A,D
B,C
B
Reference
Forbes et al. (1937)
Rummo and Sarlanis
(1974)
Weir et al. (1973)
Bolus
Bolus
5.6"
7.0
50 See comments No
10 Brake-reaction No
time
highway. Many measures of control
functions plus measures of driving
stability and information processing
load were utilized. The latter was
affected at 20% but not reliably below
that. Authors debated functional
importance of findings.
. Poor documentation. Tested automobile
simulator performance—brake,
accelerator, steering, and signals.
None.
B Wright etal. (1973)
C Wright and Shephard
(1978a)
"Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on the same data, C=single-blind study, D=nottblind study. If
no technical problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
"The original authors estimated COHb from expired air.
-------
the lower-level COHb found effects. If automobile driving is affected by COHb elevation, it
remains to be demonstrated in a conclusive manner.
10.4.2.7 Brain Electrical Activity
Electrical activity of the brain (see review by Benignus, 1984) offers the possibility of
testing the effects of COHb without the problem of selecting the most sensitive behavioral
dependent variable. It is less dependent upon subject cooperation and effort and may be a
more general screening method. The major disadvantage of the measures is the lack of
functional interpretability. The area has been plagued with poor quantification and,
frequently, a lack of statistical significance testing.
The electroencephalogram (EEG) is a recording of the continuous voltage fluctuations
emitted by the intact brain. The slow-evoked potential originally called the contingent
negative variation (CNV) is computed by averaging over trials and was linked to (among
other things) cognitive processes or expectancy (Donchin et al., 1977). The evoked potential
(EP) is the electrical activity in the brain resulting from sensory stimulation, either auditory
(AEP) or visual (VEP). The EEG, CNV, and EPs have been studied with COHb elevation.
Table 10-21 is a summary of results from these studies.
Groll-Knapp et al. (1972) reported that the CNV was decreased in amplitude in a dose-
related manner for COHb values ranging from 3 to 7.6%. In a second study, Groll-Knapp
et al. (1978) again reported that CNV amplitude was reduced by 12% COHb when subjects
missed a signal in a vigilance task. More evidence is required before the functional
significance of such an effect can be deduced but it is a potentially important finding.
Clinical EEGs were analyzed by visual inspection by Stewart et al. (1970, 1973a) and
Hosko (1970) after exposure to sufficient CO to produce COHb levels ranging up to 33%.
No effects were noticed. Groll-Knapp et al. (1978) reported similar results using spectrum
analysis on EEGs from subjects with 12% COHb. Haider et al. (1976) reported slight
changes in the EEG spectrum for COHb levels of 13%, but no tests of significance were
conducted. In view of the above studies, it seems reasonable to assume that no EEG effects
of COHb levels below at least 10% should be expected.
10-131
-------
TABLE 10-21. EFFECTS OF CARBOXYHEMOGLOBIN ON BRAM ELECTRICAL ACTIVITY
Exposure
Duration (rain)
120
Injection
120
210
410
480
420
210
>— *
o
^ 120
N)
18
180
Variable up
to 1,440
Variable
240
120
Elevated COHb
Range (%)
6.0-55.0
10.0-75.0
3.0-17.6b
6.0-12.0
11.0
10.0
12.0
5.3
7.5-42.0
9.0
3.0-12.4
Continuous
distribution up to
33.0
3.2-15.2
3.0-5.1 :
7.0-62.0°
n
15
10
20
20
10
20
20
55
6
18
9
11
6
30
6
Dependent
Variable
VEP
Tone AEP
CNV
VEP, click AEP,
CNV, and EEG
spectra
Click, AEP, and
EEG sleep stages
EEG sleep stages
Sleep stages and
EEG spectra
VEP
ERG
VEP
Sleep stages
VEP and EEG
VEP and EEG
Tone AEP
VEP
Species
Rat
Rat
Human
Human
Human
Human
Human
Human
Cat
Human
Human
Human
Human
Human
Rat
CO
Effect
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
No
No
Yes
No
Yes
Yes
Technical
Comment Critique*
First significant effect increased amplitude at 22% COHb
in cortex (at 38% in superior colliculus). Changes were
dose related.
COHb-ordinal effects beginning at approximately 45%
in rat. Small effect possible near 25% when CO was
injected ip.
Significant differences at all COHb levels above A,D
endogenous.
CNV only declared affected. No data given, only B
conclusions stated. .
•
Both affected. B
Same' conclusions as Groll-Knapp et al. (1978) B
Both changed slightly (no significance test). A
Both young (n = 33, mean age = 22.8 years) and
elderly (n = 22, mean age = 68.7 years) subjects were
tested.
Decreased p-wave amplitude. Dose-related effect
beginning at 7.5% COHb.
None. B,C
No data above 6.6% COHb shown, only results of B
sign ficance tests. Noisy environment.
No effects until COHb approximately 21%.. Only B
two subjects were tested in the high range. Effect was
an increased amplitude of peaks Nl, P2, and N2. No
statistical tests.
None. BJD
p-p Amplitude of N1-P1 peak increased in COHb-ordinal
manner beginning at 3%.
Increased amplitude at both cortex and superior colliculus
at 62% COHb. Late component amplitude decreased at
7% COHb in superior colliculus. No statistics, only
typical data given.
Reference
Dyer and Annan
(1977)
Fechter et al. (1987b)
Groll-Knapp et al.
(1972)
Groll-Knapp et al.
(1978)
Groll-Knapp et al.
(1978)
Groll-Knapp et al.
(1982)
Haider et al. (1976)
Harbin et al. (1988)
Ingenito and
Durlacher (1979)
Luria and McKay
(1979)
O'Donnell et al.
(1971b)
Stewart et al. (1970),
Hosko (1970)
Stewart et al. (1973a)
Putz et al. (1976)
Xintaras et al. (1966)
"Technical problems: A=no or unspecified statistical tests, B=multiple-significance tests on th& same'data, C=single-blind study, D=nonblind study. If no technical
problems are noted, the experiment was conducted under double-blind conditions and multiple-significance testing was not done.
bCOHb was estimated by comparison to a separate series of animals.
°COHb was estimated by the present author from exposure using published data (Montgomery and Rubin 19711.
-------
O'Donnell et al. (1971b) reported that sleep stages (as determined from the EEG) were
not distributed by COHb levels up to 12.4%. Groll-Knapp et al. (1978) and Haider et al.
(1976), however, both reported distributed sleep stages at similar COHb levels using EEG
spectra. Groll-Knapp et al. (1982) repeated their earlier study and found essentially the same
effects.
The VEP was not affected consistently by COHb elevation below approximately 22%
and usually the lowest level for effects was higher (see Table 10-21). At higher levels the
effects were dose-related (Dyer and Annau, 1977; Stewart et al., 1970; Hosko, 1970). The
above is true for both rats and humans.
A single study of visual electrophysiology has reported low-level effects of COHb
(Ingenito and Durlacher, 1979). The electroretinogram of anesthetized cats was reported to
have exhibited a reduced j3-wave amplitude beginning at 7.5%. Effects were dose-ordinal up
to 42% COHb. The contribution of the anesthesia (chloralose) to the effect as a possible
potentiator of COHb effects was not tested in the study. The authors reported that the effect
outlasted the COHb elevation and possibly was due to direct cellular CO toxitity.;
Groll-Knapp et al. (1978) found no effect of COHb (8.6%) on click AEPs during
waking, but reported increased positive-peak amplitudes when subjects were tested during
sleep at approximately 11% COHb. The finding was verified by Groll-Knapp et al. (1982).
The fact that the data were collected during sleep is potentially important.
Putz et al. (1976) conducted a double-blind study in which 30 persons v/ere exposed to
70 ppm CO for 240 min (5% COHb at the end of the session). Among other variables, the
AEP was measured. The peak-to-peak amplitude of the Nl-Pl components was increased in
a dose-ordinal manner beginning at approximately 3% COHb.
Ten millisecond tone bursts were used by Fechter et al. (1987b) to produce AEPs in
fats exposed to graded doses of injected CO. Carboxyhemoglobin levels ranged up to 75%.
Slight evaluations of the mean threshold began at about 25% COHb. Effects were first seen
at higher frequencies. All effects were reversible. During the exposure, normal body
temperature was maintained to avoid hypothermia (Annau and Dyer, 1977).
Many of the brain electrical activity measures seem to be altered by COHb elevation.
The functional significance of these changes is not clear. Sometimes an alteration is'not an
indication of a deleterious effect but merely implies some change in processing. When
10-133
-------
induced by low levels of COHb, however, any change should be viewed as potentially
serious.
10.4.2.8 Schedule-Controlled Behavior
Because of the high levels of COHb that are employed in studies of laboratory animals
using schedule-controlled behavior, effects of COHb are reported in all articles on the
subject. Table 10-22 is a summary of the literature. There are a number of problems with
the published literature, however, as seen in Table 10-22. Only a few investigators measured
COHb; instead, they simply specified the exposure parameters. Another problem is that of
hypothermia, which occurs in rats when COHb levels rise (Annau and Dyer, 1977; Mullin
and Krivanek, 1982). If hypothermia develops as a consequence of COHb elevation,
behavioral effects may be secondary to the hypothermia, not the COHb directly. None of the
experimenters attempted to control for hypothermia effects. Thus, behavioral effects of
COHb may be overestimated in the rat with respect to humans who do not exhibit
hypothermia from elevated COHb.
The level of COHb may be estimated for studies in which it was not given by use of the
data from Montgomery and Rubin (1971). The latter-published normative curves can be used
for such estimates. Schrot and Thomas (1986) and Schrot et al. (1984) have published : ,
corroborating curves. For all rat studies in which COHb was not measured, COHb levels
were estimated from exposure parameters.
With one exception (Mullin and Krivanek, 1982), effects of COHb did not occur on
schedule-controlled behavior until COHb exceeded approximately 20%. In some studies, no
effect was observed until even higher levels. It is possible, however, that a number of the
studies were insensitive because of the small numbers of subjects employed. In the study by
Mullin and Krivanek (1982), it was reported that conditioned-avoidance behavior was affected
at COHb levels as low as 12.2%. The COHb level reported in the latter study is, however,
about half of the value that would be estimated from the Montgomery and Rubin (1971) data.
It seems likely that either exposure or COHb values were erroneous in the report. If the
exposure data were correct, the effects threshold would fit the other data in the literature. It
thus appears that COHb does not affect schedule-controlled data in laboratory animals until
levels exceed 20%.
10-134
-------
TABLE 10-22. EFFECTS OF CARBOXYHEMOGLOBIN ON SCHEDULE-CONTROLLED BEHAVIOR
o
Exposure
Duration
(min)
120
1,440
75
90
48
Injection
240
30
90
90
Variable
Elevated
COHb Range
•(98) n
9.0-58.0" 5
9.0-58.8" 8
35.0-55.0" 15
8.0-54.0" 4
15.0-55.0" ?
9.0-58.0 22
12.2-54.9 6
Continuous ; 3
distribution
up to 32.0
34.0-53.0 3
' 40.0-66:0 3
15.0-40.05 4
Schedules
CRF
Body weight
MULT
combinations of
FI3 and FR30
DRL21
FI3, FR25, YES,
VR15, VR25,
DRL
CRF brain
stimulation
Behavioral screen
Appetitive
shuttling ;
.MULTFR30,
DRL 18
Multiple
sequential
responses
• FCN . ,
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Monkey
Rat
Rat
Rat
CO
Effect
Yes
Yes
Yes
Yes
Yes
Yes
Yes
'Yes
Yes
Yes
Yes
Comment
Rates fell inversely at COHb beginning at «20 %
Weight fell inversely at COHb beginning at 22%. Food
and water consumption also fell.
Rates fell inversely at COHb beginning between 32 and
48% for schedules.
Rates fell inversely at COHb beginning at «37%.
Temporal discrimination was undisturbed.
Effects were COHb ordinal beginning at «14% . DRL
was affected at COHb < 1%. Methods were poorly
described
CO was injected ip. Effects were first noted near 45 %
COHb.
Behavioral screen included reflexes, grasping, and
conditioned avoidance. Lowest level effect was on
conditioned avoidance at 12.:2%. COHb levels measured
by authors were much lower than predicted from data of
Montgomery and Rubin .(1971).
Shuttling velocity decreased as COHb beginning at
16-22%.
Rates fell beginning «45% COHb.
J ' • '
Rats repeated releamed response chain after extinction.
More time to relearn was required beginning «50 %
COHb.
Rates fell inversely at COHb beginning between 20 and
28% •.. ..;"'••' '.
Reference
Annau (1975)
Annau (1975)
Ator(1982)
Ator et al. (1976)
Beard and Wertheim
(1967)
Fountain et al. (1986)
Muffin and Krivanek
(1982)
Purser and Berrill (1983)
Schrot and Thomas
(1986)
Schrot et al. (1984)
Smith et al. (1976a)
"COHb was estimated by the present author from exposure using published data (Montgomery and Rubin, 1971).
-------
When there were frank effects on schedule-controlled behavior, they seemed all to be in
the direction of a slowing of rate or speed of response. Schedule-produced patterns of
behavior were not disrupted, in general. Thus, it appears that the effect of elevated COHb is
on some general aspect of behavioral control having to do with the rate of processing.
10.4.2.9 Summary and Discussion of Behavioral Literature
The literature regarding the effects of COHb on behavior, as seen in the above review,
does not allow clear-cut conclusions. Results of studies frequently were not replicable or
were not supported by related studies. In this section, an attempt will be made to discover
what, if any, general conclusions can be made.
Analysis of Technical Problems
It is possible that the many technical problems that were noted in the summary tables in
the Technical Critique column may account for some of the lack of agreement among
experimental results. In the following analysis, tabulations were made of all of the studies in
which either blinding or statistical analysis problems occurred. Studies were cast into
2X2 tables according to the presence or absence of a particular condition and according to
the occurrence (or not) of a COHb effect. If multiple-dependent variables were measured in
a particular experiment, that experiment was tallied as having reported a significant effect if
any one or more of the variables was reported as affected. A study was tallied as having
reported a significant effect only if the effect occurred below 10% COHb to avoid the
inclusion of frank effects that will occur if COHb is made sufficiently high. All studies were
included, regardless of what dependent variables were studied. Only human studies were
included. To help decide whether or not the technical problem in question should be inferred
to have influenced the results, a Fisher's exact test was conducted on each table. Two such
tests were conducted; therefore, the alpha level selected for each test was 0.05/2 or 0.025.
Given significant results, exploratory tests also were conducted.
Table 10-23 is a tabulation of studies according to their blinding practices. Nonblind
and single-blind studies were pooled because of the few nonblind studies. The Fisher test
yielded significant results (p = 0.015). It is impressive that the rate of reported COHb
effects was about 2.24 times as high for studies not using a double-blind design. When the
10-136
-------
TABLE 10-23. EFFECT OF BLIND CONDITIONS
Non-Double Blind Double Blind
Effects 16 6
No Effects 9 15
Fisher's exact test, p = 0.015.
five nonblind studies were dropped and the data were reanalyzed in an exploratory manner,
the rate of finding significant effects for single-blind studies was 2.275 times as high as for
double-blind studies (p = 0.017).
Table 10-24 is a tabulation of studies according to the employment of multiple-
significance tests on the same data set. The Fisher test was not significant (p = 0.22).
TABLE 10-24. EFFECT OF STATISTICAL METHODOLOGY
Effects
No Effects
Multiple-
Significance
Test Methods
13
13
Conservative-
Significance
Test Methods
9
11
Fisher's exact test, p = 0.22.
From the above analyses, it may be concluded that studies that were not conducted in a
double-blind manner tend to demonstrate more apparent COHb effects. It may be argued that
the bias thus introduced into the study is added to whatever COHb effect may be present. No
evidence was demonstrated, however, for the hypothesis that multiple statistical tests tended
to produce an inflated Type I experiment-wise error rate.
Evaluation of the Literature
In the evaluation of the literature on the behavioral effects of COHb, it is not clear how
to treat the results from studies not conducted in a double-blind manner. Although they are
biased toward reporting COHb effects, they clearly contain useful information. In the
10-137
-------
following summary, results from double-blind studies will be tabulated separately from results
of studies not conducted in a double-blind manner.
Table 10-25 summarizes literature on the behavioral effects of COHb. Both double-
blind and non-double-blind studies are tabulated. For each family of dependent variables, the
table gives the number of studies in the double-blind and non-double-blind categories.
Finally, the proportion of studies reporting a COHb effect, p(E), is given for both double-
blind and non-double-blind studies. Several conclusions may be drawn from Table 10-25.
TABLE 10-25. PROBABILITY OF EFFECTS OF CARBOXYHEMOGLOBINa
•
Dependent Variable
Absolute visual threshold
Critical flicker fusion
Misc. visual functions
Misc. auditory functions
Fine motor skills
Reaction time
Tracking
Vigilance
Continuous performance
Time estimation
Misc. cognitive function
Automobile driving
Brain electrical activity
Non-
Double
Blind
(n)
4
7
9
0
6
7
4
4
4
2
5
3
3
Double
Blind
(n)
1
3
5
3
4
5
7
4
5
4
5
2
6
Non-
Double
Blind
P(E)
0.20
0.33
0.55
N/A
0.33
0.00
0.00
0.75
0.75
0.50
0.80
0.33
0.33
Double
Blind
P(E)
0.00
0.00
0.00
0.00
0.00
0.00
0.43
0.25
0.40
0.00
0.00
0.00
0.50
"Based on numbers of studies in each category.
Those conclusions are as follows:
A. Non-double-blind studies produce a greater proportion of reported effects, even for
the individual dependent variables. This is true with the exception of tracking and
brain electrical activity. This observation supports the previous inference that non-
double-blind studies are biased toward finding more effects than are justified.
B. Studies using double-blind procedures found effects on 4 of the 14 dependent
variable families: tracking, vigilance, continuous performance, and brain electrical
activity.
10-138
-------
C. In the four dependent variable categories where COHb was found to affect
behavior, usually less than half of the reported studies found effects in double-blind
studies.
D. Sensory and cognitive effects were not found to be affected by COECb in double-
blind studies.
E. In most instances, the rate of finding COHb effects in non-double-blind studies was
high in the same dependent variables where the double-blind studies reported
effects. This observation lends further support to the findings in the double-blind
studies.
Continuous Perfotmance. It may be argued that the dependent variables of tracking,
vigilance, and continuous performance are related functionally, Each of the dependent
variables in the three categories require the continuous performance of some sort of behavior.
The response rate and/or attention demand in vigilance behavior is low compared to the other
two groups; otherwise, the behaviors are similar. Tracking is clearly a particular form of
continuous performance that was categorized separately simply because of the; homogeneity of
a group of studies that existed in the literature. It also may be argued that, despite the high
response rates in the tracking and continuous performance studies, both of these behaviors
require a strong component of sustained attention. It seems fair to conjecture, therefore, that
behaviors that require sustained attention and/or sustained performance are most sensitive to
disruption by COHb.
The group of studies of tracking, vigilance, and continuous performance offer the most
consistent and defensible evidence of COHb effects on behavior. The results across studies
is, however, far from consistent. Further examination of the three areas seems appropriate.
Compensatory tracking was studied by two groups of investigators using virtually
identical task parameters and equipment (Putz et al., 1976, 1979; Benignus et-al., 1987,
1990a). Both of the studies by Putz et al. (1976, 1979) found significant and moderately
large effects of 5% COHb. Benignus et al. (1987) reported similar but smaller significant
effects in a nearly identical experiment to Putz et al. (1976). However, in a dose-effects
study including another direct replication group, Benignus et al. (1990a) found no significant
effects, even for COHb levels of 17%. In the latter study, the means were nearly dose
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ordinal, but the changes were too small to be statistically significant. It is particularly
puzzling why the latter study, using a large number of subjects on an identical task, should
find no significant effects for even 17% COHb when three other studies (Putz et al., 1976,
1979; Benignus et al., 1987) found effects at lower levels. Three other double-blind tracking
studies of various methods found no effects of COHb levels of 12% or greater although their
task parameters were very different. '
As discussed in the above literature review, there is a similar disunity among studies on
the effects of COHb on vigilance. Because of the many failed attempts at direct replication,
the conclusions seem weaker than for tracking.
Of the five double-blind experiments in which continuous performance was measured,
three were mentioned earlier in the discussion of tracking. In these studies (direct •
replications), continuous performance was measured simultaneously with tracking (Putz et al.,
1976, 1979; Benignus et al., 1987). The latter of the three found no effects. A small study
reported continuous performance effects that were disordinal in COHb (O'Donnell et al.,
1971a). The remaining study (Benignus et al., 1977) used a different task and obtained no
COHb effects.
Multiple Performance. It is possible that COHb impairs task performance more when
multiple tasks are performed simultaneously, thus decreasing the amount of behavioral
reserve capacity. Alternatively, multiple task performance may be more alerting or
interesting, thus improving performance. To test the exploratory hypothesis mat multiple task
performance might differ from single task performance, behavioral studies (sensory and
electrophysiological excluded) were tabulated according to single/multiple task performance'
and significant/nonsignificant effects of COHb. If any given study used both single-task and
multiple-task behaviors, the study was tabulated according to the multiple-task results only.
For studies in which only single tasks were required, the study was classed as having shown
significant results if one or more variables were significant; otherwise, the study was classed
as nonsignificant. The above rules prevented any study from being tabulated more than once.
Table 10-26 is the result of the above tabulation. The exploratory Fisher's exact test
yielded p = 0.081. Although the result would have been nonsignificant by a priori rulSs, the
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TABLE 10-26. EFFECT OF SINGLE VS. MULTIPLE
TASK PERFORMANCE
Effects
No Effects
Single Task
7
14
Multiple Task
8;
5
Fisher's exact test, p = 0.081.
table shows a slight tendency toward more multitask studies showing a significant effect,
whereas more of the single-task studies found no effect.
The question of multitask vs. single-task performance sensitivity to COHb disruption
would be answered best by experiments in which the tasks were performed singly and
together within the same study. In the literature, there were only two cases in which this was
done. In both of these, one of the single tasks alone was affected more than multitask
performance (Bender et al., 1972; Gliner et al., 1983). Experiments designed to specifically
answer the question of single-task vs. multitask performance sensitivity need to be done.
COHb Formation Rate. It is possible that the rate at which COHb is formed is an
important variable in determining the effects of low-level COHb on the CNS. To explore
this possibility, studies were cast into a table according to their rate of COHb formation (fast
or slow) and whether effects were found or not. When COHb was formed to its target value
in 10 min or less, the study was tabulated as fast. Studies in which effects were found only
above 10% COHb were tabulated as no effects to avoid consideration high-level effects.
Table 10-27 is the result of the above classification. The exploratory two-sided Fisher's
exact test yielded p = 0.002. It appears that studies using slow COHb formation are more
likely to find significant effects. Experiments explicitly designed to test the hypothesis would
be needed before firm conclusions can be drawn.
TABLE 10-27. EFFECT OF RATE OF GARBOXYHEMOGLOBEV FORMATION
... . ,. • . Slow Fast
Effects '. '. 20 \ ~~ 2
No Effects 12 9
Fisher's exact test, p = 0.002.
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10.4.2.10 Hypotheses
An effort has been made to unify the dose-effects literature concerning CO and behavior
(Benignus et al., 1990b). The analyses and hypotheses of this article will be summarized in
this section. Both laboratory animal and human data were considered in this review, but only
those studies where dose-effect relationships were obtained were included, so that
extrapolations to no-effect levels could be made. The literature concerning dose-effects
functions in humans, as above, was found to be inconsistent. In studies utilizing laboratory
animals, as has been pointed out in the present review, effects of COHb elevation do not
become significant until approximately 20%. The literature for such higher levels of COHb
is quite consistent. Nonlinear, positively-accelerated functions were fitted to the laboratory
animal data to describe dose-effects relationships.
The results of studies in human subjects are less consistent in showing effects on
behavior at COHb levels less than 20%. Some well-designed studies show significant effects
from COHb levels as low as approximately 5%, whereas others do not. For purposes of
discussion, Benignus et al. (1990b) made the assumption that positive effects in humans are
not reliable below 20% and used the data from the Benignus et al. (1990a) study to fit their
nonsignificant dose-effect relationship to the same function fit to the animal data.
Extrapolation of this curve projected the human data as passing through the curves established
in animals at higher COHb concentrations. This analysis was used to support the hypothesis
that human and laboratory animal findings were similar and that frank effects of COHb
elevations in humans should not be expected below about 20% COHb.
Further support for this hypothesis conies from a consideration of the possible role of
compensatory mechanisms that may mitigate against CNS effects of CO under many
conditions. As discussed in Section 10.4.1, a proportional vasodilation occurs in the brain
in response to COHb elevation. This vasodilation is sufficient, on the average, to keep the
cerebral O2 consumption from being reduced even though the COHb has reduced the blood's
O2-carrying capacity 20 to 30% and the presence of COHb has shifted the O2Hb dissociation
curve to the left. The cerebral vasodilation may be viewed, teleologically, as a closed-loop
compensatory mechanism to assure adequate oxygenation of the brain in the presence of
elevated COHb.
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If the cerebral vasodilation is adequate in any individual and if the vasodilation is
homogeneous for all cerebral tissue, then that individual should not be behaviorally impaired
by COHb elevation. This statement assumes that the sole mechanism for CO toxicity is the
hypoxic effect of COHb. ,
The agreement between the behavioral literature and the compensatory mechanism
hypothesis is noteworthy. According to the compensatory mechanism data, O2 consumption
in the brain does not begin to decrease until COHb exceeds 20 to 30%.
The analysis of the behavioral effects data by Benignus et.al. (1990b) provides a basis
for reconciling the animal and human research results, but fails to include any safety factor
for extrapolation of animal data to humans. The possibility of effects in humans below 20%
COHb is supported by the observation that in many studies, using both laboratory animals
and humans, group means were usually shifted in the direction of deleterious effects at low
levels, but not in a statistically significant manner. In many cases, the low .power,of the
study designs may account for this inability of small effects to reach statistical reliability.
Group.mean effects were much more rarely shifted in the direction implying Improvement of
behavioral abilities with small levels of COHb. Thus, effects of COHb levels in the range of
5 to 20% on behavior of humans probably exist; however, the,conditions under which these
occur are poorly understood. Some individuals may be affected while .others .are not, but the
risk factors for these sensitive individual have not been identified to date.
10.4.2.11 Conclusions
Effects on behavior of COHb elevation above 20% have been unambiguously
demonstrated in both human and animal studies. Below this level, results are less consistent.
It seems unwise, however, to ignore frequent evidence in favor of effects on human
performance at COHb levels as low as 5%, Even if effects are small or occasional, they
might be important to the performance of critical tasks.
Some of the differences among studies of the effect of COHb on the behavior of
humans is due apparently to technical problems in the execution of experiments because
single-blind or nonblind experiments tend to yield a much higher rate of significant effects.,
than do double-blind studies. Even when non-double-blind experiments are eliminated from
consideration, however, a substantial amount of disparity remains among results of studies.
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It is possible that such residual disagreement is due to the action of an unsuspected variable
that is not being controlled across experiments.
If the compensatory CNS-blood-flow hypothesis has validity, it is possible thaMhere
exist groups that are at higher risk from COHb elevation than the usual subjects studied in the
behavioral experiments. Disease or injury might either impair the compensatory mechanism
or reduce the nonexposed O2 delivery. Aging increases the probability of such injury and
disease. It also is possible that there exist individual differences with regard to COHb
sensitivity and compensatory mechanisms. Too little is known about the compensatory
process to support anything more than the conjectures already made, but the matter certainly
warrants further attention. ;
Our understanding of the effects of CO on human behavior has not been appreciably
improved since the last criteria document was written (U.S. Environmental Protection
Agency, 1979). What is needed now are studies on the mechanisms of CO effects on
behavior and on the reliability and specific determinants of individual differences in response.
Animal studies may be particularly useful for studying mechanisms for CNS effects and
certain risk factors. Human studies can be used to characterize individual differences in
sensitivity, determine their reliability, and examine risk factors that increase sensitivity.
After susceptible populations have been identified, larger scale studies should be considered
to determine the overall risk of adverse effects in these groups.
10.5 DEVELOPMENTAL TOXICITY OF CARBON MONOXIDE
10.5.1 Introduction
Developmental toxicity has been described in the U.S. Environmental Protection
Agency's Guidelines for the Health Assessment of Suspect Developmental Toxicants (Federal
Register, 1986) as including death of the developing organism, structural abnormalities,
altered growth, and functional deficits resulting from toxic exposures that occur prior to the
subject's attaining sexual maturity. The appearance of toxic effects may occur at any time
throughout life. Concern for special vulnerability of immature organisms to toxic compounds
focuses on the possibilities that (1) a toxic exposure that is not sufficient to produce maternal
toxicity or toxicity in the adult organism will adversely affect the fetus or neonate or (2) at a
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level of exposure that does produce a toxic consequence to the adult or mother, that the fetus
or neonate suffers a qualitatively different toxic response. Toxic responses that occur early in
life, but which are not permanent, may or may not be a cause of concern. In some cases,
they truly may be transient events with no persisting consequences. However, in other cases
such results may have their own consequences for development of the organism or may
reappear under conditions of ill health produced by other toxic exposures, environmental
stresses, or exposure to pathogenic agents. Therefore, even seemingly transitory toxic effects
must be viewed as serious consequences of exposure when they occur in humans. In this
section, data are presented that describe the toxic consequences of CO exposure early in
development. These data describe the types of toxic outcomes that the immature subject may
show and also help to identify the dosage at which such toxicity is seen.
There are theoretical reasons and supporting experimental data that suggest that the fetus
and developing organism are especially vulnerable to CO. One reason for approaching the
fetus as a separate entity for purposes of regulation is that the fetus is likely to experience a
different CO exposure than the adult given identical concentrations of the gas in air. This is
due to differences in uptake and elimination of CO from fetal Hb that are documented below.
Less studied is the possibility that tissue hypoxia may differ between the fetus and adult even
at equivalent COHb concentrations as a result of differences in perfusion of critical organs, in
maturation of adaptive cardiovascular responses to hypoxia and as a result of tissue
requirements for O2. Inferences concerning these factors are obtained principally from
experimentation performed in laboratory animals in which the immature organism does show
enhanced toxicity relative to the adult. Concern must be expressed, too, for the development
of sensitive and appropriate animal models. It is necessary to bear in mind the relative state
of development of the human and laboratory animal in question at the time of birth in
developing useful animal models. For example, the neonatal rat is very immature relative to
the neonatal human at birth with respect to development of the CNS (Fechter et al., 1986),
and so a combined prenatal and neonatal exposure model may be more accurate in predicting
consequences of prenatal exposure in the human. Further, differences appeal to exist among
species in the relative affinity of fetal and adult Hb for CO. These data are reviewed by
Longo (1970).
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There exist a variety of relevant data bases that will be reviewed. These include
experimental investigations conducted using laboratory animals (and these are most
numerous); case report data collected in offspring of women exposed to generally high-level,
acute CO poisoning during pregnancy; and epidemiological data. From the standpoint of this
document, one large, but problematical body of literature concerns maternal cigarette
smoking.
Cigarette smoking constitutes a major source of exposure of the individual to CO and
this is particularly relevant for the fetus because of the high affinity of fetal Hb for CO
(Longo, 1977). Maternal smoking has been associated with a variety of untoward
consequences ranging from increased incidence of placenta previa, abruptio placentae,
spontaneous abortion, and subsequent fetal deaths to depressed birthweight, increased
numbers of hospital admissions for a broad range of complaints during at least the first
5 years of life, and poorer-than-predieted school performance during the first 11 years of life.
This literature has been thoroughly reviewed as a report to the U.S. Surgeon General
(Hasselmeyer et al., 1979). These outcomes should be cause for significant concern.
However, it is not easy to determine the extent to which CO is a causative factor. Cigarette
smoke contains a large number of toxic chemicals other than CO, and these other agents
either alone or in combination may be responsible for the untoward outcomes that are readily
associated with maternal smoking. A few epidemiological reports are reviewed below in
which it is concluded that CO, either from ambient sources or cigarette smoke, is responsible
for developmental disruption. However, these reports generally are deficient in
characterizing the level of CO exposure or,in ruling out potential contributions by other toxic
agents contained in smoke. Investigations with laboratory animals exposed to CO rather than
cigarette smoke early in development have demonstrated developmental anomalies and
persisting neurobehavioral disorders that are most relevant to this document and that are
reviewed below. Because such effects are seen at CO levels approaching values observed in
the offspring of cigarette smokers, this must be cause for serious concern. However,, it is not
possible to use the cigarette smoker literature in establishing criteria for permissible CO
exposure.
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10.5.2 Theoretical Basis for Fetal Exposure to Excessive Carbon Monoxide
and for Excess Fetal Toxicity
Hill et al. (1977) aptly described mathematical models for predicting fetal exposure to
CO based upon placenta! transport and the differences between maternal and fetal Hb affinity
for CO and O2. They predicted that for any maternal CO exposure of moderate duration that
fetal COHb levels would lag behind maternal COHb levels for several hours, but would,
given sufficient time, surpass maternal COHb levels by as much as 10% (in humans) due to
the higher CO affinity of fetal Hb than adult Hb. Moreover, they predicted a far longer
wash-out period for the fetal circulation to eliminate CO following termination of exposure
than that found in the adult. Data, accumulated in both laboratory animal and human studies,
support these conclusions.
