TOXICOLOGICAL PROFILE FOR
	

CARBON MONOXIDE
	

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
	

Public Health Service
	

Agency for Toxic Substances and Disease Registry
	

June 2012 
 

 

CARBON MONOXIDE ii 

DISCLAIMER 

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services. 
 

 

 

 

 


	


	


	


	


	

CARBON MONOXIDE iii 

UPDATE STATEMENT 

A Toxicological Profile for Carbon Monoxide, Draft for Public Comment was released in September 

2009. This edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
	

Division of Toxicology and Human Health Sciences (proposed)/
	

Environmental Toxicology Branch (proposed)
	

1600 Clifton Road NE
	

Mailstop F-62 

Atlanta, Georgia 30333
	
CARBON MONOXIDE iv 

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 CARBON MONOXIDE v 

FOREWORD
	

This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the toxic substances each profile describes. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty information are referenced. 

The profiles focus on health and toxicologic information; therefore, each toxicological profile begins with 

a public health statement that describes, in nontechnical language, a substance's relevant toxicological 

properties. Following the public health statement is information concerning levels of significant human 

exposure and, where known, significant health effects. A health effects summary describes the adequacy 

of information to determine a substance's health effects. ATSDR identifies data needs that are significant 

to protection of public health. 

Each profile: 

(A) Examines, summarizes, and interprets available toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) Determines whether adequate information on the health effects of each substance is 

available or being developed to determine levels of exposure that present a significant risk to 

human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identifies toxicologic testing needed to identify the types or levels of 

exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are federal, state, and local health professionals; 

interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other federal scientists also 

have reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Christopher J. Portier, Ph.D. 

Assistant Administrator
	

Agency for Toxic Substances and Disease Registry
	
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 CARBON MONOXIDE vi 

*Legislative Background 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List and that pose the 

most significant potential threat to human health, as determined by ATSDR and the EPA. Section 

104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile 

for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for 

substances not found at sites on the National Priorities List, in an effort to “...establish and maintain 

inventory of literature, research, and studies on the health effects of toxic substances” under CERCLA 

Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise 

necessary to support the site-specific response actions conducted by ATSDR. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 

CARBON MONOXIDE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	

CARBON MONOXIDE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Sharon Wilbur, M.A.
	

Malcolm Williams, DVM, Ph.D.
	

Robert Williams, Ph.D.
	

Franco Scinicariello, M.D., M.P.H.
	

ATSDR, Division of Toxicology and Human Health Sciences (proposed), Atlanta, GA
	

Julie M. Klotzbach, Ph.D.
	

Gary L. Diamond, Ph.D. 

Mario Citra, Ph.D.
	

SRC, Inc., North Syracuse, NY
	

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. Data Needs Review. The Environmental Toxicology Branch (proposed) reviews data needs 

sections to assure consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 
CARBON MONOXIDE x 

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CARBON MONOXIDE xi 

PEER REVIEW
	

A peer review panel was assembled for carbon monoxide. The panel consisted of the following members: 

1.		 Laurence Fechter, Ph.D., Senior Career Research Scientist, Jerry Pettis Memorial Veterans 

Medical Center, Loma Linda, California 

2.		 Jerrold Leikin, M.D., Director of Medical Toxicology, NorthShore University Health System – 

OMEGA, Glenbrook Hospital, Glenview, Illinois 

3.		 Stephen Thom, M.D., Ph.D., Professor, Emergency Medicine, University of Pennsylvania, 

Institute for Environmental Medicine, Philadelphia, Pennsylvania 

These experts collectively have knowledge of carbon monoxide’s physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
CARBON MONOXIDE xii 

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CONTENTS
	

DISCLAIMER .............................................................................................................................................. ii
	

UPDATE STATEMENT ............................................................................................................................. iii
	

FOREWORD ................................................................................................................................................ v
	

QUICK REFERENCE FOR HEALTH CARE PROVIDERS.................................................................... vii
	

CONTRIBUTORS....................................................................................................................................... ix
	

PEER REVIEW ........................................................................................................................................... xi
	

CONTENTS............................................................................................................................................... xiii
	

LIST OF FIGURES .................................................................................................................................. xvii
	

LIST OF TABLES..................................................................................................................................... xix
	

1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1
	

1.1 WHAT IS CARBON MONOXIDE? ............................................................................................. 1
	

1.2 WHAT HAPPENS TO CARBON MONOXIDE WHEN IT ENTERS THE 

ENVIRONMENT?......................................................................................................................... 2
	

1.3 HOW MIGHT I BE EXPOSED TO CARBON MONOXIDE?..................................................... 2
	

1.4 HOW CAN CARBON MONOXIDE ENTER AND LEAVE MY BODY?.................................. 3
	
	

1.5 HOW CAN CARBON MONOXIDE AFFECT MY HEALTH?................................................... 3
	

1.6 HOW CAN CARBON MONOXIDE AFFECT CHILDREN? ...................................................... 3
	

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CARBON 

MONOXIDE? ................................................................................................................................ 4
	

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
	

TO CARBON MONOXIDE? ........................................................................................................ 5
	

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ................................................................................................... 5
	
	

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................... 6
	

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9
	

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CARBON MONOXIDE
	
	

IN THE UNITED STATES ........................................................................................................... 9
	

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................... 10
	

2.3 CARBON MONOXIDE DOSE-RESPONSE RELATIONSHIPS .............................................. 20
	
	

2.4 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 20
	

3. HEALTH EFFECTS.............................................................................................................................. 25
	

3.1 INTRODUCTION........................................................................................................................ 25
	
	

3.2 DISCUSSION OF HEALTH EFFECTS...................................................................................... 30
	
	

3.2.1 Death.................................................................................................................................. 34
	

3.2.2 Systemic Effects................................................................................................................ 38
	

3.2.3 Immunological and Lymphoreticular Effects.................................................................... 97
	

3.2.4 Neurological Effects.......................................................................................................... 98
	

3.2.5 Reproductive Effects ....................................................................................................... 104
	

3.2.6 Developmental Effects .................................................................................................... 105
	

3.2.7 Cancer.............................................................................................................................. 139
	

3.3 GENOTOXICITY...................................................................................................................... 139
	
	

3.4 TOXICOKINETICS................................................................................................................... 141
	

3.4.1 Absorption........................................................................................................................... 141
	

3.4.2 Distribution ......................................................................................................................... 143
	

3.4.3 Metabolism.......................................................................................................................... 148
	

CARBON MONOXIDE xiii 
3.4.4 Elimination and Excretion................................................................................................... 154
	

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models........... 155
	

3.5 MECHANISMS OF ACTION ................................................................................................... 174
	

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 174
	

3.5.2 Mechanisms of Toxicity...................................................................................................... 176
	

3.5.3 Animal-to-Human Extrapolations....................................................................................... 182
	

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS........................... 183
	

3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................ 184
	

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 187
	

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Carbon Monoxide ......................... 188
	

3.8.2 Biomarkers Used to Characterize Effects Caused by Carbon Monoxide............................ 188
	

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 189
	

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE................................................ 192
	

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................... 193
	

3.11.1 Reducing Peak Absorption Following Exposure............................................................. 194
	

3.11.2 Reducing Body Burden ................................................................................................... 194
	

3.11.3 Interfering with the Mechanism of Action for Toxic Effects.......................................... 195
	
	

3.12 ADEQUACY OF THE DATABASE ........................................................................................ 195
	
	

3.12.1 Existing Information on Health Effects of Carbon Monoxide ........................................ 196
	

3.12.2 Identification of Data Needs............................................................................................ 196
	
	

3.12.3 Ongoing Studies .............................................................................................................. 203
	

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 207
	

4.1 CHEMICAL IDENTITY............................................................................................................ 207
	

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................... 207
	

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 211
	

5.1 PRODUCTION .......................................................................................................................... 211
	

5.2 IMPORT/EXPORT .................................................................................................................... 211
	

5.3 USE ............................................................................................................................................ 211
	

5.4. DISPOSAL................................................................................................................................. 212
	

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 213
	

6.1 OVERVIEW...............................................................................................................................213
	

6.2 RELEASES TO THE ENVIRONMENT................................................................................... 215
	

6.2.1 Air ....................................................................................................................................... 215
	

6.2.2 Water................................................................................................................................... 217
	
	

6.2.3 Soil ...................................................................................................................................... 217
	
	

6.3 ENVIRONMENTAL FATE ...................................................................................................... 218
	

6.3.1 Transport and Partitioning................................................................................................... 218
	

6.3.2 Transformation and Degradation ........................................................................................ 219
	

6.3.2.1 Air ................................................................................................................................ 219
	

6.3.2.2 Water............................................................................................................................ 219
	

6.3.2.3 Sediment and Soil ........................................................................................................ 219
	

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT.................................. 220
	

6.4.1 Air ....................................................................................................................................... 220
	

6.4.2 Water................................................................................................................................... 234
	

6.4.3 Sediment and Soil ............................................................................................................... 234
	
	

6.4.4 Other Environmental Media................................................................................................ 234
	
	

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................................ 235
	

6.6 EXPOSURES OF CHILDREN.................................................................................................. 240
	
	

CARBON MONOXIDE xiv 
6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 241
	

6.8 ADEQUACY OF THE DATABASE ........................................................................................ 241
	

6.8.1 Identification of Data Needs ...............................................................................................242
	

6.8.2 Ongoing Studies.................................................................................................................. 244
	

7. ANALYTICAL METHODS................................................................................................................ 245
	
	

7.1 BIOLOGICAL MATERIALS.................................................................................................... 245
	

7.2 ENVIRONMENTAL SAMPLES .............................................................................................. 246
	

7.3 ADEQUACY OF THE DATABASE ........................................................................................ 252
	
	

7.3.1 Identification of Data Needs ...............................................................................................252
	

7.3.2 Ongoing Studies.................................................................................................................. 253
	

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 255
	

9. REFERENCES .................................................................................................................................... 259
	

10. GLOSSARY ...................................................................................................................................... 303
	

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
	

B. USER’S GUIDE.................................................................................................................................. B-1
	
	

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
	

D. INDEX ................................................................................................................................................ D-1
	

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CARBON MONOXIDE xvii 

LIST OF FIGURES
	

2-1. Blood Carboxyhemoglobin (COHb) Levels Corresponding to Adverse Health Effects of Carbon 

Monoxide in Humans ......................................................................................................................... 21
	

3-1. Hypoxic Hypoxia Human and Carbon Monoxide Rat Curves......................................................... 102
	

3-2. Hypoxic Hypoxia Human and Carbon Monoxide Human Curves................................................... 103
	

3-3. Summary of Carbon Monoxide Uptake, Distribution, and Elimination Pathways........................... 142
	

3-4. Temporal Profile of Blood Carboxyhemoglobin (%) for Hypothetical Continuous Exposures to 

Air Carbon Monoxide at Concentrations of 25, 200, or 1,000 ppm................................................. 144
	

3-5. Oxyhemoglobin Dissociation Curve for Normal Human Blood Containing 50%
	
	

Carboxyhemoglobin and for Blood of an Anemic Human ...............................................................153
	

3-6. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
	

Hypothetical Chemical Substance .................................................................................................... 157
	

3-7. Plot of Standardized Sensitivity Coefficients for Carboxyhemoglobin (COHb) Levels Predicted
	

from the Coburn-Forster-Kane (CFK) Model for a 100 ppm Exposure to an Individual Engaged 

in Vigorous Exercise (Alveolar Ventilation Rate=30 L/Minute) ..................................................... 161
	

3-8. Structure of the Smith et al. (1994) Model....................................................................................... 164
	

3-9. Structure of the Hill et al. (1977) Maternal-Fetal Model.................................................................. 168
	

3-10. Structure of the Bruce et al. (2008) Model ..................................................................................... 172
	

3-11. Potential Signaling Pathways Modulated by Carbon Monoxide .................................................... 180
	

3-12. Existing Information on Health Effects of Carbon Monoxide ....................................................... 197
	
CARBON MONOXIDE xviii 

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CARBON MONOXIDE xix 

LIST OF TABLES 

2-1. Blood Carboxyhemoglobin Levels Corresponding to Adverse Health Effects of Carbon 

Monoxide............................................................................................................................................ 22
	

3-1. Carbon Monoxide Exposures and Carboxyhemoglobin Levels Associated with Health Effects 

from Selected Studies Representing the Lowest Adverse Effect Levels............................................ 26 

3-2. Predicted Steady-State Blood Carboxyhemoglobin (COHb) Levels.................................................. 29
	

3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide
	

Concentrations and Respiratory Disease ............................................................................................ 41 

3-4. Effects of Acute-duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients
	

with Coronary Artery Disease ............................................................................................................ 56 

3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy
	

Subjects............................................................................................................................................... 65 

3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide
	

Concentrations and Cardiovascular Disease....................................................................................... 73 

3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide
	

Concentrations and Hospital Admissions and Emergency Department Visits Related to
	

Cardiovascular Disease....................................................................................................................... 81 

3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide
	

Concentrations and Developmental Outcomes................................................................................. 107 

3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals.................. 125 

3-10. Genotoxicity of Carbon Monoxide................................................................................................. 140
	

3-11. Post-Mortem Tissue Distribution of Carbon Monoxide in Humans............................................... 146
	

3-12. Hemoglobin and Myoglobin Binding Kinetics and Equilibrium Constants for Oxygen and 

Carbon Monoxide........................................................................................................................... 151
	

3-13. Parameter Values for Coburn-Forster-Kane (CFK) Model ............................................................ 160
	
	

3-14. Parameter Values for the Smith et al. (1994) Model...................................................................... 163
	

3-15. Parameter Values for the Hill et al. (1977) Model ......................................................................... 166
	

3-16. Parameter Values for the Bruce et al. (2008) Model ...................................................................... 170
	

3-17. Heme Proteins Modulated by Carbon Monoxide ........................................................................... 178
	

3-18. Ongoing Studies on the Health Effects of Carbon Monoxide ........................................................ 204
	
4-1. Chemical Identity of Carbon Monoxide........................................................................................... 208
	

4-2. Physical and Chemical Properties of Carbon Monoxide.................................................................. 209
	

6-1. Carbon Monoxide Emissions (Thousands of Short Tons) from 1970 to 2008................................. 216
	

6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring Stations Throughout the
	

United States..................................................................................................................................... 221
	

6-3. Average Annual Estimated Non Fatal Carbon Monoxide Exposure Cases in the United States
	
	

Emergency Room Visits (2004–2006) ............................................................................................. 236
	

6-4. Carboxyhemoglobin Levels in the U.S. Population Based Upon Smoking Status........................... 238
	

7-1. Analytical Methods for Determining Carbon Monoxide in Biological Samples ............................. 247
	

7-2. Analytical Methods for Determining Carbon Monoxide in Environmental Samples ...................... 248
	

8-1. Regulations, Advisories, and Guidelines Applicable to Carbon Monoxide ..................................... 256
	

CARBON MONOXIDE xx 
 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about carbon monoxide and the effects of exposure to it. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to carbon monoxide, many factors will determine whether you will be harmed. These 

factors include the dose (how much), the duration (how long), and how you come in contact with it. You 

must also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, 

pregnancy status, and state of health. 

1.1 WHAT IS CARBON MONOXIDE? 

Carbon monoxide is a gas Carbon monoxide is a colorless, nonirritating, 

odorless, and tasteless gas. It is found in both 

outdoor and indoor air. 

Sources of carbon monoxide in the 

atmosphere 

Carbon monoxide is made when carbon in fuel 

is not burned completely. Carbon monoxide is 

produced from both human-made and natural 

sources. The most important human-made 

source of carbon monoxide arises from the 

exhaust of automobiles. 

Inside homes, improperly adjusted gas 

appliances, furnaces, wood burning stoves, and 

fireplaces are a potential source of carbon 

monoxide (see Section 1.3). 

Carbon monoxide is released from wood 

burning/volcanoes/forest fires. 

Industrial uses Carbon monoxide can be used in industry to 

synthesize many compounds such as acetic 

anhydride, polycarbonates, acetic acid, and 

polyketone. 
 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 2 

1. PUBLIC HEALTH STATEMENT 

1.2 WHAT HAPPENS TO CARBON MONOXIDE WHEN IT ENTERS THE ENVIRONMENT? 

Converts to carbon dioxide When carbon monoxide is released to the 

environment, it enters the air and remains in the 

atmosphere for an average of about 2 months. 

Eventually, carbon monoxide reacts with other 

compounds in the atmosphere and is converted 

to carbon dioxide. 

Microorganisms found in soil and water can 

also convert carbon monoxide to carbon 

dioxide. 

1.3 HOW MIGHT I BE EXPOSED TO CARBON MONOXIDE?
	

Sources of exposure All people are exposed to carbon monoxide at 

varying levels through inhalation of air. Places 

and times of the day that have a lot of vehicular 

traffic generally have higher levels of carbon 

monoxide as compared to areas of low traffic. 

You can be exposed to carbon monoxide from 

tobacco smoke whether as a smoker or from 

second-hand smoke. 

You can be exposed to carbon monoxide by 

using gas appliances or wood burning stoves 

and fireplaces. 

In emergency situations where power is lost, 

using an improperly vented generator inside a 

home or building or using gas grills, charcoal 

grills, or hibachis indoors can lead to dangerous 

levels of carbon monoxide. 

People are exposed to carbon monoxide inside 

of vehicles. 

High levels of carbon monoxide exposure have 

been observed when using recreational 

watercraft and boats. 

Gasoline-powered small engines and tools 

(e.g., gas-powered compressors or pressure 

washers) can emit high levels of carbon 

monoxide in a short period of time. 

See Chapter 6 for more information regarding 

these exposures. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 3 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN CARBON MONOXIDE ENTER AND LEAVE MY BODY? 

Carbon monoxide enters and leaves the 

body 

Carbon monoxide in the air rapidly enters all 

parts of the body, including blood, brain, heart, 

and muscles when you breathe. 

The carbon monoxide in your body leaves 

through your lungs when you breathe out 

(exhale), but there is a delay in eliminating 

carbon monoxide. 

It takes about a full day for carbon monoxide to 

leave your body. 

1.5 HOW CAN CARBON MONOXIDE AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies. 

Carbon monoxide can harm the heart, brain, 

and lungs 

Breathing high levels of carbon monoxide can 

kill you. 

Breathing lower levels of carbon monoxide can 

permanently harm your heart and brain. 

Carbon monoxide can be more harmful to you if 

you have heart or lung disease. 

1.6 HOW CAN CARBON MONOXIDE AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Breathing carbon monoxide during 

pregnancy can harm your unborn child 

Breathing high levels of carbon monoxide can 

lead to miscarriage. 

Breathing lower levels of carbon monoxide 

during pregnancy may harm the mental 

development of your child. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 4 

1. PUBLIC HEALTH STATEMENT 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CARBON MONOXIDE? 

Reduce indoor air levels of carbon The most dangerous levels of carbon monoxide 

monoxide usually occur in indoor air. High levels occur as 

a result of improperly installed or unvented 

appliances that burn natural gas, kerosene, or 

other fuels. These include stoves, furnaces, 

heaters, and generators. Make sure that all of 

your appliances are installed properly and have 

periodic maintenance performed by 

professional installers. Always follow the 

manufacturer’s recommendations on installing 

and using these devices. 

Make certain wood burning heaters and 

fireplaces are properly vented. 

Never use a gas-powered generator or burn 

charcoal indoors, as this can quickly lead to 

dangerous levels of carbon monoxide in your 

home. 

Do not use older portable propane heaters in 

enclosed indoor settings, including campers 

and tents, as dangerous levels of carbon 

monoxide can build up. Look for portable 

heaters that contain an oxygen depletion sensor 

(ODS) and are safer to use when camping. If 

oxygen levels start to fall, the sensor 

automatically shuts down the heater before it 

can produce dangerous levels of carbon 

monoxide. Older generation heaters without an 

ODS are intended for outdoor use only and 

should not be used indoors. 

Do not use gasoline-powered tools like 

pressure washers inside of homes. Substitute 

less hazardous equipment whenever possible. 

Use electric tools or tools with engines that are 

separate from the tools and can be located 

outside and away from air intakes. 

Do not let your car idle for long periods of time 

in your garage. 

Avoid tobacco smoke You can reduce your exposure to carbon 

monoxide by avoiding smoke from cigarettes 

and cigars since the smoke contains carbon 

monoxide. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 5 

1. PUBLIC HEALTH STATEMENT 

Reduce outdoor exposure to carbon 

monoxide 

You can reduce your exposure to carbon 

monoxide outdoors by avoiding running or 

exercising near busy roadways. 

Accidental carbon monoxide poisonings can 

occur from recreational water craft. Most new 

boats come with carbon monoxide detectors; 

however, the U.S. Coast Guard advises owners 

of boats built prior to 1998 to have the monitors 

inspected or replaced. 

Install carbon monoxide detectors in your 

home 

Carbon monoxide detectors can be purchased 

at home remodeling or hardware stores. It is 

important to understand that most smoke 

detectors do not detect carbon monoxide, so 

you should install carbon monoxide detectors in 

your home as well as smoke detectors. 

If your doctor finds that you have been exposed to significant amounts of carbon monoxide, ask whether 

your children might also be exposed. Your doctor might need to ask your state health department to 

investigate. 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

CARBON MONOXIDE? 

Carbon monoxide exposure can be 

measured with a blood test 

Medical devices called carbon monoxideoximeters can estimate the level of carbon 

monoxide in blood by using a simple test. 

These devices are found in clinical laboratories 

and hospitals. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 6 

1. PUBLIC HEALTH STATEMENT 

Regulations and recommendations can be expressed as “not-to-exceed” levels. These are levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value. This critical value is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. Sometimes 

these not-to-exceed levels differ among federal organizations because they used different exposure times 

(an 8-hour workday or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. 

Some regulations and recommendations for carbon monoxide include the following: 

Levels in air set by EPA EPA established an environmental limit of 

10 milligrams per cubic meter (mg/m3) (9 parts 

per million by volume [ppmv]) of carbon 

monoxide in air averaged over 8 hours. This 

limit is not to be exceeded more than once per 

year. 

Levels in workplace air set by OSHA OSHA set a legal limit of 55 mg/m3 (50 ppmv) 

for carbon monoxide in air averaged over an 

8-hour work day. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 7 

1. PUBLIC HEALTH STATEMENT 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Human Health Sciences (proposed) 

1600 Clifton Road NE 

Mailstop F-62 

Atlanta, GA 30333 

Fax: 1-770-488-4178 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS)
	

5285 Port Royal Road
	

Springfield, VA 22161
	

Phone: 1-800-553-6847 or 1-703-605-6000
	

Web site: http://www.ntis.gov/
	
 

CARBON MONOXIDE 8 

1. PUBLIC HEALTH STATEMENT 

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CARBON MONOXIDE 9 

2. RELEVANCE TO PUBLIC HEALTH
	

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CARBON MONOXIDE IN 

THE UNITED STATES 

Carbon monoxide is a colorless, odorless, non-irritating, and tasteless gas that is ubiquitous in the 

atmosphere. It arises from both natural and anthropogenic sources. It is produced as a primary pollutant 

during the incomplete combustion of fossil fuels and biomass. Carbon monoxide is also produced 

indirectly from the photochemical oxidation of methane and other volatile organic compounds (VOCs) in 

the atmosphere. Vegetation can emit carbon monoxide directly into the atmosphere as a metabolic 

byproduct, and the photooxidation of organic matter in surface waters (lakes, streams, rivers, oceans) and 

surface soils also results in the formation of carbon monoxide. Volcanic activity is an additional natural 

source of carbon monoxide in the atmosphere. The vast majority of anthropogenic carbon monoxide 

emissions arise from gasoline-powered automobile usage, although the total amount of carbon monoxide 

emitted to the environment from this source has declined significantly over the past several decades due 

to the use of catalytic converters and other emission control devices that are standard equipment on 

modern passenger vehicles. 

The annual average outdoor carbon monoxide concentrations are roughly 0.12 parts per million by 

volume (ppmv) in the Northern Hemisphere and about 0.04 ppmv in the Southern Hemisphere. These 

levels are variable throughout the course of the year, with seasonal maximum levels occurring during late 

winter in both hemispheres and minimum levels being observed during late summer. Carbon monoxide 

concentrations are reported to range from a minimum of about 0.03 ppmv during summer in the Southern 

Hemisphere to a maximum of about 0.20 ppmv at high latitudes in the Northern Hemisphere during 

winter. Urban locations with high automobile usage or a high volume of stationary emission sources such 

as refineries or power plants typically have greater atmospheric levels of carbon monoxide as compared 

to rural or remote sites. Carbon monoxide levels in indoor air are strongly influenced by the presence of 

various appliances and whether or not the occupants of the residence smoke tobacco products. Unvented 

kerosene and gas space heaters; leaking chimneys and furnaces; back-drafting from furnaces, gas water 

heaters, wood stoves, and fireplaces; gas stoves, generators, and other gasoline-powered equipment; 

automobile exhaust from attached garages; and tobacco smoke all contribute to indoor air levels of carbon 

monoxide. Average levels in homes without gas stoves vary from 0.5 to 5 ppmv. Levels near properly 

adjusted gas stoves are often 5–15 ppmv and those near poorly adjusted stoves may be ≥30 ppmv. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 10 

2. RELEVANCE TO PUBLIC HEALTH 

Exposure of the general population to carbon monoxide occurs through inhalation of outdoor and indoor 

air. Populations living in urban areas with heavy vehicular traffic or stationary sources such as petroleum 

refineries, gas and coal burning power plants, petrochemical plants, and coke oven plants are more likely 

to be exposed to higher levels of carbon monoxide from ambient outdoor air. Occupational exposure for 

employees who work in these industries and other occupations that are subject to high levels of vehicular 

exhaust (such as taxi cab drivers, traffic or bicycle police, and toll booth workers) are also likely to be 

exposed to higher levels of carbon monoxide. Firefighters or other emergency response professionals can 

be exposed to high levels of carbon monoxide. Industrial or in-home use of methylene chloride paint 

strippers in poorly ventilated areas can lead to high levels of carbon monoxide in blood since carbon 

monoxide is a metabolic byproduct of methylene chloride. Members of the public who smoke or work in 

smoke-filled environments such as restaurants, bars, and casinos where smoking is allowed are also 

exposed to higher levels of carbon monoxide than members of the population who do not smoke and are 

not frequently exposed to second-hand tobacco smoke. Section 6.5 discusses exposures to the general 

population and occupational exposures in greater detail. 

2.2 SUMMARY OF HEALTH EFFECTS 

Health effects associated with acute carbon monoxide poisoning have been extensively documented. In 

the last decade, growing evidence has revealed endogenously produced carbon monoxide (produced from 

catabolism of heme and other endogenous precursors) to be a cell signaling agent that contributes to the 

regulation of numerous physiological systems, including brain and muscle oxygen storage and utilization 

(myoglobin, neuroglobin), relaxation of vascular and extra-vascular smooth muscle, modulation of 

synaptic neurotransmission, anti-inflammation, anti-apoptosis, anti-proliferation, and anti-thrombosis (see 

Section 3.5.2, Mechanisms of Toxicity). Endogenously produced carbon monoxide is not associated with 

toxicity; carbon monoxide toxicity occurs following exposure to exogenous carbon dioxide. Toxic effects 

of carbon monoxide are due to effects on cell metabolism through hypoxic and non-hypoxic modes of 

action. Both modes of action are thought to result from the ability of carbon monoxide to bind to heme 

and alter function and/or metabolism of heme proteins. Formation of carboxyhemoglobin (COHb) 

decreases the O2 carrying capacity of blood and impairs release of O2 from Hb for its utilization in tissues. 

Current toxicological and epidemiological research has focused on examining health effects of low-level 

carbon monoxide exposures that do not result in overt carbon monoxide poisoning and attempting to 

understand the connections between carbon monoxide toxicity and carbon monoxide in vivo production 

and metabolism. This research has revealed that the heart and cardiovascular system and the brain and 

developing nervous system are particularly sensitive to carbon monoxide. These studies have also shown 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 11 

2. RELEVANCE TO PUBLIC HEALTH 

that people with ongoing cardiovascular and/or respiratory disease may be particularly vulnerable to 

carbon monoxide. 

Modes of Action of Carbon Monoxide. Carbon monoxide exerts effects on cell metabolism through 

hypoxic and non-hypoxic modes of action. Both modes of action are thought to be largely (if not 

entirely) the result of the ability of carbon monoxide to bind to heme and alter function and/or metabolism 

of heme proteins. The binding affinity of carbon monoxide for hemoglobin is over 200 times greater than 

that of oxygen for hemoglobin. Formation of COHb decreases the O2 carrying capacity of blood and 

impairs the release of O2 from Hb for its utilization in tissues. Through similar mechanisms, carbon 

monoxide decreases O2 storage in muscle cells by binding to, and displacing O2 from, myoglobin. 

Although all tissues are vulnerable to carbon monoxide-induced hypoxic injury, those having the highest 

O2 demand are particularly vulnerable, including the brain and heart. 

Most of the non-hypoxic mechanisms of action of carbon monoxide have been attributed to binding of 

carbon monoxide to heme in proteins other than Hb. Notable targets of carbon monoxide include 

components of several important physiological regulatory systems, including brain and muscle oxygen 

storage and utilization (myoglobin, neuroglobin); nitric oxide cell signaling pathway (e.g., nitric oxide 

synthase, guanylyl cyclase); prostaglandin cell signaling pathway (cyclooxygenase, prostaglandin H 

synthase); energy metabolism and mitochondrial respiration (cytochrome c oxidase, cytochrome c, 

NADPH oxidase); steroid and drug metabolism (cytochrome P450); cellular redox balance and reactive 

oxygen species (ROS; catalase, peroxidases); and various transcription factors (e.g., neuronal PAS 

domain protein, NPAS2, implicated in regulation of circadian rhythm). Non-hypoxic modes of action are 

discussed in greater detail in Section 3.5.2. 

Endogenous Carbon Monoxide. In addition to inhalation exposure to carbon monoxide in air, internal 

exposures to carbon monoxide occur as a result of production of carbon monoxide from endogenous 

precursors (e.g., heme degradation, auto-oxidation of phenols, photo-oxidation of organic compounds, 

and lipid peroxidation of cell membrane lipids) and from oxidative metabolism of exogenous precursors 

(e.g., carbon tetrachloride, dichloromethane, and other dihalomethanes). The latter two metabolic sources 

of carbon monoxide result in a carbon monoxide body burden in the absence of exposure to exogenous 

carbon monoxide in air. Endogenous carbon monoxide production rate has been estimated to be 

approximately 0.42 mL carbon monoxide at standard temperature and pressure, dry (STPD)/hour or 

0.006 mL carbon monoxide/hour-kg body weight. However, numerous physiological and disease factors 

affect the rate of endogenous production of carbon monoxide, including the menstrual cycle, pregnancy, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 12 

2. RELEVANCE TO PUBLIC HEALTH 

diseases, and stimuli that increase catabolism of Hb or other heme proteins, including hemolysis, 

hematomas, hemolytic anemias, thalassemia, and Gilbert’s syndrome. 

Growing evidence has revealed endogenous carbon monoxide to be a cell signaling agent that contributes 

to the regulation of numerous physiological systems, including brain and muscle oxygen storage and 

utilization (myoglobin, neuroglobin), relaxation of vascular and extra-vascular smooth muscle, 

modulation of synaptic neurotransmission, anti-inflammation, anti-apoptosis, anti-proliferation, and antithrombosis. This has potentially important implications for the understanding of carbon monoxide 

toxicology and dose-response relationships for the following reasons: (1) carbon monoxide modulation 

of physiological processes may underlie some aspects of the toxicity of exogenous carbon monoxide; 

(2) exogenous carbon monoxide may disrupt physiological regulation of those systems that are responsive 

to endogenous carbon monoxide (e.g., vascular resistance); and (3) exposures to exogenous carbon 

monoxide may affect carbon monoxide-mediated physiological responses at levels that approach those 

resulting from endogenous production. One implication of this is that the dose threshold for effects of 

exogenous carbon monoxide on carbon monoxide-modulated physiological systems may lie near or below 

ambient air carbon monoxide concentrations. 

Toxicokinetics. Inhaled carbon monoxide is rapidly and extensively absorbed into blood and distributes 

throughout the body. The distribution of carbon monoxide in the body largely reflects the binding of 

carbon monoxide to heme proteins (e.g., Hb, myoglobin). Measurements of total carbon monoxide 

concentrations in tissues obtained from human autopsies showed the highest concentrations in blood, 

spleen, lung, kidney, and skeletal muscle, with detectable levels also in brain and adipose tissue. 

However, as noted above (see Modes of Action of Carbon Dioxide), due to the high O2 demand of the 

brain relative to other tissues, the brain is most sensitive organ to the effects of carbon monoxide. Higher 

concentrations of carbon monoxide in blood, heart, skeletal muscle, and spleen reflect the abundance of 

the major carbon monoxide binding proteins in these tissues. In blood, carbon monoxide rapidly 

distributes into erythrocytes where it exists primarily as a complex with Hb (COHb). Carbon monoxide 

in muscle exists primarily as a complex with myoglobin (COMb). Carbon monoxide in the maternal 

system distributes to fetal tissues where it binds to fetal Hb and other heme proteins. Steady-state fetal 

blood COHb concentrations are approximately 10–15% higher than maternal blood (fetal/maternal 

ratio=1.1–1.15) and fetal blood COHb elimination kinetics are slower than maternal blood. Carbon 

monoxide binding to fetal Hb is analogously similar to maternal Hb. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 13 

2. RELEVANCE TO PUBLIC HEALTH 

Absorbed carbon monoxide is eliminated from the body by exhalation and oxidative metabolism. 

Oxidative metabolism of carbon monoxide has been estimated to be a relatively small fraction (<10%) of 

endogenous carbon monoxide elimination. Under most conditions, the dominant route of elimination of 

absorbed carbon monoxide is exhalation. The decline in blood %COHb following cessation of an 

inhalation exposure to carbon monoxide exhibits at least two kinetic phases. The fast phase is thought to 

reflect a combination of exhalation of carbon monoxide along with slower distribution of blood carbon 

monoxide to tissues that continues after cessation of exposure. The elimination half-time for the slow 

phase is approximately 100–300 minutes. The carbon monoxide elimination half-time increases with age, 

with the most pronounced increase occurring from age 2 to 20 years and is approximately 6% longer in 

males compared to females. Exercise decreases carbon monoxide elimination half-time, although 

exercise and the increase in respiration would lead to increased CO exposure, if CO is still present in 

inspired air. 

The importance of COHb as a potential biomarker of carbon monoxide exposure and hypoxia, 

particularly at low levels of exposure, has led to the development of a physiologically-based mechanistic 

model of carbon monoxide kinetics for predicting relationships between exposure and blood COHb 

levels. The model that has received the greatest attention and use in risk assessment and in clinical 

medicine is the Coburn-Forster-Kane (CFK) model. This model can be used to predict steady-state blood 

COHb levels that correspond to a given continuous inhalation exposure to carbon monoxide in a typical 

adult. The CFK model has been used to support discussions of the health effects of carbon monoxide in 

this Toxicological Profile, by providing a means for interconverting carbon monoxide exposure levels 

expressed in units of ppm or mg/m3

 and corresponding equivalent steady-state COHb% values (i.e., the 

COHb% that would be achieved with continuous exposure to the reported air carbon monoxide 

concentration). Predicted steady-state blood COHb levels corresponding to a range of carbon monoxide 

exposure concentrations are presented in the introduction to Section 3.2 (Table 3-1). Several other 

toxicokinetics models are described in Section 3.4.5. 

Acute Carbon Monoxide Poisoning. Carbon monoxide poisoning is one of leading causes of morbidity 

and mortality due to poisoning in the United States. It has been estimated that carbon monoxide 

poisoning results in over 50,000 emergency room visits per year in the United States. The principal 

mechanism of many adverse effects of carbon monoxide exposure is COHb-induced tissue hypoxia; thus, 

tissues with high oxygen requirements (e.g., brain, heart) are the most sensitive to carbon monoxideinduced hypoxia. However, other non-hypoxic mechanisms (e.g., binding of carbon monoxide to other 

heme proteins, such as myoglobin and cytochrome c oxidase) and alterations in biological and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 14 

2. RELEVANCE TO PUBLIC HEALTH 

physiological functions of endogenous carbon monoxide, likely contribute to the adverse effects of acute 

carbon monoxide poisoning. 

The extent of injury from acute carbon monoxide exposure depends upon the concentration and duration 

of exposure and the underlying health status of the exposed individual. The most commonly reported 

signs and symptoms associated with acute carbon monoxide poisoning are due to effects on the central 

nervous system and the cardiovascular system; however, because carbon monoxide exposure has the 

potential to affect nearly all tissues, the clinical presentation of acute carbon monoxide poisoning includes 

a wide range of symptoms. The severity of carbon monoxide poisoning is typically categorized as mild, 

moderate, or severe, based on clinical presentation. Signs and symptoms of mild carbon monoxide 

poisoning include headache, nausea, vomiting, dizziness, blurred vision, and occasionally cherry red lips 

and skin; headache and dizziness are the most commonly reported symptoms. Because these symptoms 

mimic flu-like viral illnesses, mild carbon monoxide poisoning can easily be misdiagnosed. Symptoms 

associated with moderate carbon monoxide poisoning may include confusion, syncope, chest pain, 

dyspnea, weakness, tachycardia, tachypnea, and rhabdomyolysis. Effects of severe poisoning may be 

life-threatening, including cardiac arrhythmias, myocardial ischemia, cardiac arrest, hypotension, 

respiratory arrest, noncardiogenic pulmonary edema, seizures, and coma. In addition to the immediateonset effects of exposure, delayed-onset development of neuropsychiatric impairment typically occurs 

from several days to approximately 3–4 weeks of exposure, with symptoms including inappropriate 

euphoria, impaired judgment, poor concentration, memory loss, cognitive and personality changes, 

psychosis, and Parkinsonism Symptoms of acute carbon monoxide poisoning in children are the same as 

those in adults. Acute carbon monoxide poisoning during pregnancy has been associated with 

spontaneous abortion and fetal death; pregnancy outcome is likely to be dependent upon the severity of 

maternal poisoning and fetal age. 

The relationship between the severity of clinical signs and symptoms of acute carbon monoxide poisoning 

and COHb levels is not well correlated. The poor correlation may be due to the length of time elapsed 

between cessation of exposure and measurement of COHb levels or to effects of supplemental oxygen 

treatment prior to COHb measurement. Generally, in healthy individuals, mild carbon monoxide 

poisoning that requires medical intervention are associated with COHb levels >20%. Fatalities due to 

carbon monoxide poisoning have been reported for a wide range of COHb levels (3–70%). Levels of 

COHb >50% are frequently fatal. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 15 

2. RELEVANCE TO PUBLIC HEALTH 

Primary Targets of Low-level Carbon Monoxide Exposure. The primary targets of low-level exposures 

to carbon monoxide (i.e., those that result in blood COHb levels <20%) appear to include the heart and 

cardiovascular system, the central nervous system, and the fetus and neonate. Adverse effects in the 

respiratory tract have been observed in human clinical studies and in animal studies at higher exposures 

than those associated with effects on the cardiovascular and central nervous systems and on development. 

A large body of epidemiologic studies has also provided evidence that ambient levels of carbon monoxide 

in air may contribute to respiratory morbidity and aggravation of ongoing respiratory disease (e.g., 

asthma; see Table 3-3). Epidemiologic studies have also examined possible associations between ambient 

air carbon monoxide concentrations and hematologic biomarkers of coagulation and inflammation. 

Although some studies have found significant associations, collectively, findings from these studies are 

inconclusive. 

Cardiovascular System. Cardiovascular effects of inhalation exposures to carbon monoxide have 

been evaluated in controlled human clinical studies, epidemiology studies, and various animal models 

(monkeys, dogs, rats, and rabbits). In general, these studies provide convincing evidence for adverse 

cardiovascular effects in association with carbon monoxide exposures that result in blood COHb levels 

≥2.4%, with effects occurring at the lowest levels in subjects with compromised cardiovascular function 

(e.g., coronary artery disease). 

Results of controlled clinical studies in patients with coronary artery disease show that acute-duration 

exposure to carbon monoxide at levels producing blood COHb levels between 2.4 and 5.9% exacerbates 

underlying cardiovascular disease, including enhanced myocardial ischemia and increased cardiac 

arrhythmias. In patients with exertional angina, carbon monoxide exposure exacerbated exercise-induced 

myocardial ischemia, including decreased time-to-onset of angina symptoms, increased duration of 

angina symptoms, decreased time-to-onset of ST-segment depression (electrocardiogram [EKG or ECG] 

change indicative of myocardial ischemia), and decreased left ventricular ejection fraction. At the lowest 

blood COHb level evaluated in patients (i.e., COHb 2.4%), time-to-onset of angina symptoms and 

ST-segment depression were significantly decreased by 4.2 and 5.1%, respectively. 

Epidemiological studies of exposure to carbon monoxide and cardiovascular outcomes have yielded 

mixed results. In general, the weight of evidence suggests that risks of certain specific outcomes 

(hospitalizations and emergency room visits related to congestive heart failure, ischemic heart disease, 

myocardial infarction, and stroke) are associated with increasing ambient carbon monoxide 

concentrations. The interpretation of these associations is complicated by the possibility that ambient air 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 16 

2. RELEVANCE TO PUBLIC HEALTH 

carbon monoxide levels may be a surrogate measure for air pollution in general. However, the 

corroborated observations of associations between carbon monoxide exposure and outcomes related to 

ischemic heart disease is particularly provocative in the context of results of human clinical studies in 

which carbon monoxide-induced hypoxia exacerbated ischemia symptoms in patients with coronary 

artery disease. Mean ambient air carbon monoxide concentrations reported in studies that have found 

carbon monoxide-associated adverse cardiovascular outcomes ranged from 0.5 to 10 ppm, with maximum 

values ranging from 2 to 50 ppm. These values correspond to approximate steady-state blood COHb 

levels of <2% for the mean and <10% for the maximum. 

Studies in animals have investigated adverse cardiovascular effects of carbon monoxide exposure over a 

much wider range of exposure conditions (e.g., exposure concentration and duration) and have evaluated 

additional outcome measures that are not possible to assess in humans. These studies provide further 

evidence of adverse cardiovascular effects of carbon monoxide exposure, including compensatory 

alterations in hemodynamics, cardiac hypertrophy, cardiac arrhythmias, and possibly atherosclerosis. 

Based on studies described above, a blood COHb concentration of 2.4% is identified as the lowestobserved-adverse-effect level (LOAEL) for adverse cardiovascular outcomes in coronary artery disease 

patients. A no-observed-adverse-effect level (NOAEL) for this effect was not identified. The LOAEL 

for COHb can be converted to an equivalent human exposure concentration (for continuous exposure) that 

would yield the same steady-state blood COHb concentration (2.4%) by implementing the CFK model. 

The human equivalent exposure concentration is approximately 14 ppm. 

Developmental Effects. Epidemiological studies have examined possible associations between 

exposure to ambient air carbon monoxide concentrations and various developmental outcomes, including 

pre-term birth, birth weight, congenital anomalies, neurodevelopment, and neonatal and infant death. 