10.5.2.1 Evidence for Elevated Fetal Carboxyhemoglobin Relative to Maternal
Hemoglobin
A fairly wide range of neonatal and maternal COHb levels has been published for
humans, probably due to wide differences in cigarette smoking patterns prior to and during
labor. In one recent study, measurement of fetal cord blood in the offspring of cigarette
smokers who smoked during labor showed fetal COHb levels 2.55 times higher than in
maternal blood. Cord blood averaged 10.1 % COHb at delivery, whereas maternal blood
averaged 5.6% COHb on the mother's arrival at the hospital and 4.1% COHb a.t delivery
(Bureau et al., 1982). These values for fetal COHb are fairly high relative to other published
sources (Longo, 1977—Table IV). However, greater fetal COHb levels have been found in
laboratory studies across a broad range of animal species if sufficient time was allowed for
COHb to equilibrate in the fetal compartment. Christensen et al. (1986) ultimately observed
higher CO levels in fetal guinea pigs than in their dams following CO exposure given near
term. Immediately following maternal exposure, at gestational age 62 to 65 days, to a bolus
of CO (5 mL given over 65 s), they reported a faster elevation in maternal COHb levels than
in fetal levels, a finding consistent with the models of Hill et al. (1977).
Anders and Sunram (1982) exposed gravid rats to 22 ppm CO for 1 h on Day 21 of
gestation and reported that fetal COHb levels averaged 12% higher than levels taken at the
same time period in the dam. These results are consistent with those of Garvey and Longo
(1978), whose study involved chronic CO exposures in rats. Dominick and Carson (1983)
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exposed pregnant sows to CO concentrations of 150 to 400 ppm for 48 to 96 h between
Gestation Days (CDs) 108 to 110. They reported fetal COHb levels that exceeded maternal
levels by 3 to 22% using a CO-Ox.
Longo and Hill (1977) similarly reported that COHb levels in fetal lambs do exceed
maternal levels once equilibrium is reached in the fetal compartment and that this washout
from the fetal blood exceeds that observed for maternal blood.
Fetal COHb kinetics may not be static throughout pregnancy. Bissonnette and Wickham
(1977) studied transplacental CO uptake in guinea pigs at approximate gestational ages 45 to
68 days. They report that placenta! diffusing capacity increases significantly with increased
gestational age and appears to be correlated with fetal weight rather than placenta! weight.
Longo and Ching (1977) also showed increases in CO diffusion rates across the placenta of
the ewe during the last trimester of pregnancy. However, they did not find a consistent
increase when diffusion rate was corrected for fetal weight (i.e., when diffusing capacity was
expressed on a per kilogram fetal weight basis).
10.5.2.2 Effect of Maternal Carboxyhemoglobin on Placental Oxygen Transport
Gurtner et al. (1982) studied the transport of O2 across the placenta in the presence of
CO by cannulating both the maternal and fetal vessels of anesthetized sheep. They measured
the transport of O2 across the placenta compared to transport of argon (Ar), urea, and
tritiated water when CO was introduced. They showed a reduction in O2 diffusing capacity
relative to Ar that appeared to be related to the level of maternal COHb. Reduction of
O2 transport was observed below 10% COHb and O2 transport approached zero at COHb
values of 40 to 50%. They interpreted these data as supporting the role of carrier-mediated
transport for O2 and suggest that CO competitively binds to this carrier. An alternative
explanation is that the introduction of CO simply reduces the amount of fetal Hb available to
bind O2. Moreover, Longo and Ching (1977), for example, were unable to alter CO
diffusing capacity across the placenta by administration of a series of drugs that bind to
cytochrome P-450. Gilbert et al. (1979) have underscored the low concentration of
cytochrome P-450 in human placenta, as compared to liver and to the very low levels found
in many other species.
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Christensen et al. (1986) suggest that maternal CO exposure may independently impair
O2 diffusion across the placenta due to the enhanced affinity of maternal Hb for O2 in the
presence of COHb (the Haldane effect). Using the guinea pig, these authors demonstrated an
initial almost instantaneous fall in fetal PO2 in arterial blood and an increase in fetal partial
pressure of CO2, which subsequently was followed by an increase in fetal COHb between
approximately 5 to 10 min (the last time point studied, but a time when fetal COHb values
were still far below maternal values). They calculated that the decrease in fetal O2 transfer
was due mostly to a decrease in maternal O2-carrying capacity, but also, perhaps up to one-
third, by the increased affinity of Hb for O2 in the presence of CO. This model assumes that
uterine perfusion remains constant under the experimental conditions used. Longo (1976)
also showed a significant dose-related drop in fetal O2 levels in blood taken from the fetal
descending artery and fetal inferior vena cava after pregnant ewes were exposed to variable
levels of CO for durations sufficient to yield COHb equilibration in both the fetal and
maternal compartments. To summarize, it has been demonstrated that the presence of
maternal COHb over a range of values results in depressed O2 levels in fetal blood. The
simplest explanations for the inverse relationship between maternal COHb and fetal O2 levels
are reduced maternal O2-carrying capacity, impaired dissociation of O2 from maternal Hb
(the Haldane effect), and reduced availability of free fetal Hb able to bind O2.
10.5.3 Measurement of Carboxyhemoglobin Content in Fetal Blood
Zwart et al. (1981a) and Huch et al. (1983) have called into question the accuracy of
spectrophotometric measurements of COHb in fetal blood using the IL 182 and 282 CO-Ox.
The CO-Ox is effectively, a spectrophotometer preset to read samples at specific wavelengths
that correspond to absorbance maxima for O2Hb, COHb, and methemoglobin determined
using adult blood samples. Different plug-in modules (IL 182) or programmed absorbance
values (IL 282) can be used to correct for species differences in the absorbance spectrum of
rat, human, dog, and cow. Some investigators have used these instruments for estimating
COHb levels in species for which the instrument has not been calibrated such as the pig and
guinea pig. Typically, individual investigators have calibrated the CO-Ox using blood
standards fully saturated with CO and with O2. The adequacy of such a procedure is not
certain. (See Section 8.5 for more details on the measurement of COHb.) Further, the
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correspondence of absorbance maxima between adult and fetal Hb for species upon which the
CO-Ox is calibrated at the factory is an empirical question for which little data are published.
Noting the finding of higher apparent COHb levels in the venous cord blood of humans than
in the uterine artery, Huch et al. (1983) examined the possibility that O2Hb in fetal blood
might interfere with accurate measurement of COHb levels in the fetus due, presumably, to
different absorbance maxima for fetal than adult blood. Working in vitro, Huch et al. (1983)
deoxygenated fetal and maternal blood by flushing a tonometer with nitrogen and 5% CO2.
They introduced a "small volume" of CO gas, measured the blood gases using the IL 282
CO-Ox, and then studied the effect of stepwise addition of O2 to the apparent COHb levels.
They showed little influence of O2 saturation upon maternal COHb, but indicate that
O2 saturation did affect readings of fetal COHb so as to overestimate COHb. This error is
particularly likely at high O2Hb concentrations. Zwart et al. (198Ib) suggest an apparent
elevation of COHb levels of approximately 2% with 40% O2Hb saturation and of
approximately 6% with O2Hb levels of 90 to 95%. Such errors do not invalidate the finding
that fetal COHb exceeds maternal values, but do bring into question the magnitude of this
difference. Whether similar errors also occur in measuring fetal COHb levels in animal
blood is uncertain and should be subjected to experimental test. The calibration of
spectrophotometers based upon fetal Hb absorbance spectra rather than automated analysis
based upon adult absorbance spectra is recommended to achieve greater accuracy in
determining absolute levels of CO in fetal blood. Vreman et al. (1984) have described a GC
method for measuring COHb that has been applied to human neonates. Because of the very
small volume of blood needed to make these measurements and because they eliminate the
problem of absorbance spectra of fetal Hb, this may be considered a useful means of
accurately assessing COHb in developing organisms. There also is a new model of the
CO-Ox (#482) that apparently allows for use of absorbance spectra based on calibration of
fetal blood.
10.5.4 Consequences of Carbon Monoxide in Development
This section presents the evidence that CO exposure during early development has the
potential of producing untoward effects. The four types of toxic outcomes—fetotoxicity,
gross teratogenicity, altered growth, and functional deficiencies in sensitive organ systems—
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are considered in order. As is the case in adult organisms, the nervous and cardiovascular
systems appear to be most sensitive to CO exposure.
10.5.4.1 Fetotoxic and Teratogenic Consequence of Prenatal Carbon Monoxide
Exposure
There is clear evidence from human and animal studies that very high levels of CO
exposure may be fetotoxic. However, there exists some question concerning the level of
exposure that causes fetal death as both the duration and concentration of maternal exposure
are critical values in determining fetal exposure. More important for the setting of ambient
air standards is the suggestion of a causal relationship between sudden infant death syndrome
(SIDS) and ambient CO levels. These data are extremely limited at present and no
conclusive correlation can be drawn between SIDS and CO.
The lowest-observed-effect level (LOEL) for fetotoxicity in laboratory animals appears
to be in the range of 500 ppm CO for rodents, but one experiment conducted in pigs suggests
that this species may be especially sensitive to this effect, showing significant fetotoxicity at
250 ppm CO for 2 to 4 days (~ 23% COHb) late in gestation. Evidence of fetotoxicity in
animals also has come from acute, high-dose experiments that are not included here because
they are not directly relevant to standard setting.
The data that suggest that prenatal CO exposure produces terata is extremely limited
and, again, conies largely from quite high exposure levels. Table 10-28 presents the reported
effects of prenatal CO exposure on fetotoxicity, teratogenicity, and growth abnormalities.
Perinatal Carbon Monoxide Exposure and Sudden Infant Death Syndrome
It has been suggested that CO may be a causative factor in SIDS. Hoppenbrouwers
et al. (1981) reported a statistical association between the frequency of SIDS and levels of
several airborne pollutants including CO, SO2, NO2, and HCs. Sudden infant death
syndrome was reported more commonly in the winter, at a time when the burning of fossil
fuels for heating would be greatest. It is interesting to note that there is a phase lag of
approximately 7 weeks between the increase in pollutant levels and the increase of SIDS or a
lag with some meaning in terms of the physiology is uncertain. Further correlations
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TABLE 10-28. TERATOGENIC CONSEQUENCES OF PRENATAL CARBON MONOXIDE EXPOSI3RE
IN LABORATORY ANIMALS
Species (Strain)
Maternal Treatment
Maternal Toxicity
Development Abnormality
References
Mouse (strain NR)
Rat (Ames-Wilson)
cp
I—I
^
Rat (Sprague-Dawley)
Rabbit (strain NR)
Mouse (GF-1) and
Rabbit (New Zealand)
5,900 or 15,000 ppra CO
for 5-8 min every other
day of gestation
3,400 ppm CO for
1 h/day for 3, 6, or
8.3 mo
750 ppm CO for 3 h/day
on GDs 7, 8, or 9
90 or 180 ppm. CO from
mating to the day before
parturition
7 or 24 h/day of 250 ppm
CO on GDs 6-15 for mice
and on GDs 6-18 for
rabbits
Acute effects: unconsciousness
(no COHb levels)
Decreased body weight, appetite,
and muscle tone; lack of grooming
(COHb levels of 60-70%)
Not reported (no COHb levels)
Not reported (COHb levels of
8-9% and 16-18%)
Transient increase in body weight
for mice in 7-h/day group; COHb
levels of 10-11 % (mice) and
13-15% (rabbits) for 7-h/day
exposures
Abortions, resorptions, and
abnormal growth of survivors
Decrease of litter size, decrease
of preweaning survival (50%
reduction of pregnancy at 3 mo,
no pregnancies induced with
longer exposures; 19% increase
of estrous cycle)
Absorptions, stillbirths, skeletal
anomalies, and decreased fetal
body weight and crown-rump
length
180 ppm: 35% mortality of
neonates, 11 % decrease hi birth
weights, and increase in
malformations; 90 ppm: 9.9 %
mortality of neonates, 13%
decrease in birth weights
Mice: increase in resorptions and
body weight with 7-h/day
exposure, decrease in body weight
and crown-rump length with
24-h/day exposure; both exposures
increased skeletal anomalies (GD
18). Rabbits: increase hi body
weight and crown-rump length
with 7-h/day exposure
Wells (1933)
Williams and Smith
(1935)
Choi and Oh
(1975)
Astrup et al.
(1972)
Schwetz et al.
(1979)
-------
TABLE 10-28 (cont'd). TERATOGENIC CONSEQUENCES OF PRENATAL CARBON MONOXIDE EXPOSURE
IN LABORATORY ANIMALS
Species (Strain)
Maternal Treatment
Maternal Toxicity
Development Abnormality
References
9
t—»
Ul
Rat (Long-Evans)
Mice-(CD-l)
Mice (CD-I)
Pig
Rabbit
Rat (Wistar)
0, 30, or 90 ppm CO or
13 % 02 in nitrogen on
GDs 3-20
125, 250, 500 ppm CO
on GDs 8-18
0, 65, 125 ppm CO on None
GDs 7-18
Decrease in successful pregnancies;
COHb levels of 4.8 and 8.8%
150-450 ppm for 48-96 h
between GDs 108-110
12 "puffs" of 2,700- Decreased maternal respiration rate
5,400 ppm CO daily from Significant maternal death rate
GDs 6-18
1,000-6,000 ppm CO
2x/dayfor2h40min
total from GDs 0-6,
7-13, 14-20, or 0-20
13% oxygen: 12% decrease in
body weight; 90 ppm CO: 14%
increase in brain weight, 24%
decrease in lung weight, serotonin
concentration decrease in brain
Increased fetal mortality significant
w/500 ppm, no effect on number
of implantation sites
Impaired righting reflex on PD 1
for 125-ppm group, impaired
negative geotaxis on PD 10 for
125-ppm group, impaired serial
righting on PD 14 for both 65-
and 125-ppm CO groups
Linear increase in number of
stillbirths significant when
maternal COHb exceeded 23 %
(approximately 2,500 ppm)
Larger number of fetal deaths.
No terata
Garvey and Longo
(1978)
Singh and Scott
(1984)
Singh (1986)
Dominick and
Carson (1983)
Rosenkrantz et al.
(1986)
Tachi and Aoyama
(1983)
Decreased fetal weight at GD 21 Tachi and Aoyama
(1986)
-------
were obtained between SIDS and the predicted level of CO and lead for the child's birth
month and between SIDS and the level of pollution at the reporting station closest to the
infant's home. These correlations are not compelling without more information on the
methods by which other possible risk factors were controlled in making the geographical
correlations. Although it is technically difficult, it would be very useful to obtain COHb
levels close to the time of death in SIDS victims as this would greatly assist in determining
the incidence of elevated CO exposure in such cases.
There have been several studies linking maternal cigarette smoking with SIDS (these are
reviewed by Hasselmeyef et al.' [1979] in the National Institute of Child Health and Human
Development report on "Smoking and Health"), but it is uncertain what the role of CO might
be in such a relationship. Thus, it is clear that severe, acute CO intoxication can be fetotoxic
although specification of maternal and fetal COHb levels is difficult because such exposures
rarely involve the achievement of steady-state COHb levels or permit careful and rapid
determination of COHb levels. More relevant to the issue of standards for ambient exposure
is the possible link between CO and SIDS, but this literature currently is insufficient to
determine whether such a relationship exists.
Fetotoxicity in Laboratory Animals
Working with CD-I strain mice, Singh and Scott (1984) found significant increases in
the number of dead or resorbed fetuses per litter and an increase in fetal mortality with
continuous CO exposure of 500 ppm from GD 8 until subjects were sacrificed at GD 18.
Although not statistically significant, they found a dose-related trend in these measures
beginning at approximately 125 ppm. The no-observed-effect level (NOEL) for these
measures was 250 ppm. There was no effect of CO on the number of implantation sites,
suggesting a fetotoxic rather than an embryopathic event. Schwetz et al. (1979) also exposed
mice to 250 ppm CO for 7 and 24 h/day on GDs 6 to 15. They found no effect on number '
of implantation sites or number of live fetuses per litter, but did show a significant elevation
in resorptions with the 7-h exposure (10 to 11% COHb) but not with 24-h per day exposures.
Dominick and Carson (1983) exposed pregnant sows to CO concentrations of 150 to
400 ppm for 48 to 96 h between GDs 108 to 110 (average gestation was 114 days). They
showed a significant linear increase in the number of stillbirths as a function of increasing CO
10-154
-------
exposure. Stillbirths were significantly elevated above control levels when the maternal
COHb levels exceeded 23% saturation. These saturation levels were obtained at
approximately 250 ppm. Carboxyhemoglobin levels were measured using an JL 182 CO-Ox
equipped with a human blood board; pig blood fully saturated with CO and with O2 were run
each day to calibrate the instrument. There was very large variability among litters at a given
concentration level in the percentage of stillbirths that occurred. Penney et.al. (1980) found
evidence of reduced litter size in rate exposed for the last 18 days of gestation to 200 ppm
CO (maternal COHb levels averaged 28%). However, Fechter et al. (1987a) did not observe
similar effects on litter size in rats exposed to levels of CO as high as 300 ppm (maternal
COHb levels of 24%).
Teratogenicity
There are very limited data (Astrup et al., 1972) suggesting increased fetal mortality ,
and malformations among rabbits exposed to 180 ppm CO throughout gestation (16 to
18% COHb). The frequency of malformations reported was very small, the historical rate of
such anomalies in the laboratory was undocumented, and so these results require replication
by other workers before they can be considered as the basis for regulation, Rosenkrantz
et al. (1986) exposed rabbits to high doses (12 puffs of 2,700 to 5,400 ppm CO) for short
time periods daily from GDs 6 to 18. Carboxyhemoglobin levels were estimated at 16%
although animals had not equilibrated with the inhaled mixture. Despite a large number of
fetal deaths, there was no evidence of terata in the CO-exposed animals.
Choi and Oh (1975) reported skeletal anomalies in rats exposed to 750 ppm CO for
3 h/day on GDs 7, 8, or 9. They also reported an excess in fetal absorptions and stillbirths
and a decrease in body length. Schwetz et al. (1979) reported no teratogenic effects but an
increase in minor skeletal variants in CF-1 mice exposed to 250 ppm CO for 24 h/day from
GDs 6 to 15,
10.5.4.2 Carbon Monoxide and Body Weight
One of the best studied and possibly one of the most sensitive measures of early CO
exposure is a depression in birth weight. The effect seen hi animals following fetal CO
exposure is generally transitory and occurs despite the fact that maternal body weight growth
10-155
-------
through pregnancy does not appear to be adversely affected. The LOEL is in the range of
150 to 200 ppm in laboratory animals. In as much as the depressed birth weight observed is
a transient event, its significance is not clear. However, in humans, low-birth weight babies
may be at particular risk for many other developmental disorders, so the effect cannot be ••,..
disregarded casually. Moreover, in humans there is a strong correlation between maternal
cigarette smoking and reduced birth weight. Whether the causative agent here is CO,
nicotine, or a combination of these or other agents is uncertain.
Studies relating, human,CO,exposure from ambient sources or cigarette smoking to ..^,..
reduced birth weight frequently have failed to take into account all sources of CO exposure.
Alderman et al. (1987), for example, studied the relationship between birth weight and
maternal CO exposure based upon neighborhood ambient CO data obtained from stationary
air-monitoring sites in Denver. They failed to show a relationship between these factors, but
failed to control for maternal cigarette smoking or possible occupational exposures to CO.
Carboxyhemoglobin measurements were not made either among the mothers or their offspring
to estimate'net exposure levels. A similar design problem is found in the study of Wouters
et al. (1987), where cord-blood COHb and birth weight were correlated. The authors report
a significant correlation between cigarette smoking and reduced birth weight, but no
correlation between cord-blood COHb and birth weight. Such data might be interpreted to
mean that CO is not the component in cigarette smoke responsible for reduced birth weight.
Such a conclusion appears to be unjustified based upon Wouters et al. (1987) because COHb
is a good estimate of recent CO exposure only. Thus it may indicate only how recently
women in this study smoked their last cigarette before delivery of the child rather than
estimating smoking rates or history throughout pregnancy.
Other studies have related indirect exposure to smoke in pregnancy with reduced birth
weights. Martin and Bracken (1986) showed an association between passive smoking
(exposure to cigarette smoke for at least 2 h/day) and reduced birth weight. Unfortunately,
sidestream smoke contains significant nicotine as well as CO, and so it is not possible to
relate this effect to CO exposure. . ...
Mochizuki et al. (1984) attempted to evaluate the role of maternal nicotine intake in
reduced birth weight and did present evidence of possibly impaired utero-placental circulation
among smokers. These changes were not related specifically to the nicotine content of the
10-156
-------
cigarettes and failed, moreover, to take into account the possible synergistic effects between
reduced perfusion that might have resulted from the vasoconstrictive effects of nicotine and
the reduced O2 availability that might have resulted from CO exposure. As noted in the
section of this report that deals with the effects of high altitude, many of the outcomes of
maternal CO exposure also are observed in offspring of women living at high altitude. These
include reduced birth weight, increased risk of perinatal mortality, and increased risk of
placental abnormalities. Limited data exist on the possibility of increased risk of CO
exposure to the fetus being carried at high altitude. Such findings are^cbiiisidered in the
section on high altitude.
Fechter and Annau (1980b) replicated earlier data from their laboratory showing
significantly depressed birth weights in pigmented rats exposed throughout gestation to
150 ppm CO. Penney et al. (1980) also found a significant depression in birth weight among
rats exposed for the last 18 days of gestation to 200 ppm CO. Penney et al. (1983) showed a
trend toward divergence in body weight among fetuses exposed to 200 ppm CO, which
developed progressively during the last 17 days of parturition, suggesting that late gestatiohal
exposure to CO may be essential to observe the effect. Storm et al. (1986) reported that
following CO exposure from the beginning of gestation through Postnatal Day (PD) 10, body
weight was depressed in a dose-dependent fashion at 75, 150, and 300 ppm CO. Moreover,
these values were all significantly lower than air-control subjects. By age 21 days, no
significant body weight differences were seefi among the test groups. At no time have
Fechter and colleagues observed evidence of maternal toxicity as identified by death, reduced
maternal weight gain, or gross physical appearance. Morris et al. (1985b) exposed neonatal
piglets chronically to CO for 21 days starting at approximately 28 days of age (200 and
300 ppm, COHb levels averaged 16 and 21%, respectively). They reported a significant
impairment in weight gain in pigs exposed to 300 ppm, but no effect in pigs exposed to
200 ppm CO.
10.5.4.3 Alteration in Cardiovascular Development Following Early Carbon Monoxide
Exposure
It is known that a variety of cardiovascular and hematopoietic changes can accompany
hypoxia in neonates and adult subjects, including elevation in Hb, hematocrit, and heart
weight. Data gathered in adult laboratory animals suggest that these changes may be related.
10-157
-------
Cardiomegaly resulting from hypoxia reflects the amount of work performed to extract an
adequate supply of O2. Whether or not the same processes occur in prenatal and neonatal
CO-induced hypoxia has been the subject of several reports (these reports are summarized in
Table 10-29). For prenatal exposure, the accumulated laboratory animal data suggest that
CO-induced cardiomegaly may be proportionately greater than in adult animals at a given
maternal CO-exposure level. Whether or not this is due to higher fetal COHb levels, as a
consequence of fetal Hb's affinity for CO is not clear. Although the cardiomegaly may
resolve when the neonatal 'subject is placed in a normal air environment, there is evidence for
a persisting increase in the number of muscle fibers. The functional significance of these
changes, if any, is uncertain. The LOEL for fetal cardiomegaly has not been well
determined. One experiment has shown significant elevation of heart weight following CO
exposures as low as 60 ppm (Prigge and Hochrainer, 1977) and there are no published dose-
response experiments that provide a NOEL. Chronic prenatal CO exposure at approximately
200 ppm results in a significant increase in the number of muscle fibers in the heart. The
NOEL for this change has not been determined.
Fechter et al. (1980) measured wet- and dry-heart weight and protein and nucleic acid
levels at several time points between birth and weaning in rats prenatally exposed to 150 ppm
CO or to air. They reported that neonates had significantly elevated wet-heart weights
despite a slightly reduced body weight at birth. Groups did not differ at birth in dry-heart
weight, total protein, or KNA or DNA levels in whole heart. No significant differences
between groups on any measure were present at PD 4 or subsequent ages studied. The data
were interpreted as evidence for cardiac edema rather than a change in heart-muscle mass
itself. The finding of a heavier heart at birth replicated the finding of Prigge and Hochrainer
(1977), who exposed rats prenatally to CO at levels as low as 60 ppm and observed a similar
increase in heart weight. Clubb et al. (1986) have conducted a comprehensive experiment in
which rats were exposed to 200 ppm CO either prenatally from GD 7 (CO/air), prenatally
and postnataUy until age 28 days (CO/CO), only postnatally for various durations (air/CO),
or to air (air/air). Subjects were sacrificed at different ages and ventricular wet and dry
weights and myocyte volume and number were measured histologically so that estimates of
cell size and cell number could be made. They observed increases in right ventricular weight
due to fetal CO exposure, and increases in left ventricular weight following neonatal CO
10-158
-------
TABLE 10-29. CONSEQUENCES OF PRENATAL CARBON MONOXIDE EXPOSURE ON CARDIOVASCULAR
DEVELOPMENT IN LABORATORY RATSa
COHb
Exposure (%)
150 ppra CO, 15
GDs 1-21
230 ppm CO, 24
GD2-PD21 24
60,125,250, ND
500 ppm CO
157,. 166, 24.9
200 ppm CO,
GDs 5-22
200 ppm CO 27.8
30, 90 ppm CO 4.8-8.8
200 ppm CO
from GD 7-PD
28 ND
GD 7-PD 1
PD 1-28
Wet-Heart
Body Weight Weight
Increased
Decreased ND
Decreased Increased
Decreased Increased
ventricles
Decreased Increased
- __ „
•
Increased
at birth
Decreased at
PD 28
Decreased at Increased at
PD 21 and birth
PD28
Heart/Body Dry-Heart Total ;
Weight Weight Hematocrit Hemoglobin
Increased Decreased ND ND
Increased ND Increased Increased
PD 5 PD 5 PD 5
Increased ND Decreased, Decreased,
250-500 ppm 250-500 ppm
Increased Increased —
Increased ND
ND .
Increased " - ND ND
Increased -- .ND
Increased — ND
Other
Nucleic acid protein
unchanged, no
significant differences
at PDs 4-21
Increased LDH M
subunit, increased
DNA content
No lasting effects of
prenatal exposure
Prenatal CO
increased myocytes
in right ventricle,
postnatal CO increased
myocytes in left
ventricle
References
Fechter et al.
(1980)
Hoffman and
Campbell
(1977)
Prigge and
Hochrainer
(1977)
Penney et al.
(1983)
Penney et al.
(1980)
Garvey and
Longo (1978)
Clubb et al.
(1986)
-------
TABLE 10-29 (cont'd). CONSEQUENCES OF PRENATAL CARBON MONOXIDE ]
CARDIOVASCULAR DEVELOPMENT IN LABORATORY RATSa
)SUREON
9
i—>
OS
o
Exposure
500 ppm CO
PDs 1-32 (CO
gradually
increased from
PDs 1-7)
300 and
700 ppm CO
PDs 1-32 (CO
gradually
increased from
PDs 1-7)
500 ppm CO
PDs 1-32 (CO
gradually .
increased from
PDs 1-7)
500 ppm CO
PDs 1-32 (CO
gradually
increased from
PDs 1-7)
COHb
(%) Body Weight
ND
Approximately Decreased in
30 and 50% 700-ppm CO
group only
in adulthood
ND Decreased
only during
CO exposure
ND Decreased
during CO
exposure
Wet-Heart
Weight
Elevated in
adulthood
Increased in
700-ppm CO
group only
in adulthood
ND
Increased
during CO
exposure
Heart/Body
Weight
Elevated in
adulthood
Increase in
700-ppm CO
group only in
adulthood
Increased
during
exposure
Increased
during CO
exposure
-
Dry-Heart Total
Weight Hematocrit Hemoglobin Other
ND Increase at ND
some ages in
adulthood
Decrease in Increased in ND
dry/wet females in
heart adulthood
weight in
females
ND ND ND
ND Increased ND
during CO
exposure
Heart rate
elevated 10-15%
in adulthood. No
effect on blood
pressure
No consistent
effect on heart
rate at 'either
exposure level.
Elevated
ventricular DNA
levels in
adulthood
Exercise in
adulthood
increased atrium
to body weight
ratio. CO in
neonatal period
produced small
additional effect
References
Penney et al.
(1984b)
Penney et al.
(1988b)
Clubb et al.
(1989)
Penney et al.
(1989)
"See glossary of terms and symbols for abbreviations and acronyms.
-------
exposure. As in the case of Fechter et al. (1980), they showed a gradual return to normal
heart weight when prenatally exposed neoflates were placed in an air environment neonatally.
They attributed the reversal of eardiomegaly hi the CO/air group to a loss in cell volume
rather than a loss in cell number (which remains elevated). Myocyte volume did not differ
between CO and air subjects at birth. Left ventricle plus septum and right ventricle cell
volumes of the CO/CO group were smaller than controls at 28 days of age despite the heavier
wet-heart weight shown by the CO/CO subjects. Clubb et al. (1986) report that prenatal CO
increased right ventricular myocyte number and that neonatal CO exposure increased left
ventricular myocytes, suggesting that eardiomegaly in early development is related to
increased hemodynamic load. This possibility is supported by reports from Penney et al.
(1983) showing that prenatal exposures to CO levels between 157 and 200 ppm during the
last 17 days of gestation did lead to a significant elevation in DNA content among treated
subjects. Moreover, hydroxyproline content, an indicator of collagen, also was increased
following the CO exposure as was cardiac LDH M subunit among the 200-ppm CO subjects.
Penney et al. (1980) compared the effects of prenatal CO exposure at a dose of
200 ppm with exposure both prenatally and neonatally until age 29 days. Neonatal CO
concentrations were elevated to 500 ppm. Cardiomegaly and depressed Hb, hematocrit, and
RBC counts were found following CO exposure. In subjects allowed to survive until young
adulthood, the HW/BW of subjects receiving CO both prenatally and neonatally still was
elevated, whereas those in the prenatal CO condition did not differ from control subjects in
this measure. Penney and colleagues have published a series of papers that propose that the
neonatal period is a time when CO exposure might produce persisting cardiovascular
consequences. Typically their experimental protocol involves exposure of rats to CO from
soon after birth until PD. 3.3. Carbon monoxide levels are increased in step-wise fashion
during the first week of neonatal life, reaching the nominal CO exposure level by PD 7. .
Spectrophotometric determination of COHb levels were reported in one manuscript published
by these authors to be approximately 30% for subjects exposed to peak CO values of
350 ppm, 40% for subjects receiving 500 ppm, and 50% for those exposed to 700 ppm CO. .
(Penney et al,, 1988b). The treatment produces significant reductions in body weight (Penney
et al., 1988b), elevated hematocrit (Penney et al., 1988b; Penney et al., 1989), and
significant increases in heart weight (left ventricle plus septum and right ventricle) above
10-161
-------
control subjects at the end of CO exposure to 350 ppm (Penney et al., 1989). The elevation
in heart weight partially recovers as subjects mature although in some studies (e.g., Penney
et al., 1984b) persistent effects were observed into adulthood when neonatal CO levels were
500 ppm. In other studies, the elevation in heart weight or the HW/BW resulting from
500-ppm CO exposure neonatally was no longer present in adulthood (e.g., Clubb et al.,
1989). Penney et al. (1984a) also suggested a 10 to 15% increase in adult heart rates
associated with neonatal exposure to 500 ppm CO, but this effect was not replicated using
350- and 750-ppm CO exposure (Penney et al., 1988b). Further, there was no evidence for
an increase in blood pressure or other functional changes that might explain the tachycardia
associated with 500-ppm CO exposure. Finally, a recent paper (Penney et al., 1989)
suggested possible additive effects of neonatal exposure to 500 ppm CO and exercise-induced
changes on adult heart size. Analysis of these effects are complicated by particularly large
effects of exercise on atrial weight rather than ventricular weight.
To summarize, there is good evidence for the development of severe cardiomegaly
following early life CO exposure at doses between 60 to 200 ppm. These effects are
transitory if exposure is prenatal and it is not clear whether they alter cardiac function or
produce latent cardiovascular effects that may become overt later in life. Persisting elevation
in heart weight results from combined prenatal CO exposure at 200 ppm and neonatal
exposure at 500 ppm. The LOEL for this effect has not been determined.
There are many published reports suggesting some residual increase in heart weight
«.
associated with neonatal CO exposures of 500 ppm and greater, maintained over the first
33 days of life. Even granting a small (10 to 15%) increase in heart rate found in one study
among subjects exposed to 500 ppm CO neonatally, there is no evidence that neonatal CO
exposure has functional consequences for experimental subjects.
10.5.4.4 Neurobehavioral Consequences of Perinatal Carbon Monoxide Exposure
The Developmental Toxicology Guidelines published by the U.S. Environmental
Protection Agency (Federal Register, 1986) recognized the importance of neurobehavioral
investigations as a means of assessing nervous system function. Behavior is an essential
function of the nervous system and abnormalities in this outcome can be diagnostic for
particular neurological disorders or for nervous system dysfunctions. The LOEL for such
10-162
-------
effects appears to be in the range of 125 to 150 ppm using a variety of behavioral tasks in
experimental animals, though isolated studies suggest possible anomalies in the range of 60 to
65 ppm. These studies are summarized in Table 10-30. There are a limited number of
human case reports that also are described here (see Table 10-31 for summary). However,
those reports generally are not adequate for evaluating a threshold for persisting
neurobehavioral impairments in children.