Results of these studies have been mixed and collectively do not provide strong evidence for 

developmental effects in association with exposures to ambient levels of carbon monoxide. In general, 

these studies examined relatively low air carbon monoxide concentrations, typical of ambient levels 

(e.g., mean concentrations ranging from 0.5 to 3 ppm, with highest reported values ≤10 ppm; see 

Table 3-8). These studies typically relied on average ambient carbon monoxide concentrations (based on 

regional air monitoring) for estimating exposures and do not necessarily represent exposures that occurred 

to individuals during any particular period of gestation. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 17 

2. RELEVANCE TO PUBLIC HEALTH 

Numerous studies on developmental effects of gestational and early postnatal exposure to carbon 

monoxide have been conducted in animals. In general, most studies evaluated effects of relatively low 

carbon monoxide concentrations (i.e., ≤300 ppm), with exposure concentrations selected to produce 

maternal COHb levels typically associated with smoking (5–10%); however, studies did not consistently 

report maternal or fetal COHb levels. Studies in animals have examined effects of carbon monoxide 

exposure on numerous developmental outcomes, including several outcomes that have not been assessed 

in epidemiological studies (e.g., auditory and immune system development). Results of animal studies 

show adverse developmental effects of gestational and early postnatal carbon monoxide exposure, 

including decreased fetal weight, adverse central nervous system development, altered peripheral nervous 

system development, cardiac effects, altered sexual behavior, immunological effects, and hematological 

effects. In addition, some studies showed that developmental effects persisted beyond the postnatal 

period, although persistence of effects was not examined in all studies. The lowest LOAEL values for 

developmental effects were obtained in studies evaluating effects of carbon monoxide on the developing 

auditory system (i.e., LOAEL 12–25 ppm); however, since other developmental outcomes were not 

assessed at this range of low carbon monoxide concentrations, it is not possible to determine if the 

developing auditory system is more sensitive to carbon monoxide exposure than other systems. 

Gestational and/or early postnatal exposure of rats to 25 ppm carbon monoxide produced morphological 

changes in the developing auditory system, including swelling, cytoplasmic vacuolization, and atrophy of 

nerve terminals innervating inner hair cells; “distorted myelin” with vacuolization in the 8th cranial nerve 

at the level of the internal auditory canal; decreased immunoreactivity of the enzymes cytochrome 

oxidase, NADH-TR, and calcium-mediated myosin ATPase; and decreased immunostaining of 

neurofilament and myelin basic protein in the organ of corti. Exposure of rat pups during the early 

postnatal period decreased action potential amplitude of the 8th cranial nerve at ≥12 ppm carbon 

monoxide and decreased otoacoustic emissions at ≥50 ppm carbon monoxide, with effects on action 

potential amplitude of the 8th nerve persisting through age 73 days. 

Based on studies described above, a maternal exposure concentration of 12 ppm is identified as a LOAEL 

for adverse neurodevelopmental outcomes in rats. This LOAEL can be converted to an equivalent blood 

COHb level in the rat by implementation of the CFK model, as adapted for the rat. The time-averaged 

blood COHb level predicted for the 16-day exposure (22 hours/day) is 1.8%. The equivalent human 

exposure concentration (for continuous exposure) that would yield the same steady-state blood COHb 

concentration (1.82%) is approximately 10 ppm. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 18 

2. RELEVANCE TO PUBLIC HEALTH 

Central Nervous System. As previously noted, acute exposure to high levels of carbon monoxide 

produces symptoms of central nervous system toxicity, including headache, dizziness, drowsiness, 

weakness, nausea, vomiting, confusion, disorientation, irritability, visual disturbances, convulsions, and 

coma. Lesions of the basal ganglia (primarily of the globus pallidus) and white matter have also been 

observed in magnetic resonance imaging (MRI) and computed tomography (CT) scans in association with 

acute carbon monoxide poisoning. Motor impairments consistent with damage to basal ganglia have been 

observed following carbon monoxide poisoning. Following acute-onset effects, delayed development of 

neuropsychiatric impairment may occur from several days to 3–4 weeks of exposure, with symptoms 

including inappropriate euphoria, impaired judgment, poor concentration, memory loss, cognitive and 

personality changes, psychosis, and Parkinsonism. Delayed neuropsychiatric impairment has been 

estimated to occur in up to 68% of patients with acute carbon monoxide poisoning. There is a poor 

correlation between initial symptom severity, and the likelihood of developing of delayed 

neuropsychiatric impairment. Exposures to carbon monoxide in utero have also been associated with 

decrements in neurodevelopment, as assessed later in childhood with neuropsychological tests. 

Based on an extensive database of acute carbon monoxide poisoning, it is generally accepted that central 

nervous system symptoms are associated with acute exposures that result in blood COHb levels ≥20%. 

However, despite extensive clinical experience, general consensus on the dose-response relationship for 

carbon monoxide-induced nervous system effects at blood COHb levels between 5 and 20% has not been 

achieved. 

Based on studies described above, a blood COHb concentration of 20% is identified as a LOAEL for 

adverse neurological outcomes, although the LOAEL range may extend below this level to 5%. These 

levels, 5 and 20%, can be converted to equivalent human exposure concentrations (for continuous 

exposure) that would yield the same steady-state blood COHb concentration by implementing the CFK 

model. The human equivalent exposure concentrations are approximately 32 ppm (COHb=5%) and 

160 ppm (COHb=20%). 

Respiratory Effects. Although cardiopulmonary arrest is an end point of fatal carbon monoxide 

poisoning, results of controlled clinical studies in healthy subjects indicate that the respiratory tract does 

not appear to be a primary target organ for carbon monoxide toxicity. Brief exposure to carbon monoxide 

at levels >1,000 ppm may decrease ventilatory performance, although conflicting results have been 

reported. Epidemiological studies have examined possible associations between ambient air carbon 

monoxide concentrations and mortality. These studies have examined relatively low carbon monoxide 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 19 

2. RELEVANCE TO PUBLIC HEALTH 

concentrations (from a toxicological perspective) that are typical of ambient conditions of the study 

period (mean concentrations ranging from 0.3 to 10 ppm with the highest values ≤30 ppm; see Table 3-3). 

Collectively, these studies have yielded mixed results, with some studies finding significant associations 

between increasing ambient air carbon monoxide concentrations and respiratory outcomes (e.g., 

exacerbation of asthma symptoms, hospitalizations and emergency room visits related to asthma) and few 

studies finding associations that persist after accounting for exposures to other air pollutants that also 

have been shown to contribute to respiratory disease risk (e.g., NO2, O3, particulate matter [PM], and 

SO2). The lack of strong evidence for associations between ambient air carbon monoxide concentrations 

at <30 ppm and pulmonary function is also consistent with the results of human clinical studies. Studies 

conducted in animals provide supporting evidence that the respiratory tract does not appear to be a 

primary target organ for carbon monoxide. Most of these studies evaluated carbon monoxide exposures 

that produced much higher COHb concentrations (i.e., COHb >50%) than those evaluated in controlled 

clinical studies in humans. In the studies that found effects on lung function (e.g., decreased compliance 

and increased airway resistance), animals had been exposed to carbon monoxide concentrations in the 

range of 8,000–28,400 ppm. 

Hematological Effects. Hematological effects of carbon monoxide include compensatory responses 

to tissue hypoxia resulting from binding of carbon monoxide to Hb (e.g., increased blood volume, Hb, 

hematocrit, and erythrocyte count and volume). Possible associations between ambient air carbon 

monoxide concentrations and biomarkers of coagulation and inflammation have been examined in 

epidemiological studies. Biomarkers examined have included inflammation markers, C-reactive protein 

(CRP), serum amyloid A (SAA), and white blood cell (WBC) count; cell adhesion markers, E-selectin, 

von Willebrand factor, antigen (vWF), ICAM-1; and coagulation markers, fibrinogen, factor VII (FVII), 

prothrombin fragment 1+2, prothrombin time (PT), and activated partial thromboplastin time (APTT). 

Although some studies found significant associations between environmental carbon monoxide exposures 

and alteration in plasma proteins, these studies do not distinguish between possible direct effects of 

carbon monoxide and/or other air pollutants directly on coagulation and immune systems from indirect 

effects that result in changes in blood biomarkers. Furthermore, findings across studies are inconsistent. 

Environmental carbon monoxide exposures were shown to correlate with elevated C reactive protein in 

one trial, but not another by the same group. Plasma fibrinogen was increased in one study, decreased in 

one study, and unchanged in two studies. Other studies reported an elevation in soluble intercellular 

adhesion molecule-1, along with decreases in coagulation factor VII, serum albumin, and prothrombin 

time. Therefore, no conclusions can be drawn at this time on whether low-level environmental exposures 

may alter plasma inflammatory or coagulation markers. Nevertheless, direct effects are plausible, given 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 20 

2. RELEVANCE TO PUBLIC HEALTH 

mechanistic studies that have revealed evidence that endogenous carbon monoxide may participate in the 

regulation of thrombosis and immune function (see Section 3.5.2, Mechanisms of Toxicity). 

2.3 CARBON MONOXIDE DOSE-RESPONSE RELATIONSHIPS 

Epidemiological and clinical studies provide evidence for a progression of some of the adverse health 

effects of carbon monoxide in humans with increasing blood levels of COHb (Figure 2-1). The 

relationship shown in Figure 2-1 does not necessarily mean that these effects result directly from the 

formation of COHb at the expense of decreasing O2Hb levels in blood (i.e., hypoxic mechanisms). Other 

important mechanisms, previously mentioned and subsequently described in greater detail in 

Section 3.5.2, (Mechanisms of Toxicity), may also contribute to these effects. COHb may serve as a 

biomarker for carbon monoxide body burden or carbon monoxide burdens in specific target tissues where 

non-hypoxic modes of actions of carbon monoxide exert effects. 

An alternative presentation of the relationship between blood COHb levels and adverse health effects is 

provided in Table 2-1. This table shows the predicted relationship between blood COHb levels that 

roughly correspond to adverse health effects and their corresponding equivalent human exposure 

concentrations that would result in the same steady-state blood COHb level. For example, in Table 2-1, a 

continuous exposure to approximately 14 ppm for a period exceeding 16 hours (i.e., sufficient to achieve 

steady state) would be expected to result in a blood COHb level of approximately 2.4%, the lower end of 

the range for cardiac effects in coronary artery disease patients. All predictions shown in Table 2-1 are 

based on the CFK model, described in Section 3.4.5 (Physiologically Based Pharmacokinetic/ 

Pharmacodynamic Models). 

2.4 MINIMAL RISK LEVELS (MRLs) 

Given the above considerations, MRLs for carbon monoxide are not proposed at this time. The rationale 

for this determination is as follows: 

(1) Growing evidence suggests that endogenous carbon monoxide production is physiologically 

regulated and plays a role in regulating various important physiological processes, including 

processes that may underlie adverse effects on the cardiovascular, immune, blood coagulation, 

and nervous systems that have been observed in human clinical studies, epidemiological studies, 

or animal studies. 

(2) Given the physiological role of endogenous carbon monoxide, it is likely that an exposure 

threshold for carbon monoxide actions, if one exists at all, would be at or near the endogenous 
 

 

 

CARBON MONOXIDE 21 

2. RELEVANCE TO PUBLIC HEALTH 

Figure 2-1. Blood Carboxyhemoglobin (COHb) Levels Corresponding to Adverse
	

Health Effects of Carbon Monoxide in Humans 

COHb % 

60 

High risk of death 

Acute and delayed onset 

neurological impairment and 

40 pathology 

20 

Neurobehavioral/ 

cognitive effects 10 

Decreases exercise stamina 

in healthy adults 

5 

Cardiac arrhythmia in coronary 

artery disease patients 

Typical level 

Endogenous production 
 

 

 

 

 

 

CARBON MONOXIDE 22 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Blood Carboxyhemoglobin (COHb) Levels Corresponding to Adverse
	

Health Effects of Carbon Monoxide
	

COHba Exposureb 

Effect (percent) (ppm) 

Endogenous production <0.5 0
 

Typical level in nonsmoker 0.5–1.5 1–8 

Increased risk of arrhythmias in coronary artery disease patients and 0.3–2b 0.5–10b
 

exacerbation of asthma (epidemiological studies)
 

Neurodevelopmental effects on the auditory system in rats 2–4b 12–25b
 

Enhanced myocardial ischemia and increased cardiac arrhythmias in coronary 2.4–6 14–40
 

artery disease patients
 

Decreased exercise stamina in healthy adults 5–8 30–50
 

Neurobehavioral/cognitive changes, including visual and auditory sensory 5–20 30–160 

effects (decreased visual tracking, visual and auditory vigilance, visual
 

perception), fine and sensorimotor performance, cognitive effects (altered time 

discrimination, learning, attention level, driving performance), and brain electrical
 

activity
 

Acute and delayed onset of neurological impairment (headache, dizziness, 20–60 160–1,000 

drowsiness, weakness, nausea, vomiting, confusion, disorientation, irritability,
 

visual disturbances, convulsions, and coma) and pathology (basal ganglia 

legions)
 

High risk of death >50 >600
 

a

Reported value, unless otherwise denoted as predicted.

b

Predicted from the Coburn-Forster-Kane (CFK) model (unless otherwise denoted as reported), with a rate of
 

endogenous carbon monoxide production assigned a value of 0.006 mL CO/kg body weight and all other parameter
 

values as noted in Table 3-13.
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 23 

2. RELEVANCE TO PUBLIC HEALTH 

production rate. Therefore, any exogenous source of carbon monoxide exposure would have the 

potential for exceeding the threshold and producing potentially adverse effects. 

(3) Although there may be an exposure level that can be tolerated with minimal risk of adverse 

effects, the currently available toxicological and epidemiological data do not identify such 

minimal risk levels. Experimental clinical studies and animal toxicology studies that identify the 

lowest LOAELs do not identify NOAELs. These LOAELs are relatively low: COHb 2.4% for 

cardiovascular effects in humans and exposure concentrations of ≥12 ppm in rats for 

developmental effects. Converting these to human equivalent exposure concentrations (i.e., 

levels of continuous exposure that would result in steady-state COHb concentration in blood 

estimated from the CFK model) yield corresponding LOAELs of 14 and 10 ppm, respectively. 

Application of appropriate uncertainty factors to these LOAELs (e.g., for extrapolation from a 

LOAEL, for extrapolation from animals to humans, and for extrapolation to sensitive 

subpopulations) would result in MRLs that are 30–100 times lower than the corresponding 

LOAELs (e.g., approximately 0.1–0.5 ppm). These values are within the range of ambient carbon 

monoxide concentrations in the United States and would result, even for acute (e.g., 14-day) 

exposures, in internal doses that would be similar to endogenous production of carbon monoxide. 

(4) Any exposure level determined to be of minimal risk at sea level would not necessarily be of 

minimal risk at higher altitudes (i.e., at lower O2 partial pressures). This would apply, in 

particular, to modes of action of carbon monoxide that involve competition between carbon 

monoxide and O2 for heme binding sites. The latter would include hypoxic mechanisms of 

actions that appear to underlie adverse cardiovascular effects of carbon monoxide (e.g., 

exacerbation of exercise-induced arrhythmias in patients who have coronary artery disease). 
 

CARBON MONOXIDE 24 

2. RELEVANCE TO PUBLIC HEALTH 

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CARBON MONOXIDE 25 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of carbon monoxide. 

It contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

Focus of the Health Effects Review. The literature on the toxicology of carbon monoxide is immense. 

Relatively recent reviews of the literature have been prepared by various organizations, including the 

World Health Organization (WHO 1999) and EPA (2000, 2009g), and numerous reviews have been 

compiled on the clinical toxicology and management of acute carbon monoxide poisoning. The review of 

the literature provided in this section is not intended to be comprehensive; rather, it is focused on the 

more important, recent developments in the toxicological and epidemiological assessment of carbon 

monoxide. Studies that have potential relevance to understanding the lower end of the dose-response 

relationship for carbon monoxide are emphasized. Typically, dose-response information is presented in 

Toxicological Profiles in Levels of Significant Exposure (LSE) tables and figures. However, this 

information on carbon monoxide has been represented in various types of units (e.g., exposure 

concentration, blood COHb), and end points are not easily assigned into categories of NOAELs or 

LOAELs (e.g., odds ratio from epidemiological studies). Therefore, in place of an LSE table, Table 3-1 

provides an overview of exposures (ppm) and blood COHb levels (percent) that have been associated 

with specific categories of health effects. Table 3-2 can be used to convert the reported ambient air 

carbon monoxide concentrations into equivalent predicted blood COHb levels. However, considerable 

uncertainty attends to these dose interconversions as well as their relevance to a particular outcome. 

Predicted COHb levels and corresponding exposure concentrations may have greater relevance to 

outcomes mediated through hypoxic mechanisms than to those mediated through non-hypoxic 

mechanisms. Furthermore, steady-state requires exposure durations of approximately 16–24 hours. 

Exposures to lower levels of carbon monoxide for longer durations and exposures to higher levels for 

shorter durations that achieve similar blood COHb levels may not yield equivalent responses. 
 

 

 

 

 

 

 

 

 

Table 3-1. Carbon Monoxide Exposures and Carboxyhemoglobin Levels Associated with Health Effects from Selected 

Studies Representing the Lowest Adverse Effect Levels 

Exposure COHb 

Study type Subjects (ppm) (%) Effect Comments Reference 

CARBON MONOXIDE

Respiratory 

Epidemiological Asthmatic children 0.3–2 NR Asthma	 Exacerbation of asthma. Associations 

confounded by co-exposure to other 

air pollutants (NO2, O3, PM10, PM2.5, 

SO2). 

Cardiovascular 

Clinical, acute Coronary artery 117 2.4 Myocardial ischemia	 Decreased time-to-onset of angina and 

exposure	 disease patients (1 hour) arrhythmia (ST-segment changes) 

(63 male adult during exercise. 

nonsmokers) 

Clinical, acute Healthy adults NR 5.1 Performance Decreased maximal exercise duration 

exposure (15 male adult and effort. No effect on heart rate or 

nonsmokers) rhythm, cardiac perfusion, or blood 

pressure. 

Epidemiological General public 0.3–2 NR Cardiovascular disease	 Increased risk of congestive heart 

failure, ischemic heart disease, 

myocardial infarction, and stroke. 

Effect size more pronounced in elderly 

and people with ongoing respiratory or 

cardiovascular disease. Associations 

confounded by co-exposure to other 

air pollutants (NO2, O3, PM10, PM2.5, 

SO2). 

Park et al. 2005a; 

Rabinovitch et al. 2004; 

Rodriguez et al. 2007; 

Schildcrout et al. 2006; 

Silkoff et al. 2005; 

Slaughter et al. 2003; 

von Klot et al. 2002; Yu 

et al. 2000 

Allred et al. 1989, 1991 

Adir et al. 1999 

Berger et al. 2006; 

D’Ippoliti et al. 2003; 

Hosseinpoor et al. 2005; 

Lanki et al. 2006; Lee et 

al. 2003b; Mann et al. 

2002; Szyszkowicz 2007; 

von Klot et al. 2005 

3. HEALTH EFFECTS 26
 

 

 

 

 

 

 

Table 3-1. Carbon Monoxide Exposures and Carboxyhemoglobin Levels Associated with Health Effects from Selected 

Studies Representing the Lowest Adverse Effect Levels 

Exposure COHb 

Study type Subjects (ppm) (%) Effect Comments Reference 

CARBON MONOXIDE

Animal study, Rats	 200 NR Cardiomegaly Left and right ventricle weights 

chronic exposure	 (20 hours/ increased by 20% (p<0.001) and 14% 

day, (p<0.001). 

72 weeks) 

Neurological 

Clinical, acute Healthy adults	 NR 5–20 Neurobehavioral/cognitive Visual and auditory sensory effects 

exposure changes	 (decreased visual tracking, visual and 

auditory vigilance, visual perception), 

fine and sensorimotor performance, 

cognitive effects (altered time 

discrimination, learning, attention level, 

driving performance), and brain 

electrical activity. 

Clinical, acute Carbon monoxide- NR 40–60 Neurological impairment Acute and delayed onset neurological 

exposure poisoned humans and pathology	 impairment (headache, dizziness, 

drowsiness, weakness, nausea, 

vomiting, confusion, disorientation, 

irritability, visual disturbances, 

convulsions, and coma) and pathology 

(basal ganglia legions). 

Animal study, Rats	 500–1,500 Neurosensory impairment Potentiates noise-induced hearing 

acute exposure	 loss, including noise-induced elevation 

of compound action potential threshold 

and auditory threshold shifts. 

Sørhaug et al. 2006 

Beningnus et al. 1994 

Chambers et al. 2008; 

Dolan 1985; Ernst and 

Zibrak 1998; Hopkins et 

al. 2006; Kao and 

Nañagas 2006; Lo et al. 

2007; Parkinson et al. 

2002; Raub and 

Benignus 2002 

Chen and Fechter 1999; 

Fechter et al. 1988; 

Young et al. 1987 

3. HEALTH EFFECTS 27
 

 

 

Table 3-1. Carbon Monoxide Exposures and Carboxyhemoglobin Levels Associated with Health Effects from Selected 

Studies Representing the Lowest Adverse Effect Levels 

Study type Subjects 

Exposure 

(ppm) 

COHb 

(%) Effect Comments Reference 

Developmental 

Animal study, 

acute exposure 

Neonatal rats 

(exposed postutero) 

12–25 NR Neurosensory 

development 

Morphological changes in the 

developing auditory system, decreased 

8th cranial nerve action potentials, and 

otoacoustic emissions in pups, which 

persisted to age 73 days. 

Lopez et al. 2003, 2008; 

Stockard-Sullivan et al. 

2003; Webber et al. 2003 

Animal study, 

acute exposure 

Neonatal rats or 

mice (exposed in 

utero) 

60–150 Neurosensory/ 

neurobehavioral 

development 

Decreased motor activity and response 

to stimulation, impaired righting 

reflexes, and impaired homing and 

memory acquisition behaviors. 

De Salvia et al. 1995; 

Fechter and Annau 1977, 

1980; Giustino et al. 

1999; Mactutus and 

Fechter 1985; Singh 

1986 

CARBON MONOXIDE

COHb = blood carboxyhemoglobin; NR = not reported 

3. HEALTH EFFECTS 28
 

 

CARBON MONOXIDE 29 

3. HEALTH EFFECTS 

Table 3-2. Predicted Steady-State Blood Carboxyhemoglobin (COHb) Levelsa 

Carbon monoxide exposure concentration (ppm) Steady-state blood COHb (percent) 

0.1 0.25 

0.5 0.32 

1 0.39 

2 0.50 

5 1.0 

10 1.8 

15 2.5 

20 3.2 

40 6.1 

60 8.7 

80 11 

100 14 

200 24 

400 38 

600 48 

800 56 

1,000 61 

a

Blood COHb levels are predicted from the Coburn-Forster-Kane (CFK) model (see Section 3.4.5 for a discussion of 

model and parameter values). 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 30 

3. HEALTH EFFECTS 

The discussion of health effects has been limited to the inhalation exposure pathway. Carbon monoxide 

exists in the environment as a gas (Henry’s law constant >50,000 atm/mol fraction, 25 °C). As a result, 

humans can be exposed to carbon monoxide from breathing and/or contact with carbon monoxide in air. 

No information is available on the dermal absorption or toxicity of carbon monoxide resulting from 

exposures to gaseous carbon monoxide. However, as is the case for other gases that are avidly absorbed 

from the lung during inhalation (e.g., O2), dermal absorption of carbon monoxide through intact skin 

would be expected to make a substantially minor contribution to absorbed carbon monoxide, relative to 

inhalation. No information is available on the absorption or toxicity of carbon monoxide resulting from 

oral exposures to gaseous carbon monoxide. Although carbon monoxide can dissolve in water (23 mL 

carbon monoxide/L water, 20 °C), appreciable concentrations in drinking water would occur only at very 

high partial pressures of carbon monoxide in air, conditions in which inhalation would be the dominant 

absorption pathway. Therefore, the only relevant pathway of exposure to humans is the inhalation 

pathway, and oral and dermal exposures are not considered further. 

3.2 DISCUSSION OF HEALTH EFFECTS 

This section of the Toxicological Profile summarizes results obtained from clinical cases of carbon 

monoxide poisoning, studies of controlled exposures conducted in humans, epidemiological studies of 

health outcomes associated with ambient air carbon monoxide concentrations, and experimental studies 

conducted in various animal models. Reported clinical studies are limited to exposures of acute duration. 

Animal studies have examined longer-duration exposures. Epidemiological studies have examined 

outcomes in the context of chronic exposures or acute variations in exposure concentrations that occur 

during chronic exposures. Some studies (e.g., clinical studies) have reported carbon monoxide doses in 

terms of blood COHb levels, while most epidemiological studies and some animal studies have reported 

exposure concentrations (e.g., ppm, mg/m3

). For comparability to human clinical studies, reported air 

carbon monoxide concentrations can be converted to corresponding equivalent steady-state COHb% 

values (i.e., the COHb% that would be achieved with continuous exposure to the reported air carbon 

monoxide concentration) through a model. This conversion has been made by application of the CFK 

model (see Section 3.4.5). Predicted steady-state blood COHb levels corresponding to a range of carbon 

monoxide exposure concentrations are presented in Table 3-2. This table can be used to convert the 

reported ambient air carbon monoxide concentrations into equivalent predicted blood COHb levels. 

Exposure concentrations are typically reported in units of ppm or mg/m3

; in the Toxicological Profile, 

exposure units are presented in units of ppmv (indicated as ppm). At standard temperature and pressure 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 31 

3. HEALTH EFFECTS 

(e.g., 25 °C, 760 Torr), the conversion factor is approximately 1 (i.e., 1 mg/m3≈0.87 ppm, 

1 ppm≈1.15 mg/m3

). 

Overview of Acute Carbon Monoxide Toxicity and Modes of Action. Carbon monoxide exerts effects on 

cell metabolism through both hypoxic and non-hypoxic mechanisms. Both types of effects are thought to 

be largely (but not entirely) the result of the ability of carbon monoxide to bind to heme and alter function 

and/or metabolism of heme proteins. The binding affinity of carbon monoxide for hemoglobin is over 

200 times greater than that of the affinity of oxygen for hemoglobin (Chakraborty et al. 2004). Formation 

of COHb decreases the O2 carrying capacity of blood and impairs release of O2 from Hb for its utilization 

in tissues. Through similar mechanisms, carbon monoxide decreases O2 storage in muscle cells by 

binding to, and displacing O2 from, myoglobin. Although all tissues are vulnerable to carbon monoxideinduced hypoxic injury, those having the highest O2 demand are particularly vulnerable, including the 

brain and heart. The developing fetus may also be a sensitive target of carbon monoxide, through 

hypoxic and/or non-hypoxic mechanisms (Carratu et al. 1993, 2000a, 2000b; De Salvia et al. 1995; Lopez 

et al. 2003, 2008; Stockard-Sullivan et al. 2003; Webber et al. 2003). 

Acute carbon monoxide poisoning is largely the result of tissue hypoxia. Signs and symptoms of carbon 

monoxide toxicity, in order of increasing severity include: (1) headache, nausea, dilation of cutaneous 

vasculature, vomiting, dizziness, and blurred vision; (2) confusion, syncope, chest pain, dyspnea, 

weakness, tachycardia, and tachypnea rhabdomyolysis; and (3) palpitations, cardiac dysrhythmias, 

hypotension, myocardial ischemia, cardiac arrest, respiratory arrest, pulmonary edema, seizures, and 

coma (Kao and Nañagas 2006). Although binding of carbon monoxide to blood Hb is a primary 

component of the hypoxic mode of action of carbon monoxide, blood COHb levels have not been shown 

to be a reliable predictor of severity of acute toxicity, in part due to time elapsed from removal from 

carbon monoxide exposure to COHb measurement and to the effects of emergency medical intervention 

(i.e., treatment with oxygen) on COHb levels prior to COHb measurement (Hampson and Hauff 2008). 

In general, typical levels of COHb in nonsmokers are <2% (Adams et al. 1988; Allred et al. 1991; 

Anderson et al. 1973; Hinderliter et al. 1989; Kleinman et al. 1989, 1998; Sheps et al. 1987, 1990). Of 

this, approximately 0.2–1.0% is derived from endogenous production of carbon monoxide (Coburn et al. 

1963; Delivoria-Papadopoulos et al. 1974; Longo 1977). Levels ranging from 2 to 6% have been shown 

to exacerbate underlying cardiovascular disease, including enhanced myocardial ischemia and increased 

cardiac arrhythmias (Adams et al. 1988; Allred et al. 1989, 1991; Anderson et al. 1973; Kleinman et al. 

1989, 1998; Leaf and Kleinman 1996b). In general, signs and symptoms of acute carbon monoxide 

poisoning can present at COHb levels ranging from 3 to 24% (Hampson and Hauff 2008; Kao and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 32 

3. HEALTH EFFECTS 

Nañagas 2006). This level overlaps with levels found immediately following cigarette smoking, up to 

approximately 10% (Kao and Nañagas 2006). More severe signs of carbon monoxide poisoning are 

poorly correlated with blood COHb, with loss of consciousness occurring at a mean level of 24.3% 

(range: 2–70%; Hampson and Hauff 2008) and fatality at a mean level of 32.1% (range: 3.0–60%; 

Hampson and Hauff 2008). Exposures that result in COHb levels >50% are frequently fatal (Dolan 

1985). Persistent neurologic sequelae, which can be delayed in onset, can also occur, including memory 

loss, impairments of concentration and language, affective disorders (e.g., depression), and Parkinsonism 

(Choi 2002; Klawans et al. 1982; Ringel and Klawans 1972), some of which may be related to pathologic 

changes in the brain (Gorman et al. 2003; Lo et al. 2007). 

Most of the non-hypoxic mechanisms of action of carbon monoxide have been attributed to binding of 

carbon monoxide to heme in proteins other than Hb. Notable targets of carbon monoxide include 

components of several important physiological regulatory systems, such as brain and muscle oxygen 

storage and utilization (myoglobin, neuroglobin); nitric oxide cell signaling pathway (e.g., nitric oxide 

synthase, guanylyl cyclase); prostaglandin cell signaling pathway (cyclooxygenase, prostaglandin H 

synthase); energy metabolism and mitochondrial respiration (cytochrome c oxidase, cytochrome c, 

NADPH oxidase); steroid and drug metabolism (cytochrome P450), cellular redox balance, and ROS 

(catalase, peroxidases); and various transcription factors (e.g., neuronal PAS domain protein, NPAS2, 

implicated in regulation of circadian rhythm). Endogenously produced carbon monoxide may participate 

in the physiological regulation of some, if not all, of these systems. This has potentially important 

implications for the understanding of carbon monoxide toxicology and dose-response relationships for the 

following reasons: (1) carbon monoxide modulation of physiological processes may underlie some 

aspects of the toxicity of exogenous carbon monoxide; (2) exogenous carbon monoxide may disrupt 

physiological regulation of those systems that are responsive to endogenous carbon monoxide (e.g., 

vascular resistance); and (3) exposures to exogenous carbon monoxide may affect carbon monoxidemediated physiological responses at levels that approach those resulting from endogenous production. 

One implication of this is that the dose threshold for effects of exogenous carbon monoxide on carbon 

monoxide-modulated physiological systems may lie near or below ambient air carbon monoxide 

concentrations. 

Epidemiological Studies. Epidemiological studies of health outcomes associated with exposure to carbon 

monoxide fall into two major categories. Some studies have examined relationships between long-term 

average ambient air carbon monoxide concentrations and health outcomes, where the air carbon 

monoxide concentrations represent averages over years or decades. Other studies have examined 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 33 

3. HEALTH EFFECTS 

associations between outcomes and air concentrations measured over relatively narrow time slices (e.g., 

1–24-hour average or maxima). These short-term studies are particularly suited to outcomes that might 

be related to short-term elevations in carbon monoxide exposure in close temporal proximity to the 

outcome of interest, which might otherwise be lost in longer-term average carbon monoxide 

concentrations (e.g., change in heart rate, heart rate variability, arrhythmia). End points that have been 

assessed in epidemiological studies include mortality, morbidly, and rates of medical assistance. 

Examples of the latter category include rates of hospital admissions or emergency room visits recorded to 

have been prompted by a given morbidity outcome, rates of activation of recorded activation of 

implantable cardioverter defibrillator (ICD) devices, and rates of rescue medication use by asthmatics. 

These studies are typically conducted using time-series analysis and Poisson regression models for 

estimated associations between carbon monoxide concentrations and outcome rates. Case-crossover 

designs have also been widely applied in air pollution epidemiology. This design offers many of the 

advantages of the case-control design (e.g., matching of individual cases and controls for potential covariables and confounders), with the additional feature of each case serving as its own control, with each 

case assigned a case exposure period, usually within a few days of the outcome measurement, and a 

control exposure period, usually some time before or after the case exposure period. Another widely 

reported design in assessment of morbidity is the panel study in which members of the study cohort, 

usually a relatively small sample, are followed individually with respect to exposures and outcomes. Also 

reported are case-control studies, retrospective and cross-sectional cohort studies, and a few prospective 

studies of mortality. 

Several important features of the epidemiological studies of ambient air carbon monoxide are of generic 

relevance to public health assessments. In particular, their utility for establishing dose-response 

relationships is limited by several factors: 

(1) Nearly all studies have relied on area monitoring for estimating exposure levels; this has the 

potential to produce errors in assigning exposure levels to individuals. 

(2) The temporal correspondence between monitored exposure levels and outcomes is highly 

uncertain. Outcomes that might be related to carbon monoxide exposure might occur in response 

to short-term elevations in carbon monoxide concentrations not captured in air monitoring data 

that are averaged over longer time periods (e.g., 24-hour average). Also, outcomes associated 

with a given exposure may have a latency period (e.g., myocardial infarction may occur days 

after the exposure that initiated the event). One approach to this problem has been to apply timeseries techniques to quantify air concentration trends and to explore lag times between exposure 

concentration trends and the time of outcome. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 34 

3. HEALTH EFFECTS 

(3) Ambient air carbon monoxide concentrations tend to be strongly correlated with other air quality 

variables that can affect cardiovascular function, either directly or indirectly (e.g., through effects 

on the respiratory tract). Typical variables that correlate with air carbon monoxide concentrations 

include particulate matter (e.g., total suspended particulates, PM10, PM2.5), NO2, O3, and SO2. 

Ignoring co-variables that contribute to risk in regression models (e.g., single-pollutant models) 

can introduce upward bias in observed associations between air carbon monoxide concentrations 

and outcomes (e.g., inflate relative risk). On the other hand, assuming that strongly correlated covariables are independent in multi-pollutant models can introduce downward bias in the carbon 

monoxide association. Although the strength of the carbon monoxide association may be 

underestimated in multi-pollutant models, for the reasons noted above, persistence of significant 

associations between the measured outcome and air carbon monoxide concentrations, when copollutants are accounted for in multivariate models, provides stronger support for a contribution 

of carbon monoxide to the outcome. Not all studies have explored multi-pollutant models; 

however, such models lend supporting evidence to the results of clinical studies that have shown 

carbon monoxide to exacerbate coronary vascular disease. 

(4) Outcomes investigated have tended to be serious, life-threatening events (e.g., cardiac arrhythmia, 

myocardial infarction, stroke, heart failure); these outcomes reflect the “late-stage” consequences 

of contributing pathophysiology that might be associated with exposures to lower levels of carbon 

monoxide for longer durations than indicated in the epidemiological studies. 

(5) Mean values of carbon monoxide exposure concentrations have ranged from 0.3 to 5 ppm, with 

the highest values ≤30 ppm. These values correspond to predicted steady-state COHb levels of 

<1% for the mean and <5% for the highest values (predicted from the CFK model). At these 

COHb levels, it is possible that only highly susceptible individuals exhibit the serious hypoxiarelated outcomes. For these and other reasons, epidemiologic studies have typically focused on 

highly susceptible populations. A typical design has been to examine associations between 

temporal trends in ambient air carbon monoxide concentrations and hospital admissions or 

emergency department visits for which the reported diagnosis was some form of cardiovascular 

and/or respiratory disease of impairment. 

3.2.1 Death 

The Centers of Disease Control and Prevention (CDC) estimated that during the period 1999–2004, 

carbon monoxide was listed as a contributing cause of death on 16,447 death certificates in the United 

States, of which 2,631 deaths were categorized as unintentional and unrelated to fires (CDC 2007). 

Typically, fatal exposures to carbon monoxide produce coma, convulsions, and cardiorespiratory arrest 

(Raub et al. 2000; Wolf et al. 2008). Symptoms preceding death can include headache, dizziness, 

weakness, nausea, vomiting, mental confusion, visual disturbances, and loss of consciousness (Choi 2001; 

Raub et al. 2000). Clinical signs of life-threatening toxicity can include cardiac arrhythmia and 

myocardial ischemia, hypotension, pulmonary edema, and seizures (Kao and Nañagas 2006). Patients 

who have been resuscitated following carbon monoxide-induced cardiac arrest have a very low prognosis 

for survival (Hampson and Zmaeff 2001). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 35 

3. HEALTH EFFECTS 

Although severe carbon monoxide toxicity is thought to primarily derive from hypoxia resulting from 

binding to, and displacement of, O2 from heme proteins, including blood Hb, the relationship between 

blood COHb levels and signs indicative of life-threatening toxicity is highly uncertain (e.g., loss of 

consciousness, convulsions, coma, cardiopulmonary depression). In a survey of 1,407 cases of acute 

carbon monoxide poisoning patients (i.e., record of history of carbon monoxide exposure, signs and 

symptoms, blood COHb >2%, treatment with hyperbaric O2), the mean blood COHb concentration was 

22.3% (95% confidence interval [CI]: 22.7, 23.9, range: 2.1–72.3; Hampson and Hauff 2008). The 

group mean was only marginally lower than in patients who lost consciousness (24.3%, 95% CI: 23.3, 

25.1, range: 2.1–73.3) or died (32.1%, 95% CI: 27.9, 36.4, range: 3.0–60.0). Although survivors had 

lower mean COHb levels (23.1, 95% CI: 22.5, 23.6) than that of fatalities, the upper end of the range 

exceeded that of fatalities (2.1–72.3%). The lower end of the range for COHb levels (2.1%) in this study 

reflects, at least in part, time delays between termination of exposure and measurement of blood COHb 

levels. However, that notwithstanding, this study suggests that blood COHb levels do not provide a 

reliable predictor of lethality. COHb levels can be converted to estimates of corresponding continuous air 

exposure levels by application of the CFK model. The mean for fatalities (32.1%) corresponds to a 

steady-state exposure (e.g., >500 minutes) to 300 ppm, or exposure to 1,000 ppm for approximately 80– 

90 minutes. 

Epidemiological Studies. Epidemiological studies have examined possible associations between ambient 

air carbon monoxide concentrations and mortality. These studies have examined relatively low carbon 

monoxide concentrations (from a toxicological perspective) that are typical of ambient conditions of the 

study period. Mean air carbon monoxide concentrations in most of the studies were <2 ppm, with highest 

values ≤10 ppm. Epidemiologic studies of ambient carbon monoxide and mortality can be grouped into 

two categories: (1) studies that have examined the relationship between exposures to carbon monoxide 

estimated from short-term (e.g., daily or monthly average) ambient air carbon monoxide concentrations; 

and (2) studies that have based exposure estimates on long-term average air carbon monoxide 

concentrations. Although both types of studies have yielded mixed results, the larger, multi-city studies 

of long-term exposure have yielded estimates of carbon monoxide-associated mortality risk that are zero 

or less than zero (Jerrett et al. 2003; Lipfert et al. 2006b; Miller et al. 2007; Pope et al. 2002). Results 

from short-term exposure studies have been more varied, with some studies showing increased mortality 

risk when carbon monoxide is considered in single-pollutant models (percent increase in mortality: 0.2– 

0.6), which did not persist when the models were adjusted for co-pollutants (Burnett et al. 2004; Dominici 

et al. 2003a, 2003b; Samoli et al. 2007). This conclusion is supported by at least one meta-analysis of 

time-series published between 1985 and 2001 (Stieb et al. 2002), which estimated excess mortality risk 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 36 

3. HEALTH EFFECTS 

(pooled meta estimate) for a 1.1 ppm increment in air carbon monoxide concentration to be 1.6 (95% CI: 

1.1, 2.1) based on a single-pollutant model and 0.7% (95% CI: -0.1, 1.5), based on a multi-pollutant 

model that included NO2, O3, PM10, and SO2 (both estimates from generalized additive model regression 

models). A study of survival among 1,073 carbon monoxide poisoning patients (followed from 1978 to 

2005) found that survivors of carbon monoxide poisoning had an increased mortality (standardized 

mortality ratio [SMR]=1.9) (95% CI: 1.6, 2.2; NIOSH Life Table analysis as reference; Hampson et al. 

2009; Leikin and Wills 2009). 

While these studies provide some evidence in support of a mortality risk associated with inhalation 

exposures to carbon monoxide, as previously discussed in the introduction to Section 3.2, their utility for 

establishing dose-response relationships for these effects are limited by several factors: (1) reliance on 

area monitoring for estimating exposure levels; and (2) relatively strong correlations between ambient air 

carbon monoxide concentrations and other air quality variables that may contribute to mortality risk. The 

discussion presented below focuses on outcomes of the most recent follow-ups of larger (e.g., multi-city) 

studies. Numerous single-city studies have also been reported; however, results of these studies are, in 

general, consistent with findings of multi-city studies. 

Three multi-city prospective mortality studies have examined possible associations between long-term 

average ambient air carbon monoxide concentrations and mortality. A prospective study examined 

mortality in a cohort of 552,138 adults in 151 U.S. metropolitan areas, enrolled in the study in 1982 and 

followed through 1998 (Pope et al. 1995, 2002). Based on estimated average ambient air carbon 

monoxide concentration during the period 1982–1998, relative risks for mortality per 1 ppm increase in 

carbon monoxide concentration (estimated from Figure 5 of Pope et al. 2002) were approximately 

0.97 (95% CI: 0.93, 1.0) for all causes of death, 0.95 (95% CI: 0.88, 0.99) for cardiopulmonary death, 

and 0.90 (95% CI: 0.83, 0.96) for lung cancer death. A reanalysis of data from the same study included a 

more extensive treatment of covariables. The relative risk for death from all causes was estimated to be 

approximately 0.98 (95% CI: 0.92, 1.03) for an increase in ambient carbon monoxide concentration from 

0.19 to 3.95 ppm (Jerrett et al. 2003). A smaller prospective study focused on cardiovascular deaths 

among postmenopausal women between the ages of 50 and 79 years (Miller et al. 2007). Women 

(n=65,893) without previous history of cardiovascular disease were enrolled in the study from 36 U.S. 

metropolitan areas during the period 1994–1998, and deaths were recorded up to mid-2003. Among the 

subset of the cohort that had complete data on ambient air pollutant levels from local monitoring stations 

(n=28,402), the hazard ratio for cardiovascular mortality was 0.92 (95% CI: 0.71, 1.21) per 1 ppm 

increase in ambient air carbon monoxide concentration based on a single-pollutant model and 0.93 (95% 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 37 

3. HEALTH EFFECTS 

CI: 0.67, 1.30) based on a multi-pollutant model that adjusted for air concentrations of NO2, O3, PM2.5, 

PM10, and SO2. A prospective study of U.S. military veterans examined mortality outcomes in 

approximately 70,000 males who had been diagnosed with hypertension (Lipfert et al. 2000, 2006a, 

2006b). Subjects were enrolled in the study in 1976 at the average age of 51 years and were followed 

through 2001 (Lipfert et al. 2006a). Mortality risk (all causes of death) was not significantly associated 

with ambient air carbon monoxide concentration. The relative risk was estimated to be 1.032 (95% CI: 

0.954, 1.117) per 1 ppm increase in air carbon monoxide concentration based on a single-pollutant model 

and 1.023 (95% CI: 0.939, 1.115) after adjustment for NO2 and O3. 

A multi-city, cross-sectional study examined mortality in all U.S. counties (excluding those of Alaska) for 

the period 1969–1997 (Lipfert and Morris 2002). Risk estimates were made for various exposure periods 

ranging from 2 to 9 years and for age categories. Estimates of mortality risk (all causes) attributable to 

average ambient air carbon monoxide concentrations for the exposure periods were mostly either not 

significant or significantly negative. Elevated risk was observed in some exposure periods for the age 

group 15–44 years; however, this outcome was not consistently observed across time periods. 