Crocker and Walker (1985) reported on the consequences of acute CO exposure in
28 children, of which 16 had COHb levels over 15% and were considered to have had
"potentially toxic" COHb levels. These children were between the ages of 8 months and
14 years. The authors report nausea, vomiting, headache, lethargy, and syncope to be the
most common signs and symptoms. A very limited follow-up investigation was performed
with these children and so no conclusions can be drawn from this work concerning persisting
effects. In addition to very large differences in the nature (dose and duration) of exposure,
the extreme variability in patient age limits the potential value of the data presented in this
work. The absence of any reports from children having COHb levels of 15% or less (a very
significant COHb level) is regrettable because these are the children one must study to
develop an understanding of the relationship between dose and effect for the purpose of
setting standards for ambient air.
Klees et al. (1985) conducted a more comprehensive study of the consequences of
childhood CO exposure on subsequent behavioral development. They report that the age at
which exposure occurred, its severity, and also the child's intellectual level at the time of
exposure also play a role in the outcome. Younger children tended to show somewhat milder
symptoms if they did recover fully than did children who were older at the time of CO
exposure. Subjects who had higher intellectual function prior to accidental exposure also
appeared to fare better after CO exposure. However, the authors stress that long-term
perceptual and intellectual consequences of CO exposure may occur that are not identified
well in short-term cursory examinations. Of 14 children followed up for 2 to 11 years after
intoxication only 1 showed no sequelae (despite COHb levels of 42% on admission to
hospital at the age of 9 years 10 months). Seven children had impairment of visual memory
and concentration, but normal IQ scores. These children had "slight or medium" exposure
10-163
-------
TABLE 10-30. NEUROBEHAVIORAL CONSEQUENCES OF PRENATAL CARBON MONOXIDE
EXPOSURE IN LABORATORY ANIMALS3
Species (strain) Maternal/Neonatal Treatment Maternal/Embryonic Toxicity
Developmental Abnormality
References
ON
Rat
(Sprague-Dawley)
Rat
(Long-Evans)
Rat
(Long-Evans)
Mouse
(Swiss-Webster)
Rat
(Long-Evans)
10,000 ppm CO for 2 or 3 h on Acute effects: loss of righting
GD 15; no cross-fostering reflex followed by coma. Litter
size normal; COHb levels of
approximately 50%
26 % increase in exploratory
activity in figure-8 maze at
PD 30 (3-h exposure)
150 ppm CO throughout
gestation; no cross-fostering
150 ppm CO throughout
gestation; no cross-fostering
CO exposure throughout
gestation; no cross-fostering
CO exposure throughout
gestation; no cross-fostering
Litter size normal; no differences
in neonatal mortality; COHb levels
of 15%
No difference in Utter size or fetal 3.3 % decreased birth weights and
mortality; COHb levels of 12.2- decrease in preweaning weights;
decreased locomotor response to
L-dopa in open field (PD 4 and
PD 14); increased rate of
habituation (PD 14)
4.9 % decreased birth weights and
decrease in preweaning weights;
decreased response to L-dopa (in
open field) at PD 1, PD 4 (also
decreased dopamine levels);
increase in rate of habituation of
activity (PD 14)
Increased errors in heat-motivated
Y-maze at PD 40
Decreased acquisition and 24-h
retention of two-way active
avoidance (PD 30); neither
multiple measures nor use of
pseudo-conditioning controls
similarly affected
ND; Maternal COHb levels of
6-11%
Maternal weight gain, gestation
length, and litter size normal;
COHb levels of 15.6%
Daughtrey and Norton
(1983)
Fechter and Annau (1976)
Fechter and Annau (1977)
Abbatiello and Mohnnann
(1979)
Mactutus and Fechtef
(1984)
-------
TABLE 10-30 (cont'd). NEUROBEHAVIORAL CONSEQUENCES OF PRENATAL CARBON MONOXIDE
EXPOSURE IN LABORATORY ANIMALS*
Species (strain) Maternal/Neonatal Treatment Maternal/Embryonic Toxicity
Developmental Abnormality
References
o
Ui
Rat
(Long-Evans)
Rat
(Long-Evans)
CO exposure throughout
gestation; no cross-fostering
ND; COHb levels of 15.6%
Mactutus and Fechter
(1985)
150 ppm CO throughout
gestation; cross-fostering
for weight measures
ND; no COHb levels
Normal two-way avoidance
acquisition with moderate or
difficult task requirements
(PD 120), but minimal (24-h) and
pronounced (28-day) decreased
retention; decreased acquisition
and retention of two-way
avoidance (PDs 300-360)
7.6% decrease in birth weights Fechter and Annau
and decreased preweaning weights; (1980a,b)
decreased negative geotaxis
(PD 3); decreased homing
behavior (PDs 3-5)
"See glossary of terms and symbols for abbreviations and acronyms.
-------
TABLE 10-31. CONSEQUENCES OF HUMAN CARBON MONOXIDE INTOXICATION DURING
EARLY DEVELOPMENT3
Characterization of
Exposure11
Approximate COHb Level
Immediate Symptoms and
Their Frequency
Persisting Symptoms and Their
Frequency after Hyperbaric 02 and
Normobaric 02 Therapy
References
Light
Medium
4-27%
6-36%
o
t—1
o\
Severe
Accidental at 13 weeks of
age
Accidental at 21 days' old
28 pediatric exposures
37%
6.7% 4 h after exposure
(> 15% at time of removal
from CO)
Threshold value at which
symptom was first observed in
any subject
15%
16.7%
19.8%
18.6%
24.5%
36.9%
Hyperreflexia (1/3) auditive
memory impairment and spatial
orientation problems (1/3)
ND (6/12)
Coma (1/12)
Unconscious (1/12)
Normal (2/12)
Coma-developmental level
Regression (language and motor)
Violent anger/nervousness (1/1)
Convulsion, hypotonic,
unconscious (1/1)
Lethargy, vomiting (1/1)
Asymptomatic
Nausea/headache
Vomiting
Lethargy
Visual symptoms/syncope
Seizures
Auditive and visual memory impairment Klees et al.
(1/3) (1985)
Anxiety or emotional instability (3/12)
Memory impairment (2/12)
Spatial/temporal disorganization
and perceptual problems (3/12)
None or questionable effect (4/12)
Persistent emotional instability (1/1)
Recovery of minor neurologic deficits
by 6 weeks (1/1)
None
Klees et al.
(1985)
Klees et al.
(1985)
Venning et al.
(1982)
O'Sullivan
(1983)
Headaches, memory deficit, decline in Crocker and
school performance (3/28) Walker (1985)
-------
o
TABLE 10-31 (cont'd). CONSEQUENCES OF HUMAN CARBON MONOXIDE INTOXICATION DURING
EARLY DEVELOPMENT3
Characterization of
Exposure15
Approximate COHb Level
Persisting Symptoms and Their
Immediate Symptoms and Their Frequency after Hyperbaric O2 and
Frequency Normobaric O2 Therapy
References
Light (6/14)
Medium (5/14)
Severe (3/14)
19-42% Somnolence (2/6)
Headache/nausea (3/6)
16-42% Incontinent (1/5)
Unconscious (4/5)
-
?-13% Vigil coma (3/3)
Perceptual (2/6)
Memory (3/6)
Emotional (1/6)
Psychomotor (1/6)
Cognitive (3/6)
Perceptual (1/5)
Memory (1/5)
Emotional (2/5)
Cognitive (2/5)
Perceptual (2/3)
Cognitive (3/3)
Klees et al.
(1985)
Klees et al.
(1985)
Klees et al.
(1985)
"See glossary of terms and symbols for abbreviations and acronyms.
Exposure duration and level of CO exposure are poorly defined in all studies. Exposures are grouped according to authors' descriptive characterization when
available rather than COHb level. The latter varies widely with group.
-------
(COHb levels in the low to mid-twenties) and no coma! The six children with serious
learning disorders did not have more severe CO exposures as judged from their COHb levels.
They include several cases where 'exposures did occur at a young age, and in children who
had psychological difficulties prior to CO exposure. This study leaves some question
concerning the relative vulnerability of children to CO as a function of their age as several of
the youngest children did make full recovery while others did not. It seems likely that the
child's age may have an influence on the duration of CO exposure that is survivable and
perhaps also on the promptness with which either hospitalization or measurement of COHb
levels is made. Further study of the outcomes of childhood CO exposures will be useful in
determining whether there are differences with respect to vulnerability to CO level. Venning
et al. (1982) report on a case of acute CO poisoning in a 13-week-old baby who had
profoundly elevated COHb levels (60% 2 h after removal from the automobile in which she
accidentally was exposed to CO). Her parents had much lower COHb values, though this
may reflect differences in concentration of CO inhaled. The child was reported to be
unconscious for 48 h, to go through convulsions over the next 18 days, but, again, to show
recovery from "minor neurological abnormalities" by 6 weeks later. There have been a series
of experiments reported in rodents that identify both persistent neurobehavioral effects of
prenatal CO exposure and also transient effects that may be symptomatic of functional delays
in development. Fechter and Annau (1980a,b) reported delays in the development of
negative geotaxis and homing in rats exposed prenatally to 150 ppm CO (maternal COHb
levels were not reported in this paper, but levels previously reported in this laboratory under
that exposure regimen are 15 to 17% [Fechter and Annau, 1977]). These data were
replicated by Singh (1986) using CD-I mice exposed to 0, 65, and 125 ppm CO from GD
7 to 18. He found that exposure at 125 ppm significantly impaired the righting reflex on
PD 1 and negative geotaxis on PD 10. He also reported impaired aerial righting among
subjects exposed prenatally to 65 or 125 ppm CO. Morris et al. (1985a) studied the
consequences of moderate CO exposure given very late in gestation. They exposed pigs to
200 and 250 ppm CO (COHb levels of 20 and 22%) from GD 109 until birth. They found
impairment of negative-geotaxis behavior and open-field activity 24 h after birth in pigs
exposed to 250 ppm. Activity in the open field was significantly reduced in subjects exposed
to both 200 and 250 ppm 48 h after birth. The significance of these behavioral dysfunctions
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is that they point to delays in behavioral.development that may themselves contribute to
impairments in the way in which the individual interacts with its environment.
There also are reports of impaired cognitive function produced by prenatal CO that may
be related to permanent neurological damage. Mactutus and Fechter (1984) showed poorer
acquisition and retention of a learned active avoidance task in rats of 30 to 31 days of age
that had received continuous prenatal exposures of 150 ppm CO. This study is noteworthy
because very careful efforts were made to distinguish cognitive deficits and performance
deficits such as motivational, emotional, or motor factors. These findings were replicated
and extended by Mactutus and Fechter (1985). They studied the effects of prenatal exposures
to 150 ppm CO (16% maternal COHb) on learning and retention in weanling, young'adult,
and aging (1-year-old) rats. They found that both the weanling and young adult rats showed
significant retention deficits, whereas in aging adults, impairments were found in both
learning and retention relative to control subjects. They interpreted these results to mean that
there are permanent neurological sequelae of prenatal CO exposure. They raise the important
issue that sensitivity of tests for consequences of early toxic exposure may reflect the
developmental status of the test subject and complexity of the task. In this case, a learning
impairment not observed in the early adult period was detected by working with aged
subjects. No systematic attempts have been made to replicate these effects using lower levels
of CO. One earlier study (Abbatiello and Mohrmann, 1979) suggested an increase in the
number of errors made by mice prenatally exposed to CO throughout gestation (maternal
COHb levels were 6 to 11%) and required to learn a maze discrimination task at 6 weeks of
age. The absence of many details concerning the manner in which the control subjects were
handled during pregnancy and the absence of details in the exposure protocol make it difficult
to draw firm conclusions from this paper. ,
10.5.4.5 Neurochemical Consequences of Prenatal and Perinatal Carbon Monoxide
Exposure
A significant number of studies have appeared concerning the consequence of acute and
chronic prenatal and perinatal CO exposure upon a variety of neurochemical, parameters.
These experiments are important because the transmission of information between nerve cells
is based upon neurochemical processes. Neurotransmitters can sometimes serve as markers
for the development of specific neurons in the brain, thereby serving as a sensitive alternative
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to histopathologic investigation, particularly when the toxic agent selectively lesions neurons
based upon a biochemical target. The absence of a specific cell group identified by
neurochemical methods may have important consequences for subsequent brain development
because the absence of targets for synapse formation can have additional consequences on
brain development. Altered neurochemical development has been observed at CO-exposure
levels lower than those necessary to produce signs of maternal toxicity or gross teratogenicity
in the neonates. Chronic prenatal and perinatal exposures to 150 to 300 ppm CO have been
shown to yield persisting alterations in norepinephrine, serotonin, and •y-aminobutyric acid <
(GABA) levels and in GABA uptake in rats. There also are a substantial number of acute
exposure studies that have demonstrated neurochemical effects of CO. However, these
generally have been conducted at life-threatening levels and are not particularly relevant to
setting ambient air standards for CO.
Storm and Fechter (1985a) and Storm et al. (1986) have carefully studied the
developing cerebellum because this structure shows a rather slow developmental pattern and
has been shown to be sensitive to hypoxic injury. The cerebellum plays prominent roles in
many diverse functions. It is a part of the extra-pyramidal motor system, and it plays an
important role in maintaining balance. The cerebellum also receives diverse sensory inputs
and plays a role in sensory-motor integration. The cerebellar cortex contains a diverse group
of neurons whose organization has been studied very well. The intrinsic neurons of the
cerebellum—those having their cell bodies and axonal processes within this structure—consist
of the granule, pyramidal, stellate, basket, and Golgi cells. The granule cells use the
excitatory amino acid glutamate as their neurotransmitter and synapse on the pyramidal cells.
The other intrinsic cells of the cerebellum appear to use the inhibitory amino acid GABA as
their neurotransmitter. The Purkinje cells, being extremely large in size, probably contribute
considerably to the total GABA levels found in the cerebellum.
The cerebellum receives several different neurotransmitter inputs from other brain
regions. The most important of these is a noradrenergic input from the brainstem, a
cholinergic link via mossy fibers, and possibly aspartate or glutamate climbing fibers.
Storm and Fechter (1985a) reported that chronic prenatal CO exposures of 150 ppm CO
(approximately 16 to 18% COHb based upon other research in this laboratory) decreased
cerebellar wet weight, but increased norepinephrine levels in this structure when expressed
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either in terms of concentration (nanograms per milligram wet weight) or total cerebellar
content above control values between the ages of 14 to 42 days. This period represented the
duration of the experiment. Although this persisting elevation in norepinephrme cannot be
considered permanent, it is the case that rats do obtain normal adult values of monoamine
neurotransmitters at about the age of 40 to 45 days. There was no effect of CO treatment on
norepinephrine levels in the cerebral cortex. Because noradrenergic neurons have their cell
bodies outside of the cerebellum and project axons that terminate on cell bodies in this
structure, Storm and Fechter's data may reflect an effect of increased noradrenergic
innervation secondary to toxic injury to target neurons in the cerebellum. Consistent with
this hypothesis, Storm et al. (1986) reported deficits in cerebellar weight, but more
importantly deficits in markers of GABA-ergic activity in the cerebellum following prenatal
and perinatal CO exposures. GABA is thought to be an inhibitory neurotransmitter present in
several neurons that are intrinsic to the cerebellum. Subjects in this experiment received 0,
75, 150, and 300 ppm CO (corresponding maternal COHb levels were 2.5, 11.5, 18.5, and
26.8%) from the beginning of gestation until PD 10. Neurochemical measurements were
made either on PD 10 or on PD 21. They showed reduced total GABA levels in the
cerebellum following either 150- or 300-ppm CO exposure at both measurement times. They
also reported a significant reduction in total GABA uptake, but not glutamate uptake in
synaptosomes prepared from cerebella of 21-day-old neonates. Glutamate is an excitatory
neurotransmitter found within the cerebellum. Histological markers of cerebellar toxicity also
were obtained that were compatible with the neurochemical data and these are described
below under histopathology.
In a subsequent paper, Storm and Fechter (1985b) evaluated norepinephrine and
serotonin levels at PDs 21 and 42 in four different brain regions (pons/medulla, neocortex,
hippocampus, and cerebellum) following chronic prenatal exposures to 75, 150, and 300 ppm
CO. They reported that norepinephrine and serotonin concentrations decreased linearly with
dose in the pons/medulla at 21 but not 42 days of age (i.e., evidence of a transient effect);
the LOEL was 150 ppm. Norepinephrine increased linearly with CO dose in the neocortex at
42, but not at 21 days of age. They also showed that cerebellar weight was significantly
reduced for the 150- and 300-ppm-exposed rats when measured on PD 21 and for the
300-ppm-exposed rats at 42 days of age.
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10.5.4.6 Morphological Consequences of Acute Prenatal Carbon Monoxide
Profound acute CO exposures do result in obvious neurological pathology that can be
predicted to be inconsistent with life or with normal neurological development. These data
are not as relevant to setting standards for ambient air quality as they are in demonstrating
both the danger of accidental high-level CO exposures and in providing possible insight into
the susceptibility of the developing brain to toxic exposure. The one possible exception is a
study conducted in fetal pigs exposed via the mother to 300 ppm CO for 96 h (Dominick and
Carson, 1983). The authors reported quite marked sensitivity to the CO as reflected in
fetotoxicity, but also identified multifocal hemorrhages and vacuolation of the neuropile ''"
throughout the cortical white matter and brain stem. They also observed cerebellar edema
with swollen oligodendrocytes and astrocytes, two nonneuronal cell types that have important
roles in supporting neural function. ,
Okeda et al. (1986) studied the effects of 2,000- to 3,000-ppm CO exposure for 76 to
150 min in cats of different gestational ages. They suggest a different pattern of neurological
damage in cats exposed late versus those exposed early to the CO. In late gestation, the
primary changes were seen in cerebral white matter and the brain stem. The basal ganglia
and thalamus were affected less and the cerebral cortex was even less affected. Kittens
exposed to CO at an early gestational age show less histopathology than those exposed later.
Cerebral white matter and the basal ganglia tended to be most affected by early CO exposure.
Daughtrey and Norton (1982) studied the effect of exposing pregnant rats (GD 15) to
1,000 ppm CO for 3 h on CNS development of the fetuses on GD 16. Estimated maternal
COHb levels reached about 50%. They reported 13 to 28% fetotoxicity (lethality) and
described hemorrhagic infarcts and the most consistent damage to the ventral germinal matrix
overlying the caudate nucleus. Further study (Daughtrey and Norton, 1983) indicated
damage to the dendritic branches of Golgi type n neurons in the CO exposed fetuses.
Storm et al. (1986) showed that exposure of rats to 300 ppm CO (maternal COHb levels
of 26.8%) throughout gestation and until Day 10 after gestation resulted in a noticeably
smaller cerebellum at PD 21. The cerebellum of exposed neonates had fewer fissures than
normal controls.
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Full characterization of the histopathological effects of very low, subchronic CO
exposure on development are impeded by the absence of additional research in the published
literature.
10.5.5 Summary
The data reviewed provide strong evidence that prenatal CO exposures of 150 to
200 ppm (=15 to 25% maternal COHb levels) produce reductions in birth weight,
cardiomegaly, delays in behavioral development, and disruption in cognitive function in
laboratory animals of several species. Isolated experiments suggest that some of these effects
may be present at CO concentrations as low as 60 to 65 ppm (=6 to ll%.CQHb) maintained
throughout gestation. The current data from human children suggesting a link between
environmental CO exposures and SIPS are weak, but further study should be encouraged.
Human data from cases of accidental high dose CO exposures are difficult to use in
identifying a LOEL or NOEL for this agent because of the small numbers of cases reviewed
and problems in documenting levels of exposure. However, such data, if systematically
gathered and reported, could be useful in identifying possible ages of special sensitivity to CO
and cofactors or other risk factors that might identify sensitive subpopulations.
10.6 OTHER SYSTEMIC EFFECTS OF CARBON MONOXIDE
Studies (see Table 10-32) reviewed in the previous criteria document (U.S.
Environmental Protection Agency, 1979) and again in Chapter 9 of this document suggest
that, enzyme metabolism of xenobiotic compounds may be affected by CO exposure
(Montgomery and Rubin, 1971; Kustov et al., 1972; Pankow and Ponsold, 1972, 1974;
Martynjuk and Dacenko, 1973; Swiecicki, 1973; Pankow et al., 1974; Roth and Rubin,
1976a,b). Most of the authors have concluded, however, that effects on metabolism at low
COHb levels (< 15%) are attributable entirely to tissue hypoxia produced by increased levels
of COHb because they are no greater than the effects produced by comparable levels of
hypoxic hypoxia. At higher levels of exposure, where COHb concentrations exceed 15 to
20%, there may be direct inhibitory effects of CO on the activity of mixed-function oxidases,
but more basic research is needed (see Section 9.4). The decreases in xenobiotic metabolism
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TABLE 10-32. OTHER SYSTEMIC EFFECTS OF CARBON MONOXIDE
Exposure1'1'
Increasing exposure to
3,000 ppm at 100 days
0.8 or 3.0 % until death
250, 500, and
1,000 ppm for 24 h
Accidental exposure
50 ppm
17 ppm
250-3,000 ppm for
90 min
50 ppm for 3 mo
Subcutaneous CO at
7.2 and 9.6 mol/kg;
40 injections in 53 days
COHb°
ND
n « 3645
71.3% or
79.2%
ND
3.4-32%
ND
ND
20-60%
ND
50%
Subjects)
Rat
Rat
(n = 5 per
group)
Rat
(n - 36)
Human
(n = 6)
Rat
(n = 92)
Rat
(n-95)
Rat
(n = 10-20
per group)
Rat
(n = 100)
Rabbit
(n = 40)
Dog
(n = 4)
Rat
(n = 20-30)
Observed Effects*
Few weight gains during first 100 days,
increased weight gain in last 200 days
Increased plasma levels of leucine
aminopeptidase. No change in state-4
respiration of mitochondria, decreased state-3
rate in CO-exposed rats
Decreased food and water intake, decreased
weight gain
Increased serum phosphocreatine-kinase
Decreased liver cytochrome oxidase, increased
liver succinate dehydrogenase
Increased aspartate and alanine amino
transferase activity
Prolonged response to hexobarbital at
1,000 ppm and to zoxazolamine at 250 ppm
No effect on body weight
Increased leucine aminopeptidase activity in
the liver with single and repeated injections,
increased liver weight with repeated injections
Conclusions
No significant body weight
effect
Acute CO poisoning caused
damage to liver mitochondria
Significant body weight effect
Diffuse myolysis indicative of
acute renal failure
Tissue hypoxia
Tissue hypoxia
Decreased xenobiotic
metabolism
No significant body weight
effect
Reference
Campbell (1934)'
Katsumata et al.
(1980)
Koob et al. (1974)°
Kuska et al. (1980)
Kustov et al.
(1972)°
Martynjuk and
Dacenko (1973)°
Montgomery and
Rubin (1971)"
Musselman et al.
(1959)°
Pankowand
Ponsold (1972,
1974)c
-------
TABLE 10-32 (cont'd). OTHER SYSTEMIC EFFECTS OF CARBON MONOXIDE
Exposure"'1"
COHb° Subject(s)
Observed Effectsd
Conclusions
Reference
-
CO exposure combined
with 1 % ethanol
500 ppm
40-50% Rat
Increased leucine aminopeptidase activity in the
Pankow and
(n = 110) liver, enlarged liver with ethanol
ND
Ponsold (1974)c
Pankow et al.
(1974)°
Rat Decreased rate of hexobarbital metabolism, no Hypoxic hypoxia more effective Roth and Rubin
ND
5,000 and 10,000 ppm ND
for 3 min, 6-12 times
daily for 3-4 weeks
50 ppm for 95 h/week ND
up to 2 years; 1- to
3-mo exposures
1 % for 15 min , ND ,
400-500 ppm for ND
168' days
0.24% for 42-180 days ND
(n = 7-8
per group)
Rat -
Guinea pig
(n=V-9
per group)
Rat
(n = 336)'
Mouse
(n = 767)
Rat". . .
" ' (n = 60)
Rat .
(n = 136)
Mice
(n = 81) •
effect on hepatic blood flow
Decreased rate of hexobarbital metabolism in
isolated liver, CO hypoxia more effective than
hypoxic hypoxia
Increased number of alveolar macrophages and
PMNs in lung lavage, reduced number of
plague-forming cells in spleen with high
exposure1 '
No effect on body weight
Stimulation of adrenergic system
Trend toward lower body weight
Planimetric measurement of increased bone
tissue in parietal bones, sternum, lumbar
>-. vertebrae, .and ribs; expansion of marrow
cavities in ribs^ parietal bones-, and femurs
than CO-hypoxia in inhibiting
drug metabolism in vivo
No direct inhibition of drag
metabolism by CO binding to
liver cytochrome P-450
Altered immune capacity with
CO exposure
No significant body weight
effect
• " •• -
Increased carbohydrate
metabolism
No significant body weight
effect ""•'"' '•'•'•••
CO-induced increased blood
flow caused excessive bone
formation • * - . •
(1976b)
Roth and Rubin
(1976b)
Snella and
Rylander(1979)..
Snipfel and
Bquley (1970)°
SwiecicM
(1973);
Theodore et al.
(1971)°
Zebro et al.
(1983)
"Exposure concentration, duration, and activity level. " -•.-,•.•- •.;••-'.
bl ppm" = "i'.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 »C, 760 mmHg; 1% = 10,000 ppm.
"Estimated or measured blood carboxyhemoglobin (COHb) level; ND = not determined.
dSee glossary of terms and symbols for abbreviations and acronyms. , ,
"Cited in U.S. Environmental Protection Agency (1979). ,. ••:'.. • '. -
-------
shown with CO exposure might be important to individuals receiving treatment with drugs.
The implications of this effect are discussed in Section 12.3.
The effects of CO on tissue metabolism noted above may partially explain the body
weight changes associated with CO. Short-term exposure to 250 to 1,000 ppm for 24 h was
reported previously to cause weight loss in laboratory rats (Kobb et al., 1974) but no
significant body weight effects were reported in long-term exposure studies in laboratory
animals at CO concentrations ranging from 50 ppm for 3 months, to 3,000 ppm for 300 days
(Theodore et al.', 1971; Musselman et al., 1959; Campbell, 1934; Stupfel and Bouley, 1970),
It is quite probable that the initial hypoxic stress resulted in decreased weight gain followed
by compensation for the hypoxia with continued exposure by adaptive changes in the blood
and circulatory system (see Section 10.3). It is known, however, that CO-induced hypoxia
during gestation will cause a reduction in the birth weight of laboratory animals. Although a
similar effect has been difficult to demonstrate in humans exposed to CO alone, there is a
strong correlation between maternal cigarette smoking and reduced birth weight. (See
Section 10.5 for a more complete discussion of fetal effects of CO exposure.)
Inhalation of high levels of CO, leading to COHb concentrations greater than 10 to
15%, have been reported to cause a number of systemic effects in laboratory animals as well
as effects in humans suffering from acute CO poisoning. Tissues of highly active oxygen
metabolism, such as heart, brain, liver, kidney, and muscle, may be particularly sensitive to
CO poisoning. The impairment of function in the heart and brain caused by CO exposure is '
well known and has been described in other sections of this chapter. Other systemic effects
of CO poisoning are not as well known and are, therefore, less certain. There are reports in
the literature (see Table 10-32) of effects on liver (Katsumata et al., 1980), kidney (Kuska
et al., 1980), and bone (Zebro et al., 1983). Results from one additional study in adult
guinea pigs suggest that immune capacity in the lung and spleen was affected by intermittent .
exposure to high levels of CO for 3 to 4 weeks (Snella and Rylander, 1979). It generally is
agreed that these systemic effects are caused by the severe tissue damage occurring during
acute CO poisoning due to (1) ischemia resulting from the formation of COHb, (2) inhibition
of O2 release from O2Hb, (3) inhibition of cellular cytochrome function (e.g., cytochrome
oxidases), and (4) metabolic acidosis.
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The effects of CO on visual acuity and dark adaptation, caused primarily by CNS
alterations, were described previously (see Section 10.4). Besides central, effects, however,
acute CO exposure can cause damage at the sensory end-organ level. Observed ocular effects
from acute CO poisoning range from retinal hemorrhages (Dempsey et al., 1976; Kelley and
Sophocleus, 1978) to blindness (Duncan and Gumpert, 1983; Katafuchi et al., 1985). In
addition, peripheral neuropathy and tortuous retinal vessels have been described after chronic,
intermittent exposure to low levels of CO over a 16-month period (Trese et al., 1980). The
authors of the latter report speculated that increased blood flow from low-level, chronic
exposure to CO may lead to the development of a compensatory retinal vascular tortuosity.
With high-level, acute exposures to CO, the compensation will not take place and localized
vascular hemorrhages result. .
Finally, exposure to CO has been associated with direct and indirect mutagenic activity
(van Houdt et al., 1987), as measured by the Salmonella/microsome test (Ames et al., 1975).
When tested in human populations living in the San Francisco Bay area, however, no
significant association was found between ambient levels of CO and site-specific cancer
incidence (Selvin et al., 1980). A case-control study of persons with newly diagnosed
multiple myeloma living in four geographical locations of the United States found an
increased risk for self-respondents reporting an exposure to combustion products including
CO (Morris et al., 1986). The difference in number of cases was small when compared to
geographically matched controls and the exposure was not defined well. Given the limited
information available at this time, it is unlikely that exposure to CO would contribute
significantly to the development of cancer in nonoccupationally exposed individuals.
10.7 ADAPTATION, HABITUATION, AND COMPENSATORY
RESPONSES TO CARBON MONOXIDE EXPOSURE
This section considers whether or not exposure to CO eventually will lead to the
development of physiological responses that tend to offset some of the deleterious effects.
Although there is possibly a temporal continuum in such processes, in this review the term
"adaptation" will be used to refer to long-term phenomena, and the term "habituation" will
refer to short-term processes. Allusions will be made, where possible, to the physiological
10-177
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chain of events by which adaptation and habituation come about, but extensive reductive
explanations will be avoided. The term "compensatory mechanism" will be used to refer to
those physiological responses that tend to ameliorate deleterious effects, whether in the long-
term or short-term case.
10.7.1 Short-Term Habituation
Arguments have been made for the possibility that there exist short-term compensatory
mechanisms for CO exposure. These hypothetical mechanisms have been (1) based upon
physiological evidence, and (2) used to account for certain behavioral findings reported in the
literature.
There is physiological evidence for responses that would compensate for the deleterious
effects of CO in a very short time span. As discussed in Section 10.4, CO exposure has been
demonstrated to produce an increased CBF, which is apparently produced by cerebrovascular
vasodilation. It also has been shown (Doblar et al., 1977; Miller and Wood, 1974;
Traystman, 1978; Zorn, 1972), however, that the tissue PO2 values for various CNS sites fall
in proportion to COHb, despite the increased blood flow. Apparently, the PO2 values would
fall considerably more without the increased blood flow. Although the published graphs of
these data do not show very short time intervals, it appears that tissue PO2 falls immediately
and continuously as COHb rises. Although there is no evidence for time delays or for
threshold effects in these data, it is noteworthy that only very high CO levels were employed.
Thus, the saturation rates were high, and time lags or thresholds would be difficult to detect.
As discussed in Section 10.3, both coronary blood flow and O2 extraction in the
peripheral musculature increase as COHb rises. These, too, are compensatory mechanisms,
but mechanisms that have been shown to be only partly effective. None of the studies
present evidence of time lags or threshold effects, because only terminal or near-asymptotic
values were reported.
The behavioral work upon which short-term habituation hypotheses have been
predicated are mostly human studies, where CO exposure at very low levels or at very early
exposure times (well before asymptotic saturation) have shown performance decrements that
were not apparent with higher or longer exposures (Section 10.4). Depending upon the
particular version, the habituation hypothesis holds that there might exist some threshold
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value of CO below which no compensation would be initiated, or that there might be some
time lag in the compensatory mechanism so that the early effects of CO exposures would
later subside. The behavioral data to support this contention have been controversial and
need to be examined closely.
Most of the hypotheses about compensatory mechanisms were based, however, upon
post hoc reasoning to explain empirical findings, not upon results from experiments to test the
existence or nature of such mechanisms. Disregarding hypothesized time lags and thresholds,
without the compensatory mechanisms, CO would apparently have even more deleterious
effects and the threshold for such effects would be lower.
10.7.2 Long-Term Adaptation
Adaptation is an all-inclusive term that incorporates all of the acute or chronic
adjustments of an organism to a stressor. It does not indicate (or predict) whether the
adjustments are initially or eventually beneficial or detrimental. Acclimatization is an
adaptive process that results in reduction of the physiological strain produced by exposure to
a stressor. Generally, the main effect of repeated,, constant exposure to the stressor is
considered to result in an improvement of performance or a reduced physiological cost. Both
of these phenomenon tend to exploit the reserve potential of the organism.
It generally is agreed that adaptation to lowered levels of oxygen tension and oxygen-
carrying capacity can occur with continued hypoxic exposure. This is evident especially in
healthy individuals living for lengthy periods of time at high terrestrial altitudes. It should be
noted, however, that there is no assurance that individuals moving from low altitudes to
higher ones will attain the physiological adjustment to the higher altitudes that is observed in
natives (viz. natives of the Andes and Himalayas). Prominent features of prolonged altitude
exposures are increases in Hb concentration and hematocrit. Additional alterations are right
ventricular hypertrophy, pulmonary artery vasoconstriction, possible changes in cardiac
output, and increased blood volume due to increases in the red cell mass.
Whether or not adaptation can occur in individuals chronically exposed to various
ambient concentrations of CO remains unresolved. Concern for CO intoxication in England
and Scandinavia led to the speculation that adaptational adjustments could occur in humans
(Grut, 1949; Killick, 1940). These concerns were directed to situations where high ambient
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CO concentrations were present. There are only a few available studies conducted in
humans.
Killick (1940), using herself as a subject, reporte4 that she developed acclimatization as
evidenced by diminished symptoms, slower heart rate, and the attainment of a lower COHb
equilibrium level following exposure to a given inspired CO concentration. Interestingly,
Haldane and Priestley (1935) already had reported a similar finding as to the attainment of a
different COHb equilibrium following exposure to a fixed level of CO in the ambient air.
Killick (1948) repeated her CO-exposure studies in an attempt to obtain more precise
estimations of the acclimatization effects she had noted previously. The degree of
acclimatization was indicated by (1) a diminution in severity of symptoms during successive
exposure to the same concentrations of CO, and (2) a lower COHb level after acclimatization
than that obtained prior to acclimatization during exposure to the same concentrations of
inhaled CO.
Before using herself as a subject, Killick (1937) studied the effects of CO on laboratory
animals. Mice were exposed to successively higher concentrations of CO, which in a period
of 6 to 15 weeks reached levels of 2,300 to 3,275 mg/m3 (2,000 to 2,850 ppm) CO and
produced 60 to 70% COHb. The nonadapted mice exhibited much more extreme symptoms
when exposed to such levels. A control group was used to partially rule out effects of
selection of CO-resistant animals.
Clark and Otis (1952) exposed mice to gradually increasing CO levels over a period of
14 days until a level of 1,380 mg/m3 (1,200 ppm) was reached. When exposed to a
simulated altitude of 34,000 ft, survival of the CO-adapted groups was much greater than
controls. Similarly, Clark and Otis (1952) acclimatized mice to a simulated altitude of
18,000 ft and showed that these altitude-adapted mice survived 2,875 mg/m3 (2,500 ppm)
CO better than controls. Wilks et al. (1959) reported similar effects in dogs.
Gorbatow and Noro (1948) showed that rats given successive daily short-term exposures
could tolerate, without loss of consciousness, longer and longer exposures. Their
CO-exposure levels were 2,875 to 11,500 mg/m3 (2,000 to 10,000 ppm). Increases in
tolerance to CO began to be evident as early as the fourth or fifth day of exposure and still
were occurring as late as the 47th day. Nonexposure for several days eliminated some of the
adaptation. Similar results were reported by Zebro et al. (1976).
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Chronic CO exposure of rats increases Hb concentration, hematocrit, and erythrocyte
counts via erythropoietin production (see Section 10.3.4). Penney et al. (1974b) concluded
that the threshold for the erythropoietin response was 100 ppm (9.26% COHb). Cardiac
enlargement, involving the entire heart during CO exposure (compared to right ventricular
hypertrophy with high-altitude exposure), is induced when ambient CO is near 200 ppm,
producing COHb levels of 15.8% (Penney et al., 1974b). Blood volume of the rat exposed
for 7.5 weeks to CO exposures peaking at 1,300 ppm nearly doubled and erythroeyte mass
more than tripled (Penney et al., 1988a). After 42 days of continuous exposure to 500 ppm,
rat blood volume almost doubled, primarily as a consequence of increases in erythrocytes
(Davidson and Penney, 1988). It should be noted that all the demonstrated effects on tissues
and fluids are induced by long-term exposures to high CO concentrations. McGrath (1989)
exposed rats for 6 weeks to altitudes ranging from 3,300 ft (ambient) to 18,000 ft and to
concentrations of CO ranging from 0 to 500 ppm. At 9 and 35 ppm CO, where COHb levels
ranged from 0.9 to 3.3%, there were no significant changes in body weight, right ventricular
weight, hematocrit, or Hb. Small but nonsignificant changes in these variables were
measured when the CO concentration was 100 ppm and COHb levels ranged from 9.4 to
10.2%. This is consistent with the observations noted above (Penney et al., 1974b)—that the
threshold for erythropoietin effects was 100 ppm.
Besides the level of exposure, the time course of exposure to CO also is important. As
discussed in Section 10.3.4, Hb increases in laboratory animals exposed to CO after about
48 h, and continues to increase in the course of continued exposure until about 30 days,
depending perhaps upon exposure level. This hemopoietic response to long-term CO
exposure is similar to that shown for long-term hypoxic hypoxia, except that it is slower to
start and tends to offset CO hypoxic effects.
1 - ' - - " • • '
Most investigators have at least implied that increased Hb level is the mechanism by
which adaptation occurs. Certainly this explanation is reasonable for the studies showing
increased survival in groups adapted for several days. Little has been done, however, to
elucidate the extent to which such increases offset the deleterious effects of CO. The
probability that some adaptation occurs is supported theoretically due to Hb increases, and
empirically in the findings of laboratory animal studies measuring survival time. But
adaptation has not been demonstrated for specific health effects other than survival time.
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Compensatory increases in Hb are not without deleterious consequences of their own,
such as cardiac hypertrophy (see Section 10.3.4). The Hb increases also are not entirely
compensatory at all CO levels in view of the fact that deleterious effects still occur at some
CO levels for many physiological systems. It is possible, however, that without such
mechanisms as Hb increases, CO effects would be worse or would occur at lower exposure
concentrations.
10.7.3 Summary
The only evidence for short- or long-term COHb compensation in humans is indirect..
Experimental animal data indicate that COHb levels produce physiological responses that tend
to offset other deleterious effects of CO exposure. Such responses are (1) increased coronary
blood flow, (2) increased CBF, (3) increased Hb through increased hemopoiesis, and
(4) increased O2 consumption in muscle.
Short-term compensatory responses in blood flow or O2 consumption may not be
complete or might even be lacking in certain persons. For example, from laboratory animal
studies it is known that coronary blood flow is increased with COHb, and from human
clinical studies it is known that subjects with ischemic heart disease respond to the lowest
levels of COHb (6% or less). The implication is that in some cases of cardiac impairment,
the short-term compensatory mechanism is impaired.
From neurobehavioral studies, it is apparent that decrements due to CO have not
occurred consistently in all subjects, or even in the same studies, and have not demonstrated a
dose-response relationship with increasing COHb levels. The implication from these data
suggests that there might be some threshold or time lag in a compensatory mechanism such as
increased CBF. Without direct physiological evidence in either laboratory animals or,
preferably, humans, this concept only can be hypothesized. The observed results from the
neurobehavioral studies could be explained by differences or problems in experimental
protocols or due to possible nonrandom sampling.
The idea of a threshold or a time lag in compensatory mechanisms should not be
rejected entirely, however. There simply is no direct evidence. Studies need to be
performed to (1) measure CBF and tissue PO2 with low COHb levels at various ambient
concentrations of CO to determine early and low-level effects accurately, and (2) design
10-182
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behavioral studies where threshold effects or time lags are factors in the experimental
protocols that can be explicitly studied.
The mechanism by which long-term adaptation would occur, if it could be demonstrated
in humans, is assumed to be an increased Hb concentration via a several-day increase in
hemopoiesis. This alteration in Hb production has been demonstrated repeatedly in animal
studies, but no recent studies have been conducted indicating or suggesting that some
adaptational benefit has or would occur. Furthermore, even if the Hb increase is a signature
of adaptation, it has not been demonstrated to occur at low ambient concentrations of CO.
The human studies of the 1940s have not been replicated, so the question of adaptation
remains unresolved. '
10-183
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Winn, H. R.; Rubio, R.; Berne, R. M. (1981) Brain adenosine concentration during hypoxia in rats. Am. J.
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Winneke, G. (1974) Behavioral effects of methylene chloride and carbon monoxide as assessed by sensory and
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10-213
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Wouters, E. J. M.; de Jong, P. A.; Cornelissen, P. J. H.; Kurver, P. H. J.; van Oel, W. C.; van Woensel,
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10-214
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11. COMBINED EXPOSURE OF CARBON MONOXIDE
WITH OTHER POLLUTANTS, DRUGS,
AND ENVIRONMENTAL FACTORS
11.1 HIGH ALTITUDE EFFECTS OF CARBON MONOXIDE
11.1.1 Introduction
Precise estimates of the number of people exposed to carbon monoxide (CO) at high
altitude are not readily available. As of 1980, however, more than 4.2 million people
(Lindsey, 1989) were living at altitudes in excess of 1,524 m (5,000 ft). Moreover,
estimates obtained from several states with mountainous regions (i.e., California, Nevada,
Hawaii, and Utah) indicate that more than 35 million tourists may sojourn in high altitude
areas during the summer and winter months.
The potential effects on human health of inhaling CO at high altitudes are complex.
Whenever CO binds to hemoglobin (Hb) it reduces the amount of Hb available to carry
oxygen (O2). People at high altitudes already live in a state of hypoxemia, however, because
of the reduced partial pressure of oxygen (PO2) in the air. Carbon monoxide, by binding to
Hb, intensifies the hypoxemia existing at high altitudes by further reducing transport of O2 to
the tissues. Hence, the effects of CO and high altitude usually are considered to be additive.
This consideration does not take into account the fact that within hours (perhaps sooner)
of arrival at high altitude, certain physiological adjustments begin to take place.
Hemoconcentration occurs and the increased Hb concentration offsets the decreased O2
saturation and restores O2 concentration to pre-ascent levels. Consequently, the simple
additive model of carboxyhemoglobin (COHb) and altitude hypoxemia may be valid only
during early altitude exposure.
The visitor newly arrived to higher altitudes may be at greater risk from CO than the
adapted resident, however, because of a noncompensated respiratory alkalosis from
hyperventilation, lower arterial Hb saturation without a compensatory absolute polycythemia
(therefore greater hypoxemia), and hypoxia-induced tachycardia. (See Section 12.5 for
further discussion of this topic.)
11-1
-------
Several factors tend to exacerbate ambient CO levels at high altitude (Kirkpatrick and
Reeser, 1976). For example, automobile CO emissions are likely to be higher in mountain
communities. Early studies on automobile emissions showed that automobiles tuned for
driving at 1,610 m (5,280 ft) emit almost 1.8 times more CO when driven at 2,438 m
(8,000 ft). Automobiles tuned for driving at sea level emit almost four times more CO when
driven at 2,438 m. Moreover, automobile emissions are increased by driving at reduced
speeds, along steep grades, and under poor driving conditions. Therefore, large influxes of
tourists driving automobiles tuned for sea-level conditions into high-altitude resort areas may
drastically increase pollutant levels in general, and CO levels in particular (National Research
Council, 1977). Although emissions data comparing sea-level and high-altitude conditions
for the current automobile fleet are not yet available, newer automobile engine technologies
should significantly reduce CO emissions in general, as well as CO emissions at high altitude.
Heating devices (space heaters and fireplaces) used for social effect, as well as warmth, are a
second factor contributing to CO emissions in mountain resort areas. Finally, population
growth in mountain areas is concentrated along valley floors; this factor combined with the
reduced volume of air available for pollutant dispersal in valleys causes pollutants, including
CO, to accumulate in mountain valleys. As a result of these factors, the National Ambient
Air Quality Standards (NAAQS) for CO of 9 ppm is exceeded frequently in Denver, CO,
(altitude 1,610 m) during the winter months (Haagenson, 1979).
Because of concern for CO exposure at high altitudes, it has been suggested that the
NAAQS for CO set at sea level is probably too high for altitudes of 1,500 m and above. An
example of supporting data for this opinion were studies conducted before 1950 on the
psychophysiological effects of high altitude and CO-induced hypoxia. These studies provided
evidence for a concept that there are physiologically equivalent altitudes dependent on the
ambient concentration of CO. In 1976, the states of California and Nevada adopted ambient
standards for the Lake Tahoe air basin (1,900 m, 6,231 ft) that were more stringent than the
NAAQS (i.e., 6 ppm rather than 9 ppm).
Mitchell et al. (1979) justified this concept by stating that "equivalent
carboxyhemoglobin levels observed at sea level would occur during exposure to lower
ambient CO concentrations at 1,500 m." The high-altitude standard was calculated from the
model developed by Coburn et al. (1965). This model was developed for quasi-steady-state
11-2
-------
responses to low CO concentrations, such as those produced endogenously, however, and was
not intended to apply to other, exogenous sources of CO (see Chapter 9 for a description of
the model). Collier and Goldsmith (1983) acknowledged that an error was made in the
original calculations for the California-Nevada high-altitude standard. They expanded the
computations to include factors relating to the ambient CO concentrations and altitude and
concluded, based on their model calculations, that the expected altitude effect would be small.
11.1.2 Carboxj hemoglobin Formation
The effects of high altitude on COHb formation have been considered in a theoretical
paper by Collier and Goldsmith (1983). Transforming and rearranging the Coburn-Forster-
Kane (CFK) equation (Coburn et al., 1965), these workers derived an equation expressing
COHb in terms of endogenous and exogenous sources of CO. Thus,
vrnz
SCO=-^ — 1+ C0 (11-1)
1Q6K K
where
z-
DLCO
Pc°2
c 2
M x SO2
where SCO is the percent COHb; FfO is the fraction of inspired CO in parts per million;
PB is the barometric pressure in torr; Vco is the rate of CO production in milliliters per
minute at standard temperature and pressure, dry (STPD); DLCO is the CO diffusing capacity
in milliliters per minute-torr; VA is the alveolar ventilation in milliliters per minute at STPD;
Pc<92 i§ tne mean partial pressure of pulmonary capillary O2 in torr; M is the Haldane
coefficient; and SO2 is the percent oxyhemoglobin (O2Hb).
11-3
-------
According to this relationship, a given partial pressure of CO will result in a higher
percent COHb at high altitudes (where PO2 is reduced). Thus, Collier and Goldsmith (1983)
calculate that humans breathing 8 ppm CO will have equilibrium COHb levels of 1.4% at sea
level and 1.6, 1.8, and 1.8%, respectively, at 1,530, 3,050, and 3,660 m (Table 11-1).
Moreover, these workers calculate an increase in COHb at altitude even in the absence of
inhaled CO (due to endogenous production of CO).
TABLE 11-1. CALCULATED EQUILIBRIUM VALUES OF PERCENT
CARBOXYHEMOGLOBIN AND PERCENT OXYHEMOGLOBIN IN HUMANS
EXPOSED TO AMBIENT CARBON MONOXIDE AT VARIOUS ALTITUDES
Ambient CO
(ppm)
0
4
8
12
16
Sea
%
COHb
0.20
0.8
1.4
2.1
2.7
Level
%
O2Hb
97.3
96.8
96.2
95.6
95.1
1.530
%
' COHb
0.26
0.9
1.6
2.3
2.9
m
%
02Hb
93.6
93.0
92.5
91.9
91.4
3.050
%
COHb
0.35
1.1
1.8
2.5
3.2
m
%
02Hb
82.4
82.1
81.7
81.3
80.9
%
COHb
0.37
1.1
1.8
2.5
3.2
3,660 m
%
O-Hb
73.3
73.1
72.9
72.7
72.5
Notes: The table is for unacclimatized, sedentary individuals at one level of activity ( V O2 = 500 mL/min).
Source: Adapted from Collier and Goldsmith (1983).
11.1.3 Cardiovascular Effects
There are studies comparing the cardiovascular responses to CO with those to high
altitude, but there are relatively few studies of the cardiovascular responses to CO at high
altitude (see Table 11-2). Forbes et al. (1945) reported that CO uptake increased during
6 min of exercise of varying intensity on a bicycle ergometer at an equivalent altitude of
4,877 m (16,000 ft). The increased CO uptake was caused by altitude hyperventilation
stimulated by decreased arterial O2 tension and not by diminished barometric pressure.
Pitts and Pace (1947) reported that pulse rate increased in response to the combined
stress of high altitude and CO, The subjects were 10 healthy men who were exposed to
simulated altitudes of 2,134, 3,048, and 4,572 m (7,000, 10,000, and 15,000 ft) and inhaled
3,000 or 6,000 ppm CO to Obtain COHb levels of 6 or 13%, respectively. The mean pulse ,
11-4
-------
TABLE 11-2. SUMMARY OF EFFECTS OF CARBON MONOXIDE AT ALTITUDE
Exposurea>b
Alt = 4,877m
CO = 3,000-4,000 ppm
6 min exercise
Alt - 1,524-1,848 m
CO = 1, 500-2, 000 ppm
Alt = 3,070-4,555 m
CO = 2,800-5,600 ppm
Simulated alt = 2,134,
3,048, 4,572 m (16, 14,
11% 02 + N2)
CO = 3,000 or 6,000 ppm .
Treadmill exercise
Alt = 2,134-4,877 m
CO = 100-300 ppm
CO in rebreathing system
PflO2 varied from 650 to
40 mmHg
CO administered at
constant rate
COHb0 Subject
— Human
(n=3)
5-10% Human
(n=5)
5-22% Human
(n=20)
6 and 13% Human
(n=10)
1.1-20.5% Human
(n=4)
— Dog
(n=31)
2-75% Dog
(n=4)
Dependent
Variabled
Blood CO
Flicker-fusion
frequency (FFF)
Critical flicker
frequency (CFF),
body sway (BS),
red visual field
(RVF)
Pulse rate
Visual sensitivity
14CO in blood
"
Rate of increase in
COHb
Results'1
CO uptake increased
with altitude
FFF decreased with CO
at altitude
CFF, BS, and RVF
impaired by altitude;
no added effect of CO
Pulse rate during and
5 min after exercise
increased with altitude
and COHb
CO decreased visual
sensitivity
No change in 14CO
activity in blood when
P.Oo varied from 40 to
a £1 i A
650 mmHg; HCO
decreased to 50%
control when PflO2
decreased below
40 mmHg
COHb increased at
constant up to 50%; at
50%, rats of COHb
formation decreased
Comments
Caused by altitude
hyperventilation.
FFF not affected by
altitude or COHb alone;
8-10% COHb reduced
altitude tolerance by
1,215 m.
No correlation of any
response with COHb.
Effects of CO may be
masked by
compensatory effect.
Response to 1 % COHb
equivalent to increase
in altitude of 335 ft.
The effects of CO and
altitude are additive.
Recovery from the
detrimental effects of
CO lagged behind
elimination of CO from
blood.
With severs arterial
hypoxemia
(P.O2 <40 nunHg),
xIO shifts into
extravascular tissue.
Suggests that at high
COHb levels, CO shifts
into extravascular
space.
Reference
Forbes et al. (1945)e
Lilienthal and Fugitt
(1946)6
Vollmer et al. (1946)e
Pitts and Pace (1947)e
Halperin et al. (1959)e
Luomanmaki and
Coburn (1969)
Luomanmaki and
Coburn (1969)
-------
TABLE 11-2 (cont'd). SUMMARY OF EFFECTS OF CARBON MONOXIDE AT ALTITUDE
Exposure8'''
Alt = 305-3,109 m
Smokers
Alt = 2,438 m
Alt = 4,500 m
CO = 4,300 ppm
Every second hour for
3-5 hours
Alt = 3,109 m
Smokers
Alt = 3,048m
CO bolus followed by
40 ppm.
Bicycle exercise
Alt = 1,610 m
, CO = 100% bolus
Alt = 1,524 m
CO = 160-200 ppm
6 weeks
COHbc Subject
4.77-6.66% Human
(n=62)
5% Human
20% Human
(n=16)
0.4-7.14% Human
(n=49)
4.2% Human
(n=12)
5% Human
(n=9)
20% Goat
(n=6)
Dependent
Variable*1
COHb levels
Visual sensitivity
Capillary permeability
to protein (CP)
COHb and O2 affinities
Cardiac output, stroke
volume (SV), arterial-
mixed venous O2
- difference (A-V)
Work performance
Cardiac index (CI),
Stoke volume (SV),
Heart rate (HR),
Ventricular contractility
Result
COHb in smokers
higher at altitude than
at sea level
Visual sensitivity
decreased by CO at
altitude
CP increased with CO
but not with altitude;
plasma volume
decreased with altitude
COHb levels and O2
affinities decreased in
polycythemic smokers
on cessation of smoking
At altitude, cardiac
output increased and
SV and A-V decreased
in nonsmokers; no
effect on smokers
Increased working HR,
and shortened post-
exercise LV ejection
time; lowered anaerobic
threshold
No effect on CI, SV,
HR, and Vmax during
exposure
-
Comments'*
5% COHb depresses
visual sensitivity as
much as 2,438-
3,048 in. The effects
of altitude and CO are
additive.
Increase in CP appears
unique to CO
(nonhypoxic effect).
02 dropped to lower
than normal sea level
values in polycythemic
smokers on cessation of
smoking.
Smokers may be
partially adapted to
hypoxic environments
and CO.
CO impaired exercise
performance to same
degree as at sea level.
After removal from
CO, both HR and
Vmax were depressed.
Reference
Brewer et al. (1970)
McFarland (1970),
McFarland et al.
(1944)e
Parving (1972)e
Brewer etal. (1974)e
Wagner et al. (1978)e
Weiser et al. (1978)e
James et al. (1979)
-------
TABLE 11-2 (cont'd). SUMMARY OF EFFECTS OF CARBON MONOXIDE AT ALTITUDE
Exposurea'b COHb0
Alt = 3, 100m ' 1.8-6.2%
Smokers
.
Alt = 4,572 m 34.1 and 36.2%
CO = 500 ppm
6 weeks
Alt = 5,486m 5.8, 11.1,
CO = 50, 100, and 4.26%
500 ppm'- .. ,
6 weeks
Alt = 4,572m 8.4% -
CO = 100 ppm
6 weeks
Alt =» 55, 1,524, 2.56 - 4.42%
2,134, and 3,048 m
CO = 0, 50, 100, and
150 ppm
Alt = 55 and 2,134 m 0.2 - 0.7%
CO = 0 and 9 ppm for
8h
Subject
Human
(n=44)
Rat
(n=24)
Rat
(n=22)
Rat
(n=24)
Human
(n=23)
(11 men,
12 women)
Human
. (n=17)
Dependent
Variabled
Infant birth weights
Hematocrit (Hct),
mean electrical
axis (MEA),
HW/BW ratios
Cardiac hypertrophy,
coronary capillarity
Hot ratio and weights:
BW, HW, RV, LV+S,
Pituitary (PIT)
Maximum aerobic
capacity (VO2 max)
Maximum aerobic
capacity (VO2 max)
Resultsd
Maternal smoking
associated with 2 to 3
times greater reduction
in infant birth weight
than at sea level
Hot increased by
altitude and CO; MEA
shifted left with CO,
right with altitude
RV hypertrophy and
coronary capillarity
increased with altitude
Alt iBW, tHct, TRV,
THT, tPiT; CO_ THct,
TLV+S
VO2 max decreased at
2,134m (4%) and
3,048m (8%); VO2
max decreased slightly
with increasing ambient
CO
VO2 max decreased
7-10% with increasing
altitude at 0 ppm CO; •
similar effects were
found after 8-h
exposure to 9 ppm CO,
regardless of exercise
level
Comments
COHb levels measured
in mothers were
inversely related to
infant birth weight.
Effects of altitude and
CO on Hct, MEA, and
HW/BW were additive.
Increase in coronary
capillarity was blocked
by CO.
Effects produced by
altitude were not
intensified by 100 ppm
CO.
Altitude- and CO-
hypoxia independently
affect VO2 max;
decreased COHb with
increasing altitude was
due, in part, to
decreased driving CO
pressure.
"fyC>2 max was reduced
in all subjects at altitude
regardless of the
ambient CO level and
prior .ventilation (i;e.,
intermittently exercising
or resting during
exposure). •
Reference
Moore et al. (1982)
Cooper et al. (1985)
McDonagh et al. (1986)
McGrath (1988)
Horvath et al.
(1988 a,b)
Horvath and Bedi
(1989)
aExposure altitude, concentration, and duration conditions.
bl ppm =* 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm at 25 °C, 760 mm Hg.
cEstimated or measured blood carboxyhemoglobin (COHb) levels.
See glossary of terms and symbols for abbreviations and acronyms.
eCited in U.S. Environmental Protection Agency (1979, 1984).
-------
rate during exercise and the mean pulse rate during the first 5 min after exercise were
correlated with and increased with the COHb concentration and simulated altitude. The
authors concluded that the response to a 1 % increase in COHb level was equivalent to that
obtained by raising a normal group of men 102 m (335 ft) in altitude. This relationship was
stated for a range of altitudes from 2,134 to 3,048 m (7,000 to 10,000 ft) and for increases
in COHb up to 13%.
Weiser et al. (1978) studied the effects of CO on aerobic work at 1,610 m (5,280 ft) in
young subjects rebreathing from a closed-circuit system containing a bolus of 100% CO until
COHb levels reached 5%. They reported that this level of COHb impaired exercise
performance at high altitude to the same extent as that reported at sea level (Horvath et al.,
1975). Because these subjects were Denver residents and fully adapted to this altitude,
however, they would have had an arterial O2 concentration the same as at sea level (about
20 mL O2/dL). Hence, 5% COHb would lower arterial O2 concentration about the same
amount at both altitudes and impair work performance at altitude to the same extent as at sea
level. In the Weiser study, breathing CO during submaximal exercise caused small but
significant changes in cardiorespiratory function; the working heart rate increased and
postexercise left ventricular ejection time did not shorten to the same extent as when filtered
air was breathed. Carbon monoxide exposure lowered the anaerobic threshold and increased
minute ventilation at work rates heavier than the anaerobic threshold due to increased blood
lactate levels.
Wagner et al. (1978) studied young smokers and nonsmokers who exercised at 53% of .
their maximal oxygen uptake (VO2 max) at 760 and 523 torr. Carboxyhemoglobin levels
were raised to 4.2%. While at altitude with these elevated COHb levels, nonsmokers
increased their cardiac output and decreased their arterial-mixed venous Q2 differences.
Smokers did not respond in a similar manner. Smokers, with their initial higher Hb
concentrations, may have developed some degree of adaptation to CO and/or high altitude.
In a complex study involving four altitudes ranging from sea level up to 3,048 m
(10,000 ft) and four ambient CO concentrations (up to 150 ppm), Horvath et al. (1988a,b)
evaluated COHb levels during a maximal aerobic capacity test. They concluded that
^v*O2 max values determined in men and women were only slightly diminished due to
increased ambient CO. Carboxyhemoglobin concentrations attained at maximum were highest
11-8
-------
at 55 m (4,42%) and lowest at 3,048 m (2.56%) while breathing 150 ppm CO (Figure 1-1-1).
This was attributed to the reduced partial pressure of CO at high altitude. No additional
effects that could be attributed to the combined exposure to high altitude and CO were found.
Independence of the altitude and CO hypoxia was demonstrated under the condition of
performing a maximum aerobic capacity test. The reductions in VO2 max due to high
altitude and to the combined exposure of ambient CO and high altitude were similar.
Horvath and Bedi (1989) studied 17 nonsmoking young men to determine the alterations
in COHb during exposure to 0 or 9 ppm ambient CO for 8 h at sea level of an altitude of
2,134 m (7,000 ft). Nine subjects rested during the exposures and eight exercised' for the last
10 min of each hour at a mean ventilation of 25 L (DTPS). All subjects performed a
maximal aerobic capacity test at the completion of their respective exposures. At the low CO
concentrations studied, the CFK equation estimated COHb levels to be 1.4% (Peterson and
Stewart, 1975). Carboxyhemoglobin concentrations fell in all subjects during their exposures
to 0 ppm CO at sea level or 2,134 m. During the 8-h exposures to 9 ppm CO, COHb levels
rose linearly from approximately 0.2 to 0.7% (Figure 11-2), No significant differences in
uptake were found whether the subjects were resting or intermittently exercising. Levels of
COHb were similar at both altitudes. A portion of the larger estimate of COHb determined
by the CFK equation could be accounted for by the use of an assumed blood volume.
Maximal aerobic capacity was reduced approximately 7 to 10% consequent to altitude
exposure during 0 ppm CO. These values were not altered following 8-h exposure to 9 ppm
CO in either resting or exercising individuals. •••..'
11.1.4 Chronic Studies
There have been few studies of the long-term effects of CO at altitude and these were
conducted in various laboratory animal species (see Table 11-2). James et al. (1979) studied
cardiac function in six unsedated goats that were chronically instrumented and exposed to
160 to 200 ppm CO (20% COHb) for 6 weeks at 1,524 m (5,000 ft). Cardiac index and
stroke volume were unchanged during and after the exposure. Heart rate and contractility of
the left ventricular myocardium were unchanged during exposure to CO, but both were
depressed during the first week after removal of the CO. The authors concluded that if there
11-9
-------
Control COHb - 0.67 * 0.15%
0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150
Carbon Monoxide Level, ppm
•H Maximum SHH 5 Minute Post Maximum
Control COHb - 0.81 ± 0.23%
-2
1IIIfIIIIIITlTT ,
0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150
Carbon Monoxide Level, ppm
Mgure 11-1. Increment in percent carboxyhemoglobin (COHb) over basal (control)
levels at the end of a maximum aerobic capacity test and at the fifth
minute of recovery from the test hi a typical (A) male subject and a typical
(B) female subject. Altitudes are 55, 1,524, 2,134, and 3,048 m, whereas
exercise was conducted with ambient concentrations of 0, 50, 100, and 150
ppm carbon monoxide.
Source: Horvath et al. (1988a,b).
11-10
-------
A
1.0
0.8
I 0.6 -I
I
>> 0.4-1
O 0.2-
0.0
B
Q—Q 2134m
A-—A 55m
O O Oppm
Resting Subjects
1.0-1
0.8
0.6-1
| 0.4
"0.2-
0.0
d
1 I 1 I 1 I
01 2 3 45
Time, h
8 M
a — D
Active Subjects
55m
O O Oppm
P
//
O
01
4 5 6
Time, h
7 8 M
PM
Figure 11-2. Change in carboxyhemoglobin (COHb) concentration during 8-h exposures
to 0 to 9 ppm carbon monoxide for (A) resting and (B) exercising subjects.
Altitudes are sea level (55 m) and 2,134 m (7,000 ft). The maximal (M)
values were obtained immediately after completing the maximal aerobic
capacity test begun at 8 h. Hie PM values represent COHb concentrations
obtained 40 min after completing the maximal exercise test. The 0 ppm
curve represents the mean changes at both altitudes.
Source: Horvath and Bedi (1989).
11-11
-------
was a decrease in intrinsic myocardial function during the CO exposure, it may have been
masked by increased sympathetic activity.
McGrath (1988, 1989) studied cardiovascular, body, and organ weight changes in rats
exposed continuously for 6 weeks to (1) ambient altitude, (2) ambient altitude plus CO,
(3) simulated high altitude, and (4) CO at high altitude. Altitudes ranged from 3,300 ft
(1,000 m) to 18,000 ft (5,486 m) and CO concentrations ranged from 0 to 500 ppm.
Carbon monoxide had no effect on body weight at any altitude. There was a tendency
for hematocrit (Hct) to increase even at the lowest concentration of CO (9 ppm), but the
increase did not become significant until 100 ppm. At 10,000 ft (3,048 m), there was a
tendency for the total heart weight to increase in rats inhaling 100 ppm CO. Although its
effects on the heart at high altitude are complex, CO had little effect on the right ventricle in
concentrations of 500 ppm or less; it did not exacerbate any effects due to altitude. There
was a tendency for the left ventricle weight to increase with exposure to 35 ppm CO at high
altitude, but the increase was not significant until 100 ppm CO. Heart rate, blood pressure,
cardiac output, and peripheral resistance were unaffected by exposure to 35 ppm CO or
10,000-ft altitude, singly or in combination. The author concluded that 6 weeks of exposure
to 35 ppm CO does not produce measurable effects in the healthy laboratory rat, nor does it
exacerbate the effects produced by exposure to 10,000-ft altitude.
The data reported by McGrath (1988, 1989) are generally in agreement with findings
reported by other investigators. Carboxyhemoglobin obtained at the end of the 6 weeks of
exposure to CO are presented in Figure 11-3. The COHb concentrations at 3,300 ft
(1,006 m) were 0.6, 0.9, 2.4, 3.7, and 8.5% for ambient CO levels of 0, 9, 35, 50, and
100 ppm, respectively. This relationship can be expressed as:
%COHb = 0.115 + 0.08* (11-2)
where x is the CO exposure in parts per million. The correlation coefficient (r) for this
relationship was 0.99. The data from other altitudes were not sufficient to calculate the rate
of increase. Exposure of rats to 500 ppm and altitudes up to 18,000 ft resulted in COHb
levels of 40 to 42%.
11-12
-------
11
10 H
9
«£
c- 8 H
5
& 7 _j
, 7 H
A 18,000 ft
<015,000 ft
• 10,000ft
• 3,300ft
20
100
Ambient Carbon Monoxide, ppm
Figure 11-3. The effects of altitude and ambient carbon monoxide exposure on
carboxyhemoglobin in Fischer 344 rats.
An interesting, but not unexpected, finding in this study was that high-altitude residence
in the absence of exogenous CO resulted in increased basal COHb concentrations. These
values were 0.6, 1.3, 1.7, and 1.9% for altitudes from 3,300 to 18,000 ft (1,006 to
5,486 m). These increases can be expressed as:
%COHb = 0.0000914 + 0.26687*
(11-3)
where x is altitude, in feet. The correlation coefficient (r) for this relationship was 0.99.
Whether or not similar increases in basal COHb concentrations would be observed in humans
adapted to altitude needs to be determined. Presumably, because there are marked elevations
in Hb and Hct in residents of high altitudes, a greater endogenous CO production might be
present. In this study, 100 ppm CO exposure induced no effects on body, right ventricle,
total heart, adrenal, spleen, or kidney weights, but it did increase Hct ratios and left ventricle
11-13
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weights. There was no significant interaction between altitude and CO on any parameter
except kidney weight. The author concluded that although there was a tendency for Hct
ratios, spleen weights, and total heart weights to be elevated by combined CO-altitude
exposure, the results were not significant and, in general, the effects produced by 4,572-m
altitude were not intensified by exposure to 100 ppm CO.