Several multi-city studies have found significant associations between increasing short-term average 

ambient air carbon monoxide concentration and increasing mortality risk when carbon monoxide is 

considered in single-pollutant models, with the associations attenuated when models were adjusted for 

other co-pollutants. A time-series study examined mortality in 82 U.S. cities during the period 1987– 

1994 (Dominici et al. 2003b; HEI 2005; Samet et al. 2000). In the Dominici et al. (2003b) analysis of 

these data, a 1 ppm increase in ambient air carbon monoxide concentration (lag 1 day) was associated 

with increased mortality (from all causes) of 0.46% (95% CI: 0.18, 0.73). Mortality risk was not 

significant after adjustment for air concentration of PM10 alone or for PM10 and NO2. A time-series study 

examined morality in 12 Canadian cities during the period 1987–1994 (Burnett et al. 2004). Mortality 

risk (all non-accidental causes) was significantly associated with ambient air carbon monoxide 

concentration (lag 1 day) in single-pollutant models, with an increase of 0.68% (t=3.12) per 1.02 ppm 

increases in air carbon monoxide concentration. However, the association did not persist when adjusted 

for NO2 (0.07%, t=0.30). A time-series analysis examined mortality in 19 European cities during the 

period 1990–1997 (Samoli et al. 2007). This study found a significant association between carbon 

monoxide and total non-accidental and cardiovascular mortality in single-pollutant models. The 

estimated effect size varied depending on the model applied. The effect size for total mortality based on a 

single-pollutant model ranged from 0.59% increase (95% CI: 0.41, 1.79) to 1.20% (95% CI: 0.63, 1.77) 

per 1 mg/m3

 increase in carbon monoxide concentration (0–1-day lag). The effect on cardiovascular 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 38 

3. HEALTH EFFECTS 

mortality ranged from 0.8% increase (95% CI: 0.53, 1.07) to 1.25 (95% CI: 0.30, 2.21). Inclusion of 

black smoke or NO2 in the models substantially decreased the estimated risk attributable to carbon 

monoxide, with the effect sizes no longer significant in some models. 

3.2.2 Systemic Effects 

Respiratory Effects. Although cardiopulmonary arrest is an end point of fatal carbon monoxide 

poisoning, results of controlled clinical studies in healthy subjects indicate that the respiratory tract does 

not appear to be a primary target organ for carbon monoxide toxicity. Brief exposure to carbon monoxide 

at levels >1,000 ppm may decrease ventilatory performance, although conflicting results have been 

reported (Chevalier et al. 1966; Fisher et al. 1969; Koike et al. 1991; Ren et al. 2001; Vesely et al. 2004). 

Epidemiological studies have examined possible associations between ambient air carbon monoxide 

concentrations and mortality. These studies have examined relatively low carbon monoxide 

concentrations (from a toxicological perspective) that are typical of ambient conditions of the study 

period (mean concentrations ranging from 0.3 to 10 ppm with the highest values ≤30 ppm). Collectively, 

these studies have yielded mixed results, with some studies finding significant associations between 

increasing ambient air carbon monoxide concentrations and respiratory outcomes (e.g., exacerbation of 

asthma symptoms, hospitalizations and emergency room visits related to asthma) and few studies finding 

associations that persist after accounting for exposures to other air pollutants that also have been shown to 

contribute to respiratory disease risk (e.g., NO2, O3, particulate matter, and SO2). The lack of strong 

evidence for associations between ambient air carbon monoxide concentrations at <30 ppm and 

pulmonary function is also consistent with the results of human clinical and animal studies. Studies 

conducted in animals provide supporting evidence that the respiratory tract does not appear to be a 

primary target organ for carbon monoxide (EPA 1991, 2000; Sørhaug et al. 2006). 

Clinical Studies. Few controlled clinical studies have evaluated adverse respiratory effects of carbon 

monoxide exposure. Available clinical studies have been conducted in small numbers (i.e., 4–12) of 

healthy subjects under acute exposure conditions (Chevalier et al. 1966; Fisher et al. 1969; Koike et al. 

1991; Ren et al. 2001; Vesely et al. 2004). No controlled clinical studies evaluating respiratory effects of 

intermediate- or chronic-duration exposure in healthy subjects or of any duration exposure in patients 

with underlying respiratory diseases were identified. 

Results of controlled clinical studies in healthy subjects indicate that brief exposure to carbon monoxide 

may decrease ventilatory performance, although conflicting results have been reported; however, based 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 39 

3. HEALTH EFFECTS 

on results of available clinical studies, the respiratory tract does not appear to be a major target organ for 

carbon monoxide. Exposure of 10 healthy subjects to 5,000 ppm carbon monoxide for 2–4 minutes 

(COHb 4%) decreased inspiratory capacity by 7.5% (p<0.05), total lung capacity by 2.1% (p<0.02), and 

mean resting diffusing capacity of lungs by 7.6% (p<0.05) (Chevalier et al. 1966). However, other 

studies have found no effects of acute carbon monoxide exposure on ventilatory function. No changes in 

ventilatory mechanics (vital capacity, functional residual capacity, airway conductance, lung volume, 

pulmonary resistance, dynamic lung compliance, diffusing capacity) were observed in four healthy 

subjects exposed to carbon monoxide producing blood COHb levels of 11–20% (Fisher et al. 1969). 

Exposure to 1,000 ppm carbon monoxide for 10–30 minutes (COHb ~10%; 10 subjects) (Ren et al. 2001) 

or 1,200 ppm carbon monoxide for 30–45 minutes (COHb 10.2%; 10 subjects) (Vesely et al. 2004) did 

not affect resting ventilation. During submaximal exercise challenge, acute exposure of 10 subjects to 

carbon monoxide producing blood COHb levels of 11–20% did not alter ventilation mechanics (Koike et 

al. 1991). The reason for these conflicting results is not apparent, although the small number of subjects 

evaluated in each study may have been a contributing factor. 

Epidemiological Studies. Epidemiological studies of exposure to carbon monoxide and respiratory 

outcomes fall into two major categories: (1) studies that have assessed respiratory morbidity in 

association with ambient air carbon monoxide concentrations; and (2) studies that have evaluated 

associations between ambient air carbon monoxide concentrations and the incidence of hospital 

admissions and/or emergency room visits related to respiratory disease (e.g., time-series studies, casecrossover). Collectively, these studies have yielded mixed results. Although some studies found 

significant associations between increasing ambient air carbon monoxide concentrations and respiratory 

outcomes (e.g., exacerbation of asthma symptoms, hospitalizations and emergency room visits related to 

asthma), few studies examined the robustness of the association in models that adjust for exposures to 

other air pollutants that also have been shown to contribute to respiratory disease risk (e.g., NO2, O3, 

particulate matter, and SO2). While these studies provide some evidence in support of adverse respiratory 

effects of inhalation exposures to carbon monoxide, as previously discussed in the introduction to 

Section 3.2, their utility for establishing dose-response relationships for these effects are limited by 

several factors: (1) reliance on area monitoring for estimating exposure levels; (2) uncertainty in 

knowledge of temporal correspondence between monitored exposure levels and outcomes; (3) relatively 

strong correlations between ambient air carbon monoxide concentrations and other air quality variables 

that can affect respiratory function; and (4) relatively low carbon monoxide exposures studied. Mean 

values of carbon monoxide exposure concentrations have ranged from 0.3 to 10 ppm, with the highest 

values ≤30 ppm. These concentrations are well below those explored in experimental studies that found 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 40 

3. HEALTH EFFECTS 

minimal or no effects of carbon monoxide on pulmonary function in association with acute exposures to 

carbon monoxide (i.e., ≥1,000 ppm). The relatively low carbon monoxide concentrations studied in 

epidemiological studies, together with concurrent exposures to other air pollutants that may have more 

pronounced effects on respiratory function, may have contributed to the mixed results of these studies and 

relatively weak associations with carbon monoxide that have been observed (e.g., odds ratios and relative 

risks very close to 1). The lack of strong evidence for associations between ambient air carbon monoxide 

concentrations at <30 ppm and pulmonary function is also consistent with the results of human clinical 

and animal studies. 

The presentation of epidemiology is organized by major categories of respiratory outcomes for which the 

studies were designed to evaluate, including pulmonary function, asthma and exacerbation of asthma 

symptoms, and hospital admissions and emergency room visits related to respiratory disease. Study 

conclusions are presented in the text, with selected supporting details presented in tabular form 

(Table 3-3). Although most studies explored various time lags between monitored air carbon monoxide 

concentrations and outcomes, as well as various sample strata, for the sake of brevity, only selected 

representative time lags (usually, those indicative of the strongest associations to carbon monoxide) are 

presented in the table. Where co-pollutant models have been explored, these results are also presented. 

Studies of Pulmonary Function. Studies of possible associations between inhalation exposures to carbon 

monoxide and effects on pulmonary function have yielded mixed results (Chen et al. 1999; Fischer et al. 

2002; Lagorio et al. 2006; Penttinen et al. 2001; Rabinovitch et al. 2004; Silkoff et al. 2005; Timonen et 

al. 2002). Several of these studies examined subjects who had ongoing lung disease (e.g., asthma, chronic 

obstructive lung disease) and who might be more sensitive to agents that affect pulmonary function 

(Canova et al. 2010; Rabinovitch et al. 2004; Silkoff et al. 2005; Timonen et al. 2002). Mean ambient air 

carbon monoxide concentrations in these studies ranged from 0.5 to 10 ppm, with the highest values 

≤30 ppm (Lagorio et al. 2006). Studies that explored multi-pollutant models found that the association 

with carbon monoxide persisted (Canova et al. 2010) or was substantially weakened when adjustments 

were made for air particle matter (Penttinen et al. 2001). Therefore, is it difficult to sort out the effects of 

carbon monoxide from those of other urban air pollutants that have strong correlations with air carbon 

monoxide concentrations and that also could have affected pulmonary function. 

Studies of children have yielded mixed results that are further complicated by lack of assessment of 

models in which correlated concentrations of other air pollutants were included (Chen et al. 1999; Fischer 

et al. 2002; Rabinovitch et al. 2004; Timonen et al. 2002). A study conducted in the San Joaquin Valley, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Lung function 

Canova et al. 2010 

Period: 2004–2005 

Location: Padua, Italy 

Chen et al. 1999 

Period: 1995–1996
 

Location: Taiwan 

Fischer et al. 2002 

Period: NR 

Location: Utrecht, Netherlands 

Lagorio et al. 2006
 

Period: 1999 

Location: Rome, Italy
 

Park et al. 2005a 

Period: 2002 

Location: Incheon, Korea 

Outcome: Lung function (PEF, 

FEV1)
 

Design: Panel
 

Sample: n=40 chronic asthmatics
 

(n=19 followed for 2 years), age 15–
 

44 years
 

Outcome: Lung function (FVC,
 

FEV1, FEV1/FVC, FEF25–75%, PEF)
 

Design: Cross-sectional
 

Sample: n=941, age 8–13 years
 

Outcome: Lung function (FVC,
 

FEV1, PEF, MMEF) 

Design: Panel study
 

Sample: n=68, age 10–11 years
 

Outcome: Lung function (FVC,
 

FEV1) 

Design: Time-series panel study
 

Sample: Patients (age 50–
 

80 years) diagnosed with COPD
 

n=11; asthma, n=11; IHD, n=7
 

Outcome: Lung function (PEF
 

variability (>20%), mean PEF);
 

Design: Panel
 

Sample: n=64 bronchial
 

asthmatics, age 16–75 years
 

Avg time: 8 hours 

Median: 1.72 mg/m3 

Range: 0.6–5.2 mg/m3 

Avg time: 1 hour maximum 

Range: 0.4–3.6 ppm 

Avg time: 24 hours 

Mean: 0.80 ppm 

Range: 0.28–1,34 ppm 

Avg time: 24 hours 

Mean: 6.5 ppm 

Range: 1.4–25.2 ppm 

Avg time: 24 hours 

Mean: 0.6 ppm 

SD range: 0.09–0.15 ppm 

Increment: 1 mg/m3
 

β Coefficient (SE, p, % change); lag 1 day:
 

Morning PEF deviations (L/minute)
 

CO: -8.50 (3.54, 0.02, -2.60)
 

CO+SO2: -8.23 (3.41, 0.02, -2.52)
 

CO+NO2: -8.64 (3.52, 0.01, -2.64)
 

CO+PM10: -10.52 (4.18, 0.01, -3.22)
 

CO+SO2+PM10+NO2: -10.70 (4.15, 0.01, -3.27)
 

Increment: NR 

β Coefficient (SE), lag 2 days for 24 hours avg CO: 

FVC (mL) -147.71 (64.48)
 

FEV1 (mL) -82.42 (60.95)
 

Increment: 100 μg/m3
 

NO% increase (95% CI): 

28.2 (6.9, 53.9) 

No significant associations with lung function end 

points 

Increment: 1 mg/m3 

No significant associations with lung function end 

points 

Increment: NR 

β Coefficient (SE): 

Mean PEF (L/minute): -10.103 (2.7146) 

CARBON MONOXIDE 3. HEALTH EFFECTS 41
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Penttinen et al. 2001 Outcome: Lung function (PEF) Avg time: 24 hours Increment: 0.2 mg/m3 

Period: 1996–1997 Design: Panel Median: 0.35 ppm β Coefficient (SE); lag 1 day: 

Location: Helsinki, Finland Sample: n=57 adult asthmatics Range: 0.09–0.96 ppm PEF deviations (L/minute) 

CO: -1.08 (0.36) 

CO+PNC: -0.67 (0.64); 1 

Mortimer et al. 2008 Outcome: Lung function (FVC, Avg time: 8 hours Increment: ~1 ppm 

Period: 1989–2000 FEV1, PEF, FEF25–75, FEV1/FVC, maximum β Coefficient (SE); 

Location: San Joaquin Valley, FEF25–75/FVC, FEF25, FEF75) Mean: 1–1.5 ppm FEV1/FVC: -0.0073 (0.0016) 

California Design: Cohort Range: maximum ~6 ppm FEF25–75/FVC: -0.2179 (0.0446) 

Sample: n=232 asthmatic children, % Decrease: 

age 6–11 years FEV1/FVC: 2.5% 

FEF25–75/FVC: 4.8% 

Rabinovitch et al. 2004 Outcome: Lung function (FEV1, Avg time: 24 hours Increment: 0.4 ppm 

Period: 1999–2002 PEF) Mean 1.0 ppm No significant associations with lung function end 

Location: Denver, Colorado Design: Panel study Range: 0.3, 3.5 ppm points 

Sample: n=41–63 asthmatics, age 

6–12 years 

Silkoff et al. 2005 Outcome: Lung function (FEV1, Pollutant: CO Increment: 1 ppm 

Period: 1999–2001 PEF) Avg Time: 24 hours Significant association with decreasing FEV1 in 

Location: Denver, Colorado Design: Panel Mean: 1 ppm second winter season of study, but not in first 

Sample: n=16–18, former smokers, Range: 0.3–3.8 ppm (β coefficients reported graphically) 

age ≥40 years 

Timonen et al. 2002 Outcome: Lung function (FVC, Avg time: 24 hours Increment: 0.32 mg/m3 

Period: 1994 FEV1, MMEF, AEFV) Mean: 0.5 ppm β Coefficient (SE), lag 2 days: 

Location: Kuopio, Finland Design: Panel Range: 0.09–2.4 ppm Baseline FEV1 (mL): 11.7 (SE: 5.77, p<0.05) 

Sample: n=33 with respiratory Exercise ΔFEV1 (%): 0.087 (0.26) 

symptoms, age 7–12 years 

CARBON MONOXIDE 3. HEALTH EFFECTS 42
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Asthma and exacerbation of asthma symptoms 

Clark et al. 2010 Outcome: Asthma Avg time: 24 hours 

Period: 1999–2000 Design: Birth cohort case-control Mean: 0.62 mg/m3 

Location: British Columbia, Sample: n=3,248 25th–75th%: 0.52– 

Canada cases,16,240 controls, age birth– 0.71 mg/m3 

5 years 

Hwang et al. 2005 Outcome: Asthma Avg time: 1 year 

Period: 2001 Design: Cross-sectional Mean: 0.66 ppm 

Location: Taiwan Sample: n=32,672, Range: 0.42–0.96 ppm 

age 6–15 years 

Park et al. 2005a Outcome: Asthma symptoms Avg time: 24 hours Increment: NR 

Period: 2002 Design: Panel Mean: 0.6 ppm 

Location: Incheon, Korea Sample: n=64 bronchial SD range: 0.09–0.15 ppm 

asthmatics, age 16–75 years 

Rabinovitch et al. 2004 Outcome: Asthma symptoms, Avg time: 24 hours 

Period: 1999–2002 rescue inhaler use Mean 1.0 ppm 

Location: Denver, Colorado Design: Panel study Range: 0.3–3.5 ppm 

Sample: n=41–63 asthmatics, age 

6–12 years 

Rodriguez et al. 2007 Outcome: Respiratory symptoms Avg time: 8 hours Increment: NR 

Period: 1996–2003 Design: Panel Mean 1.4 ppm 

Location: Perth, Australia Population: n=263, age 0–5 years Range: 0.01–8.0 ppm 

Increment: 0.1 mg/m3
 

Adjusted OR (95% CI)
 

CO (in utero exposure): 1.07 (1.04, 1.11)
 

CO (1st year exposure): 1.10 (1.06, 1.13)
 

Increment: 0.1 ppm
 

Adjusted OR (95% CI)
 

CO: 1.045 (1.017, 1.074)
 

CO+SO2: 1.066 (1.034, 1.099)
 

CO+PM10: 1.079 (1.047, 1.112)
 

CO+O3: 1.063 (1.1, 1.474)
 

CO+SO2+O3: 1.111 (1.074, 1.15)
 

CO+PM10+ O3: 1.119 (1.084, 1.155)
 

No significant association with asthma symptoms
 

Increment: 0.4 ppm
 

β Coefficient (SE), 3-day moving avg:
 

Asthma exacerbation: 1.012 (0.913, 1.123)
 

Rescue inhaler: 1.065 (1.001, 1.133)
 

OR (95%CI), wheeze/chest rattle, lag 5 days: 

lag 0 days: 1.089 (0.968, 1.226)
 

lag 5 days: 1.136 (1.016, 1.26)
 

lag 0–5 days: 1.035 (1.005, 1.066)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 43
 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Schildcrout et al. 2006 Outcome: Asthma symptoms; 

Period: 1993–1995 rescue inhaler use 

Location: 8 North American Design: Panel 

cities Sample: 990 asthmatics, age 5– 

12 years 

Silkoff et al. 2005 Outcome: Asthma symptoms; 

Period: 1999–2001 rescue inhaler use 

Location: Denver, Colorado Design: Panel 

Sample: n=16–18, former smokers, 

age ≥40 years 

Slaughter et al. 2003 Outcome: Asthma severity; 

Period: 1993–1995 medication use 

Location: Seattle, Washington Design: Panel 

Sample: n=133 asthmatics, age 5– 

13 years 

von Klot et al. 2002 Outcome: Asthma symptoms; 

Period 1996–1997 medication use 

Location: Erfurt, Germany Design: Panel 

Sample: 53 asthmatics, age 37– 

77 years 

Yu et al. 2000 Outcome: Asthma symptoms 

Period: 1993–1995 Design: Panel 

Location: Seattle, Washington Sample: n=133 asthmatics, age 5– 

13 years 

Avg time: 24 hours 

10th–90th%: 0.4–2.4 ppm 

Avg time: 24 hours 

Mean: 1 ppm 

Range: 0.3–3.8 ppm 

Avg time: 24 hours 

Median: 1.47 ppm 

25th–75th%: 0.23–1.87 ppm 

Avg time: 24 hours 

Mean: 0.8 ppm 

Range: 0.3–2.3 ppm 

Avg time: 24 hours 

Mean: 1.6 ppm 

Range: 0.65–4.18 ppm 

Increment: 1.0 ppm
 

OR (95% CI), asthma symptoms, lag 0 days: 

CO: 1.08 (1.01, 1.14)
 

CO+NO2 1.07 (1, 1.14)
 

CO+PM10: 1.08 (1.01, 1.15)
 

CO+SO2 1.07 (0.99, 1.16)
 

Increment: 1 ppm
 

No significant associations with asthma symptoms
 

or rescue medications
 

Increment: 0.67 ppm
 

OR (95% CI), asthma severity, lag 1 day: 

Asthma severity: 1.21 (1.08, 1.35)
 

Rescue inhaler use: 1.09 (1.03, 1.16)
 

Increment: 0.6 mg/m3
 

OR (95% CI); wheezing prevalence, 5-day avg: 

CO: 0 1.13 (1.05, 1.22)
 

CO+MC0.01–2.5: 1.15 (1.04, 1.27)
 

CO+NC0.01–0.1: 1.09 (0.98, 1.22)
 

Increment: 1.0 ppm
 

OR (95% CI), lag=2 days: 

1.26 (1.09, 1.46) 

CARBON MONOXIDE 3. HEALTH EFFECTS 44
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Hospital admissions and emergency room visits related to respiratory disease 

Arbex et al. 2009 Outcome: COPD 

Period: 2001–2003 Design: Time series 

Location: São Paulo, Brazil Sample: All ages 

Burnett et al. 2001 Outcome: Asthma, acute 

Period: 1980–1994 bronchitis/bronchiolitis; croup; 

Location: Toronto, Canada pneumonia HAs 

Design: Time series 

Sample: <2 years 

Cakmak et al. 2006 Outcome: Respiratory disease HAs 

Period: 1993–2000 Design: Time-series 

Location: 10 Canadian cities Sample: All ages 

Karr et al. 2006 Outcome: Acute bronchiolitis HAs 

Period: 1995–2000 Design: Case-crossover 

Location: Southern California Sample: Age ≤1 year 

Linn et al. 2000 Outcome: Asthma, COPD, 

Period 1992–1995 pulmonary HAs 

Location: Los Angeles, Design: Time-series 

California Sample: Age 0–29, ≥30 years 

Lin et al. 2003 Outcome: Asthma HAs 

Period: 1981–1993 Design: Case-crossover 

Location: Toronto, Canada Sample: Age 6–12 years 

Lin et al. 2005 Outcome: Respiratory infection 

Period: 1998–2001 HAs 

Location: Toronto, Canada Design: Case-crossover 

Sample: Age <15 years 

Avg time: 8 hours 

Mean: 2.71 ppm 

25th–75th%: 1.9–3.2 ppm 

Avg time: 1 hour 

Mean: 1.18 ppm 

25th–75th%: 1.3–2.3 ppm 

Avg time: 24 hours 

Mean: 0.8 ppm 

Range: 0.0–6.5 ppm 

Avg time: 24 hours 

Mean: 17 ppm 

Range: 0.004–9.6 ppm 

Avg time: 24 hours 

Mean: 1.0–2.1 ppm 

Range: 0.3–5.3 ppm 

Avg time: 24 hours 

Mean: 1.18 ppm 

Range: 0–6.1 ppm 

Avg time: 24 hours 

Mean: 1.16 ppm 

Range: 0.38–2.45 ppm 

Increment: 1.3 ppm
 

% Increase (95% CI), lag 0–6 days:
 

CO: 12.9% (1.3, 25.9)
 

Increment: 1.9 ppm
 

% Increase (t value), lag 0–1 day: 

CO: 19.20% (3.48)
 

CO+O3: 14.30% (2.6)
 

Increment: 0.8 ppm
 

% Increase(95% CI), lag 2.8 days: 

CO: 0.60% (0.20, 1)
 

CO+SO2+NO2+O3: -0.20% (-0.70, 0.30)
 

Increment: 1.36 ppm
 

OR (95% CI), lag 1 day:
 

All: 0.99 (0.96, 1.02)
 

Age 25–29 weeks: 0.86 (0.68, 1.1)
 

Increment: 1.0 ppm
 

β (SE): Asthma, <30 years: 0.036 (0.016, p<0.05)
 

Asthma ≥30 years: 0.028 (0.010, p<0.05) 

COPD, ≥30 years: 0.019 (0.007, p<0.05)
 

Increment: 0.5 ppm
 

OR (95% CI), lag 1 day: 

Males CO: 1.05 (1, 1.11)
 

Males CO+PM: 1.05 (0.99, 1.11)
 

Females CO: 1.00 (0.93, 1.06)
 

Females CO+PM: 1.00 (0.93, 1.07)
 

Increment: 0.44 ppm
 

OR (95% CI), lag 0–5 days:
 

Males, CO: 1.13 (1.02, 1.25)
 

Males, CO+PM: 1.08 (0.97, 1.20)
 

Females, CO: 1.05 (0.93, 1.18)
 

Females, CO+PM: 1.02 (0.90, 1.15)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 45
 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Peel et al. 2005 

Period: 1993–2000 

Location: Atlanta, Georgia 

Slaughter et al. 2005 

Period: 1995–2001 

Location: Spokane, Washington 

Tolbert et al. 2007 

Period: 1993–2004 

Location: Atlanta, Georgia 

Outcome: Asthma; COPD, 

pneumonia EDVs 

Design: Time-series 

Sample: Ages all, 2–18 years 

Outcome: Respiratory, asthma; 

COPD, respiratory infection HAs 

and EDVs 

Design: Time-series 

Sample: All ages, adults 

Outcome: Asthma; COPD; URI, 

pneumonia; bronchiolitis EDVs 

Design: Time-series 

Sample: All ages 

Avg time: 1 hour maximum 

Mean: 1.8 ppm 

10th–90th%: 0.5–3.4 ppm 

Avg time: 24 hours 

5th–95th%: 1.25–3.05 ppm 

Avg time: 1 hour maximum 

Mean: 1.6 ppm 

Range: 0.1–7.7 ppm 

Increment: 1.0 ppm
 

RR (95% CI); lag 0–13 days: 

All respiratory: 1.066 (1.045, 1.087)
 

Asthma: 1.076 (1.047, 1.105)
 

Pneumonia: 1.045 (1.011, 1.080)
 

COPD: 1.032 (0.975, 1.092), 1.026 (1.004, 1.048;
 

lag=0–2 days)
 

No significant associations after adjustment for
 

PM10, NO2, or O3
 

Increment: 1.0 ppm
 

RR (95% CI); lag 3 days: 

Respiratory EDV:1.03 (1.00, 1.06)
 

Asthma EDV: 1.06 (1.00, 1.11)
 

COPD EDV, Adults: 1.01 (0.93, 1.10)
 

Respiratory HA: 0.99 (0.96, 1.03)
 

Asthma HA: 1.00 (0.91, 1.11)
 

COPD HA: Adults: 0.97 (0.88, 1.06)
 

Increment: 1.22 ppm
 

RR (95% CI), lag 3 days: 

Respiratory diseases: 1.016 (1.009, 1.022)
 

Not significant after adjustment for O3, NO2, or
 

PM10
 

CARBON MONOXIDE 3. HEALTH EFFECTS 46
 

 

 

 

 

 

 

 

Table 3-3. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Respiratory Disease
	

Study Design features CO exposure Effect size 

Yang et al. 2003 Outcome: Respiratory disease HA Avg time: 24 hours Increment: 0.54 ppm 

Period: 1986–1998 

Location: Vancouver, Canada 

Design: Case-crossover 

Sample: Ages <3; ≥65 years 

Mean: 0.98 ppm 

25th–75th%: 0.62–1.16 pm 

OR (95% CI), lag 1 day: 

<3 years, CO: 1.04 (1.01, 1.07) 

<3 years, CO+O3: 1.04 (1.01, 1.07) 

<3 years, CO+O3+NO2+SO2: 1.02 (0.96, 1.08) 

≥65 years, CO: 1.02 (1.00, 1.04) 

≥65 years, CO+O3: 1.02 (1.00, 1.04) 

≥65 years, CO, O3, NO2, SO2: 0.96 (0.93, 1.00) 

Zanobetti and Schwartz 2006 

Period: 1995–1999 

Outcome: Pneumonia HAs 

Design: Case-crossover 

Avg time: 24 hours 

25th–75th%: 0.39–0.60 ppm 

Increment: 0.475 ppm 

% Increase (95% CI): 

Location: Boston, Sample: All ages 5.45 (1.10, 9.51; lag 0 days) 

Massachusetts 5.12 (0.83, 9.16; lag 0–1 day) 

CARBON MONOXIDE

AEFV = area under the expiratory flow-volume curve; Avg = average; CI = confidence interval; CO = carbon monoxide; COPD = chronic obstructive pulmonary disease; 

EDV = emergency department visit; FEF = forced expiratory flow; FEF25–75 = forced expiratory flow at 25–75% of vital capacity; FEV1 = forced expiratory volume at 

1 second; FVC = forced vital capacity; HA = hospital admission, IHD = ischemic heart disease; MC = particle mass concentration; MMEF = maximal midexpiratory flow; 

NC = particle number concentration; NR = not reported; OR = odds ratio; PEF = peak expiratory flow; PNC = particle number concentration/count; RR = relative risk; 

SD = standard deviation; SE = standard error; URI = upper respiratory infection 

3. HEALTH EFFECTS 47
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 48 

3. HEALTH EFFECTS 

California examined lung function in a cohort of 232 asthmatic children (age 6–11 years) and found that 

long-term average exposures to carbon monoxide in infancy and childhood (age 0–6 years) was 

associated with significant decreasing forced expiratory volume in 1 second (FEV1)/forced vital capacity 

(FVC) and forced midexpiratory flow rate (FEF25–75)/FVC (Mortimer et al. 2008). Mean air carbon 

monoxide concentrations during the study period ranged from approximately 1 to 1.5 ppm, with the 

highest values ≤6 ppm. The effect sizes (per 1 ppm increase in air carbon monoxide concentration) were 

approximately 2.5% decrease in FEV1/FVC and 4.8% decrease in FEF25–75/FVC. A panel study 

conducted in Denver, Colorado (1999–2002) examined lung function in asthmatic children (n=41–63, age 

6–12 years) and did not find a significant association between air carbon monoxide concentration and 

pulmonary function end points, FEV1, and peak expiratory flow (PEF) (Rabinovitch et al. 2004). The 

mean air carbon monoxide concentration in the study was 1.0 ppm (range: 0.3–3.5 ppm). A similar panel 

study conducted in Kuopio, Finland examined lung function in children (n=33, age 7–12 years) who were 

diagnosed with chronic respiratory disease symptoms (Timonen et al. 2002). Increasing air carbon 

monoxide concentration was associated with decreasing FVC and FEV1, when measured at rest, but not 

during exercise. Other air pollutants were also associated with decrements in baseline pulmonary 

function (particulate matter, NO2); however, multi-pollutant models were not explored. The air carbon 

monoxide concentrations in this study were similar to that in the Rabinovitch et al. (2004) study (mean 

0.6 mg/m3 [0.5 ppm], range: 0.1–2.8 mg/m3 [0.09–2.4 ppm]). A cross-sectional cohort study conducted 

in Taiwan (1995–1996) included asthmatic children (n=941, age 8–13 years; Chen et al. 1999). A 

significant association was found between increasing air carbon monoxide concentration and decreasing 

FVC; however, multi-pollutant models were not explored. Peak daily air carbon monoxide 

concentrations ranged from 0.4 to 3.6 ppm. Fischer et al. (2002) examined possible associations between 

carbon monoxide and pulmonary function in a panel of children (n=68, age 10–11 years) in The 

Netherlands. Increasing air carbon monoxide concentration was not associated with FVC, FEV1, PEF, or 

maximal midexpiratory flow (MMEF); however, it was associated with increasing levels of expired 

endogenous nitric oxide radical (NO•). Here again, multi-pollutant models were not explored. The mean 

air carbon monoxide concentration in this study was 0.9 mg/m3

 (0.8 ppm) (range: 0.3–1.5 mg/m3 [0.3– 

1.3 ppm]). 

Results of studies of pulmonary function in adults have also been mixed and conflicting (Canova et al. 

2010; Lagorio et al. 2006; Penttinen et al. 2001; Silkoff et al. 2005). A panel study of adult asthmatics 

(n=40, mean age 39 years) conducted in Padua, Italy (2004–2005) followed 19 subjects for 2 years. 

Increasing air carbon monoxide concentration was associated with decreasing morning and evening PEF, 

and the association persisted when adjusted for co-exposure to SO2, NO2, and particulate matter (Canova 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 49 

3. HEALTH EFFECTS 

et al. 2010). Another panel study of adult nonsmoking asthmatics (n=57, mean age 53 years) conducted 

in Helsinki, Finland (1996–1997) found that increasing air carbon monoxide concentration was associated 

with decreasing PEF; however, the association was not significant when adjusted for particulate matter 

(Penttinen et al. 2001). The mean air carbon monoxide concentration was 0.4 mg/m3

 (0.3 ppm) (range: 

0.1–1.1 mg/m3 [0.09–0.96 ppm]). A panel study of adult former smokers, diagnosed with chronic 

obstructive pulmonary disease (COPD), conducted in Denver, Colorado (1999–2001, n=16–18, age 

≥40 years) found somewhat conflicting results. A significant association between increasing air carbon 

monoxide concentration and decreasing FEV1 was found in the second winter season of the study, but not 

in the first winter season of the study (Silkoff et al. 2005). Air carbon monoxide concentrations were not 

significantly different in the two seasons (mean: 1.1–1.2 ppm; ranges: 0.3–3.8 and 0.4–2.8 ppm), 

although concentrations of other air pollutants (e.g., PM10, PM2.5, and NO2) were higher in the second 

winter season, suggesting that other air pollutants may have contributed to the associations attributed to 

carbon monoxide in single-pollutant models. The study conducted by Lagorio et al. (2006) is notable 

because it included relatively high air carbon monoxide concentrations (mean range: 1.8 [spring]– 

10.6 [winter] ppm; range: 1.5–25.1 ppm). This panel study examined adults (n=29, age 18–80 years) in 

Rome, Italy (1999) who were diagnosed with asthma, COPD, or ischemic heart disease. Increasing air 

carbon monoxide concentration was not significantly associated with lung function parameters, and multipollutant models were not explored. A panel study conducted in Incheon, Korea that examined lung 

function in asthmatics (n=57, ages 16–75 years) found a significant association between air carbon 

monoxide concentrations and decreasing PEF; however, multi-pollutant models were not explored (Park 

et al. 2005a). The mean air carbon monoxide concentration was 0.6 ppm. 

Studies of Asthma Incidence (or Prevalence) and Exacerbation of Asthma Symptoms. A birth cohort 

case-control study (n=3,248 cases, 16,240 controls) conducted in British Columbia, Canada, examined 

associations between exposures to carbon monoxide in utero or in the first year after birth and diagnoses 

of asthma up to ages 5 years (Clark et al. 2010). The odds ratio for asthma diagnosis was 1.07 (95% CI: 

1.04, 1.11) for in utero exposure and 1.10 (95% CI: 1.06, 1.13) for exposure during the first year, both 

expressed per 0.1 mg/m3

 (0.09 ppm) increase in carbon monoxide concentration. A cross-sectional study 

examined asthma diagnoses among school-age children (n=32,672, age 6–15 years) in Taiwan (Hwang et 

al. 2005). The odds ratio for 0.1 ppm increases in air carbon monoxide concentration (annual average) 

was estimated to be 1.045 (95% CI: 1.017, 1.074) and persisted after adjustment for O3, PM10, and/or SO2 

in multi-pollutant models. The mean air carbon monoxide concentration was 0.6 ppm (range: 0.4– 

0.9 ppm). Several studies have examined possible associations between ambient air carbon monoxide 

concentrations and asthma symptoms (e.g., coughing, wheezing, chest tightness, shortness of breath, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 50 

3. HEALTH EFFECTS 

inhaler use). Results of these studies have been mixed; however, collectively, these studies provide 

evidence for associations between increasing air carbon monoxide concentration and increasing severity 

of asthma (Park et al. 2005a; Rabinovitch et al. 2004; Rodriguez et al. 2007; Schildcrout et al. 2006; 

Silkoff et al. 2005; Slaughter et al. 2003; von Klot et al. 2002; Yu et al. 2000). One of the larger studies 

examined asthma symptoms in a panel of 990 children (ages 5–12 years) in eight North American cities 

(1993–1995, Schildcrout et al. 2006). A 1 ppm increase in air carbon monoxide concentration (lag=0 

days) was associated with an odds ratio of 1.08 (95% CI: 1.01, 1.14) for asthma symptoms. The 

association remained significant after adjusting for NO2, PM10, or SO2 in two-pollutant models. Air 

carbon monoxide concentrations ranged from approximately 0.4 to 2.4 ppm (10th–90th percentile range). 

Significant associations with increasing carbon monoxide concentration were also found when rescue 

medication use was evaluated as the asthma symptom end point. 

The above results are consistent with those of several smaller panel studies. A study conducted in Seattle, 

Washington examined asthma symptoms (Yu et al. 2000) and asthma severity (Slaughter et al. 2003) in a 

panel of 133 asthmatic children (age 5–13 years). The mean air carbon monoxide concentration was 

1.6 ppm (range: 0.6–4.8 ppm; Yu et al. 2000). Both studies found significant associations between 

ambient air carbon monoxide and asthma symptoms. In the Yu et al. (2000) study, a 1 ppm increase in air 

carbon monoxide (lag=2 days) was associated with an odds ratio of 1.26 (95% CI: 1.09, 1.46) for asthma 

symptoms. In the Slaughter et al. (2003) study, a 0.67 ppm increase in air carbon monoxide concentration 

was associated with an odds ratio of 1.21 (95% CI: 1.08, 1.35) for an increase in severity of asthma 

attack. A significant association with increasing carbon monoxide concentration was also found when 

rescue medication use was evaluated as the asthma severity end point (Slaughter et al. 2003). 

Rabinovitch et al. (2004) also found a significant association between increasing air carbon monoxide 

concentrations and increasing rescue medication use in a study of children in Denver, Colorado (1999– 

2002, n=41–63, age 6–12 years). A panel study of 263 children (age 0–5 years) in Perth, Australia, who 

were not diagnosed with asthma, also found a significant association between air carbon monoxide 

concentration and wheezing/chest rattle (Rodriguez et al. 2007). 

Results of studies conducted in older asthmatic subjects have been mixed (Park et al. 2005a; Silkoff et al. 

2005; von Klot et al. 2002). In a panel of 53 asthmatic adults (age 37–77 years) in Erfurt, Germany 

(1996–1997), a 0.6 mg/m3

 (0.5 ppm) increase in air carbon monoxide concentration (5-day average) was 

associated with an odds ratio of 1.13 (95% CI: 1.05, 1.22) for prevalence of wheezing; however, the 

association was attenuated when adjusted for ultrafine particle number concentration in air. Two other 

panel studies of asthmatics, one conducted in Incheon, Korea (2002, n=54, age 16–76 years; Park et al. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 51 

3. HEALTH EFFECTS 

2005a) and one in Denver, Colorado (n=16 or 18, age ≥40 years, Silkoff et al. 2005), did not find 

significant associations between air carbon monoxide concentrations and asthma symptoms. 

Studies of Hospital Admissions and Emergency Room Visits Related to Respiratory Symptoms. A large 

number of studies have examined associations between ambient carbon monoxide concentrations and 

rates of hospital admissions (e.g., Burnett et al. 2001; Cakmak et al. 2006; Karr et al. 2006; Lin et al. 

2003, 2005; Linn et al. 2000; Slaughter et al. 2005; Yang et al. 2003; Zanobetti and Schwartz 2006) or 

emergency room visits related to respiratory disease (e.g., Arbex et al. 2009; Peel et al. 2005; Slaughter et 

al. 2005; Tolbert et al. 2007). Collectively, these studies provide evidence for associations between 

increasing carbon monoxide concentrations and increasing risk of respiratory symptoms that trigger the 

need for medical assistance. However, only a few studies have examined associations in multi-pollution 

models; therefore, relative contributions of other air pollutants to the reported outcomes are highly 

uncertain. 

In studies that did evaluate multi-pollutant models, the associations between carbon monoxide 

concentrations and outcomes persisted in some studies (Burnett et al. 2001; Lin et al. 2003; Yang et al. 

2003), but not in others (Lin et al. 2005; Peel et al. 2005; Tolbert et al. 2007). In a time-series analysis 

conducted in Toronto, Canada (1980–1994), Burnett et al. (2001) found a significant association between 

increasing air carbon monoxide concentrations and hospital admissions for asthma, acute bronchitis/ 

bronchiolitis, croup, and pneumonia in children (age <2 years). A 1.9 ppm increase in air carbon 

monoxide concentration (lag: 0–1 day) was associated with a 19.2% increase in hospital admissions, 

which remained elevated when adjusted for air O3 concentration. A case-crossover study of hospital 

admissions of children (ages 6–12 years) for asthma in Toronto, Canada (1981–1993) found that a 

0.5 ppm increase in air carbon monoxide concentration was associated with an odds ratio (lag: 1 day) of 

1.05 (95% CI: 1.00, 1.11) in males but not in females (odds ratio: 1.00, 95% CI: 0.93, 1.06) and 

persisted in males after adjustment for particulate matter (Lin et al. 2003). Another case-crossover study 

directed at respiratory infections in children (age <15 years, males), also conducted in Toronto, Canada 

(1988–2001), estimated the odds ratios for a 0.44 ppm increase in air carbon monoxide concentration 

(lag: 0–5 days) to be 1.13 (95% CI: 1.01, 1.25) and 1.08 (95% CI: 0.97, 1.20) after adjustment for PM10 

and PM10–2.5 (Lin et al. 2005), respectively. Odds ratios for females were not significant. Yang et al. 

(2003) conducted a case-crossover study of hospital admissions for various respiratory disease categories 

in Vancouver, Canada (1986–1998) and found that an increase in carbon monoxide concentration of 

0.5 ppm was associated with odds ratios of 1.04 (95% CI: 1.01, 1.07) for children (age <3 years) and 

1.02 (95% CI: 1.00, 1.04) for elderly adults (age ≥65 years). The associations persisted when adjusted 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 52 

3. HEALTH EFFECTS 

for air O3 concentration. In a time-series analysis of >400,000 emergency room visits for respiratory 

disease in Atlanta, Georgia (1993–2000), the estimated risk ratio for a 1 ppm increase in air carbon 

monoxide concentration (lag: 0–13 days) was 1.076 (95% CI: 1,047, 1.105) for all ages and 1.019 (95% 

CI: 1.004, 1.035) for asthma visits in children aged 2–18 years (Peel et al. 2005). The associations were 

not significant when adjusted for other air pollutants in two-pollutant models (e.g., PM10, NO2, or O3). 

This study also found a significant risk ratio for emergency room visits related to pneumonia (risk ratio: 

1.045, 95% CI: 1.011, 1.080; lag: 0–13 days). A revisit to the Atlanta, Georgia study, with the study 

period expended to 1993–2004 (Tolbert et al. 2007), found essentially similar results as reported in Peel et 

al. (2005). The risk ratio for all emergency room visits for all respiratory disease categories was 

1.016 (95% CI: 1.009, 1.022) per 1.22 ppm increase in 1-hour maximum carbon monoxide concentration 

(lag: 3 days); however, the association was attenuated in models that adjusted for O3, NO2, or PM10. 

Studies that examined COPD admissions and emergency room visits yielded mixed results (Arbex et al. 

2009; Peel et al. 2005; Slaughter et al. 2005; Yang et al. 2003). In the Yang et al. (2003) time-series 

study, conducted in Vancouver, Canada (1994–1998), the risk ratio for a 0.5 ppm increase in air carbon 

monoxide concentration (lag: 0–6 days) was 1.14 (95% CI: 1.03, 1.23) for COPD hospital admissions. 