McDonagh et al. (1986) studied cardiac hypertrophy and ventricular capillarity in rats
exposed to 5,486 m (18,000 ft) and 50, 100, and 500 ppm CO. Coronary capillarity
increased after exposure to 5,486 m for six weeks, but this response was blocked by CO.
Right ventricular thickness was increased by altitude, but was not increased further by CO.
At 500 ppm CO, the right ventricular hypertrophy was attenuated, but the results are
uncertain due to the high mortality in this group. Left ventricular thickness also was
increased at 5,486 m (18,000 ft) and was increased further by CO. The authors concluded
that because the ventricular thickness is increased while capillarity is reduced, it is possible
that the myocardium can be underperfused in the altitude plus CO group.
Cooper et al. (1985) evaluated the effects of CO at altitude on electrocardiograms
(EKGs) and cardiac weights in rats exposed for 6 weeks to (1) ambient (amb), (2) ambient
+ 500 ppm CO (amb+CO), (3) 4,572 m (15,000 ft) (alt), and (4) 4,572 m + 500 ppm CO
(alt+CO). Carboxyhemoglobin values were 36.2 and 34.1% in the amb+CO and alt+CO
groups, respectively. Hematocrits were 54 + 1, 77+ 1, 68 ± 1, and 82+1% in the amb,
amb+CO, alt, and alt+CO groups, respectively. In the amb+CO, alt, and alt+CO groups,
respectively, the mean electrical axis shifted 33.2° left, 30° right, and 116.4° right. Heart
weight to body weight ratios were 2.6, 3.2, 3.2, and 4.0 x 10~3 in the amb, amb+CO, alt,
and alt+CO groups, respectively. Whereas CO increased left ventricular weight, and alt
increased right ventricular weight, alt+CO increased both. Changes in EKG were consistent
with changes in cardiac weight.
These results indicate that whereas CO inhaled at ambient altitude causes a left
electrical axis deviation, CO inhaled at 4,572 m exacerbates the well-known phenomenon of
right electrical axis deviation. Thus, the results from chronic animal studies indicate that
there is little effect of CO on the cardiovascular system of rats exposed to CO concentrations
of 100 ppm or less and altitudes up to 3,030 m (10,000 ft). f
11-14
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Exposure to CO from smoking may pose a special risk to the fetus at altitude. Moore
et al. (1982) reported that maternal smoking at 3,100 m was associated with a two- to
threefold greater reduction in infant birth weight than has been reported at sea level.
Moreover, COHb levels of 1.8 to 6,2% measured in all pregnant subjects were inversely
related to infant birth weight. Earlier, Brewer et al. (1970, 1974) reported that the mean
COHb level in smokers at altitude is higher than in smokers at sea level, and that subjects
who smoked had greater O2 affinities than nonsniokers. Moreover, cessation of smoking by
polycythemic individuals at altitude results in a marked reduction in COHb and a decrease in
Hb-O2 affinity to values less than those reported for normal individuals at sea level. The
chronic effects of altitude and CO exposure are summarized in Table 11-3.
TABLE 11-3. CHRONIC EFFECTS OF ALTITUDE AND CARBON
MONOXIDE EXPOSURE
Effect
Hemoglobin
Hematocrit
Pulmonary arterial pressure
Cardiac hypertrophy
Right ventricle
Both ventricles
Cardiac output2
Blood volume
Body weight
Altitude
. t
t
- t : :
t .
Tt
t
I
Carbon Monoxide
, , 't: • .
t
' J - ' ' ' '
t
?
t
-
"Initial increase that later returns to baseline value.
11.1.5 Neurobehavioral Effects
The neurobehavioral effects following CO exposure are controversial and should,
.therefore, be interpreted with extreme caution. Weaknesses in the experimental design and
reporting of effects are described in detail in Section 10.4. Those neurobehavioral studies
specifically concerned with CO exposure at altitude are reviewed briefly in this section.
11-15
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McFarland et al. (1944) reported changes in visual sensitivity occurring at a COHb
concentration of 5% or at a simulated altitude of approximately 2,432 m (8,000 ft). later,
McFarland (1970) expanded on the original study and noted that a pilot flying at 1,829 m
(6,000 ft) breathing 0.005% CO in air is at an altitude physiologically equivalent to
approximately 3,658 m (12,000 ft). McFarland stated that sensitivity of the visual acuity test
was such that even the effects of small quantities of CO absorbed from cigarette smoke were
clearly demonstrable. In subjects inhaling smoke from three cigarettes at 2,286 m (7,500 ft),
there was a combined loss of visual sensitivity equal to that occurring at 3,048 to 3,353 m
(10,000 to 11,000 ft). Results from the original study were confirmed by Halperin et al.
(1959), who also observed that recovery from the detrimental effects of CO on visual
sensitivity lagged behind elimination of CO from the blood.
Lilienthal and Fugitt (1946) reported that combined exposure to altitude and CO
decreased flicker-fusion frequency (FFF) (i.e., the critical frequency in cycles per second at
which a flickering light appears to be steady). Whereas mild hypoxia (that occurring at
2,743 to 3,658 m [9,000 to 12,000 ft]) alone impaired FFF, COHb levels of 5 to 10%
decreased the altitude threshold for onset of impairment to 1,524 to 1,829 m (5,000 to
6,000ft).
The psychophysiological effects of CO at altitude are a particular hazard in high-
performance aircraft (Denniston et al., 1978). Acute ascent to altitude increases ventilation
via the stimulating effects of a reduced PO2 on the chemoreceptors. The increased
ventilation causes a slight increase in blood pH and a slight leftward shift in the O2Hb
dissociation curve. Although such a small shift would probably have no physiological
significance under normal conditions, it may take on physiological importance for aviators
required to fly under a variety of operational conditions and to perform tedious tasks
involving a multitude of cognitive processes. The leftward shift of the O2Hb dissociation .
curve may be further aggravated by the persisting alkalosis caused by hyperventilation
resulting from anxiety. The potential for this effect has been reported by Pettyjohn et al.
(1977), who reported that respiratory minute volume may be increased by 110% during final
landing approaches requiring night-vision devices. Thus, the hypoxia-inducing effects of
CO inhalation would accentuate the cellular hypoxia caused by stress- and altitude-induced
hyperventilation.
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11.1.6 Compartmental Shifts
Studies by Luomanmaki arid Coburn (1969) suggest that CO in very high
concentrations may pose a special threat at higher altitudes. These workers report that during
hypoxia, CO shifts out of the blood and into the tissues in anesthetized dogs. In experiments
using CO containing carbon isotope 14 (14CO), they observed that radioactivity in blood did
not change when arterial O2 tension increased from 50 to 500 mm Hg. However,
14CO activity in blood decreased to 50% of control levels when arterial PO2 decreased below
40 mm Hg; 14CO shifted back into the blood when arterial PO2 returned to normal. Because
there was no significant difference between splenic and central venous 14CO radioactivity
either before or after the 14CO shift, these workers excluded the possibility that the 14CO had
been sequestered in the spleen.
Luomanmaki and Coburn (1969) also studied the shift of CO out of the blood during
hypoxia by administering CO into a rebreathing system and measuring the rate at which blood
COHb increased. They reasoned that if the partition of CO between vascular and
extravascular stores remained constant, the increase in blood COHb should be proportional to
the amount of CO administered. They found that COHb increased at a constant rate up to a
saturation of 50%. With additional CO, there was a decrease in the rate at which COHb
increased; this suggests that proportionally greater amounts of CO were entering the
extravascular stores. At 50% COHb (corresponding to an arterial PO2 of 90 mm Hg), the
rate of COHb formation became nonlinear. Agostoni et al. (1980) presented a theoretical
model supporting these observations; they developed equations predicting that decreasing
venous PO2 causes CO to move out of the vascular compartment and into skeletal and heart
muscle. This increases the rate at which carboxymyoglobin is formed in the tissues.
The shift of CO out of the blood has been further demonstrated in studies (Horvath
et al., 1988a,b) conducted on both men and women undergoing maximal aerobic capacity
tests at altitudes of 55, 1,524, 2,134, and 3,058 m and CO concentrations' of 0, 50, 100, and
150 ppm. Carbon monoxide at maximum work shifted info extravascular spaces and returned
to the vascular space within 5 min after exercise stopped (Figure 11-4). This liberation of
CO was related to the concentration of COHb achieved as noted by the regression equation:
11-17
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y = 0.0017 + 0.3047*
(11-4)
where x is the COHb concentration at exhaustion.
1.2-
If)
1.0-
;§ 0.8-
0.6-
a
0.2-1
Y -0.0017 + 0.3047 X
r - 0.9126
Sy--0.1337
1.4
1.8
I T I
2.2 2.6
r i T ! n i
3 3.4 3.8
4.2 ' 4.6
Maximum Carboxyhemoglobin, %
Blgure 11-4. Relationship between increase .in percent carboxyhemoglobin (COHb)
observed at the end of a 5-min recovery period and COHb concentration
present at exhaustion after attainment of maximum aerobic capacity.
Source: Horvath et al. (1988a,b).
11.1.7 Conclusions
Although there are many studies comparing and contrasting inhaling CO with exposure
to altitude, there are relatively few reports on the effects of inhaling CO at altitude. There
are data to support the possibility that the effects of these two hypoxia episodes are at least
additive. These data were obtained at CO concentrations that are too high to have much
11-18
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significance for regulatory concerns. There also are data that indicate decrements in visual
sensitivity and EFF in subjects exposed to CO (5 to 10% COHb) at higher altitudes. These
data, however, are somewhat controversial.
There are even fewer studies of the long-term effects of CO at high altitude. These
studies generally indicate few changes at CO concentrations below 100 ppm and altitudes
below 4,572 m (15,000 ft). A provocative study by McDonagh et al. (1986) suggests that
the increase in ventricular capillarity seen with altitude exposure may be blocked by CO.
The fetus may be particularly sensitive to the effects of CO at altitude; this is especially true
with the high levels of CO associated with maternal smoking.
11.2 CARBON MONOXIDE INTERACTIONS WITH DRUGS
11.2.1 Introduction
There is little direct information on the possible enhancement of CO toxicity by
concomitant drug use or abuse; however, there are some data suggesting cause for concern.
There is evidence that interactions of drug effects with CO exposure can occur in both
directions; that is, CO toxicity may be enhanced by drug use and the toxic or other effects of
drugs may be altered by CO exposure. Nearly all the published data that are available on CO
combinations with drugs concern psychoaetive drugs. Possible interactions of CO with other
classes of drugs (e.g., those likely to be used in patients with cardiovascular disease who also
are at risk for CO exposure) will be discussed elsewhere in this document (see Section 12.4).
Another related area of concern that will be reviewed elsewhere is interactions of CO with
other toxicants (see Section 11.3).
The use and abuse of psychoactive drugs and alcohol is ubiquitous hi society. Because
of CO's well-established effects on brain functioning, interactions between CO and
psychoactive drugs could be anticipated. Unfortunately, very little systematic research has
addressed this question. In addition, very little of the research that has been done has utilized
models for_expected effects for treatment combinations. Thus, often it is not possible to ,
assess whether the combined effects of drugs and CO exposure are additive or differ from
additivity. It is important to recognize that even additive effects of combinations can be of
clinical significance, especially when the individual is unaware of the combined hazard.
11-19
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11.2.2 Alcohol
The effects of combined CO exposure and alcohol (ethanol) administration have been
the most extensively studied interaction. The previous criteria document (U.S.
Environmental Protection Agency, 1979) reviewed two human studies that examined
combinations of CO and alcohol. A study from the Medical College of Wisconsin (1974)
found no effects of alcohol doses resulting in blood alcohol levels of about 0.05% and COHb
levels in the general range of 8 to 9%, either alone or in combination, on a number of
psychomotor behavioral tasks. The lack of sensitivity of these measures to alcohol doses
known to affect performance under many other conditions, as well as other problems in the
study design, raises the question of the adequacy of this study to detect interactive effects.
Rockwell and Weir (1975) studied the interaction of CO exposures resulting in nominal 0, 2,
8, and 12% COHb levels with alcohol doses resulting in nominal 0.05% blood alcohol levels
for effects on actual driving and driving-related performances in young, nonsmoking college
students. Dose-related effects of CO for perceptual narrowing and decreased eye movement
were observed. In addition, effects were observed on some measures by this dose of alcohol
alone. An effect-addition model was used to evaluate the aleohol-CO interaction. In
combination, the effects of CO and alcohol were often additive, and there was a supra-
additive alcohol-CO interaction at 12% COHb levels. Although the 1979 review highlighted
the lack of an interaction effect except at high COHb concentrations, it should be noted that
interaction effects for this study were defined as effects greater than the sum of the effects of
the treatments alone. Thus, this extensive study in human subjects provides some evidence
that driving-related performances already disrupted by alcohol could be further compromised
by CO exposure.
Because of a concern that persons exposed to CO may not be able to detect odors that
would indicate a fire or other hazardous condition, especially when consuming alcohol,
Engen (1986) conducted a carefully controlled study of combined CO-alcohol exposure in
human subject volunteers. The detection of a threshold concentration of the smoky odor of
quaiacol was evaluated using signal-detection analysis. The dose of alcohol given resulted in
blood alcohol levels of about 0.04 to 0.07% and CO exposure resulted in COHb values of
7.0 to 7.7%. In signal detection studies, d' is a measure of detection threshold, with higher
values reflecting greater detection. The average d' for the four treatment conditions was as
11-20
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follows: air only (1.95), CO only (2.34), alcohol only (2.20), and alcohol plus CO (1.64).
Although not statistically significant, there was a tendency for both alcohol arid CO to
improve odor detection compared to air only. When alcohol and CO were combined, the
odor detection was significantly poorer than after either treatment alone, but it was not
significantly poorer than the air control. One of the features of signal detection.analysis is
that it allows the separation of treatment effects on sensory sensitivity from effects on
performance that would influence the reporting of the signal. Thus, in this study it was
found that these changes in odor detection produced by alcohol and CO occurred in the
absence of an effect of any of the experimental treatments on reporting bias. Thus, one could
conclude that the result of combined alcohol and CO exposure was to eliminate the small
improvement in odor sensitivity produced by exposure to either treatment alone. The
relevance and importance of these small changes in odor detection are not readily apparent,
especially because none of the treatments were significantly different from air control;
however, they do suggest that a CO-alcohol interaction on odor thresholds may exist. An
incidental finding of this study was that alcohol did not alter COHb concentrations after
exposure to CO; nor did CO exposure affect blood alcohol levels produced by a fixed dose of
oral alcohol.
There also have been a number of animal studies of combinations of alcohol and CO.
Although there is some evidence that alcohol metabolism can be reduced in rat liver in situ by
a COHb level of 20% (Topping et al., 1981), an in vivo study in mice found no effects of
CO exposure on alcohol metabolism (Kim and Carlson, 1983). Compared to levels in control
mice, 8-h/day exposure to 500 ppm CO (COHb levels averaged 28%) for 1, 3, or 5 days had
no effect on blood alcohol levels when 2.2 g/kg of alcohol was administered intraperitoneally
(ip) after 5.5 h of exposure on each of these days. On the other hand, Pankow et al. (1974)
provide some evidence that high doses of CO associated with COHb levels of greater than
50% decreased blood alcohol levels in rats 30 min after a very large dose of alcohol
(4.8 g/kg). They also reported that this dose of alcohol significantly lowered COHb levels
associated with a very large subcutaneous dose of CO. These high-dose combinations were
also associated with additive effects on enzyme markers of hepatotoxicity, but no interactions
were observed when lower doses of CO were given.
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In contrast to the inconsistent metabolic effects seen with combinations of CO and
alcohol, results of two behavioral studies in animals have shown substantial interaction
effects. Mitchell et al. (1978) studied the interaction of inhaled CO with two doses of
alcohol (0.6 and 1.2 g/kg) in rats using two behavioral measures. Sensorimotor
incapacitation was assessed by failure to remain on a rotating rod. An additional measure of
motor effects was the inability to withdraw the leg from a source of electric shock. The
length of exposure to approximately 2,000 ppm CO before the animals failed in these
performances was decreased in a dose-dependent manner by alcohol. Carboxyhemoglobin
determinations made at the time of behavioral incapacitation were inversely related to alcohol
dose. For example, nearly 50% COHb levels were required to impair rotorod performance
in the absence of alcohol, whereas after 1.2 g/kg ethanol, less than 45% COHb levels
produced the same effect. Unfortunately, data were not provided on the effects of these
doses of alcohol in the absence of CO exposure to help determine the nature and magnitude
of the interaction effects.
Knisely et al. (1989) recently reported a large interaction of CO exposure and alcohol
administration on operant behavior in animals. Mice that had been trained to lever press for
water reinforcement were tested with 1.1 g/kg alcohol and various doses of CO, alone and in
combination. An unusual feature of this study was that both alcohol and CO were
administered by ip injection. The authors provide evidence that this route of CO exposure
results in COHb formation and behavioral effects comparable to those seen after inhalation
exposure (Knisely et al., 1987). The results of the interaction study were evaluated by
comparing the effects of the combinations to those expected by summing the effects of each
treatment alone. A dose of alcohol that had little effect on rates of lever pressing when given
alone resulted in large rate-decreasing effects when given in combination with doses of CO
that also had no effects when given alone. Supra-additive effects with alcohol were obtained
by a dose of CO as low as 7.5 mL/kg, which when given alone was associated with COHb
levels of approximately 20%. Significant supra-additive effects also were obtained with
higher doses of CO. Typically, behavioral effects of CO alone were not seen under these test
conditions until COHb saturations greater than 40 to 50% were obtained (Knisely et al.,
1987). Thus, alcohol about doubled the acute toxicity of CO in this study.
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11.2.3 Barbiturates
There has been some interest in the interaction of CO with barbiturates because
prolongation of barbiturate effects can.reflect effects of toxicants,on drug metabolism. In an
early evaluation of the functional significance of the binding of CO to cytochrome P-450,
Montgomery and Rubin (1971), examined the effects of CO exposure on the duration of action
of hexobarbital and the skeletal muscle relaxant zoxazolamine in rats. Both drugs are largely
deactivated by the hepatic mixed-function oxidase (MFO) system. Although CO was found
to dose-dependently enhance both hexobarbital sleeping time and zoxazolamine paralysis,
subsequent research indicated that this was probably not due to a specific inhibition of the
MFO system by CO, but rather a, nonspecific effect of hypoxia, because even greater effects
could be produced at a similar level of arterial O2 produced by hypoxic hypoxia
(Montgomery and Rubin, 1973; Roth and Rubin, 1976). In support of the, lack of effects of
CO on drug metabolism, Kim and Carlson (1983) found no effect of CO exposure on the
plasma half-life for either hexobarbital or zoxazolamine in mice. This would suggest that
something other than a metabolic interaction may be responsible for the enhancement of
in vivo effects of these drugs by CO.
There have been two studies of the interaction of CO and pentobarbital using operant
behavior in laboratory animals. McMillan and Miller (1974) found that exposure of pigeons
to 380 ppm CO, a concentration that had little effect on behavior when given alone, reduced
the response rate, thereby increasing effects of an intermediate dose of pentobarbital. On the
other hand, the disruptive effects of all doses of pentobarbital on the temporal patterning of
fixed-interval responding was enhanced markedly by 1030 ppm CO. This concentration of
CO by itself did not alter response patterning, but did lower overall rates of responding. In
the study described more fully above in the section on alcohol interactions (Section 11.2.2),
Knisely et al. (1989) found generally additive effects of ip CO administration with the effects
of pentobarbital in mice responding under a fixed-ratio schedule. In that study, the
interaction of CO with pentobarbital was not as evident as the interaction with alcohol,
suggesting that general conclusions about CO interactions with central nervous system
depressant drugs may not be possible.
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11.2.4 Other Psychoactive Drugs
Even more limited data are available on interactions of CO exposure with other
psychoactive drugs. In the study by Knisely et al. (1989), described above (Sections 11.2.2
and 11.2.3), of interactions of ip CO administration with psychoactive drugs on operant
behavior of mice, d-amphetamine, chlorpromazine, nicotine, diazepam, and morphine were
studied in addition to alcohol and pentobarbital. As with alcohol, a suggestion of greater
than additive effects were obtained from combinations of CO with both d-amphetamine and
chlorpromazine; however, in these cases the differences from additivity did not reach
statistical significance. Effects of CO in combination with nicotine, caffeine, and morphine
were additive. McMillan and Miller (1974) also found evidence for an interaction of CO and
^-amphetamine on operant behavior in pigeons. In this study, CO concentrations as low as
490 and 930 ppm were able to modify the behavioral effects of d-amphetamine.
11.3 COMBINED EXPOSURE TO CARBON MONOXIDE AND OTHER
AIR POLLUTANTS AND ENVIRONMENTAL FACTORS
Exposure to a single air pollutant at ambient concentrations may have no harmful
biological effects. In real life, however, exposure occurs not only to a single agent but also
to multiple agents, resulting in potential interactions between them. The result of the
interactions may be of an additive, synergistic, or antagonistic nature. Another possible
interaction is potentiation, a condition in which a pollutant that is noneffective at a given
exposure level may enhance the toxicity of another pollutant given simultaneously. Exposure
to CO frequently occurs in the natural environment in combination with other combustion
products and air pollutants.
In this section, both human and animal effects associated with combined exposure to
CO and other air pollutants and environmental factors are reviewed. Although a number of
studies in the literature have tested exposure to combined pollutants, fewer studies actually
have been designed to test specifically for interactions between CO and the other exposure
components. Therefore, this section emphasizes only those studies providing a combined
treatment group where pollutant exposure levels are reported. The COHb levels resulting
from CO exposure also are given if they were reported in the original manuscripts. The
11-24
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toxicity data discussed stress the newer literature published since 1979 in order to update the
information reviewed in the previous Air Quality Criteria .Document (U.S. Environmental
Protection Agency, 1979). . , ,
11.3.1 Exposure in Ambient Air
Photochemical air pollution usually is associated with two or more pollutants, consisting
mainly of CO, sulfur oxides, ozone (Q3), nitrogen oxides, peroxyacetyl nitrates-.(PANs), and
organic peroxides. The gaseous compounds that constitute tobacco smoke are CO, hydjrogen
cyanide (HCN), and nitric oxide (NO). As urban living, industrial employment, and
cigarette smoking bring humans into direct contact with CO and other pollutants, it seems
appropriate to determine if combined exposure to these pollutants has detrimental health
effects. ...-.• : -,-..',"
Several studies have been conducted to determine the effects resulting from combined
exposure to CO and other pollutants. The experimental details (e.g., concentrations and
duration of treatment) and the associated effects for each study are summarized in
Table 11-4. A brief discussion of the major findings follows. ' '
Murphy (1964) observed an increase in blood COHb levels in mice and rats exposed to
CO plus O3 for 6 h as compared with mice exposed to CO alone. However, another study
(DeLucia et al., 1983) in adults exposed to CO plus O3 during exercise showed no synergistic
effects on blood COHb levels or pulmonary or cardiorespiratory thresholds. Similarly,
simultaneous exposure to CO plus O3 plus nitrogen dioxide (NO^ for 2 h produced no
consistent changes (synergistic or additive) in pulmonary function indices and physiological
parameters hi young, male subjects (Hackney et al., 1975a,b).
Combined exposure to CO and PAN exerted no greater effect on the work capacity of;
healthy men (young and middle-aged smokers and nonsmokers) than did exposure to CO
alone. Increases in blood COHb levels of smokers during the CO or CO plus PAN exposures
were observed (Drinkwater et al., 1974; Raven et al., 1974a,b; Gliner et al., 1975).
GroU-Knapp et al. (1988) reported that combined exposure of rats to CO plus NO for
3 h caused a significant (p<0.01) increase in mean methemoglobin (metHb) levels when
compared with metHb levels in rats exposed to NO alone. No significant changes were
observed in blood COHb levels as compared with exposure to CO alone or to GO plus NO.
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TABLE 11-4. COMBINED EXPOSURE TO CARBON MONOXIDE AND OTHER POLLUTANTS
Pollutant Concentration No./Scx/Spccies
Treatment8
Observed Effects'1
Reference
a\
CO
CO
CO
°3
CO
°3
NO2
CO
PAN
300 ppm
0.7S ppm
280 ppm
3 ppm
100 ppm
0.3 ppm
30 ppm
0.25 ppm
0.30 ppm
.50 ppm
0.27 ppm
9-10/-b/mouse and
rat
9/-b/mice
24/M/huinan
24/F/human
(smokers and
nonsmokers)
10/M/human
(smokers)
10/F/human
(nonsmofcers)
Exposed to 300 ppm CO alone or
0.75 ppm O3 + 300 ppm CO for
6 h; blood COHb levels were
determined
Exposed to 280 ppm CO alone or
3 ppm 03 + 280 ppm CO for
6h
Exposed during exercise (four 1-h
rides on a bicycle to filtered air
only; 0.3 ppm Og alone; 100 ppm
CO alone; or 0.3 ppm O<> +
100 ppm CO); blood COHb,
pulmonary function,
cardiorespiratory performance,
blood lactate levels, and
subjective symptoms were
examined
Exposed to Og alone and in
combination with NO2 and CO
for 2 h with secondary stress of
heat and intermittent light
exercise; subjective symptoms
were recorded; pulmonary
function and physiological studies
were conducted
Subjects exposed to filtered air
only; 50 ppm CO alone;
0.27 ppm PAN alone; .or 50 ppm
CO + 0.27 ppm PAN for 5 min
at two different temperatures,
25 and 35 °C (relative humidity
30%); were tested for maximal
aerobic power, metabolic
temperature, and .
cardiorespiratory responses
Simultaneous exposure produced higher COHb levels (30.456 Murphy (1964)
in rats and 18.9% in mice) than exposure to CO alone (25.8%
in rats and 14.8% in mice).
COHb levels were 24.3% in mice exposed to CO + O3 Murphy (1964) -
compared with 19.2% in mice exposed to CO alone.
Exposure to Og + CO did not elicit a synergistic effect. DeLucia et al. (1983)
Combined exposure did not alter the threshold(s) of aay subject - ' •
for appearance of adverse effects due to Og alone. Exposure
to CO alone caused a mean increase in COHb (5.8%) levels
compared with exposure not involving CO.
No consistent synergistic or additive effects were observed hi
subjects exposed to Og + M>2 + CO in any parameter
measured, except for increases in blood CQHb (levels not
reported).
Maximal aerobic power was not affected by any pollutant
conditions. The heart rate was significantly (p <0.05) greater
in the CO group compared with the filtered-air group.
Metabolic and thermo-regulatory responses were not different
in the various pollutant environments. Increases in COHb
levels of smokers during the CO or CO + PAN exposures
were observed.
Hackney et al. (1975 a,b)
Drinfcwater et al. (1974),
Gliner et al. (1975),
Raven et al. (1974a,b)
-------
TABLE 11-4 (cont'd). COMBINED EXPOSURE TO CARBON MONOXIDE AND OTHER POLLUTANTS
Pollutant Concentration No./Sex/Species
Treatment8
Observed Effects8
Reference
CO 100 ppm
500 ppm
NO 10 ppm
50 ppm
CO
NO
HCN
CO
NO,
CO
SO,
CO
SO2
CO
S02
200 ppm
5 ppm
0.5 ppm
20 ppm
67,5 ppm
0.5 ppm
7.5 ppm
20 ppm
67.5 ppm
0.5 ppm
10 ppm
250 ppm
25 ppm
250 ppm
70 ppm
15/M/rat
(Long-Evans)
12/M/rabbit
(New Zealand
white)
24/M/rat
24/F/rat
(Sprague-Dawley)
24/M/rat
24/F/rat
(Sprague-Dawley)
32-40/F/mouse
(CF-1)
20/F/rabbit
(New Zealand
white)
Exposed to clean air only; 100 or
500 ppm CO alone; 10 or 50 ppm NO
alone; 100 ppm CO + 10 ppm NO; or
500 ppm CO + 50 ppm NO for 3 h;
changes in discrimination learning and
brain activity were measured
Exposed to 0.5 ppm HCN + 5 ppm
NO + 200 ppm CO for 2 weeks
Exposed to clean air only; 0.5 or
7.5 ppm NO^ alone; 20 or 67.5 ppm
CO alone; 0,5 pprn NO2 + 67.5 ppm
CO; or 7.5 ppm NO^ + 20 ppm CO
continuously, 24 h/day, 7 days/week
for 52 weeks; chronic toxisity was
assessed
Exposed to clean air only; 0.5 or 10
ppm SO£ alone; 20 or 67.5 ppm CO
alone; 0.5 ppm SO2 + 67.5 ppm CO;
or 10 ppm SC<2 + 20 ppm CO
continuously, 24 h/day, 7 days/week
for 52 weeks; chronic tqxicity was
Exposed to filtered air only; 25 ppm
SO2 alone; or 25 ppm SO + 250 ppm
CO for 7 h/day during Days 6 through
15 of gestation; teratogenic potential
was evaluated
Exposed to filtered air only, 70 ppm
SO2 alone, or 70 ppm SOo, +
250 ppm CO for 7 h/day during Days
6 to 18 of gestation; teratogenic
potential was evaluated "
No significant changes were observed in COHb levels
between any treatment groups. Exposure to 100 ppm CO
+ 10 ppm NO significantly (p<0.01) increased mean
metHb levels when compared to NO (10 ppm) alone.
Combined exposure caused significant behavioral effects
at both levels. Combined exposure also affected early
auditory-evoked potential components (Pin an^ Nqn);
the effect was more pronounced at higher dose level
(500 ppm CO + 50 ppm NO) than at the lower levels,
indicating a dominant role for NO.
Combined exposure to the three noxious gases caused no
morphological changes in the lung, pulmonary and
coronary arteries, or aorta..
No consistent changes in pulmonary function indices
were observed in any of the groups exposed to the
pollutants alone or in combination with CO.
Hematological and biochemical changes were within the
normal range. Combined exposure to CO + M>2 did
not increase the severity of the histopathological changes
observed in the lungs of rats exposed to NO2 alone.
Combined exposures caused no consistent changes in
pulmonary function indices, hematology, or biochemical
or histological parameters.
Exposure to SO2 alone or SO2 + CO caused no
teratogenic effects.
No teratogenicity was observed.
Groll-Knapp et al. (1988)
Hugod (1979)
Busey (1972)
Busey (1972)
Murray et al. (1978)
Murray et al. (1978)
-------
TABLE 11-4 (cont'd). COMBINED EXPOSURE TO CARBON MONOXIDE AND OTHER POLLUTANTS
Pollutant Concentration No ./Sox/Species
Treatment*
Observed Effect/
Reference
00
CO
S02
CO
PbClBr
3 mg/nr
6 mg/m
0.5 mg/m3
67.5 ppm
0.6 ppm
CO 100 ppm
CH2C12 1,000 ppm
CO 1,500 ppm
CH2C12 2,000 ppm
3/-b/humtn
24/M/rat
24/F/rat
(Sprague-Dawley)
5/M/rat
(Wistar)
-VVdpg
(Cowenose
Mongrel)
Exposed to pure air for 5 nun;
6 mg/m3 CO for 20 min; 6 mg/in3 CO
+ 0.5 mg/m3 S02 for 5 min;
0.5 mg/m3 S02 for 25 min; 6 mg/m3
CO 4- 0.5 mg/m3 for 25 min; or
3 mg/m3 CO + 0.5 mg/m3 S02 for
25 min; variations in ocular sensitivity
to light and color vision were tested
Exposed to clean air alone; 67.5 ppm
CO alone; 0.6 ppm PbClBr alone; or ,
to 0.6 ppm PbClBr -f 67.5 ppm CO
continuously 24 h/day, 7 days/week
for 52 weeks; chronic toxicity was
Exposed to clean air only; 100 ppm
CO alone; 1,000 ppm CH2C12 only; or
100 ppm CO + 1,000 ppm CS2ch
for 3 h; mixed-function oxidase activity
and blood COHb levels were examined
Exposed to 1,500 ppm CO for 25 min
followed by a 2-h exposure to
2,000 ppm CH2C12 in air also
containing 150 ppm CO; effects on the
cardiovascular system were evaluated
Inhalation of 6 mg/m3 CO +• 0.5 mg/m3 S02 for 5 min
or CO alone for 20 min caused significant differences in
light and color sensitivity when compared to controls.
No consistent changes in pulmonary function,
hematology, or biochemistry were observed between the
treatment groups. Combined exposure to CO + PbClBr
did not increase the incidence of histological changes
observed in the kidneys of rats exposed to PbClBr alone.
Combined exposure had an additive effect. Blood COHb
was significantly (p<0.001) increased in rats exposed to
CO -f CE^CIj (14.6%) compared with with CO alone
(8.8%). Combined exposure significantly (p<0.005)
increased the ethoxycoumarin-0-deethylase activity in
the kidneys. Treatment had no effect on liver
microsomal oxidation.
Combined exposure of CO + CH2C12 had no effect on
the physiologic response due to CO, instead CO
antagonized the responses due to CH2CI2.
Mamatsashvili (1967)
Busey (1972)
Kurppa et al. (1981)
Adams (1975)
aSee glossary of terms and symbols for abbreviations and acronyms.
Information was not reported in the original manuscript.
-------
Combined exposure also caused significant behavioral changes. Hugod (1979) reported that
combined exposure to CO plus NO plus HCN for 2 weeks produced no morphological
changes in the lungs, pulmonary arteries, coronary arteries, or aortas of rabbits.
In a 1-year inhalation toxicity study, no adverse toxic effects were seen in groups of rats
exposed to relatively low levels of CO plus NO2 or CO plus sulfur dioxide (SC>2) as
compared with rats exposed to one of these pollutants alone (Busey, 1972). Murray et al.-
(1978) observed no teratogenic effects in offspring of mice or rabbits exposed to CO plus
SO2 for 7 h/day during gestation Days 6 to 15 or 18, respectively.
Halogenated hydrocarbons, such as the dihalomethanes (e.g., methylene bromide,
methylene iodide, and methylene chloride [CE^CtJ) are widely used as organic solvents.
These chemicals are metabolized in the body to produce CO, which is readily bound to Hb.
Therefore, any additional exposure to CO, producing higher COHb levels, could possibly
cause greater health effects. For example, up to 80% of inhaled CH2C12 will be metabolized
to CO. Inhalation of 500 to 1,000 ppm, therefore, would result in COHb levels of over
14%. This elevation in COHb can not only have a significant effect when combined with CO
exposure, but the CO resulting from metabolism generally requires a longer time to dissipate
(Kurppa, 1984).
In one study, combined exposure to CO plus CH2C12 for 3 h had an additive effect on
blood COHb levels in rats (Kurppa et al., 1981). On the other hand, Adams (1975) reported
that combined exposure to CO plus CH2C12 did not have an additive effect on the physiologic
response in the cardiovascular systems of dogs due to CO; instead* CO antagonized the
responses due to CH2C12.
11,3.2 Exposure to Combustion Products
A common condition in an atmosphere produced by a fire is the presence of a rapidly
changing combination of potentially toxic gases (primarily CO, carbon dioxide [COJ, and
HCN), reduced O2 levels (hypoxic hypoxia), and high temperatures. Combined exposure to
these gases occurs during smoke inhalation under conditions of hypoxic hypoxia. In addition,
both CO and CO2 are common products of carbon-containing materials; consequently,
accidental exposure to high levels of CO will rarely occur without simultaneous exposure to
CO2. Exposure to CO and HCN is of concern because both CO and HCN produce effects by
11-29
-------
influencing tissue O2 delivery. Increased COHb reduces O2-carrying capacity and may
interfere with tissue O2 release, whereas HCN inhibits tissue respiration. Studies were '
conducted to determine the toxicological interactions of the combustion products with and
without reduced 02. (Also see Section 10.4.1.5 for more discussion on CO and HCN.)
Several studies have investigated the effects resulting from combined exposure to CO
and combustion products from fires. The experimental details and the associated effects for
each study are summarized in Table 11-5. The following is a brief discussion of the major
findings.
Rodkey and Collison (1979) reported a significant (p<0.02) decrease in mean survival ;
time in mice jointly exposed until death to CO plus CO2 compared with mice exposed to CO
alone. In contrast, Crane (1985) observed no differences in the times-to-incapacitation or
times-to-death in rats exposed until death to various concentrations of CO plus CO2. In a
recent study, Levin et al. (1987a) demonstrated a synergistic effect between CO and CO2 in
rats exposed to various concentrations of CO plus CO2. Simultaneous exposure to nonlethal
levels of CO2 (1.7 to 17.3%) and to sublethal levels of CO (2,500 to 4,000 ppm) caused
deaths in rats both during and following (up to 24 h) a 30-min exposure. Although the
equilibrium levels of COHb were not changed by the presence of CO2, the rate of COHb
formation was 1.5 times greater in rats exposed to CO plus CQ2 than in rats exposed to CO
alone. The synergistic effects of CO2 on CO toxicity were also observed at other exposure
times (Levin et al., 1988a).
Combined exposure to CO plus HCN had an additive effect in rats as evidenced by
increases in mortality rate (Levin et al., 1987b, 1988a). Results from this series of .
experiments showed that the exposed animals died at lower CO concentrations as the levels of
HCN increased. In the presence of HCN, COHb at equilibrium was less than that measured
in the absence of HCN; however, the initial rate of COHb formation was the same. This
apparent depressive effect of HCN on COHb formation may explain the reason for the low
COHb levels (<50%) seen in some people who died in a fire (Levin et al., 1987b). In
contrast, Hugod (1979) reported that lower levels of exposure to HCN alone or to CO plus
HCN for 1 to 4 weeks produced no morphological changes in the lung, pulmonary and
coronary arteries, or aorta of rabbits. .:;•
11-30
-------
TABLE 11-5. COMBINED EXPOSURE TO CARBON MONOXIDE AND COMBUSTION PRODUCTS
Combustion
Product
Concentration No./Sex/Species
Treatment8
Observed Effects8
Reference
CO
C00
6,000 ppm 6/F/rat " Exposed to 6,000 ppm CO alone;
2.1,2.3, '. (NMRI) 6,000ppmCO + 2J or4,5% CO2;
4.5,5.4% or 6,000 ppm CO + 2.3 or 5.4%
CO2 until death; O2 concentrations
were either 14 or 21%; mean survival
time (MST) and fatal blood COHb
level were measured
CO
co2
5,000-14,000 ppm
4-13%
-b/-b/rat
CO
C°2
Exposed to concentrations ranging
from 5,000 to 14,000 ppm CO alone
or with C02 concentrations ranging
from 4 to 13 % continuously until
death; synergistic effects (times-to-
incapacitation ([tj]) or the times-to-
death ([tj]) were evaluated
1,470-6,000 ppm 6/M/rat Exposed to 1,470 to 6,000 ppm CO
1.7-17.3 % (Fischer 344) or 2,500 to 4,000 ppm CO + 1.7 to
17.3% CO2 for 30 min; lexicological
interactions (mortality and COHb
formation) were evaluated
The MST was significantly (p < 0.02) decreased in
rats'exposed to 6,000 ppm CO + 2.1% CO2
(18.4 min) or 4.5% CQ2 (16.8 min) compared with
CO alone (22.4 min) in the presence of 21% O2.
Exposure to 14%' O2 + 6,000 ppm CO decreased
the MST to 9.6 min; addition of 2.3% or 5.4% CO2
had no further effect on MST- Combined exposure
(CO + CO2) had no effect on fatal blood COHB.
No synergistic effects were observed; no significant
CO2. changes were observed in the end points (tj or
tj) for added CO2 compared to end points for CO
alone.
Rodkey and Collison (1979)
Crane (1985)
Exposure to CO alone caused deaths at levels of
4,600 to 6,000 ppm and at COHb levels of >83%.
Deaths were primarily due to the high COHb, low
O2Hb, and hypoxia. Combined exposure to
32,500 ppm CO +1.7 to 17.3% CO2 caused deaths
during exposure and the following 24-h period. No
mortality occurred in rats at <2,500 ppm CO alone
regardless of CO2 concentrations. The rate of COHb
formation was 1.5 times greater in rats exposed to
2,500 ppm CO + 5.25% CO2 than in rats exposed to
2,500 ppm CO alone. The COHb equilibrium level
was the same (78%) for the combined exposure, but
was reached in 10 min in the presence of CO2 and
20 min in the absence of CO2. Combined exposure
increased the concentration of .COHb, caused severe
acidosis, and prolonged the recovery of aoidosia
following cessation of exposure. Exposure to CO2
alone produced no mortality or incapacitation. The
30 min LC
-------
TABLE 11-5 (cont'd). COMBINED EXPOSURE TO CARBON MONOXIDE AND COMBUSTION PRODUCTS
Combustion
Product
Concentration No^Sex/Spccies
Treatment*
Observed Effects8
Reference
N>
CO 1,220-4,600 ppm 6/M/rat 30 min LC50 of CO in fflk was
HCN 44-160 ppm (Fischer 344) 4,600 ppm; 30 min LC50 of HCN in
per each ak was 160 ppm. In combination,
experiment exposed to 1220 to 3420 ppm CO and
44 to 130 ppm HCN for 30 mm}
three gas combinations (CO, low O^,
and 5% CO^ were also examined;
lethality and COHb formation were
measured as lexicological end points
CO > 1000 ppm 6/M/rat Exposed to varying concentrations of
HCN >25ppm (Fischer 344) CO or HCN for 1, 2, 5, 10, 20, 30,
C02 5 % per each and 60 min; combined exposure of
low O2 10-15% experiment CO + CO2 and CO + HCN for 5 to
60 min; 3- and 4-gas combinations
involving CO, HCN, low O2, and
5% CO, were also studied for
exposures of 30 min
CO 200 ppm 12-24/M/rabbU Exposed to 0.5 ppm HCN alone or
HCN 0.5 ppm (albino) 0.5 ppm HCN + 200 ppm CO for
1 or 4 weeks; morphological changes
in the lung, pulmonary arteries,
coronary arteries, or aorta were
evaluated
CO 6.63-0.66% 10/M/mouse Mice were exposed to clean air or to
0.325-0.375% (ICR) atmospheric concentrations of,
KCN 4-9 mg/fcg 0.63-0.66% CO for 3 min
1-6.35 mg/kg (pretreatment) and then injected ip
with 4-9 mg/kg KCN
In another experiment, mice were
pretreated with either saline
(0.1 ml/10, ip) or KCN (1 to
6,35 mg/kg, ip) and then were
exposed via inhalation to CO in the
>r< . .-• range of 0.325 to 0.375% CO for
4 min; lethality and blood CO and
cyanide concentrations were measured
Combined exposure to CO + HCN bad an additive
effect ag evidenced by increased mortality. As the
concentrations of HCN increased, the animals died
at lower CO concentrations and presented lower
levels of COHb at death. When rats were exposed
to 1,470 ppm CO alone or 1,450 ppm CO +
100 ppm HCN, the initial rate of COHb formation
was the same in the presence or absence of HCN;
however, the final COHb level was lower in the
presence of HCN, indicating a depressive effect of
HCN on CO uptake and the COHb formation.
LCjQ values ranged from 107,000 ppm (1 nun) to
4,900 ppm (60 min) for CO and 3,000 ppm (1 min)
to 90 ppm (60 min) for HCN; toxicity of CO +
HCN was additive for 5 to 60 min; except for the
5 min exposure, the presence of 5 % CO2 decreased
the LCjQ values of CO. For multiple combinations,
toxicity of CO + HCN + reduced O2 (10-15%)
was additive whereas C02 (5 %) was synergistio
with any one or combinations of all the other gases.
Exposure to HCN alone or in combination with CO
produced no morphological changes in the lung,
pulmonary arteries, coronary arteries, or aorta.
The U>50 value was significantly (p<0.05) lower
for KCN (6.51 mg/kg) in CO-pretreated mice than
in air-pretreated mice (7.90 mg/kg).
Sublethal doses of KCN (3.5 to 6.35 mg/kg)
produced a synergistic effect in mortality: 40-100%
mortality in KCN-preteeated mice compared to
10-20% in saline-pretreated mice. There were no
differences in CO or cyanide blood levels between
these treatment groups.
Levin et al. (1987b)
Levin et al. (1988a,b)
Hugod (1979)
Norris et al. (1986)
-------
TABLE 11-5 (cont'd). COMBINED EXPOSURE TO CARBON MONOXIDE AND COMBUSTION PRODUCTS
Combustion
Product
Concentration No./Sex/Species
Treatment8
Observed Effects8
Reference
CO
KCN
CO
(under
conditions of
hypoxic
hypoxia)
CO
(under
conditions of
hypoxic
hypoxia)
1,000 ppm 20/M/mouse Preexposed to 1,000 ppm CO for 4 h
2,500 ppm (Swiss Webster) followed by a single ip injection of
7.5 mg/kg 7.5 mg/kg KCN, 24-h later; effects
on KCN-induced lethality were
studied
Preexposed to 7.5 mg/kg KCN 0P)
24 h prior to exposure to 2,500 ppm
CO for 2 h; effects on KCN-induced
lethality were studied
CO: 6,000 ppm 6/F/rat Exposed to 6,000 ppm CO until death
©2= 14 or 21 % (NMR1) in the presence of either 14 or 21 %
O2; MST and fatal blood COHb
levels were measured
CO: 500, 1,000, 20/M/mouse Mice were preexposed to 500 or
or 2,500 ppm (Swiss Webster) 1,000 ppm CO for 4 h and then
O2:7orlO% exposed 24-h later to 2,500 ppm CO
for2h
Preexposed to 500 or 1,000 ppm CO
for 4 h and then exposed to 7% O2
for 2 h, 24-h later
Preexposed to 10% O2 for 4 h and
then exposed to 2,500 ppm CO for
2h, 24-h later
Preexposed to 1,000 ppm CO or 10%
O2 for 4 h and then exposed to
2,500 ppm CO for up to 2 h, 24-h
later
No alterations in lethality in CO + KCN group as
compared with control + KCN group.
Pretreatment with KCN had no significant effect on
lethality associated with subsequent exposure to CO.
MST was significantly (p<0.01) decreased in the
presence of low (14%) O2 (9.6 min) compared to
that of high (21%) O2 (22.4 min) levels.
A significantly (p<0.01) higher level of COHb was
observed in rats treated with 14% O2 (89.4%)
compared with those treated with 21% O2 (83.4%).
Preexposure to CO caused a significant (p<0.05)
decrease in lethality during subsequent exposures to
CO.
Preexposure to CO followed by exposure to 02 had
no effect on lethality. Preexposure to CO had no
protective effect against hypoxic hypoxia.
Preexposure to O2 followed by exposure to CO
significantly (p<0.05) decreased lethality compared
to controls.
Preexposure to either CO or O^ na<^no significant
effect on O2-consumption level. Alterations in CO
lethality were not associated with alterations in
COHb levels.
Winston and Roberts (1975)
Rodkey and Collison (1979)
Winston and Roberts (1975)
-------
TA^LE 11-5 (cont'd). COMBINED EXPOSURE TO CARBON MONOXIDE AND COMBUSTION PRODUCTS
Combustion
Product
CO
(under
conditions of
hypoxic
hypoxia)
Concentration
CO: 500 or
1,000 ppm
O2: 6-21 % or
11.8-20.5%
No^Sex/Specics
- /M/mouse
(Swiss Webster)
Treatment"
Exposed to reduced O2 (6-21 %)
alone or reduced O2 (11.8 to 20.5%)
+ 500 ppm CO, or 20.2% 02 +
1,000 ppm CO for 20 min; animals
were subjected to behavioral tests that
determined reaction time and
performance of the animals in a
mouse pole-jump apparatus.
Observed Effects8
Reaction time gradually increased with a decrease in
O2 to 10%. At <10% O2, reaction time increased
dramatically and animal performance decreased
almost immediately. At reduced O2 levels + CO,
the decreases in performance were even greater than
those seen in mice exposed to reduced O2 levels
only. At 20% O2 (close to ambient level)
+ 1,000 ppm CO, performance was nearly
completely degraded.
Reference
Cagliostro and bias (1982)
aSee glossary of terms and symbols for abbreviations and acronyms.
Data not provided in the published manuscript.
-------
Combined exposures to CO plus potassium cyanide (KCN) have produced conflicting
results. Norris et al. (1986) reported that the dose that is lethal to 50% of test subjects
(LD50) values were significantly lower in mice pretreated with CO prior to ip injection of
KCN. Sublethal doses of KCN produced a synergistic effect on mortality. On the other
hand, Winston and Roberts (1975) observed no alterations in lethality in mice pretreated with
CO and then treated with ip injections of KCN.
A number of studies examined the effects of CO administered under conditions of
hypoxic hypoxia. Rodkey and Collison (1979) observed a lower mean survival time and a
higher level of COHb in mice exposed to CO in the presence of low O2 (14%) than in those
exposed to an ambient O2 (21%) level. Winston and Roberts (1975) showed that preexposure
of mice to CO, followed by exposure to 7% O2 24-h later, had no effect on lethality as
compared with controls exposed to 7% O2 only. Thus, preexposure to CO had. no protective
effect against hypoxic hypoxia. However, preexposure to 10% O2 caused a significant
decrease in lethality in mice exposed 24-h later to CO. Alterations in colethality were not
associated with alterations in COHb levels. In a behavioral study in mice, Cagliostro and
Islas (1982) showed that reaction times gradually increased with a decrease in O2 levels to
10%. At < 10% O2, reaction time increased dramatically. At reduced O2 levels and in the
presence of CO, the decreases in performance were even greater than those observed in mice
exposed to reduced O2 levels alone.
Three and four gas combinations of combustion products were also examined (Levin
et al., 1988b). The combinations tested included CO, CO2, HCN, and reduced O2. Carbon
dioxide showed synergistic effects when tested with any of the other gases. The other gases
were additive with CO.
11.3.3 Exposure to Other Environmental Factors
11.3.3.1 Environmental Heat
Several of the studies (Drinkwater et al., 1974; Raven et al., 1974a,b; Gliner et al.,
1975) describing the effects of CO exposure alone and CO combined with PAN on exercise
performance in healthy adult men, reviewed in Sections 10.3.2 and 11.3.1, also evaluated the
effects of heat stress. Subjects were exposed to 50 ppm CO and/or 0.27 ppm PAN in
environmental exposure chamber conditions of 30% relative humidity at 25 and 30 °C. In
11-35
-------
these studies, O2 uptake
-------
hair cells at the basal end of the cochlea. Auditory threshold loss for the combined exposure
was evident at all frequencies tested but was greatest for high-frequency tones. A previous
pilot study by Young et al. (1987) conducted at 1,200 ppm CO also showed that combined
exposure to noise and CO produced high-frequency shifts of greater magnitude than those
produced by exposure to noise alone. The CO levels used in these studies, however, are
much greater than those encountered in the typical ambient environment, or even in the
typical occupational environment. Thus, it is difficult to predict how relevant these studies
are to actual conditions of human exposure that are encountered in everyday life.
Results from the toxicologic studies in rats suggest that combined exposure to noise and
CO may be important in evaluating potential risk to exposed humans. An early
epidemiologic study by Lumio (1948) in operators of CO-fueled vehicles found significantly
greater permanent hearing loss than expected after controlling for possible confounding
factors. More recently, SulkowsM and BojarsM (1988) studied age-matched workers with
similar length of duty employed in foundry, cast iron, and cast steel positions of a mining
devices factory where CO and noise exposure varied. Careful otological and audiometric
examinations were performed on these workers. The group exposed to the combined effects
of 95 dBA noise and a mean concentration of 41 ppm CO did not experience any greater
hearing loss than the groups exposed only to noise (96 dBA) or CO (45 ppm). In fact, a
permanent threshold shift was significantly larger in workers exposed to noise alone than
those exposed to the combined influence of CO and noise. This study needs to be verified,
however, at similar, relevant exposure levels before any definitive conclusions can be made
regarding the potential of lower-level CO to potentiate noise-induced auditory loss in humans.
11.3.4 Summary
Much of the data concerning the combined effects of CO and other pollutants found in
the ambient air are based on animal experiments. Only a few human studies are available.
Early studies in healthy human subjects by Hackney et al. (1975a,b), Raven et al. (1974a,b),
Gliner et al. (1975), and Drinkwater et al. (1974) on common air pollutants such as NO2,
O3, or PAN and more recent work on CO plus O3 by DeLucia et al. (1983) failed to show
any interaction from combined exposure.
11-37
-------
In animal studies, no interaction was observed following combined exposure of CO and,
ambient air pollutants such as NO2 or SO2 (Hugod, 1979; Busey, 1972; Murray et al.,
1978). However, an additive effect was observed following combined exposure of high ,
levels of CO plus NO (Groll-Knapp et al., 1988), and a synergistic effect was observed after
combined exposure to CO and O3 (Murphy, 1964).
lexicological interactions of combustion products, primarily CO, CO2, and HCN, at
levels typically produced by indoor and outdoor fires, have shown, a synergistic effect
following CO plus CO2 exposure (Rodkey and Collison, 1979; Levin et al., 1987a) and an
additive effect with CO plus HCN (Levin et al., 1987b). Additive effects were also observed
when CO, HCN, and low O2 were combined; adding CO2 to this combination was
synergistic (Levin et al., 1988b). Additional studies are needed, however, to evaluate the
effects of CO under conditions of hypoxic hypoxia.
Finally, laboratory animal studies (Yang et al., 1988; Fechter et al., 1988; Young
et al., 1987) suggest that the combination of environmental factors such as heat stress and
noise may be important determinants of health effects occurring in combination with exposure
to CO. Of the effects described, the one potentially most relevant to typical human
exposures is a greater decrement in exercise performance seen when heat stress is combined
with 50 ppm CO (Drinkwater et al., 1974; Raven et al., 1974a,b; Gliner et al., 1975).
11.4 ENVIRONMENTAL TOBACCO SMOKE
A common source of CO for the general population comes from tobacco smoke, along
with other primary sources arising from the environment. Exposure to tobacco smoke not
only affects the COHb level of the smoker, but under some circumstances, such as in poorly
ventilated spaces, tobacco smoke exposure also can affect nonsmokers. For example, acute ,
exposure (1 to 2 h) to smoke-polluted environments has been reported to cause an incremental
increase in nonsmokers' COHb of about 1% (Jarvis, 1987), In addition to CO, other
products inhaled by the affected individuals, such as NO2, HCN, nicotine, and carcinogens ;
contained in tobacco smoke, may produce physiological and biochemical effects in both the ,
smoker and nonsmoker. Possible pathological changes due to the interaction of CO and these
11-38
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other constituents of tobacco smoke that may occur in the lungs and other tissues remain to
be elucidated.
A detailed discussion of the possible health effects due to CO emitted from, tobacco
smoke is beyond the scope of this document. Those interested in the problems related to
smoking tobacco (i.e., carcinogenesis and cardiovascular and pulmonary disease) should refer
to review documents specifically concerned with these matters (Surgeon General of the
United States, 1983; U.S. Department of Health, Education and Welfare, 1979, 1972). In
addition, a number of sources have reviewed the potential health effects of tobacco smoke on
nonsmokers (U.S. Environmental Protection Agency, 1990; Fielding and Phenow, 1988;
Hulka, 1988; Mohler, 1987; Surgeon General of the United States, 1986; National Research
Council, 1986).
Tobacco smoking has been found to result in higher COHb levels than exposure to
ambient concentrations of CO. The actual quantity of CO entering the lung depends on the
form in which tobacco is smoked, the pattern of smoking, and the depth of inhalation
(Robinson and Forbes, 1975). Very little CO (approximately 5%) is absorbed in the mouth
and larynx, therefore most of the CO available for binding to Hb must reach the alveoli in
order to raise the level of COHb present in the blood. The CO concentration in tobacco
smoke is approximately 4.5% (45,000 ppm). It has been estimated that a smoker may be
exposed to 400 to 500 ppm CO for the approximately 6 min that it takes to smoke a typical
cigarette, producing an average baseline COHb of 4%, with a typical range of 3 to 8%.
Heavy smokers can have COHb levels as high as 15%. In comparison, nonsmokers average
about 1% COHb in their blood. (See Chapter 8 for more information on CO exposure in the
population.) As a result of the higher baseline COHb levels, smokers may actually be
excreting more CO into the air than they are inhaling from the ambient environment.
Smokers may even show an adaptive response to the elevated COHb levels, as evidenced by
increased red cell volumes or reduced plasma volumes (Smith and Landaw, 1978a,b). For
these reasons, the U.S. Environmental Protection Agency (EPA) previously has not
considered active smokers in determining the need for a margin of safety for the CO NAAQS
(Federal Register, 1980). This position was affirmed by the Clean Air Scientific Advisory
Committee of EPA's Science Advisory Board during review of the previous CO criteria
document (U.S. Environmental Protection Agency, 1979).
11-39
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The effects of CO from tobacco smoke have been discussed in other sections of the
document. Human experimental studies suggested that acute effects of tobacco smoke on
maximal exercise performance are similar to those described for healthy subjects exposed to
CO. Prospective and retrospective epidemiological studies identified tobacco smoke as one of
the major factors in the development of cardiovascular disease. Tobacco smoke may
contribute to the development and/or aggravation of effects in exposed individuals,through the
action of several independent or complementary mechanisms, one of which is the formation
of significant levels of COHb. Unfortunately, attempts to separate the CO effects of tobacco
smoke from the potential effects of other substances present in the smoke have been
unsuccessful. (For a discussion of these studies, see Section 10.3.)
In summary, although tobacco smoke is another source of CO for smokers as well as
nonsmokers, it is also a source of other chemicals with which environmental CO levels could
interact. Available data strongly suggest that acute and chronic CO exposure attributed to
tobacco smoke can affect the cardiopulmonary system, but the potential interaction of CO
with other products of tobacco smoke confounds the results. In addition, it is not clear if
incremental increases in COHb caused by environmental exposure would actually be additive
to chronically elevated COHb levels due to tobacco smoke, because some physiological
adaptation may take place. There is, therefore, a need for further research to describe these
relationships better.
11-40
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12. EVALUATION OF SUBPOPULATIONS
POTENTIALLY AT RISK TO
CARBON MONOXIDE EXPOSURE
12.1 INTRODUCTION
Most of the information on the human health effects of carbon monoxide (CO)
discussed in Chapter 10 of this document has concentrated on two carefully defined
population groups—young, healthy, predominantly male adults and patients with diagnosed
coronary artery disease. On the basis of the known effects described, patients with
reproducible exercise-induced ischemia appear to be best established as a sensitive group
within the general population that is at increased risk for experiencing health effects (i.e.,
decreased exercise duration due to exacerbation of cardiovascular symptoms) of concern at
ambient or near-ambient CO-exposure concentrations that result in earboxyhemoglobin
(COHb) levels of 6% or less. A smaller sensitive group of healthy individuals experience
decreased exercise duration at similar levels of CO exposure, but only during short-term
maximal exercise. Decrements in exercise duration in the healthy population, therefore,
would be mainly of concern to competing athletes rather than for nonathletic people carrying
out the common activities of daily life.
It can be hypothesized, however, from both theoretical work and from experimental
research on laboratory animals that certain other groups in the population are at potential risk
to exposure from CO. The purpose of this chapter is to explore the potential effects of CO in
population groups that have not been studied adequately, but that could be expected to be
susceptible to CO because of underlying physiological status due to gender differences, aging,
preexisting disease, or because of the use of medications or alterations in their environment.
These probable risk groups include (1) fetuses and young infants; (2) pregnant women;
(3) the elderly, especially those with compromised cardiopulmonary or cerebrovascular
functions; (4) individuals with obstructed coronary arteries, but not yet manifesting overt
symptomatology of coronary artery disease; (5) individuals with congestive heart failure;
(6) individuals with peripheral vascular or cerebrovascular disease; (7) individuals with
hematological diseases (e.g., anemia) that affect oxygen (O^-carrying capacity or transport in
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the blood; (8) individuals with genetically unusual forms of hemoglobin (Hb) associated with
reduced O2-carrying capacity; (9) individuals with chronic obstructive lung diseases;
(10) individuals using medicinal or recreational drugs having effects on the brain or
cerebrovasculature; (11) individuals exposed to other pollutants (e.g., methylene chloride)
that increase endogenous formation of CO; and (12) individuals who have not been adapted to
high altitude and are exposed to a combination of high altitude and CO.
Little empirical evidence currently is available by which to specify health effects
associated with ambient or near-ambient CO exposures for most of these probable risk
groups. Where the previous chapters dealt with documented evidence of CO exposure
through controlled or natural laboratory investigations, this chapter will be more speculative.
An effort will be made to determine the anticipated effects of CO in special subpopulations
that form a significant proportion of the population at large.
12.2 AGE AND GENDER AS RISK FACTORS
The fetus and newborn infant are theoretically susceptible to CO exposure for several
reasons. Fetal circulation is likely to have a higher COHb level than the maternal circulation
due to differences in uptake and elimination of CO from fetal Hb. Because the fetus also has
a lower O2 tension in the blood than adults, any further drop in fetal O2 tension due to the
presence of COHb could have a potentially serious effect. The newborn infant with a
comparatively high rate of O2 consumption and lower O2-transport capacity for Hb than most
adults also would be potentially susceptible to the hypoxic effects of increased COHb. Newer
data from laboratory animal studies on the developmental toxicity of CO suggest that
prolonged exposure to high levels (> 100 ppm) of CO during gestation may produce a
reduction in birthweight, cardiomegaly, and delayed behavioral development (see
Section 10.5). Human data are scant and more difficult to evaluate, but further research is
warranted. Additional studies, therefore, are needed hi order to determine if chronic
exposure to CO, particularly at low, near-ambient levels, can compromise the already
marginal conditions existing in the fetus and newborn infant.
The effects of CO on maternal-fetal relationships are not understood well. In addition
to fetuses and newborn infants, pregnant women also represent a susceptible group because
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pregnancy is associated with increased alveolar ventilation and an increased rate of
O2 consumption that serves to increase the rate of CO uptake from inspired air. A perhaps
more important factor is that pregnant women experience hemodilution due to the
disproportionate increase in plasma volume as compared to erythrocyte volume. This group,
therefore, should be studied to evaluate the effects of CO exposure and elevated COHb
levels.
Seventy percent of the population of the United States survive to 65 years of age and
30% reach 80 years of age or more (Brody et al., 1987). In 1982, about 40% of the total
population over age 65 were 75 years of age or older, corresponding to about 10.7 million
subjects. The percentage of the population reaching 75 years of age or older is expected to
increase to 49% by the year 2000 and to 56% by the year 2080, making it one of the fastest
growing segments of the population. Thus, the aging population represents a potentially large
subgroup that may be at risk to CO exposure.
Changes in metabolism with age (Astrand and Rodahl, 1986; McArdle et al., 1986)
may make the aging population particularly susceptible to the effects of CO. Maximal
O2 uptake declines steadily with age. The rate of decline in the population is difficult to
determine, however, partly because of the wide range of values reported in the cross-sectional
and longitudinal studies published in the literature, and partly because of confounding factors
such as heredity, changes in body weight and composition, and level of physical activity.
Keeping in mind that large individual variability exists in the population, maximal O2 uptake
has been estimated to decline in an average inactive person at a rate of about 0.5 mL/kg/year
(Stamford, 1988; Larson and Bruce, 1986). The rate of decline is only about 0.35
mL/kg/year in persons with very active life-styles, at least in the younger age groups
(Stamford, 1988; Larson and Bruce, 1986).
By the time an average healthy, nonsmoking male reaches the age of 65 years, the
maximal O2 uptake will be about 23 + 5 mL/kg/min. At 75 years of age, 'the maximal
O2 uptake will be about 17 + 5 mL/kg/min. The decline in maximal O2 uptake with age
seems to be the same in females, as well. However, because females have about 20 to 25 %
lower maximal O2 uptake, when expressed in milliliters per kilogram per minute, the -
corresponding values will occur about 5 to 8 years earlier in females. In physically active
individuals, the corresponding values will occur about 10 to 15 years later compared to the
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average sedentary person. Inactivity is a prevalent condition, however, especially in the
elderly and in females.
The average person needs about 10 mL/kg/min in maximal O2 uptake to meet daily
metabolic requirements. Thus, many healthy males at 75 years of age, and many healthy
females at 67 years of age, are on the borderline with respect to being able to perform many
ordinary daily activities. It is quite possible, therefore, that even low levels of CO exposure
might be enough to critically impair O2 delivery to the tissues in this aging population and
severely limit daily metabolic requirements. Because females have a longer life expectancy
than males, the aging female population potentially at greater risk to CO exposure would be
expected to be larger than the aging male population.
12.3 RISK OF CARBON MONOXIDE EXPOSURE IN INDIVIDUALS
WITH PREEXISTING DISEASE
12.3.1 Subjects with Coronary Artery Disease
Coronary heart disease remains the major cause of death and disability in the United
States. According to the most recent data compiled by the American Heart Association
(1989), persons with diagnosed coronary artery disease numbered 5 million in 1987 and
current estimates are as high as 7 million, or about 3% of the total population (U.S.
Department of Health and Human Services, 1990; Collins, 1988). These individuals have
myocardial ischemia, which occurs when the heart muscle receives insufficient O2 delivered
by the blood. For some, exercise-induced angina pectoris can occur. In all patients with
diagnosed coronary artery disease, however, the predominant type of ischemia, as identified
by ST segment depression, is asymptomatic (i.e., silent). In other words, patients who
experience angina usually have more ischemic episodes that are asymptomatic.
Unfortunately, some individuals in the population have coronary artery disease but are totally
asymptomatic. It has been estimated that 5% of middle-aged men develop a positive exercise
test (Epstein et al.} 1988; Erikssen and Thaulow, 1984), one of the signs of ischemia,
A significant number of these men will have angiographic evidence of coronary artery disease
(Epstein et al., 1988, 1989; Conn, 1988). Nationally, more than 1 million heart attacks
occur each year, half of them being fatal (American Heart Association, 1989). About 10 to
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15% of all myocardial infarctions are silent (Kannel and Abbott, 1984; Epstein et al., 1988).
Of the 500,000 survivors of hospitalized myocardial infarction, about 10% are asymptomatic ,
but have signs of ischemia. Thus, many more persons, as many as 3 to 4 million Americans
(American Heart Association, 1989), are not aware that they have coronary hisart disease and
may constitute a high-risk group.
Persons with both asymptomatic and symptomatic coronary artery disease have a limited
coronary flow reserve and, therefore, will be sensitive to a decrease in O2-carrying capacity
induced by CO exposure (see Section 10.3.2). In addition, CO might exert a direct effect on
vascular smooth muscle, particularly in those individuals with an already damaged vascular
endothelium. Naturally occurring vasodilators like acetylcholine cause a release of
endothetium-derived relaxing factor that precedes the onset of vascular smooth muscle
relaxation. Oxyhemoglobin (O2Hb) and oxymyoglobin will antagonize these smooth muscle
relaxant effects. Although no clinical studies have been done, in vitro studies suggest that
CO may inhibit the effects of O2Hb on the action of acetylcholine (Ignarro et al., 1987).