A study conducted in São Paulo, Brazil found a 12.9% (95% CI: 1.3, 25.9) increase in COPD-related 

emergency room visits in association with a 1.9 ppm increase in air carbon monoxide concentration (lag: 

0–6 days) (Arbex et al. 2009). On the other hand, significant associations between air carbon monoxide 

concentration and COPD hospital admissions or emergency room visits were not found in a time-series 

study conducted in Spokane, Washington (1995–2001; Slaughter et al. 2005). In the Peel et al. (2005) 

time-series study conducted in Atlanta, Georgia (1993–2000), relative risks for emergency room visits for 

COPD per 1 ppm increase in carbon monoxide concentration were 1.03 (95% CI: 1.00, 1.05) for lag 0– 

2 days and 1.03 (95% CI: 0.98, 1.09) for lag 0–13 days. The air carbon monoxide concentrations in these 

studies were similar (10th–90th percentile range: approximately 1.25–4.3 ppm) 

Animal Studies. Most studies evaluating adverse respiratory effects of carbon monoxide in animals were 

conducted using carbon monoxide exposures that produced much higher COHb concentrations (i.e., 

COHb >50%) than those evaluated in controlled clinical studies in humans. Even at these high 

exposures, results of animal studies support those of controlled clinical studies indicating that the 

respiratory tract is not a major target organ for carbon monoxide. Animal studies published prior to 2000 

have been reviewed in detail by the EPA (1991, 2000); therefore, these reviews largely form the basis of 

the following discussions for animals studies published prior to 2000. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 53 

3. HEALTH EFFECTS 

Studies investigating adverse respiratory effects of carbon monoxide have evaluated the lung function and 

morphology, with most studies evaluating effects of brief exposure (i.e., a few minutes to <1 hour). In 

acute-duration studies, alterations in lung function (decreased compliance and increased airway 

resistance) were observed in rabbits and cats exposed to 8,000–28,400 ppm carbon monoxide for <1 hour 

(COHb >60%); however, no changes in lung function were observed in dogs exposed to 8,000– 

14,000 ppm carbon monoxide for 10–20 minutes (COHb 18–59%) (EPA 1991). In an intermediateduration study, continuous exposure of rats to 50 ppm carbon monoxide for 21 days (COHb not reported) 

did not alter the pulmonary pressure-flow relationship (Carraway et al. 2002). Blood COHb 

concentrations were not reported for the Carraway et al. (2002) study; however, the CFK rat model 

predicts that COHb concentrations at the end of the 21-day exposure period would have been 

approximately 7%. Results of these studies suggest that carbon monoxide-induced changes in pulmonary 

function occur only following exposure to high carbon monoxide concentrations. 

Studies evaluating effects of acute-duration carbon monoxide exposure on lung morphology have 

reported conflicting results (EPA 1991). Minimal changes in type 2 epithelial cells (fragmentation of 

lamellar bodies) and nonciliated bronchiolar cells (dilation of smooth endoplasmic reticulum and 

increased mitochondrial cristae) were reported in mice exposed to 50–90 ppm carbon monoxide for 1– 

5 days (COHb <10%) (Niden 1971). The study results were not presented in detail and the toxicological 

significance of these finding is not known; however, changes to the smooth endoplasmic reticulum and 

mitochondrial cristae are consistent with a compensatory response to altered electron transport due to 

possible carbon monoxide-induced interference with cytochromes involved in electron transport. In 

rabbits exposed to 8,000 ppm for 30 minutes (COHb 63%), examination of lung tissue by electron 

microscopy showed alveolar epithelial edema with detachment of the endothelium from the basement 

membrane (Fein et al. 1980). However, no morphological changes in lung tissue were observed 

following acute exposure (30 minute to 5 hours) of dogs and rabbits at carbon monoxide exposure 

producing blood COHb levels of 18–39% or following intermediate-duration exposure (6 weeks) of 

rabbits to 200 ppm carbon monoxide (COHb 11.9–19%) (Fisher et al. 1969; Hugod 1980). Results of a 

recent study in rats exposed chronically to 200 ppm carbon monoxide (COHb 14.7%) for 20 hours/day for 

72 weeks showed no histopathological changes to lung tissue (Sørhaug et al. 2006). 

Cardiovascular Effects. Cardiovascular effects of inhalation exposures to carbon monoxide have 

been evaluated in controlled human clinical studies, epidemiology studies, and various animal models 

(monkeys, dogs, rats, and rabbits). In general, these studies provide convincing evidence for adverse 

cardiovascular effects in association with carbon monoxide exposures that result in blood COHb levels 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 54 

3. HEALTH EFFECTS 

≥2.4%, with effects occurring at the lowest levels in subjects with compromised cardiovascular function 

(e.g., coronary artery disease). Results of controlled clinical studies in patients with coronary artery 

disease show that acute-duration exposure to carbon monoxide at levels producing blood COHb levels 

between 2.4 and 5.9% exacerbates underlying cardiovascular disease, including enhancing myocardial 

ischemia and increasing cardiac arrhythmias. 

In healthy subjects, acute exposure to carbon monoxide at concentrations producing blood COHb levels 

of 3.35 and 20.5% resulted in compensatory cardiovascular responses and decreased exercise 

performance consistent with COHb-induced decreased O2 carrying capacity of the blood; however, 

subjects did not exhibit exercise-induced adverse cardiovascular effects (e.g., evidence of myocardial 

ischemia or cardiac arrhythmias). Continuous exposure of healthy subjects, which included smokers, to 

carbon monoxide resulting in blood COHb levels of 2.4 and 5.1% produced several P-wave deviations 

(P-wave inversion, increased amplitude, decreased amplitude, and changes in P-wave direction) under 

resting conditions, although similar findings have not been reported in other studies. 

Epidemiological studies of exposure to carbon monoxide and cardiovascular outcomes have yielded 

mixed results, although, in general, the weight of evidence suggests that risks of certain specific outcomes 

are associated with increasing ambient carbon monoxide concentrations (hospitalizations and emergency 

room visits related to congestive heart failure, ischemic heart disease, myocardial infarction, and stroke). 

The corroborated observations of associations between carbon monoxide exposure and outcomes related 

to ischemic heart disease are particularly provocative in the context of results of human clinical studies in 

which carbon monoxide-induced hypoxia exacerbated ischemia symptoms in patients with coronary 

artery disease. Mean ambient air carbon monoxide concentrations reported in studies that have found 

carbon monoxide-associated cardiovascular outcomes ranged from 0.5 to 10 ppm, with maximum values 

ranging from 2 to 50 ppm. These values correspond to approximate steady-state blood COHb levels of 

<2% for the mean and <10% for the maximum. 

Studies in animals have investigated adverse cardiovascular effects of carbon monoxide exposure over a 

much wider range of exposure conditions (e.g., exposure concentration and duration) and have evaluated 

additional outcome measures that are not possible to assess in humans. These studies provide further 

evidence of adverse cardiovascular effects of carbon monoxide exposure, including compensatory 

alterations in hemodynamics, cardiac hypertrophy, cardiac arrhythmias, and possibly atherosclerosis. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 55 

3. HEALTH EFFECTS 

Human Clinical Studies 

Studies of Patients with Cardiovascular Disease. The effects of acute-duration carbon monoxide 

exposure on cardiovascular function have been evaluated in several controlled clinical studies in patients 

with underlying cardiovascular disease (Adams et al. 1988; Allred et al. 1989, 1991; Anderson et al. 

1973; Dahms et al. 1993; Hinderliter et al. 1989; Kleinman et al. 1989, 1998; Leaf and Kleinman 1996b; 

Sheps et al. 1987, 1990) and in healthy subjects (Adir et al. 1999; Davies and Smith 1980; Hausberg and 

Somers 1997; Horvath et al. 1975; Kizakevich et al. 2000; Morse et al. 2008; Resch et al. 2005; Vogel 

and Gleser 1972; Zevin et al. 2001). In general, similar effects of acute-duration carbon monoxide 

exposure were not observed in studies on healthy study subjects, due to functional cardiovascular 

compensatory mechanisms (e.g., vasodilation and increased cardiovascular output) that protect against 

COHb-induced tissue hypoxia. Mechanisms contributing to cardiac effects of carbon monoxide in 

patients with coronary artery disease have not been conclusively established. Under conditions of cardiac 

ischemia, tissue hypoxia secondary to elevated COHb levels is thought to be a contributing factor. 

However, other direct cellular effects of carbon monoxide on cardiac muscle may also be important. 

These include modulation of coronary arteriole calcium-activated potassium channels. These channels 

are required for membrane hyperpolarization and flow-induced dilation and are reversibly activated by 

carbon monoxide under normoxic conditions, but they are inhibited when hypoxic/ischemic conditions 

prevail (Wang and Wu 1997; Wang et al. 1997a, 1997b). 

Controlled clinical studies conducted in small numbers of patients with underlying coronary artery 

disease have evaluated effects of carbon monoxide exposure on myocardial ischemia. Patients evaluated 

had a diagnosis of coronary artery disease with exertional angina (i.e., exercise-induced angina or stable 

angina) and/or ventricular arrhythmia. Most studies were conducted using a randomized, double-blind, 

crossover design, with cardiovascular function assessments conducted during exercise challenge, either 

during or immediately following carbon monoxide exposure. Carbon monoxide exposures (concentration 

and duration) were designed to reach target blood COHb levels between 2 and 6%; exposure durations 

ranged from 1 to 4 hours via an environmental chamber, with carbon monoxide concentrations ranging 

from 42 to 357 ppm. Effects of carbon monoxide exposure were evaluated by comparison to assessments 

conducted during room air exposure and at corresponding COHb concentrations of <1%. Additional 

experimental details for each study are summarized in Table 3-4. 

Results of controlled clinical studies in patients with coronary artery disease show that acute-duration 

exposure to carbon monoxide at levels producing blood COHb levels between 2.4 and 5.9% exacerbates 
 

 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure	 Outcomes assessed Results 

Adams et al.	 30 nonsmokers 

1988	 (22 men, 8 women; 

mean age: 

58 years; age range 

36–75 years) 

diagnosed with 

coronary artery 

disease with 

exertional angina 

pectoris 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

2 test days: 1-hour exposure 

to room air (measured COHb 

prior to exercise challenge: 

1.6±0.1%a

) or CO (measured 

COHb prior to exercise 

challenge: 5.9±0.1%a

; mean 

CO concentration: 100– 

200 ppm). COHb measured 

by CO-Ox. 

Duration of exercise, 

time-to-onset of exerciseinduced angina 

symptoms and ischemic 

ST-segment changes 

(EKG), radionuclide 

ventriculograph 

(ventricular ejection 

fraction), systolic blood 

pressure. Results for CO 

exposure compared to 

room air exposure. 

Mean duration of exercise: Decreased 

by 6.5% (p<0.05) following CO 

exposure, compared to air exposure. 

Time-to-onset of angina symptoms: 

Using actuarial analysis, subjects more 

likely to experience angina symptoms 

earlier in exercise following CO vs. air 

exposure (p<0.05). 

Time-to-onset of ischemic ST-segment 

changes: No effect of exposure. 

Systolic blood pressure: No effect of 

exposure. 

Ventricular ejection fraction: Left 

ventricular ejection fraction at 

submaximal exercise was decreased 

following CO exposure, compared to air 

exposure (p<0.05). 

NOAEL: Not established 

LOAEL: COHb 5.9% 

CARBON MONOXIDE 3. HEALTH EFFECTS 56
 

 

 

 

 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure	 Outcomes assessed Results 

Allred et al.	 63 male 

1989, 1991	 nonsmokers (age 

range: 41– 

75 years) 

diagnosed with 

coronary artery 

disease with 

exertional angina 

pectoris and 

ischemic 

ST-segment 

changes on EKG 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(treadmill) 

administered 

prior to and 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

3 test days: 1-hour exposure 

to room air (measured COHb 

prior to exercise challenge: 

0.70±0.02%a

), low CO 

(measured COHb prior to 

exercise challenge: 

2.38±0.05%a

; mean CO 

concentration: 117 ppm, 

range 42–202 ppm), or high 

CO (measured COHb: 

4.66±0.09%a

; mean CO 

concentration: 253 ppm, 

range 143–357 ppm). COHb 

measured by GC. 

Time-to-onset of 

exercise-induced angina 

symptoms and ischemic 

ST-segment changes 

(EKG), total exercise 

duration, heart ratesystolic blood pressure 

double product. Effects 

determined based on 

comparison (percent 

change) for pre- and postexposure exercise 

challenge outcomes on 

each test day. Results for 

each CO exposure 

compared to room air 

exposure. 

Time-to-onset of angina symptoms: 

Decreased by 4.2% (p=0.027) for low
 

CO exposure and 7.1% (p=0.002) for
 

high CO exposure, compared to room
 

air exposure.
 

Time-to-onset of ischemic ST-segment
 

changes: Decreased by 5.1% (p=0.01)
 

for low CO exposure and 12.1%
 

(p≤0.0001) for high CO exposure, 

compared to room air exposure. 

Mean duration of exercise: Decreased 

by 1.7% (p=0.29) for low CO exposure 

and 6.2% (p≤0.0001) for high CO 

exposure, compared to room air 

exposure. 

Heart rate-systolic blood pressure 

double product: No effect of CO 

exposure. 

NOAEL: Not established 

LOAEL: COHb 2.38% 

CARBON MONOXIDE 3. HEALTH EFFECTS 57
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Anderson et al. 

1973 

Dahms et al. 

1993 

10 men (5 smokers, 

5 nonsmokers; 

mean age: 

49.9 years) 

diagnosed with 

coronary artery 

disease with 

exertional angina 

pectoris 

33 nonsmokers 

(28 men, 5 women; 

mean age: 

58 years; age 

range: 36– 

75 years) 

diagnosed with 

coronary artery 

disease with 

chronic ventricular 

arrhythmias 

Randomized, 

cross-over, 

double-blind; 

following COHb 

elevation to 

target levels, 

patients were 

administered 

exercise 

challenge test 

(treadmill) under 

maintenance 

CO exposure. 

Randomized, 

cross-over, 

double-blind; 

following COHb 

elevation to 

target levels, 

patients were 

administered 

exercise 

challenge test 

(treadmill) under 

maintenance 

CO exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

3 test days: 4-hour exposure 

to room air (measured 

COHb, prior to exercise 

challenge: 1.3%), low CO 

(measured COHb: 2.9%; CO 

concentration: 50 ppm), or 

high CO (measured COHb: 

4.5%; CO concentration: 

100 ppm). COHb measured 

by spectrometry. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

3 test days: 1-hour exposure 

to room air (measured COHb 

by CO-Ox, prior to exercise 

challenge: 0.7), low CO 

(measured COHb: 3.2%; 

mean CO concentration: 

159 ppm), or high CO 

(measured COHb: 5.1%; 

mean CO concentration: 

292 ppm). Maintenance 

exposure on the CO 

exposure days was to 19 and 

31 ppm for the low and high 

COHb exposures, 

respectively. COHb 

measured by CO-Ox. 

Time-to-onset and 

duration of angina 

symptoms. 

Frequency of ventricular 

arrhythmias evaluated 

during exposure, during 

exercise (under 

maintenance exposure), 

1–6 hours after cessation 

of exposure, and 7– 

16 hours after cessation 

of exposure. Primary 

outcome was frequency 

of exercise-induced 

ventricular arrhythmias. 

Results for CO exposure 

compared to room air 

exposure. 

Time-to-onset of angina symptoms: 

Decreased by 4.2% (p=0.027) for low 

CO exposure and 7.1% (p=0.002) for 

high CO exposure, compared to room 

air exposure. 

Duration of angina symptoms: No 

effect for low CO exposure; duration 

increased (p<0.01) for high CO 

exposure, compared to room air 

exposure. 

NOAEL: Not established 

LOAEL: COHb 2.9% 

No effect of CO, compared to room air, 

on frequency of ventricular arrhythmia 

under any conditions assessed. 

NOAEL: COHb 5.9% 

LOAEL: Not established 

CARBON MONOXIDE 3. HEALTH EFFECTS 58
 

 

 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Hinderliter et al. 

1989 

10 nonsmokers 

(7 males, 

3 females; mean 

age: 61 years) 

diagnosed with 

coronary artery 

disease with angina 

and low baseline 

ventricular ectopy 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

3 test days: 1-hour exposure 

to room air (measured COHb 

following exposure: 

1.4±0.5%b

), low CO 

(measured COHb following 

exposure: 4.0±0.4%b

; CO 

concentration: 100 ppm), or 

high CO (measured COHb 

following exposure: 

5.8±0.4%b

; CO 

concentration: 200 ppm). 

COHb measured by CO-Ox. 

Ventricular arrhythmia. No effect of CO, compared to room air,
 

Results for CO exposure on frequency of ventricular arrhythmia.
 

compared to room air
 

exposure. NOAEL: COHb 5.9%
 

LOAEL: Not established 

CARBON MONOXIDE 3. HEALTH EFFECTS 59
 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure	 Outcomes assessed Results 

Kleinman et al.	 24 male 

1989	 nonsmokers (mean 

age: 59 years; age 

range: 49– 

66 years) 

diagnosed with 

coronary artery 

disease with stable 

angina pectoris 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

2 test days: 1-hour exposure 

to room air (measured COHb 

following exposure: 

1.4±0.1%c

) or CO (measured 

COHb following exposure: 

3.0±0.1%c

; mean CO 

concentration: 100 ppm). 

COHb measured by CO-Ox. 

Time-to-onset and 

duration of angina 

symptoms, time-to-onset 

of ischemic ST-segment 

changes (EKG), heart 

rate, systolic blood 

pressure, oxygen update 

at angina. Results for CO 

exposure compared to 

room air exposure. 

Time-to-onset of angina: Decreased by
 

5.89% (p<0.046) following CO
 

exposure, compared to room air
 

exposure.
 

Duration of angina symptoms: 

Increased by 8.33% (not statistically
 

significant) following CO exposure,
 

compared to room air exposure.
 

Time-to-onset of ischemic ST-segment
 

changes: Decreased by 19.05%
 

(p<0.044) following CO exposure,
 

compared to room air exposure.
 

Oxygen uptake at angina: Decreased 

by 2.15% (p<0.04) following CO
 

exposure, compared to room air
 

exposure.
 

Systolic blood pressure: No effect of
 

exposure.
 

Heart rate: No effect of exposure.
 

NOAEL: Not established 

LOAEL: COHb 3.0% 

CARBON MONOXIDE 3. HEALTH EFFECTS 60
 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Kleinman et al. 

1998; Leaf and 

Kleinman 1996b 

17 male 

nonsmokers (mean 

age: 66 years; age 

range: 58– 

83 years) living at 

or near sea level, 

diagnosed with 

coronary artery 

disease with 

exertional angina 

pectoris 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure at sea 

levels and under 

conditions 

simulating high 

altitude. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

4 test days: 2-hour exposure 

to room air at sea level 

(measured COHb following 

exposure: 0.6±0.3%b

), room 

air at artificial high elevation 

(measured COHb following 

exposure: 0.6±0.3%b

), CO at 

sea level (measured COHb: 

3.9±0.5%b

; mean CO 

concentration: 100 ppm), or 

CO at artificial high elevation 

(measured COHb: 

4.0±0.6%b

; mean CO 

concentration: 100 ppm), 

COHb measured by CO-Ox. 

Time-to-onset and 

duration of angina 

symptoms, ST-segment 

depression and 

preventricular 

contractions (EKG), peak 

(end-exercise) heart rate, 

blood pressure, oxygen 

update, and carbon 

dioxide output. Results 

for CO exposure 

compared to room air 

exposure. 

Time-to-onset of angina: Decreased by 

9.1% (p<0.05) following CO exposure at 

sea level and by 7.6% (p<0.05) 

following CO exposure at high altitude, 

compared to matched room air 

exposure. 

Duration of angina symptoms: No 

effect of CO exposure. 

ST-segment changes: No effect of CO 

exposure. 

Preventricular contractions: No effect 

of CO exposure 

Peak heart rate: Increased (p<0.05) for 

CO at high altitude compared to CO at 

sea level and to room air at high 

altitude. 

Peak blood pressure: Increased 

(p<0.05) for CO at high altitude 

compared to room at CO at sea level. 

Oxygen uptake and carbon dioxide 

output: Decreased (p<0.05) by CO 

exposure at sea level and high altitude. 

NOAEL: Not established 

LOAEL: COHb 3.9–4.0% 

CARBON MONOXIDE 3. HEALTH EFFECTS 61
 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure	 Outcomes assessed Results 

Sheps et al.	 30 nonsmokers 

1987	 (age range: 38– 

75 years) 

diagnosed with 

coronary artery 

disease with 

exertional angina 

pectoris 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

2 test days: 1-hour exposure 

to room air (measured COHb 

following exposure: 

1.5±0.05%b

) or CO 

(measured COHb following 

exposure: 4.1±0.05%b

; CO 

concentration: 100 ppm). 

COHb measured by CO-Ox. 

Time-to-onset and 

duration of angina 

symptoms, ST-segment 

depression, 

cardiovascular function 

(heart rate, blood 

pressure, rate x pressure 

product, peak exercise 

workload, left ventricular 

ejection fraction), 

exercise duration. 

Results for CO exposure 

compared to room air 

exposure. 

No statistically significant CO-induced 

changes for any outcomes, except for a 

small (0.5% decrease; p=0.049) in 

maximal ejection fraction. Study authors 

did not consider this change to be 

clinically significant. 

NOAEL: COHb 4.1% 

LOAEL: Not established 

CARBON MONOXIDE 3. HEALTH EFFECTS 62
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-4. Effects of Acute-Duration Exposure to Carbon Monoxide on Cardiovascular Function in Patients with
	

Coronary Artery Disease
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Sheps et al. 

1990 

41 nonsmokers 

(36 men, 5 women; 

mean age: 

62.8 years; age 

range: 47– 

77 years) 

diagnosed with 

coronary artery 

disease 

Randomized, 

cross-over, 

double-blind; 

exercise 

challenge tests 

(bicycle) 

administered 

immediately 

following each 

exposure. 

Patients administered one of 

the following treatments (via 

environmental chamber) on 

3 test days: 1-hour exposure 

to room air (measured COHb 

following exposure: 

1.46±0.07%a

), low CO 

(measured COHb following 

exposure: 4.01±0.06%a

; CO 

concentration: 100 ppm), or 

high CO (measured COHb 

following exposure: 

5.91±0.08%a

; CO 

Ventricular arrhythmia 

(EKG) and ventricular 

ejection fraction 

(radionuclide 

ventriculography), blood 

pressure, heart rate, 

exercise duration. 

Results for CO exposure 

compared to room air 

exposure. 

For COHb 4.01%: No effects on any 

parameter evaluated. 

For COHb 5.91%: During exercise, 

statistically significant changes in single 

premature ventricular depolarizations 

(36% increase; p=0.03), complex 

premature ventricular depolarizations 

(6.3% increase; p=0.02), heart rate 

(3.2% increase; p=0.01). 

NOAEL: COHb 4.01% 

LOAEL: COHb 5.91% 

concentration: 200 ppm). 