Carbon monoxide exposure in patients with a diseased endothelium, therefore, could
accentuate acetylcholine-induced vasospasm and aggravate silent ischemia.
12.3.2 Subjects with Congestive Heart Failure
Congestive heart failure is a major and growing public health problem in the
United States. It has been estimated that approximately 3 million Americans suffer from
heart failure, and moreover, because the prevalence of heart failure is known to increase with
age, improvements in the average life expectancy of the general population would be
expected to increase the magnitude of the problem over the next few decades.
Today, about 75% of the patients with heart failure are above the age of 60 years
(Brody et al., 1987). About 400,000 new cases of heart failure are diagnosed every year in
the United States, resulting in about 1.6 million hospitalizations. The mortality rate is high,
between 15 and 60% per year. The onset of death is often sudden and because about 65% of
heart failure patients have serious arrhythmias, this sudden death is thought to be due to
arrhythmia. Each year 200,000 patients die. The mortality is highest in New York Heart
Association Class 4 patients or in patients with a low maximal O2 uptake (below
10 mL/kg/min).
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Patients with congestive heart failure have a markedly reduced circulatory capacity and,
therefore, may be very sensitive to any limitations in O2-carrymg capacity. Thus, exposure
to CO certainly will reduce their exercise capacity and even will be dangerous, especially if
CO is determined to be proarrhythmogenic (see Section 10.3.2). The etiology of heart
failure is diverse, but the dominating disease is coronary artery disease. The large portion of
heart failure patients with coronary artery disease, therefore, might be even more sensitive to
CO exposure.
>'" • . .
12.3.3 Subjects with Other Vascular Diseases
Peripheral vascular disease is present in about 7% of both the male and female
population and is more prevalent above 65 years of age. Cerebrovascular disease also is
present in about 6.6% of both the male and female population of the same ages. Both of
these conditions often are found in subjects with coronary artery disease. Both conditions
also are associated with a limited blood flow capacity and, therefore, should be sensitive to
CO exposure. It is not clear, however, how low levels of exposure to CO will affect these
individuals. Only one study (Aronow et al., 1974), reviewed in the previous criteria
document (U.S. Environmental Protection Agency, 1979), has been reported on patients with
peripheral vascular disease. Ten men with diagnosed intermittent claudication experienced a
significant decrease in time to onset of leg pain when exercising on a bicycle ergometer after
breathing 50 ppm CO for 2 h (2.8% COHb). Further research is needed, therefore, to better
determine the sensitivity of subjects with vascular disease to CO.
12.3.4 Subjects with Anemia and Other Hematologic Disorders
Clinically diagnosed low values of Hb, characterized as anemia, are a relatively
prevalent condition in the United States. If the anemia is mild to moderate, an inactive
person is often asymptomatic. However, due to the limitation in the O2-carrying capacity
resulting from the low Hb values, an anemic person should be more sensitive to low-level CO
exposure than a person with normal Hb levels (see Section 10.3.2). If anemia is combined
with other prevalent diseases, such as coronary artery disease, the individual also will be at
an increased risk to CO exposure. Anemia is more prevalent in women and in the elderly,
already two potentially high-risk groups. An anemic person also will be more sensitive to the
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combination of CO exposure and high altitude. Additional studies are needed, therefore, in
order to determine the susceptibility of this group to CO exposure.
Individuals with hemolytic anemia often have higher baseline levels of COHb because
the rate of endogenous CO production from heme catabolism is increased. One of the many
causes of anemia is the presence of abnormal Hb in the blood. For example, in sickle-cell
disease, the average lifespan of red blood cells with abnormal hemoglobin S (Hb S) is
12 days compared to an average of 88 days in healthy individuals with normal Hb (Hb A).
As a result, baseline COHb levels can be as high as 4% (Solanki et al., 1988). In subjects
with Hb Zurich, where affinity for CO is 65 times that of normal Hb, COHb levels range
from 4 to 7% (Zinkham et al., 1980).
There are over 350 variants to normal human Hb (Zinkham et al., 1980). In the Hb S
variant, sickling takes place when deoxy Hb S in the red blood cell reaches ai critical level
and causes intracellular polymerization. Oxygenation of the Hb S molecules in the polymer,
therefore, should lead to a change in molecular shape, breakup of the polymer, and
unsickling of the cell. Carbon monoxide was considered at one time to be potentially
beneficial because it ultimately would reduce the concentration of deoxy Hb S by converting
part of the Hb to COHb. Exposure to CO, however, was not considered to be an effective
clinical treatment because high COHb levels (>20%) were required.
Other hematologic disorders can cause elevated concentrations of COHb in the blood.
Ko and Eisenberg (1987) studied a patient with Waldenstrom's Macroglobulinemia. Not only
was the COHb saturation elevated, but the half-life of COHb was about 3 times longer than
in a normal individual. Presumably, exogenous exposure to CO, in conjunction with higher
endogenous CO levels, could result in critical levels of COHb. However, because CO also
can modify the characteristics of unstable Hb, as demonstrated in patients with Hb S, it is not
known how ambient or near-ambient levels of CO would affect individuals with these
disorders.
12.3.5 Subjects with Obstructive Lung Disease
Chronic obstructive pulmonary disease (COPD) is a prevalent disease especially among
smokers. It is estimated (U.S. Department of Health and Human Services, 1990; Collins,
1988) that 14 million persons ( — 6% of the total population) suffer from COPD in the United
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States and that a large number (>50%) of these individuals have limitations in their exercise
performance demonstrated by a decrease in O2 saturation during mild to moderate exercise.
In spite of their symptoms, many of them (—30%) continue to smoke and already may have
COHb levels of 4 to 8%. Subjects with hypoxia are also more likely to have a progression
of the disease resulting in severe pulmonary insufficiency, pulmonary hypertension, and right
heart failure. Studies by Aronow et al. (1977) and Calverley et al. (1981), reviewed in
Section 10.3.2, suggest that individuals with hypoxia due to chronic lung disease such as
bronchitis and emphysema may be susceptible to CO during submaximal exercise typically
found during normal daily activity.
The prevalence of chronic asthma in the United States is estimated to be as high as
12 million persons or about 5% of the total population (U.S. Department of Health and
Human Services, 1990). There has been evidence that hospital admissions for asthma have
increased considerably in the past few years, particularly among individuals less than 18 years
of age. Because asthmatics also can experience exercise-induced airflow limitation, it is
likely that they also would be susceptible to hypoxia. It is not known, however, how
exposure to CO would affect these individuals.
12.4 SUBPOPULATIONS AT RISK FROM COMBINED EXPOSURE TO
CARBON MONOXIDE AND OTHER CHEMICAL SUBSTANCES
12.4.1 Interactions with Psychoactive Drugs
There is almost a complete lack of data on the possible toxic consequences of combined
CO exposure and drug use. The most extensively studied interaction has been combined
exposure to CO and alcohol. The previous criteria document (U.S. Environmental Protection
Agency, 1979) reviewed an extensive human study of alcohol-CO interactions on driving
performance (Rockwell and Weir, 1975). In this study of actual driving behavior, alcohol
and CO effects were often additive, and at 12% COHb concentrations, combined effects were
observed that were greater than the sum of the effects of CO and alcohol alone. Two animal
studies of alcohol-CO combinations (Mitchell et al., 1978; Knisely et al., 1989) also provide
evidence that the effects of alcohol on behavior can be enhanced by exposure to high
concentrations of CO.
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Thus it seems prudent to tentatively conclude that the behavioral effects of alcohol may
be exacerbated under some conditions of CO exposure. What is not known is the range of
behavioral effects for which this occurs, the quantitative nature of the interaction, the
mechanism of the combined effects, or the minimal COHb. concentrations needed to see an
interaction. Further research on this clearly is needed. This is particularly the case when
one considers the role of alcohol in our society and the likelihood of frequent opportunities
for combined alcohol use and GO exposure. Some statistics from the recent report to
Congress on alcohol and health illustrate the potential problem (National .Institute on Alcohol
Abuse and Alcoholism, 1987). In 1984, the estimated per capita alcohol consumption per ,
year in the United States was 2.65 gal of pure alcohol per person over the age of 14. -The
National Institute on Alcohol Abuse and Alcoholism estimates mat two-thirds of the U.S.
population over the age of 18 drink alcohol, and one-half of these are moderate to heavy :,
drinkers. Nearly 50% of all accidental deaths are alcohol related. Even a small interaction
of CO exposure with alcohol would be magnified by the high incidence of these
combinations. .
Other studies of interactions of CO and drugs have been conducted; however, not nearly
enough data exist upon which one could draw even tentative conclusions concerning
populations at risk. Some evidence from animal research indicates that CO exposure may
alter the effects of pentobarbital, ^-amphetamine, and chlorprpmazine (McMillan and Miller,
1974; Knisely et al., 1989). Because these drugs represent diverse classes of psyehoactive
drugs, and many other classes have not been examined at all, it must be concluded that this is
an area of concern for which it is difficult at the present time to make recommendations that
will have an effect on air quality standards. The lack of data on possible interactions of CO.
exposure and drug use was identified in both the 1979 criteria document and an addendum to
that, document (U.S. Environmental Protection Agency, 1979, 1984). Little has changed .
since then. . . ...
12.4.2 Interactions with Cardiovascular Drugs
There are limited data currently available to determine if there is a possible interaction
between CO exposure and different cardiovascular drugs. Drugs used to treat patients with
coronary artery disease, such as beta blockers, calcium-channel blockers, and nitrates, should
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be tested for potential interaction with CO because those patients already are high-risk
subjects. Patients with angina that were used as subjects in studies on the effects of CO
exposure (see Section 10.3) also were treated with these classes of drugs. Unfortunately,
drug interactions were not investigated in most of the studies. Only AUred et al. (1991;
1089a,b) analyzed their data for potential medication effect, and no interactions with CO
were found. The only other available data dealt with the interaction of CO with-beta bloekers
and calcium bloekers in smokers. Deanfield et al. (1984) studied 10 smoking patients with
stable angina in a double-blind placebo-controlled study. He studied two beta bloekers,
atenolol and propranolol, and one calcium blocker, nifedipine. The patients underwent
exercise tests and Holter monitoring both when they still were smoking and after they had
: -• i
stopped smoking for one mpnth. The performance and results from Holter monitoring , .
showed improvement after the patients refrained from smoking. The difference was largest
for nifedipine. Blood levels of propranolol were increased when the patients stopped
smoking; levels of nifedipine and atenolol were unchanged. Part of the decreased efficacy of
the drugs while smoking might be due to lower plasma levels and part of it might-be due to
some interaction on a cellular level. However, it currently is not known if the interaction
was due to nicotine and/or CO.
Another of the high risk groups using multiple medications are heart-failure patients.
They often use digitalis; diuretics; vasodilators; and recently, inhibitors of angiotensin-
converting enzyme. If CO exposure modifies the responses to those drugs, the patients'
status may deteriorate when the plasma levels of a drug are lower or the patients may develop
side effects when the plasma levels of a drug are higher. Due to the large number of high-
risk patients with coronary artery disease and heart failure that use often very potent and
multiple mediations, this area needs to be addressed carefully through further research.
12.4.3 Mechanisms of Carbon Monoxide Interactions with Drugs:
Need for Further Research .
Because data are generally lacking on CO-drug interactions, it should be useful to
speculate on some of the mechanisms by which CO might be expected to alter drug effects,
or vice versa, and discuss possible populations at risk due to these potential interaction
effects.
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12.4.3.1 Metabolic Effects
A mechanism by which CO might be expected to interact with many drugs is through
the modification of drug metabolism. CO is known to bind to cytochrome P-450 in vitro
(Gray, 1982), but the significance of this under physiological conditions is not known.
Another section of this document (see Section 9.4) reviews the interactions of CO with
oxidative metabolism and concludes that clinically relevant inhibition of these systems
probably does not occur under most conditions of exposure. If further research provides
evidence that these important drug-metabolizing systems are significantly compromised as a
result of ambient CO exposure, then drugs dependent upon these systems for activation or
deactivation would interact with CO exposures. If changes in drug metabolism occur as a
result of CO exposure, this would be of considerable practical importance. It might be
necessary to alter prescribing practices in heavily exposed populations. More research on this
is needed.
12.4.3.2 Central Nervous System Depression
In the absence of systematic data on the interactions of CO with psychoactive drugs, it
is necessary to hypothesize mechanisms by which such interactions might occur. In the 1984
addendum (U.S. Environmental Protection Agency, 1984), it was speculated that "drugs with
primary or secondary central nervous system (CNS) depressant effects should be expected to
exacerbate the neurobehavioral effects of CO," presumably because of the generally
depressant effects on the nervous system of CO itself. On the other hand, one might also
argue the converse, that CNS-depressant drugs, because they might reduce cerebral
metabolism and hence O2 utilization, could lessen the neurobehavioral effects of CO. It
should be obvious that speculation on these matters, in the absence of data, cannot be ,
expected to yield answers upon which regulatory decisions could be made. On the other
hand, because of the overall sensitivity of the CNS to perturbations, it is possible that
interactions of these types could occur and may even be quite pronounced. Clearly, more
research on this is needed because we cannot rely on scientific speculation.
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12.4.3.3 Alteration in Cerebral Blood Flow
Another mechanism by which CO could be speculated to interact with certain drugs is
through modification of cerebral blood flow. Brain hypoxia resulting from CO exposure may
result in compensatory increases in cerebral blood flow (Doblar et al., 1977). Drugs that
have vasoconstrictive effects on cerebral circulation could be hypothesized to interfere with
this compensatory mechanism and thus exacerbate the neurobehavioral toxicity of CO. The
methylxanthines, such as caffeine and theophylline, have well-established central
vasoconstrictive effects (Rail, 1980) and thus could be hypothesized to enhance CO-induced
brain hypoxia. On the other hand, their vasodilatory effects in the periphery (Rail, 1980)
might enhance the vasodilatory effects of CO. Because of the widespread use of
methylxanthines, these possible interactions may be of particular significance.
As the O2-carrying capacity of the blood decreases with CO poisoning, many organs,
including the brain, will compensate their blood flow to try and maintain proper tissue
oxygenation. Several studies using radiolabeled microspheres to measure cerebral blood flow
have demonstrated autoregulation and increased blood flow in response to CO (Koehler et al.,
1982). However, if the brain O2 supply is inadequate despite increased blood flow, further
metabolic changes will undoubtedly occur. The consequences of these metabolic changes
with respect to their effect on the regulation of brain blood flow is uncertain. More simply,
damage resulting from lack of proper brain oxygenation may alter the brain vasculature's
ability to regulate brain blood flow. Damage to the vasculature previously has been shown to
alter the vasculature's response to vasoactive agents. For example, it is known that following
ischemia-induced injury and other types of brain injury; the brain releases polyunsaturated
fatty acids from its phospholipids (Gardiner et al., 1981). These free fatty acids may be
metabolized enzymatically to compounds such as prostaglandins and leukotrienes with effects
on the cerebral vasculature. For example, the metabolism of arachidonic acid generates
prostaglandins and O2 free radicals that can cause cerebral vasodilation in normal animals.
However, when these radicals are produced 'in excess, as in acute, extreme hypertensive
episodes, the free radicals initiate peroxidation of other unsaturated fatty acids (Kukreja et al.,
1986). These peroxides and O2 radicals cause damage to the vascular endothelium and
decrease the brain's capacity to regulate blood flow in response to changes in arterial carbon
dioxide (Wei et al., 1981). Additionally, the vascular damage caused by these O2 radicals
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alters the normal cerebral arterial response to vasoactive agents, including neurotransmitters.
For example, acetylcholine, which is normally a dilator of cerebral arterioles, produces
vasoconstriction after free radical-induced damage (Wei et.al., 1985). Potentially, therefore,
in an injured brain, acetylcholine may decrease an already inadequate blood flow.
Conceptually, tissue hypoxia produced by CO may stimulate arachidonic acid
metabolism and production of prostaglandins and free radicals in a manner similar to hypoxia
caused by ischemia or trauma. Production of vasodilator free radicals or vasodilator
prostaglandins may be a mechanism by which the brain increases its blood flow in response
to CO. Assuming this is the case, therapeutic agents or drugs of abuse that modify the
arachidonic acid cascade may alter the brain's capacity to increase blood flow in response to
CO. For example, if aspirin, indomethacin, or other cyclooxygenase inhibitors are present
during exposure to CO, the brain's capacity to increase its flow may be diminished due to
decreased capacity to form dilator prostanoids and free radicals. An instance where this sort
of possibility is known to occur is in neonatal animals, and possibly in neonatal humans.
Investigators recently have shown in neonatal animals that indomethacin markedly diminished
the brain's capacity to increase its blood flow in response to hypoxia (Leffler and Busija,
1987).
A possible interaction between CO and nitrite exposure also might be predicted.
Nitrites can be expected to oxidize Hb to methemoglobin, leaving less Hb to bind either to
O2 or CO. However, because CO has a greater affinity than O2 for Hb, it is most likely to
expect additive effects in reduction of O2Hb. In addition, some organic nitriteis such as.amyl
nitrite, used to relieve angina pain, and butyl nitrite, an abused substance, produce significant
peripheral vasodilation and, consequently, an abrupt drop in blood pressure and subsequent
tachycardia. These potent cardiovascular effects, which also result from CO exposure, might
interfere with the enhanced cardiac output, particularly the output to sensitive organs such as
the brain. To date, there are no published data on the combined effect of CO and nitrite
exposure. However, there are limited data showing reasonably parallel consequences on
auditory function when CO and butyl nitrite are given individually to rats (Fechter et al.,
1987, 1989).
Additionally, recent evidence shows that acetylcholine stimulates arachidonic acid
metabolism (Busija et al., 1988). Whether or not hypoxia increases arachidonic acid
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metabolism via stimulation of acetylcholine release is uncertain; however, exogenous
acetylcholine is known to stimulate brain prostaglandin production. Assuming that
endogenous acetylcholine release in response to CO-induced hypoxia is important, other
agents such as atropine or scopolamine, which block muscarinic receptors, could reduce the
vasodilator response to CO. In an opposite manner, cholinesterase inhibitors (e.g.,
organophosphate or carbamate insecticides) that penetrate the blood-brain barriers may
magnify the dilator response to CO. Other agents that may modify the capacity of the brain's
blood flow to regulate in response to CO are agents that cause an acute, large increase in
blood pressure, thus inducing excess free radical production, lipid peroxidation, and abnormal
vascular reactivity. Such an agent might include for example, cocaine, which when
administered in large doses causes acute transient hypertension.
Although the above points are speculative, the possibility that therapeutic agents and
drugs of abuse may alter the brain vasculature's capacity to respond to CO is a subject that
bears further consideration and investigation.
12.4.4 Interactions with Other Chemical Substances in the Environment
Besides direct ambient exposure to CO, there are other chemical substances in the
environment that can lead to increased COHb saturation when inhaled. Halogenated
hydrocarbons used as organic solvents undergo metabolic breakdown by cytochrome P-450 to
form CO and inorganic halide. Possibly the greatest concern regarding potential risk in the
population comes from exposure to one of these halogenated hydrocarbons, methylene
chloride (CH^CL^), and some of its derivatives. Almost a million kilograms are produced
each year, making it the second highest source of CO in the environment. Although it is
present in ambient air emissions, the highest concentrations of CH^Cl^ occur from various
sources such as paint removers, cleaners, propellants, and from industrial manufacturing ,
(see r" S. Environmental Protection Agency, 1987; 1985a,b).
From available experimental studies (see Section 11.3), it is not clear if combined
exposure to CO and CH2C12 would produce an additive effect in humans. Theoretically,
acute CH2C12 exposure can result in a steady production of endogenous CO in tissues that
contain cytochrome P-450, such as the lung, liver, kidney, heart, and brain. Any histotpxic
hypoxia produced at the tissue level combined with hypoxic hypoxia due to the formation of
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COHb from endogenous as well as exogenous CO exposure could place exposed individuals
at risk.
12.5 SUBPOPULATIONS EXPOSED TO CARBON MONOXIDE AT
HIGH ALTITUDES
For patients with coronary artery disease, restricted coronary blood flow limits
O2 delivery to the myocardium. Carbon monoxide also has the potential for compromising
O2 transport to the heart. For this reason, such patients have been identified as the
subpopulation most sensitive to the effects of CO. A reduction in the partial pressure of
oxygen (PO2) in the atmosphere, as at high altitude, also has the potential for compromising
O2 transport. Therefore, patients with coronary artery disease who visit higher elevations
might be unusually sensitive to the added effects of atmospheric CO.
Before considering the combined effects of CO and atmospheric hypoxia, it is important
to distinguish between the long-term resident of high altitude, as compared with the newly
arrived visitor from low altitude. Specifically, the visitor will be more hypoxemic than the
fully adapted resident for the following reasons. Initially, the visitor will exhibit relative
hypoventilatioii, particularly during sleep, because ventilatory adaptation requires several
days. The result will be a lowering of arterial PO2, a fall in arterial O2 saturation, and a
reduction in arterial O2 content. This hypoxemia will stimulate the sympathetic nervous
system to increase heart rate, myocardial contractility, and systemic arterial blood pressure
(Grover et al., 1986). These factors combine to increase cardiac work, calling for an
increase in coronary blood flow. In addition, the initial increase in ventilation will produce a
respiratory alkalosis that, in turn, will increase the affinity of Hb for O2 and thereby interfere
with O2 release to the tissues.
Over several days following arrival at high altitude, a number of mechanisms will
operate to lessen the initial impact of atmospheric hypoxia. Ventilation will increase
progressively, and this will elevate arterial O2 tension, saturation, and content. A decrease in
plasma volume increases hemaiocrit (hemoconcentration), with an associated increase in the
O2-carrying capacity (Hb concentration) of the blood; at this point, the polycythemia is only
relative not absolute. Nevertheless, this will increase further the arterial O2 content.
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Although increased sympathetic activity persists, cardiac beta-receptor responsiveness
decreases, mitigating the initial tachycardia. This combined with a decreased in cardiac
stroke volume leads to a return of cardiac output to normal (or even subnormal) levels
(Grover et al., 1986). Compensation for the initial respiratory alkalosis returns blood pH
towards normal. Concurrently, there is an increase in the concentration of
2,3-diphosphoglycerate within the red cells, the net effect being not only a return of Hb-O2
affinity to normal, but actually to levels lower than prior to ascent. This facilitates the
release of 02 to the tissues, an effect that more than offsets the slight decrease in arterial
O2 saturation. For the heart, this is particularly important, for it removes the demands for
increased coronary blood flow at moderate altitude (Grover et al., 1976).
For the long-term resident at high altitude, systemic blood pressure returns to
(or below) values normal for sea level (Marticorena et al., 1969). Cardiac output remains at
(or below) levels normal for sea level (Hartley et al., 1967). Tissue capillary density
increases, thereby enhancing O2 delivery. Consequently, demands on the coronary
circulation are not increased. An absolute polycythemia develops (i.e., total red cell mass
plateaus at levels greater than at sea level). As a consequence, the normal turnover of this
greater mass of red cells results in an increase in the endogenous production of CO (Johnson,
1968).
Based on these considerations, the population subgroup at greatest risk from CO
exposure would be the newly arrived transient visitors to high altitudes. By binding Hb, CO
would further reduce arterial O2 content (i.e., increase hypoxemia). In addition, CO would
augment the effect of alkalosis by further increasing the affinity of Hb for O2, thereby
impairing O2 delivery even more. Both factors would increase demands for greater coronary
blood flow. These initial risks would decline progressively if the visitor remains long enough
to complete physiological adaptation. The period of increased risk is probably prolonged in
the elderly because adaptation to high altitude proceeds more slowly with increasing age (Dill
etal., 1963, 1985; Robinson etal., 1973).
Not surprisingly, the total number of transient visitors to high altitude far exceeds the
resident population. Ironically, it is these same transient visitors who contribute most to
atmospheric CO pollution in the mountains (e.g., automobile engines not tuned to high
altitude or inefficient wood-burning fireplaces used for social effect in vacation cabins). In
12-16
-------
addition, newly arrived visitors are often unaware of the physiological effects of high altitude
(plus CO), and hence are prone to overexertion, which would increase the potential hazard.
For a variety of reasons, COHb concentrations tend to be higher in high-altitude residents
than seen at low altitude (Johnson, 1968).
One would postulate that the combination of high altitude with CO would pose the
greatest risk to persons newly arrived at high altitude who have underlying cardiovascular
disease, particularly because they are usually older individuals. Surprisingly, this hypothesis
has never been tested adequately. In fact, there are virtually no data on how patients with
known or suspected coronary artery disease respond to a sojourn at moderately high altitude
(8,000 to 12,000 ft or higher) with or without added CO exposure. In two pilot studies., the
risk from altitude alone at least appears to be minimal (Otin, 1970; Khanna et al., 1976).
Among 148,000 persons (10% over 50 years of age) trekking in Nepal to altitudes up to
18,000 ft, there were no cardiac deaths and only three helicopter evacuations for cardiac
problems (Shlim and Houston, 1989). Nevertheless, the need remains for a rigorous test of
the hypothesis. .
If the cardiovascular effects of atmospheric hypoxia at high altitude are augmented by
added exposure to CO, then patients already hypoxic from chronic obstructive lung disease
should also be at increased risk from CO at altitude. Paradoxically, this does not appear to
be true, again .at least for brief exposure to altitude alone, even though hypoxemia is
exaggerated (Graham and Houston, 1978; Schwartz et al., 1984). This may reflect the
decrease in air density at high altitude, which reduces both the work of breathing (Thoden
et al., 1969) as well as the effective degree of airway obstruction in such patients (Kryger
etal., 1978).
Although limited observations do not indicate an increased risk from exposure to
moderate altitude (without added CO) for patients with either cardiovascular or obstructive
airway disease, this does not imply that prolonged residence at altitude is well tolerated.
Individuals with these disorders, although successfully living at higher altitudes initially, tend
to leave these altitudes as they reach older age. Outward migration of older individuals with
these disorders has been described for the higher elevations in the state of Colorado
(Regensteiner and Moore, 1985). These elderly residents living at altitudes above 8,000 ft
12-17
-------
left primarily due to poor health. Heart disease and lung disease (each 41 %) accounted for
the majority of reasons for leaving their high-altitude homes.
It is known {hat low birth weights occur in both infants born at altitudes above 6,000 ft
as well as infants born near sea level whose mothers had elevated COHb levels due to
cigarette smoking (see Section 11.1). It has also been shown that COHb levels in smokers at
high altitude are higher than in smokers at sea level (Brewer et al., 1970). Although it is
probable that the combination of hypoxic hypoxia and hypoxia resulting from ambient
exposure to CO could further reduce birth weight at high altitude and possibly modify future
development, no data are presently available to support this hypothesis. A study conducted in
Colorado (Alderman et al., 1987) failed to find a strong relationship between risk of low •
birth weight and maternal exposure to neighborhood CO estimated from stationary monitors.
The combination, however, of maternal smoking and 6,000 ft altitude did result in lower
birth weights than those due to altitude alone. >
12-18
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12-23
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APPENDIX
GLOSSARY OF TERMS AND SYMBOLS
Abbreviations, Acronyms, and Symbols
A
X
[C0]ave
[COHb]
[COMb]
[OH']
2
ave
T
12C160
12C180
14,
51
CO
Cr
2,3-DPG
131
85
I
Kr
7-mode
99mTcDTpA
A-aDO2
ACD
ACGIH
ACH
ADD (m)
Angstrom
Chi
Average concentration of CO
Concentration of COHb in blood, as milliliters of CO per milliliter of
blood (STPD)
Concentration of COMb in tissues
Micrometer
Average concentration of the hydroxyl radical
Sigma (sum of terms)
Atmospheric lifetime
Carbon monoxide containing oxygen isotope 16
Carbon monoxide containing oxygen isotope 18
Carbon monoxide containing' carbon isotope 14
Chromium-51
2,3-diphosphoglycerate
Iodine-131
Krypton-85
137-second driving cycle test
Radiolabeled diethylene triamine pentacetic acid
Greater than
Less than
Approximately
Alveolar-arterial oxygen gradient [also P(A-a)O2 difference]
Acid citrate dextrose
American Conference of Governmental Industrial Hygienists
Air changes per hour
Additive constant specification
A-l
-------
ADP
AEP
A/F
AIRS
a.k.a.
Alt
amb
ANOVA
ANSI
AT
atm
A-V
BEI
BF
BLIS
BS
BTPS
Btu
BW
C
Ca
CAA
CAD
CALINB3 Model
CASAC
C(a-v)02
cb
CBF
cc
Cco
CEQ
Cff
CFF
CFK
CFKE
cGMP
Adenosine 5'-phosphate
Auditory evoked potential
Air-to-fuel ratio
Aerometric Information Retrieval System (U.S. EPA)
Also known as
Altitude above sea level
Ambient
Analysis of variance
American National Standards Institute
Argon
Atmosphere
Arterial-mixed venous O2 difference
Biological exposure index
Blue flame (heater)
Bibliographic Literature Information System
Body sway
Body temperature and pressure, saturated with water vapor
British thermal unit
Body weight
Celsius
Calcium
Clean Air Act
Coronary artery disease
A form of dispersion modeling
Clean Air Scientific Advisory Committee
Arteriovenous O9 content difference
£t •-1 •
Concentration of carbon monoxide for a bulk mixture
Cerebral blood flow .
Cubic centimeter (also cm3)
Concentration of carbori monoxide in the sample
President's Council on Environmental Quality,
Critical flicker fusion
Critical flicker frequency
Coburn-Forster-Kane
Coburn-Forster-Kane equation
Cyclic guanosine monophosphate
A-2
-------
CH2C12
CH3CC13
CH4
CHD
CI
CI
CID
q(t)
cm
cm3
CMRO2
CN
CNS
CNV
CO
CO
C02
COH
COHb
COLD
COMb
CO-Ox
COPD
CP
CRF
CRT
CVD
CVS-72
CVS-75
Cyt
d1
dBA
dF/dt (max)
dL
DLCO
Methylene chloride
Methylchloroform
Methane
Coronary heart disease
Cardiac index
Confidence interval
Cubic inch displacement
The air pollutant concentration to which an individual is exposed at
any point in time t
Centimeter(s)
Cubic centimeter (also cc)
Cerebral O2 consumption
Cyanide
Central nervous system
Contingent negative variation (slow-evoked potential)
Carbon monoxide
Cardiac output
Carbon dioxide
Carbon monoxide hypoxia
Carboxyhemoglobin
Chronic obstructive lung disease
Carboxymyoglobin
CO-Oximeter
Chronic obstructive pulmonary disease
Capillary permeability to protein
Continuous reinforcement schedule
Cathode-ray tube
Cardiovascular disease
Constant volume sample cold start test
Constant volume sample test including cold and hot starts
Cytbchrome
Measure of detection threshold
Decibels (A-scale)
Time derivative of maximal force
Deciliter
Diffusing capacity for CO
A-3
-------
DL°2
DNA
DpCO
dP/dt
DPGs
DR
EGG
EDRF
EDTA
EEG
EKG
EP
EPA
ERG
ETS
f
FACO(Bh)
*B
FCN
Fco
FDA
FEF
FEVj
FFF
FI
FjCO
FID
FjOfc
FMVCP
%
FR
FRC
ft
FVC
Diffusing capacity for O2
Deoxyribonucleic acid
Carbon monoxide diffusion coefficient across the placenta
Time derivative of pressure
Diphosphoglycerides :
Differential reinforcement of flow rates schedule
Electrocardiogram (also EKG) '
Endothelium-derived relaxing factor
Ethylenediaminetetraacetic acid
Electroencephalogram ,,
Electrocardiogram (also, ECG) •
Evoked potential '.
Environmental Protection Agency
Electroretinogram
Environmental tobacco smoke
Fetal , , . .
Flow rate of carbon monoxide for a bulk mixture
Air flow rate
Alveolar carbon monoxide measured by breath-holding
Breathing frequency (also %)
Fixed consecutive number schedule
Carbon monoxide flow rate
Food and Drug Administration
Forced expiratory flow (see definition)
Forced expiratory volume (at one minute)
Flicker-fusion frequency
Fixed interval schedule
Volumetric fractional concentration of CO in dry inspired air
Flame ionization detector
Fraction of inspired O2
Federal Motor Vehicle Control Program
Breathing frequency (also fg) r
Fixed ratio schedule
Functional residual capacity
Feet •; .• • • •:.-•
Forced vital capacity - •• ,
A-4
-------
g
GABA
GC
GD
GFC
g/mi
GMP
h
H*
H2
HANES
Hb
Hb A
HBO
HbO2
HbS
HCN
HCs
Hct
HDL
He
HEI
Hg
HgO
HH
HO2*
H20
HR
HT
HW/BW
IHD
K
KCN
K,
•eff
Gram
Y-aminobutyric acid
Gas chromatograph
Gestation day
Gas filter correlation
Grams per mile
Guanosine monophosphate
Hour
Hydrogen atom (free radical)
Hydrogen molecule
Health and Nutrition Examination Survey
Hemoglobin
Normal hemoglobin
Hyperbaric oxygen
Oxyhemoglobin
Abnormal hemoglobin found in individuals with sickle-cell disease
Hydrogen cyanide
Hydrocarbons
Hematocrit
High-density lipoprotein
Helium
Health Effects Institute
Mercury
Mercuric oxide
Hypoxic hypoxia
Hydroperoxyl free radical
Water
Heart rate
Total heart weight
Heart weight to body weight ratio
Ischemic heart disease (see definition of angina)
Iodine pentoxide
Intraperitoneal
Warburg partition coefficient
Potassium cyanide
The effective reaction rate constant
A-5
-------
K3Fe(CN)6
kg
JcJ
km
KPM
L
LC50
LDH
LDL
LDV
LOAEL
LOEL
LPG
LV
m
m3
M
Mb
MEA
MEMs
MET
metHb
MFO
mg
mi
MI
min
mL
MLDH
MMFR
mo
mol
MRFIT
Potassium fenicyanide ,
Kilogram
Kilojoule, IxlO10 ergs, 0.948 Btu ,
Kilometer
Michaelis-Menten constant
Kilopondmeters per minute
Liter
Concentration that is lethal to 50% of test subjects (used in inhalation
studies) , . ,
Dose that is lethal to 50% of test subjects
Lactate dehydrogenase
Low-density lipoprotein
Light-duty vehicle
Lowest-observed-adverse-effect level
Lowest-observed-effect level
Liquefied petroleum gas
Left ventricle
Maternal
Cubic meter
Haldane coefficient or parameter
Myoglobin • •
Mean electrical axis
Microenvironmental monitors
Basal metabolic equivalent
Methemoglobin .
Mixed-function oxidase
Milligram •
Mile
Myocardial infarction
Minute
Milliliter
Myocardial lactate dehydrogenase
Maximum mid-expiratory flow rate
Month
Mole
Multiple risk factor intervention trial ,
A-6
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MS
MSA
MSHA
MST
MULT(m)
n
N2
NAAQS
NADPH
NaHCO3
NAMS
NASA
NBS
ND
NDIR
NEDS
NEM
NG
NHANES
M(CO)4
NIOSH
NIST
nm
NO
N02
NO3
N20
NOAEL
NOEL
NOX
NR
O*
02
03
OH*
O2Hb
Mainstream smoke
Metropolitan Statistical Area
Mine Safety and Health Administration
Mean survival time
Multiplicative constant specification
Number " :
Nitrogen
National Ambient Air Quality Standards
Reduced nicotinamide adenine dinucleotide phosphate
Sodium bicarbonate ' :
National Air Monitoring Stations
National Aeronautics and Space Administration
National Bureau of Standards, now NIST
Not determined '
Nondispersive infrared
National Emissions Data System
NAAQS Exposure Model
Natural gas
National Health and Nutrition Examination Survey
Nickel tetracarbdnyl
National Institute for Occupational Safety and Health
National Institute of Standards and Technology
Nanometer
Nitric oxide
Nitrogen dioxide • -
Nitrate .•..-.-. : •-.- ..
Nitrous oxide
No-observed-adverse-effect level
No-observed-effect level
Nitrogen oxides
No response
Oxygen free radical
Oxygen • - •-• '- ?
Ozone
Hydroxyl free radical
Oxyhemoglobin '
A-7
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O2Mb
P
P
P(A-a)O2
PAH
PAN
PbCffir
PCO
PC02
PC02
PD
PEMs
PET
PfCO
PGI2
pH
PIT
PMN
ppbv
ppra
ppmra
PR
PW
0
r
R
Oxymyoglobin
Pressure in atmospheres
Propane
Partial pressure of O2 at 50% saturation of hemoglobin
Alveolar-arterial oxygen pressure difference
Partial pressure of CO2 in arterial blood
Partial pressure of CO2 in alveolar gas
Polyaromatie hydrocarbon
Peroxyaeetyl nitrate
Partial pressure of O2 in arterial blood
Barometric pressure
Lead chlorobromide
Partial pressure of CO
Mean partial pressure of pulmonary capillary O2
Partial pressure of CO2
Postnatal day
Personal exposure monitors
Positron emission tomography
Partial pressures of CO in the fetal placenta! capillaries
Prostacyclin
Hydrogen-ion concentration (see Definitions)
Partial pressure of CO in humidified inspired air
Pituitary
Partial pressures of CO in the maternal placenta! capillaries
Polymorphonuclear neutrophil leukocytes
Partial pressure of O2
Parts per billion by volume
Parts per million by volume (milligrams per liter)
Parts per million by mass (milligrams per kilogram)
Pulmonary resistance
Placental weight
Overall perfusion rate
Oxygen consumption of tissues or cells (also
Correlation coefficient
Ratio of CO to O2 at 50% inhibition
A-8
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RBC
rCBF
RV
RV
RVF
s
S
SaO2
SA02
SAROAD
scf
SCN
SCO
SD
SE
SEM
SF6
SHAPE
SHED
SI
SIDS
SIPs
SLAMS
SMR
S02
SP
SR
SRMs
SS
ST
STPD
SV
t
t1
Coefficient of determination = .
Red blood cell
Regional cerebral blood flow
Right ventricle
Residual volume
Red visual field v,
Second
Septum .
Arterial oxygen saturation
Alveolar oxygen saturation
U.S. EPA centralized data base; superceded by AIRS (q.v.)
Standard cubic foot
Thiocyanate
Percent COHb of total Hb
Standard deviation
Standard error
Standard error of the mean
,- - - "• ' -' - - - r ; ' -
Sulfur hexafluoride
Simulation of Human Activity and Pollutant Exposure
Sealed housing for evaporative determination
Stroke index
Sudden infant death syndrome
State Implementation Plans
State and Local Air Monitoring Stations
Standardized mortality ratio
Sulfur dioxide ,
Mean stroke power
Systemic resistance
Standard Reference Materials
Sidestream smoke
Segment of the EKG (see Definitions)
Standard temperature and pressure, dry
Stroke volume
Time
Postexposure time in minutes
Time-to-death
A-9
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TEAM
TEM
Tg
TH
THC
*
TLC
TSP
TTS
TV
TWA
UV
tJVGSHs
VC
VD
VHP
VFT
VLDL
VMT
voc
VPD
VPD
VA/0
vco
VCO2
Vmax
VO2
VO2
Total Exposure Assessment Methodology
Transmission electron microscopy
Teragram(s); 1012 grams; 106 metric tons
Total hydrocarbon
Total hydrocarbon content
Time-to-incapacitation - .
Total lung capacity
Total suspended particulates
Temporary threshold shifts
Tidal volume (also VT)
Time-weighted average
Ultraviolet
Unvented gas space heaters
Vital capacity
Physiological dead space volume
Visual evoked potential
Ventricular fibrillation threshold
Very low density lipoprotein
Ventricular contractility
Vehicle-miles traveled
Volatile organic compound
Ventricular premature depolarization
Vehicles per day
Tidal volume (also TV)
Ventilation rate
Alveolar ventilation rate
Ventilation to perfusion ratio
Rate of endogenous production of CO
Rate of carbon dioxide production
Dead-space ventilation per minute
Minute ventilation; expired volume per minute
Inspired volume per minute
Maximum expiratory flow
Oxygen uptake by the body
Oxygen consumption of tissues or cells (also QO2)
•A-10
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VO2 max Maximal oxygen uptake (maximal aerobic capacity)
w Watt
w/ With
WBC White blood cell
WF White flame (heater)
WHW Wet-heart weight
x Mean
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Definitions
Acclimatization: The physiological and behavioral adjustments of an organism to changes in
its environment.
Adaptation: Changes in an organism's structure or habit that help it adjust to its surroundings.
Additivity: A pharmacologic or toxicologic interaction in which the combined effect of two or
more chemicals is approximately equal to the sum of the effect of each chemical alone.
(Compare with: antagonism, synergism.)
Adiabatic warming: The temperature increase produced in a descending air mass as pressure
increases with decreasing altitude.
Air pollutant: Any substance in air that could, if in high enough concentration, harm humans,
other animals, vegetation, or material. Pollutants may include almost any natural or .. -:
artificial composition of matter capable of being airborne. They may be in the form of
solid particles, liquid droplets, gases, or in combinations of these forms. Generally,
they fall into two main groups: (1) those emitted directly from identifiable sources and
(2) those produced in the air by interaction between two or more primary pollutants, or
by reaction with normal atmospheric constituents, with or without photoactivation.
Exclusive of pollen, fog, and dust, which are of natural origin, about 100 contaminants
have been identified and fall into the following categories: solids, sulfur compounds,
volatile organic chemicals, nitrogen compounds, oxygen compounds, halogen
compounds, radioactive compounds, and odors.
Air pollution: The presence of contaminant or pollutant substances in the air that do not
disperse properly and interfere with human health or welfare, or produce other harmful
environmental effects.
Air pollution episode: A period of abnormally high concentration of air pollutants, often due
to low winds and temperature inversion, that can cause illness and death.
Air quality criteria: The levels of pollution and lengths of exposure above which adverse
health and welfare effects may occur.
Air quality standards: The level of pollutants prescribed by regulations that should not be
exceeded during a specified time in a defined area.
Alveolar-arterial oxygen pressure difference [P(A-a)O2]: The difference in partial pressure of
oxygen in the alveolar gas spaces and that in the systemic arterial blood, measured in
torr.
Alveolar carbon dioxide pressure (PACO2): Partial pressure of carbon dioxide in the air
contained in the lung alveoli.
A-12
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Alveolar oxygen partial pressure (P^^): P31^ pressure of oxygen in the air contained in
the alveoli of the lungs.
Alveolus: A hexagonal or spherical air cell of the lungs. The majority of alveoli arise from
the alveolar ducts, which are lined with the alveoli. An alveolus is an ultimate
respiratory unit where the gas exchange takes place.
Ambient air: Any unconfined portion of the atmosphere: open air, surrounding air.
Ambient air quality standards: (See: Criteria Pollutants and National Ambient Air Quality
Standards.)
Anatomical dead space (VDanat): Volume of the conducting airways down to the level where,
during air breathing, gas exchange with blood .can occur, a region probably situated at
the entrance of the alveolar ducts.
Angina pectoris (angina): A spasmodic, strangling sensation or heavy chest pain, often
radiating to the arms, especially the left, due most often to lack of oxygen to the heart
muscle (myocardial ischemia) and precipitated by effort or excitement.
Angiography: Radiographic visualization of blood vessels following introduction of contrast
material; used as a diagnostic aid for such conditions as cerebrovascular attacks (strokes)
and myocardial infarctions (heart attacks). (Also, see radionuclide angiography.)
Antagonism: A pharmacologic or toxicologic interaction in which the combined effect of two
chemicals is less than the sum of the effect of each chemical alone; the chemicals either
interfere with each other's actions, or one interferes with the action of the other.
(Compare with: additivity, synergism.)
Arrhythmia: Any variation from the normal rhythm of the heartbeat.
Arterial oxygen saturation (SaO^: Percent saturation of dissolved oxygen in arterial blood.
Arterial partial pressure of carbon dioxide (PaCO^: Partial pressure of dissolved carbon
dioxide in arterial blood.
Arterial partial pressure of oxygen (PaO2): Partial pressure of dissolved oxygen in arterial
blood.
Atmosphere (atm): A standard unit of pressure representing the pressure exerted by a 29.92 in
(760 mm) column of mercury at sea level at 45° latitude and equal to 1,000 g/cm2.
The whole mass of air surrounding the Earth,, composed largely of oxygen and nitrogen.
ATPS condition (ATPS): Ambient temperature and pressure, saturated with water vapor.
These are the conditions existing in a water spirometer.
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Biologically effective dose: The amount of the deposited or absorbed contaminant that reaches
the cells or target site where an adverse effect occurs or where an interaction of that
contaminant with a membrane surface occurs.
BTPS conditions (BTPS): Body temperature and pressure, saturated with water vapor. These
are the conditions existing in the gas phase of the lungs. For humans, the normal
temperature is taken as 37 °C, the pressure as the barometric pressure, and the partial
pressure of water vapor as 47 torr.
Carbon dioxide (CO^: A colorless, odorless, nonpoisonous gas, which results from fossil fuel
combustion and is normally a part of the ambient air.
Carbon dioxide production (VCO^: Rate of carbon dioxide production by organisms, tissues,
or cells. Common units: milljliter CO2 (STPD) per kilogram-minute.
Carbon monoxide (CO): An odorless, colorless, toxic gas formed by incomplete combustion,
with a strong affinity for a variety of metal-containing proteins found in nature. The
metalloproteins of greatest interest in mammalian tissues include O2-earrier proteins
such as hemoglobin, myoglobin, and metalloenzymes such as the cytochromes. Tile
competitive relationship between CO and O2 for the active sites of these metalloproteins
can affect the transport, absorption, and utilization of O2 by the tissues.
Carboxyhemoglobin (COHb): Hemoglobin in which the iron is associated with carbon
monoxide. The affinity of hemoglobin for carbon monoxide is about 240 to 250 times
greater than for oxygen.
Carboxymyoglobin (COMb): Myoglobin in which the iron is associated with carbon
monoxide. The affinity of myoglobin for carbon monoxide is about 25 to 40 times
greater than for oxygen.
Central nervous system (CNS): The portion of the nervous system that includes the brain and
spinal cord, and their connecting nerves.
Chronic obstructive lung disease (COLD): This term refers to diseases of uncertain etiology
characterized by persistent slowing of airflow during forced expiration. It is
recommended that a more specific term, such as chronic obstructive bronchitis or
chronic obstructive emphysema, be used whenever possible. Synonymous with chronic
obstructive pulmonary disease (COPD).
Combustion: Burning, or rapid oxidation, accompanied by release of energy in the form of
heat and light. A basic cause of air pollution.
Combustion product: Substance produced during the burning or oxidation of a material.
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Criteria: Descriptive factors taken into account by EPA in setting standards for various
pollutants. These factors are used to determine limits on allowable concentration levels
and to limit the number of violations per year. When issued by EPA, the criteria
provide guidance to the states on how to establish their standards.
Criteria pollutants: The Clean Air Act requires EPA to set National Ambient Air Quality
Standards for certain pollutants known to be hazardous to human health. EPA has
identified and set standards to protect human health and welfare for six pollutants:
ozone, carbon monoxide, total suspended particulates, sulfur dioxide, lead, and nitrogen
oxides. The term "criteria pollutants" derives from the requirement that EPA must
describe the characteristics and potential health and welfare effects of these pollutants.
It is on the basis of these criteria that standards are set or revised.
Diffusing capacity of .the lung (DL, DLCO, DLCO2, DLO2>: Amount of gas (CO, CO2, O2)
commonly expressed as milliliters of gas (STPD) diffusing between alveolar gas and
pulmonary capillary blood per torr mean gas pressure difference per minute, that is,
milliliter gas per minute-torr. Synonymous with transfer factor and diffusion factor.
Dose: The amount of a contaminant that is absorbed or deposited in the body of an exposed
organism for an increment of time— usually from a single medium. Total dose is the
sum of doses received by a person from a contaminant in a given interval resulting from
interaction with all environmental media that contain the contaminant. Units of dose
and total dose (mass) are often converted to units of mass per volume of physiological
fluid or mass of tissue, (Also, see internal dose and biologically effective dose.)
Dose-response relationship: A relationship between (1) the dose, often actually based on
"administered dose" (i.e. , exposure) rather than absorbed dose, and (2) the extent of
toxic injury produced by that chemical. Response can be expressed either as the
severity of injury or proportion of exposed subjects affected.
Electrocardiogram (ECG, EKG): A graphic tracing of the variations in electrical potential
caused by the excitation of the heart muscle and detected by electrodes at the body
surface. The normal electrocardiogram shows deflections resulting from arterial and
ventricular activity that are identified by waves and segments. The P wave is produced
by atrial depolarization (excitation), the QRS complex is produced by ventricular
depolarization, and the ST segment and T wave are produced by ventricular
repolarization (recovery) . The manifestations of atrial repolarization are normally
submerged in the QRS complex. The U wave is an inconsistent finding, believed to be
due to slow repolarization of the papillary muscles. The magnitude and configuration of
the individual waves vary with the location of the detecting electrodes.
Emission: Pollution discharged into the atmosphere from smokestacks, other vents, and
surface areas of commercial or industrial facilities; from residential chimneys; and from
motor vehicle, locomotive, or aircraft exhausts.
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Emission factor: The relationship between the amount of pollution produced and the amount
of raw material processed. For example, an emission factor for a blast furnace making
> • iron would be the number of pounds of particulates per ton of raw materials.
Emission inventory: A Hst, by source, of the amount of air pollutants discharged into the
atmosphere of a community. It is used to establish emission standards.
Emission standard: The maximum amount of air polluting discharge legally allowed from a
single source, mobile or stationary.
Environment: The sum of all external conditions affecting the life, development, and survival
of an organism, including air, water, food, and soil media. Regarding air, it refers to
all indoor and outdoor microenvironments, including residential and occupational
settings.
EPA: The U.S. Environmental Protection Agency; established in 1970 by Presidential
Executive Order, bringing together parts of various government agencies involved with
the control of pollution.
Episode (pollution): An air pollution incident in a given area caused by a concentration of
atmospheric pollution reacting with meteorological conditions that may result in a
significant increase of health effects in the exposed population. Although most
commonly used in relation to air pollution, the term also may be used in connection
with other kinds of environmental events such as a massive water pollution situation.
Exceedance: A pollutant concentration greater than a defined threshold or established
standard; ah* pollution standards often define the second exceedance as a formal
violation.
Exposure: An event that occurs when there is contact at a boundary between a human and the
environment with a contaminant of a specific concentration. Instantaneous exposure
refers to the concentration that a person comes into contact with at a particular instant
of time; integrated exposure refers to the integral of the instantaneous exposure over a
defined time period; and average exposure refers to the integrated exposure divided by a
defined averaging time.
Fetus: The postembryonic stage of the developing young. In humans, from the end of the
second month of pregnancy up to birth.
Forced expiratory flow (FEFx): Related to some portion of the forced vital capacity curve.
Modifiers refer to the amount of the forced vital capacity already exhaled when the
measurement is made.
Forced expiratory volume (FEV): Denotes the volume of gas that is exhaled in a given time
interval during the execution of a forced vital capacity. Conventionally, the times used
are 0.5, 0.75, or 1 s, symbolized FEV0 5, FEV0 75, FEVL0. These values often are
expressed as a percent of the forced vital capacity (e.g., [FEVj 0/FVC] x 100).
A-16
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Forced vital capacity (FVC): Vital capacity performed with a maximally forced expiratory
effort. ;
Free radical: Any of a variety of highly reactive atoms or molecules characterized by having
an unpaired electron, often identified by a superscript dot (e.g., OH*).
Gas chromatography (GC): A method of separating and analyzing mixtures of chemical
substances. A flow of gas causes the components of a mixture to migrate differentially
from a narrow starting zone in a special porous, insoluble sorptive'medium. The
pattern formed by zones of separated pigments and of colorless substances in this
process is called a chromatogranr, and can be analyzed to obtain the concentration of '
identified pollutants.
Haldane Relationship: Under conditions of chemical equilibrium for the reactions binding
oxygen (O2) and carbon monoxide (CO) to hemoglobin (Kb), the following (Haldane)
relationship is assumed to hold (Coburn, Forster, and Kane, 1965).
c ^ =M —
[O2HbJ [COHb} :-..
where PcCO2is the mean pressure of dissolved O2 in mm Hg; [O2Hb] is the'
concentration of oxyhemoglobin in milliliter gas STPD per milliliter blood; Mistiie CO
chemical affinity of hemoglobin, also called the Haldane coefficient or parameter;
PCCO is the mean pressure of dissolved CO in mm Hg; and [C0H&] is the
concentration of carboxyhemoglobin in milliliter gas STPD per milliliter blood..
Hematocrit (Hct): The percentage of the volume of red blood cells in whole blood.
Hemoglobin (Hb): A hembprotein naturally occurring in most vertebrate blood, consisting of
four polypeptide chains (the globulin) to each of which there is attached a heme group.
The heme is made of four pyrrole rings and a divalent iron (Fe2+-protoporphyrin) that
combines reversibly with molecular oxygen. Hemoglobin transports .'oxygen from.,the
lungs to the tissues as oxyhemoglobin (O2Hb) and returns carbon dioxide to the lungs as
hemoglobin carbamate, completing the respiratory cycle.
Hydrocarbons (HC): Chemical compounds that consist entirely of carbon and hydrogen.
Hypoxemia: A state in which the oxygen pressure and/or concentration in arterial and/or
venous blood is lower than its normal value at sea level. Normal oxygen pressures at
sea level are 85 to 100 torr in arterial blood and 37 to 44 torr in mixed venous blood.
In adult humans, the normal oxygen concentration is 17 to 23 mL 62/100 mL arterial
blood; in mixed venous blood at rest, it is 13 to 18 jnL O2/100 mL, bipod.
A-17
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Hypoxia: Any state in which the oxygen in the lung, blood, and/or tissues is abnormally low
compared with that of a normal resting human breathing air at sea level. If the partial
pressure of oxygen is low in the environment, whether because of decreased barometric
pressure or decreased fractional concentration of oxygen, the condition is termed
environmental hypoxia. Hypoxia when referring to the blood is termed hypoxemia.
Tissues are said to be hypoxic ^hen their partial pressure of oxygen is low, even if
there is no arterial hypoxemia, as in "stagnant hypoxia," which occurs when the local
circulation is low compared to the local metabolism. ,
In vitro: (1) "In glass"; a test-tube culture. (2) Any laboratory test using living cells taken
from an organism.
In vivo: In the living body of a plant or animal. In vivo tests are those laboratory
experiments carried out on whole animals or human volunteers.
Indoor air: The breathing air inside a habitable structure or conveyance.
Indoor air pollution: Chemical, physical, or biological contaminants in indoor air.
Internal dose: Refers to the amount of the environmental contaminant absorbed in body tissue
or interacting with an organ's membrane surface.
Inversion: An atmospheric condition caused by a layer of warm air preventing the rise of
cooler air trapped beneath it. This prevents the rise of pollutants that might otherwise
be dispersed and can cause an air pollution episode. ,
Isotope: A variation of an element that has the same atomic number but a different weight
because of its neutrons. Various isotopes of the same element may have different .
radioactive behaviors.
Lapse rate: Vertical temperature gradient in the atmosphere: usually negative (i.e., decreasing
with altitude). (See "inversion.")
Lowest-observed-adverse-effect level (LOAEL): The lowest dose or exposure level of a
chemical in a study at which there is a statistically, or biologically significant increase, in
the frequency or severity of an adverse effect in the exposed population as compared
with an appropriate, unexposed control group.
Lowest-observed-effect level (LOEL): In a study, the lowest dose or exposure level at which
a statistically or biologically significant effect is observed in the exposed population
compared with an appropriate, unexposed control group.
Lung volume (V^: Actual volume of the lung, including the volume of the conducting ."'
airways.
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Maximal aerobic capacity ( VO2 max): The rate of oxygen uptake by the body during
repetitive maximal respiratory effort. Synonymous with maximal oxygen consumption
and maximal oxygen uptake.
Methemoglobin (MetHb): Hemoglobin in which iron is in the ferric state. Because the iron is
oxidized, methemoglobin is incapable of oxygen transport. Methemoglobins are formed
by various drugs and occur under pathological conditions. Many methods for
hemoglobin measurements utilize methemoglobin (chlorhemoglobin, cyanhemoglobin).
Microenvironment: A three-dimensional space with a volume in which contaminant
concentrations are spatially uniform during some specific interval.
Minute ventilation (Vg): Volume of air breathed hi one minute. It is a product of tidal
volume (VT) and breathing frequency (fB). (See ventilation.)
Minute volume: Synonymous with minute ventilation.
Modeling: An investigative technique using a mathematical or physical representation of a
system or theory that accounts for all or some of its known properties. Models are
often used to test the effect of changes of system components on the overall
performance of the system.
Monitoring: Periodic or continuous testing or measurement of pollutants or toxic substances in
various environmental media, or in humans, animals, and other, living things; used to
determine level of compliance with statutory requirements/standards.
Myoglobin (Mb): A relatively small globular protein containing an iron-porphyrin heme group
that is involved in the transport of oxygen from capillaries to mitochondria in skeletal
muscles. Myoglobin may contribute to muscle function by serving as an oxygen store
or by enhancing intracellular diffusion of oxygen.
National Ambient Air Quality Standards (NAAQS): Air quality standards established by EPA
that apply to outside air throughout the country. (See criteria pollutants.)
Nitric oxide (NO): A gas formed by combustion under high temperature and high pressure in
an internal combustion engine. It changes into nitrogen dioxide in the ambient air and
contributes to photochemical smog.
Nitrogen dioxide (NO^: The result of nitric oxide combining with oxygen in the atmosphere.
A major component of photochemical smog.
Nitrogen oxides (NOX): Compounds of nitrogen and oxygen in ambient air, such as nitric
oxide (NO) and others with a higher oxidation state of nitrogen '\ of which nitrogen
dioxide (NO^ is the most important toxicologically.
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No-observed-adverse-effect level (NOAEL): The highest experimental dose at which there are
no statistically or biologically significant increases in frequency or severity of adverse
health effects, as seen in the exposed population compared with an appropriate,
unexposed population. Effects may be produced at this level, but they are not
considered to be adverse.
No-observed-effect level (NOEL): The highest experimental dose at which there is no
statistically or biologically significant increases in frequency or severity of effects seen
in the exposed population compared With an appropriate, unexposed population.
Nbrmoxia: A state in which the partial pressure of oxygen in the inspired gas is equal to that
of air at sea level, about 150 mm Hg.
Oxygen consumption ( VO2, QO^: Rate of oxygen uptake of organisms, tissues, or cells.
Common units: milliliter O2 (STPD) per kilogram-minute or milliliter O2 (STPD) per
kilogram-hour. For whole organisms, the oxygen consumption commonly is expressed
per unit surface area or some power of the body weight. For tissue samples or isolated
cells, QO2 = /*L O2/h/mg dry weight.
Oxygen saturation (SO^: The amount of oxygen combined with hemoglobin, expressed as a
percentage of the oxygen capacity of that hemoglobin. In- arterial blood, SaO2.
Oxygen uptake ( VO^: Amount of oxygen taken up by the body from the environment, by
the blood from the alveolar gas, or by an organ or tissue from the blood. When this
amount of oxygen is expressed per unit of time one deals with an "oxygen uptake rate."
"Oxygen consumption" refers more specifically to the oxygen uptake rate by all tissues
of the body and is equal to the oxygen uptake rate of the organism only when the
oxygen stores are constant.
Oxy hemoglobin: Hemoglobin in combination with oxygen. It is the form of hemoglobin
present in arterial blood.
Ozone (O3): Found in two layers of the atmosphere, the stratosphere and the troposphere.
In the stratosphere (the atmospheric layer beginning 7 to 10 miles above the Earth's
surface), ozone is a form of oxygen found naturally that provides a protective layer
shielding the earth from ultraviolet radiation's harmful health effects on humans and the
environment. In the troposphere (the layer extending up 7 to 10 miles from the Earth's
surface), ozone is a chemical oxidant and major component of photochemical smog.
Ozone can seriously affect the human respiratory system and is one of the most
prevalent and widespread of all the criteria pollutants for which the Clean Air Act
required EPA to set standards. Ozone in the troposphere is produced through complex,
sunlight-activated chemical reactions involving nitrogen oxides, which are among the
primary pollutants emitted by combustion sources,' and hydrocarbons, which are
released into the atmosphere through the combustion, handling, and processing of
petroleum products. ,
A-20 ,
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Peroxyacetyl nitrate (PAN): Pollutant created by action of the ultraviolet component of
sunlight on hydrocarbons and nitrogen oxides in the air; an ingredient of photochemical
smog.
pH: A measure of the effective acidity or alkalinity of a liquid or solid material. It is
expressed as the negative logarithm of the hydrogen ion concentration. Pure water has
a hydrogen ion concentration equal to 10~7 M/L at standard conditions (25 °C). The
negative logarithm of this quantity is 7. Thus, pure water has a pH value of
7 (neutral). The pH scale is usually considered as extending from 0 to 14. A pH less
than 7 denotes acidity; greater than 7 denotes alkalinity.
Photochemical smog: Air pollution caused by sunlight-activated chemical reactions among
various pollutants emitted from different sources.
Physiological dead space (VD): Calculated volume that accounts for the difference between
the pressures of carbon dioxide in expired and alveolar gas (or arterial blood).
Physiological dead space reflects the combination of anatomical dead space and alveolar
dead space, the volume of the latter increasing with the importance of the nonuniformity
of the ventilation/perfusion ratio in the lung.
Pollution: Generally, the presence of matter or energy whose nature, location, or quantity
produces undesired environmental effects.
Population: A group of interbreeding organisms of the same kind occupying a particular
space. Generieally, the number of humans or other living creatures in a designated
area.
Radionuclide angiography: Visualization of blood vessels by injecting a source of gamma
radiation into the bloodstream and observing the area of interest with a scintillation
camera.
Residual volume (RV): That volume of air remaining in the lungs after maximal exhalation.
The method of measurement should be indicated in the text or, when necessary, by
appropriate qualifying symbols.
Respiratory frequency (fR): The number of breathing cycles per unit of time. Synonymous
with breathing frequency (fB).
Smog: Air pollution associated with oxidants. (See photochemical smog.)
Smoke: Particles suspended in air after incomplete combustion of materials.
Spectrophotometry: A technique in which visible, ultraviolet, or infrared radiation is passed
through a substance or solution and the intensity of light transmitted at various
wavelengths is measured to determine the spectrum of light absorbed.
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STPD conditions (STPD): Standard temperature and pressure, dry. These are the conditions
of a volume of gas at 0 °C, at 760 torr, without water vapor. A STPD volume of a
given gas contains a known number of moles of that gas.
Sulfur dioxide (SO^: A colorless gas with pungent odor, primarily released from burning of
fossil fuels containing sulfur, such as coal.
Synergism: A pharmacologic or toxicologic interaction in which the combined effect of two
or more chemicals is greater than the sum of the effects of each chemical alone.
(Compare with: additivity, antagonism.) ^
Tidal volume (TV): That volume of air inhaled or exhaled with each breath during quiet
breathing, only used to indicate a subdivision of lung volume. When tidal volume is
used in gas exchange formulations, the symbol VT should be used.
Time-weighted average (TWA): The average airborne exposure that shall not be exceeded in
any 8-h shift of a 40-h work week.
Torr: A unit of pressure equal to 1,333.22 dynes/cm2 or 1.33322 millibars. The torr is equal
to the pressure required to support a column of mercury 1-mm high when the mercury
is of standard density and is subjected to standard acceleration. These standard
conditions are met at 0 °C and 45° latitude, where the acceleration of gravity is
980.6 cm/s2. In reading a mercury barometer at other temperatures and latitudes,
corrections, which commonly exceed 2 torr, must be introduced for these terms and for
the thermal expansion of the measuring scale used. The torr is synonymous with the
pressure unit mm Hg.
Total human exposure: Accounts for all exposures a person has to a specific contaminant,
regardless of environmental medium or route of entry (inhalation, ingestion, and dermal
absorption). Sometimes total exposure is used incorrectly to refer to exposure to all
pollutants in an environment. Total exposure to more than one pollutant should be
stated explicitly as such.
Total lung capacity (TLC): The sum of all volume compartments or the volume of air in me
lungs after maximal inspiration. The method of measurement'should be indicated, as
with residual volume.
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Ventilation: Physiological process by which gas is renewed in the lungs. The word
Ventilation sometimes designates ventilatory flow rate (or ventilatory minute volume),
which is the product of the tidal volume multiplied by the ventilatory frequency.
Conditions usually are indicated as modifiers; that is,
VB = Expired volume per minute (BTPS), and
Vj = Inspired volume per minute (BTPS).
Ventilation often is referred to as "total ventilation" to distinguish it from "alveolar
ventilation." (See ventilation, alveolar.)
Ventilation, alveolar (VA): Physiological process by which alveolar gas is removed .
completely and replaced with fresh gas. Alveolar ventilation is less than total
ventilation because when a tidal volume of gas leaves the alveolar spaces, the kst part
does not get expelled from the body but occupies the dead space, to be relnspired with
the next inspiration. Thus the volume of alveolar gas actually expelled completely is
equal to the tidal volume minus the volume of the dead space. This truly complete
expiration volume times the ventilatory frequency constitutes the alveolar ventilation.
Ventilation, dead-space (VD): Ventilation per minute of the physiologic dead space (wasted
ventilation), BTPS, defined by the following equation:
VD - VE(PaCO2 - PECO^I
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REFERENCES
American College of Chest Physicians - American Thoracic Society (1975). Pulmonary terms and symbols:
a report of the ACCP-ATS Joint Committee on pulmonary nomenclature. Chest 67: 583-593.
Bartels, H.; Dejours, P.; Kellogg, R. H.; Mead, J. (1973) Glossary on respiration and gas exchange. Journal
Applied Physiology 34: 549-558.
Collier, C. R,; Goldsmith, J. R. (1983) Interactions of carbon monoxide and hemoglobin at high altitude.
Atmospheric Environment 17: 723-728.
National Academy of Sciences (1991) Human exposure assessment for airborne pollutants. Advances and
opportunities. Washington, DC: National Research Council.
U, S. Environmental Protection Agency (1989) Glossary of environmental terms and acronym list. Washington,
DC; Office of Communications and Public Affairs; report no. 19K-1002.
U. S. Environmental Protection Agency (1989) Glossary of terms related to health, exposure, and risk
management. Research Triangle Park, NC: Air Risk Information Support Center; report no.
EPA/450/3-88/016. Available from: NTIS, Springfield, VA; PB89-184584/XAB.
*U3.GOVERNMENTPRINTING OFFICE: 1992 -6"t8 .003/60025
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