COHb measured by CO-Ox. 

CARBON MONOXIDE

a

Mean±standard error (SE). b

Mean±standard deviation (SD). c

Means; report does not indicate if SD or SE. 

CO = carbon monoxide; COHb = carboxyhemoglobin; CO-Ox = CO oximetry; EKG = electrocardiogram; GC = gas chromatography; LOAEL = lowest-observed-adverseeffect level; NOAEL = no-observed-adverse-effect level 

3. HEALTH EFFECTS 63
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 64 

3. HEALTH EFFECTS 

underlying cardiovascular disease, including enhanced myocardial ischemia and increased cardiac 

arrhythmias. In patients with exertional angina, carbon monoxide exposure exacerbated exercise-induced 

myocardial ischemia, including decreased time-to-onset of angina symptoms (Adams et al. 1988; Allred 

et al. 1989, 1991; Anderson et al. 1973; Kleinman et al. 1989, 1998; Leaf and Kleinman 1996b), 

increased duration of angina symptoms (Anderson et al. 1973; Kleinman et al. 1989), decreased time-toonset of ST-segment depression (EKG change indicative of myocardial ischemia) (Allred et al. 1989, 

1991; Kleinman et al. 1989), and decreased left ventricular ejection fraction (Adams et al. 1988). At the 

lowest blood COHb level evaluated in patients (i.e., COHb 2.4%), time-to-onset of angina symptoms and 

of ST-segment depression were significantly decreased by 4.2 and 5.1%, respectively (Allred et al. 1989, 

1991). In contrast, no carbon monoxide-induced exacerbation of exertional angina, based on time-toonset of angina symptoms and ST-segment depression and duration of angina symptoms, were observed 

at a blood COHb level of 4.1% (Sheps et al. 1987). Clinical evaluations in angina patients with 

ventricular arrhythmias have yielded mixed results on the effects of carbon monoxide-induced ventricular 

arrhythmias (Dahms et al. 1993; Hinderliter et al. 1989; Sheps et al. 1990). At a blood COHb level of 

5.9%, but not 4.0%, single and complex premature ventricular depolarizations were significantly 

increased by 36 and 6.3%, respectively (Sheps et al. 1990). However, at this same blood COHb level, 

carbon monoxide exposure did not increase ventricular arrhythmias in other studies (Dahms et al. 1993; 

Hinderliter et al. 1989). Reasons for conflicting results in these studies are not readily apparent, although 

numbers of patients evaluated were small and the severity of underlying coronary artery disease may have 

varied in each study. 

Studies of Healthy Subjects. Several controlled clinical studies in small numbers of healthy subjects have 

evaluated effects of acute-duration exposure to carbon monoxide on exercise performance, including 

cardiovascular function. In general, study protocols were similar to those used in clinical studies on 

patients with coronary artery disease, although typical carbon monoxide exposures were for shorter 

durations (a few minutes to ≤1 hour) to higher carbon monoxide concentrations (50–3,000 ppm) and 

produced slightly higher blood COHb levels (2.4–20.5%). However, one study exposed subjects 

continuously for 7 days (Davies and Smith 1980). Additional experimental details for each study are 

summarized in Table 3-5. 

Results of several controlled clinical studies in healthy subjects show that carbon monoxide exposures 

that resulted in blood COHb levels between 3.35 and 20.5% decreased exercise performance, including 

decreased exercise duration (Adir et al. 1999); decreased maximal exercise effort or maximal aerobic 

capacity (Adir et al. 1999; Horvath et al. 1975; Vogel and Gleser 1972); decreased resistance to muscle 
 

 

 

 

 

 

Table 3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy Subjects
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Adir et al. 1999 

Davies and 

Smith 1980 

15 healthy 

nonsmoking men 

(mean age: 

26 years; age 

range: 18– 

35 years) 

Groups (14– 

15/group) of 

matched healthy 

(information on 

sex not reported; 

age range: 17– 

27 years) 

Randomized, 

cross-over, 

double-blind; 

exercise challenge 

tests (bicycle) 

administered 

immediately 

following each 

exposure. 

Randomized, 

parallel group. 

Subjects administered 

one of the following 

treatments (via closed 

breathing circuit) on 

2 test days: 3– 

4-minute exposure to 

room air (COHb: 

0.59±0.08%a

) or CO 

(measured COHb: 

5.1±0.65%a

; CO 

concentration not 

reported). COHb 

measured by CO-Ox. 

Continuous exposure 

to room air (COHb 

0.5%), low CO (15 ppm 

CO; COHb 2.4%), or 

high CO (50 ppm CO; 

COHb 7.2%) for 

7 days. 

Level of anaerobic 

respiration (plasma 

lactate/pyruvate ratio), 

cardiac arrhythmia (EKG), 

heart rate and blood 

pressure (resting and 

peak), cardiac perfusion 

(thallium heart 

scintigraphy), exercise 

duration, maximal effort 

(metabolic equivalent 

units). 

EKG; no statistical 

analysis conducted. 

Anaerobic respiration: No effect of CO
 

exposure.
 

Cardiac arrhythmia: No effect of CO
 

exposure.
 

Cardiac perfusion: No effect of CO
 

exposure.
 

Heart rate and blood pressure: No effect of
 

CO exposure.
 

Exercise duration: Decreased by 10.4%
 

(p=0.0012) for CO exposure compared to air
 

exposure.
 

Maximal effort: Decreased by 12.4%
 

(p=0.001) for CO exposure compared to air
 

exposure.
 

NOAEL: Not established 

LOAEL: COHb 5.1% 

P-wave changes: P-wave deviations of 

≥0.1 mV observed in 3/15 subjects at low 

CO and 6/15 at high CO, compared to 

0/14 for room air. 

Marked ST-segment depression: 

1/15 subject (a heavy smoker) at low CO 

exposure. 

NOAEL: Not established 

LOAEL: COHb 2.4% 

CARBON MONOXIDE 3. HEALTH EFFECTS 65
 

 

 

 

Table 3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy Subjects
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Hausberg and 10 healthy Randomized, 

Somers 1997	 subjects (8 men, double-blind, 

2 women; mean vehicle (air) 

age: 27 years); controlled. 

9/10 were 

nonsmokers 

Subjects were 

assessed under vehicle 

control (room air), then 

administered CO 

(1,000 ppm for 

30 minutes, followed by 

100 ppm for 

30 minutes); COHb 

increased from 

0.2±0.1%b for room air 

exposure to 8.3±0.5%b 

during the first 

30 minutes of 

exposure; COHb levels 

were maintained during 

the second 30 minutes 

of CO exposure. 

COHb measured by 

CO-Ox. 

Forearm blood flow No effects of CO treatment on any
 

(plethysmography), blood parameter evaluated.
 

pressure, heart rate,
 

minute ventilation, muscle NOAEL: COHb 8.3%
 

sympathetic nerve activity LOAEL: Not established
 

(microneurography).
 

CARBON MONOXIDE 3. HEALTH EFFECTS 66
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy Subjects
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Horvath et al. 4 healthy men Randomized, Subjects administered 

1975 (mean age: single-blind, cross- one of the following 

24.6 years; age over; exercise treatments (via 

range: 23– challenge tests environmental 

33 years); (treadmill) to chamber) on 3 test 

3/4 were exhaustion days (exposure 

nonsmokers administered duration not reported): 

immediately Vehicle exposure to 

following each room air (measured 

exposure. COHb following 

exposure: 

0.33±0.06%b

), low CO 

(measured COHb 

following exposure: 

3.35±0.14%b

; CO 

concentration: 

75 ppm), or high CO 

(measured COHb 

following exposure: 

4.30±0.30%b

; CO 

concentration: 

100 ppm). Method for 

measuring COHb not 

reported. 

EKG, maximal aerobic EKG: No effect of CO exposure.
 

capacity (maximal oxygen Maximal aerobic capacity: Decreased at
 

consumption), work time, high CO exposure (p<0.05).
 

ventilatory volume. Ventilatory volume and work times: 

Decreased at low and high CO exposure 

(p<0.05). 

NOAEL: Not established 

LOAEL: COHb 3.35% 

CARBON MONOXIDE 3. HEALTH EFFECTS 67
 

 

 

 

 

 

 

 

 

Table 3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy Subjects
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Kizakevich et al. 

2000 

Morse et al. 

2008 

Resch et al. 

2005 

16 healthy 

nonsmoking men 

(age range: 18– 

29 years) 

12 healthy 

nonsmoking men 

(mean age: 

25 years) 

6 healthy 

nonsmoking men 

(mean age: 

26 years) 

Randomized, 

cross-over (no 

details on blinding 

reported); upper 

(handcrank) and 

lower body 

(treadmill) exercise 

challenges at 

submaximal effort 

administered 

following 

exposure. 

Cross-over; 

skeletal muscle 

fatigue challenge 

administered 

following 

exposure. 

Randomized, 

cross-over, 

double-blind. 

Subjects exposed to 

CO (concentrations 

1,000–3,000 ppm) for 

4–6 minutes, followed 

by maintenance CO 

exposure (27– 

100 ppm) on separate 

test days: Room 

air (COHb 1.8%); 

CO-1 (COHb 5.0%); 

CO-2 (COHb 9.8%); 

CO-3 (COHb 14.8%); 

or CO-4 (COHb 

19.2%). COHb 

measured by CO-Ox. 

Room air or 3,000 ppm 

for 6 minutes (COHb 

6.2%). 

Subjects administered 

the following 

treatments: Room air 

(COHb 1.2%), 500 ppm 

for 30 minutes (COHb 

8.5%, or 500 ppm for 

30 minutes (COHb 

9.4%). 

Cardiac rhythm, output, 

stoke volume, heart rate, 

and contractility, time-topeak ejection time, blood 

pressure. 

Leg strength, muscle 

fatigue assessed during 

voluntary and electrically 

evoked muscle 

contractions. 

Retinal and submacular 

choroidal blood flow. 

Cardiac rhythm: No effects of CO exposure, 

compared to room air exposure; no 

arrhythmias or ST-segment depression. 

Compensatory changes associated with 

reduced oxygen carrying capacity: 

Significant increases in heart rate at all CO 

exposures and cardiac contractility at COHb 

9.8%. 

NOAEL: Not established 

LOAEL: COHb 5.0% 

Resistance to muscle fatigue decreased 

under voluntary (13% decrease; p<0.05) 

and electrically evoked stimulation (12.5% 

decrease; p<0.05). No effect on leg 

strength. 

NOAEL: Not established 

LOAEL: COHb 6.2% 

Significant increases in retinal and choroidal 

blood flow and retinal vessel diameter at 

COHb ≥8.5%. Study authors state that the 

relationship of this finding to tissue hypoxia 

is unknown. 

NOAEL: Not established 

LOAEL: COHb 8.5% 

CARBON MONOXIDE 3. HEALTH EFFECTS 68
 

 

 

 

 

 

 

Table 3-5. Effects of Acute-Duration Carbon Monoxide Exposure on Cardiovascular Function in Healthy Subjects
	

Reference Study subjects Design Exposure Outcomes assessed Results 

Vogel and	 8 men, including 

Gleser 1972	 3 smokers (age 

range: 20– 

23 years) 

Zevin et al. 2001	 12 healthy men 

(smokers; age 

range: 27–47) 

Randomized, 

cross-over (no 

details on blinding 

reported); exercise 

challenges 

administered 

during exposure. 

Single-blind, crossover. 

1-hour exposure to air 

(COHb 1.0–1.7%) or 

225 ppm CO (COHb 

18.6–20.5%). 

Subjects exposed to 

three treatments for 

durations of 7 days 

each: Room air (COHb 

0.4%), 1,200 ppm CO 

inhalation 20 times/day 

(~every 45 minutes, 

20 times/day to 

simulate smoking 

(COHb 6%), or 

20 cigarettes/day 

(COHb 5%). 

Maximal oxygen uptake 

assessed at rest and at 

submaximal and maximal 

exercise. 

Heart rate, blood pressure, 

catecholamine release, 

platelet activation, white 

blood cell count, 

C-reactive protein 

(inflammation marker). 

At rest, no effect of CO exposure. At 

submaximal exercise, no change in oxygen 

uptake due to compensatory increase in 

cardiac output. At maximal exercise, 

oxygen uptake decreased by 23% 

(p<0.001). 

NOAEL: Not established 

LOAEL: COHb 18.6–20.5% 

CO exposure: No effect on serum levels of 

c-reactive protein or platelet factor 4, heart 

rate, blood pressure, or catecholamine 

release, compared to room air. 

Smoking: Significant elevation in serum 

levels of CRP and platelet factor 4, 

increased heart rate, or catecholamine 

release, compared to room air. No effect on 

blood pressure. 

NOAEL (CO): COHb 6% 

LOAEL (CO): Not established 

CARBON MONOXIDE 3. HEALTH EFFECTS

a

Mean± standard deviation (SD). b

Mean± standard error (SE).
 c

Means; report does not indicate if SD or SE.
 

CO = carbon monoxide; COHb = carboxyhemoglobin; CO-Ox = CO oximetry; EKG = electrocardiogram; LOAEL = lowest-observed-adverse-effect level; NOAEL = noobserved-adverse-effect level
 

69
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 70 

3. HEALTH EFFECTS 

fatigue (Morse et al. 2008); and induced compensatory increases in heart rate and cardiac output 

(Kizakevich et al. 2000; Vogel and Gleser 1972). The above effects of exercise performance are 

consistent with COHb-induced decreased O2 carrying capacity of the blood and normal physiological 

compensatory mechanisms. Evaluations on the potential for carbon monoxide exposure to produce 

exercise-induced cardiac arrhythmias similar to those observed in patients with coronary artery disease 

(i.e., ST-segment depression and premature ventricular contractions) have yielded negative results at 

blood COHb levels up to 5.1% (Adir et al. 1999; Horvath et al. 1975; Kizakevich et al. 2000), although 

the potential for carbon monoxide-induced cardiac arrhythmias during exercise challenge was not 

evaluated at higher blood COHb levels. In subjects (including smokers and nonsmokers) exposed 

continuously for 7 days and evaluated at rest, EKG showed several P-wave deviations (P-wave inversion, 

increased amplitude, decreased amplitude, and changes in P-wave direction) in 3/15 subjects exposed to 

15 ppm carbon monoxide (COHb 2.4%) and in 6/15 subjects exposed to 50 ppm carbon monoxide 

(COHb 5.1%), compared to 0/14 in subjects exposed to room air (Davies and Smith 1980). In one 

subject, a heavy smoker, marked ST-depression also was observed. However, interpretation of these 

findings is limited due to lack of statistical analyses and of evaluation for potential confounding factors 

(e.g., smoking, medication use). Other studies evaluating effects of a single 1-hour exposure to carbon 

monoxide (Hausberg and Somers 1997) or repeated brief exposures to carbon monoxide (approximately 

once every 45 minutes to simulate smoking; Zevin et al. 2001) on cardiovascular function (blood 

pressure, heart rate, forearm blood flow) under resting conditions showed no effects at blood COHb levels 

up to 8.3%. 

In conclusion, results of controlled clinical studies in patients with cardiovascular disease provide 

compelling evidence that acute-duration exposure to carbon monoxide resulting in COHb levels of 2.4– 

5.8% exacerbates cardiovascular morbidity (myocardial ischemia and cardiac arrhythmias). Effects at 

lower blood COHb levels have not been evaluated. However, it should be noted that patients with more 

severe cardiovascular disease may be more sensitive than patients evaluated in these clinical studies. In 

healthy subjects, acute exposure to carbon monoxide at concentrations producing blood COHb levels of 

3.35 and 20.5% resulted in compensatory cardiovascular responses and decreased exercise performance 

consistent with COHb-induced decreased O2 carrying capacity of the blood; however, subjects did not 

exhibit exercise-induced adverse cardiovascular effects (e.g., evidence of myocardial ischemia or cardiac 

arrhythmias). Continuous exposure of healthy subjects, which included smokers, to carbon monoxide 

resulting in blood COHb levels of 2.4 and 5.1% produced P-wave deviations under resting conditions, 

although similar findings have not been reported in other studies. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 71 

3. HEALTH EFFECTS 

Epidemiological Studies. Epidemiological studies of exposure to carbon monoxide and cardiovascular 

outcomes fall into two major categories: (1) studies that have assessed cardiovascular morbidity in 

cohorts or individuals (e.g., case-crossover, case-control) in association with ambient air carbon 

monoxide concentrations; and (2) studies that have evaluated associations between air carbon monoxide 

concentrations and the incidence of hospital admissions and/or emergency room visits related to 

cardiovascular disease (e.g., time-series studies, case-crossover). Collectively, these studies have yielded 

mixed results, although, in general, the weight of evidence suggests that risks of certain specific outcomes 

are associated with increasing ambient carbon monoxide concentrations (hospitalizations and emergency 

room visits related to congestive heart failure, ischemic heart disease, myocardial infarction, and stroke). 

Corroborated observations of association between carbon monoxide exposure and outcomes related to 

ischemic heart disease are consistent with results of human clinical studies that have shown that carbon 

monoxide-induced hypoxia exacerbates symptoms of coronary artery disease. Therefore, it is plausible 

that in certain susceptible populations, such as individuals who have ongoing cardiac impairment that 

would make them vulnerable to ischemia, exposure to carbon monoxide could contribute to triggering 

ischemic episodes and cardiac sequelae. While these studies provide some evidence in support of adverse 

cardiovascular effects of inhalation exposures to carbon monoxide, their utility for establishing doseresponse relationships for these effects are limited by several factors: (1) reliance on area monitoring for 

estimating exposure levels; (2) uncertainty in knowledge of temporal correspondence between monitored 

exposure levels and outcomes; (3) relatively strong correlations between ambient air carbon monoxide 

concentrations and other air quality variables that can affect respiratory function; (4) tendency of 

outcomes investigated to be serious, life-threatening events (e.g., cardiac arrhythmia, myocardial, 

infarction, stroke, heart failure) and reflect the “late-stage” consequences of contributing pathophysiology 

that might be associated with exposures to lower levels of carbon monoxide for longer durations than 

indicated in the epidemiological studies; and (5) relatively low carbon monoxide exposures studied. 

Mean values of carbon monoxide exposure concentrations have ranged from 0.3 to 4.6 ppm, with the 

highest values ≤30 ppm. These values correspond to predicted steady-state COHb levels of <1% for the 

mean and <5% for the highest values (predicted from the CFK model). The latter range is consistent with 

COHb levels observed in a study of emergency department admissions for cardiopulmonary complaints 

(Leikin and Vogel 1986). At these COHb levels, it is possible that only highly susceptible individuals 

exhibit the serious cardiovascular outcomes that have been studied. Clinical studies described previously 

in this section of the Toxicological Profile have found that exposures to carbon monoxide that produce 

COHb levels of 2.4–5% can exacerbate underlying cardiovascular disease, including exercise-induced 

angina and cardiac arrhythmia; however, higher levels (3–20%) can be tolerated without producing such 

effects, even under exertion, in healthy individuals. For these and other reasons, epidemiologic studies 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 72 

3. HEALTH EFFECTS 

have typically focused on highly susceptible populations. A typical design has been to examine 

associations between temporal trends in ambient air carbon monoxide concentrations and hospital 

admissions or emergency department visits for which the reported diagnosis was some form of 

cardiovascular disease of impairment. 

The presentation of the epidemiology is organized by major categories of cardiovascular outcomes for 

which the studies were designed to evaluate, including studies of heart rate and heart rate variability, 

cardiac arrhythmia, ischemic heart disease and related subcategories (e.g., myocardial infarction), heart 

failure, stroke, and blood pressure. Study conclusions are presented in the text, with selected supporting 

details presented in tabular form. Although most of the studies explored various time lags between 

monitored air carbon monoxide concentrations and outcomes, as well as various sample strata, for the 

sake of brevity, only those indicative of the strongest associations to carbon monoxide are presented in 

the tables. Where co-pollutant models have been explored, these results are also presented. 

Studies of Heart Rate (HR) and Heart Rate Variability (HRV). Studies of associations between exposure 

to carbon monoxide and various measures of HR and HRV have yielded mixed results (Table 3-6). 

Carbon monoxide exposure concentrations in these studies represent relatively narrow time periods (e.g., 

averages over 1–5 days prior to the end point assessment). Mean values of carbon monoxide exposure 

concentrations ranged from 0.3 to 4.6 ppm, with the highest values ≤30 ppm (predicted steady-state 

COHb%: <5). Significant associations between increasing carbon monoxide exposure and increasing 

HR were found in some studies (Liao et al. 2004; Peters et al. 1999) and not in others (Gold et al. 2000). 

Assessments of HRV found significant associations with increasing carbon monoxide exposure in some 

studies (Dales 2004; Riojas-Rodriguez et al. 2006; Schwartz et al. 2005; Tarkiainen et al. 2003; Timonen 

et al. 2006) and no associations with HRV in other studies (Chan et al. 2005; Gold et al. 2000; Holguin et 

al. 2003; Liao et al. 2004; Park et al. 2005b). In general, associations for HRV end points were not robust 

for various measures of HRV across studies. For example, assessments of standard deviation of the 

normal-to-normal interval (SDNN) yielded significant associations in some studies (Dales 2004; 

Schwartz et al. 2005; Timonen et al. 2006) and not in others (Chan et al. 2005; Gold et al. 2000; Liao et 

al. 2004; Park et al. 2005b; Tarkiainen et al. 2003). 

Three studies are particularly notable for their relatively large size. Park et al. (2005b) assessed HRV in 

497 male subjects (age range: 21–82 years) of the Boston Normative Aging Study and linked these data 

to local measurements of air pollutant concentrations (carbon monoxide, PM2.5, O3, NO2, SO2). The mean 

carbon monoxide exposure concentration was 0.50 ppm (24-hour average, range: 0.13–18 ppm). The 
 

 

 

 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Heart rate and heart rate variability 

Chan et al. 2005 

Period: 2001–2002 

Location: Taipei, Taiwan 

Dales 2004 

Period: NR 

Location: Toronto, Canada 

Gold et al. 2000
 

Period: 1997 

Location: Boston,
 

Massachusetts
 

Holguin et al. 2003 

Period: 2000 

Location: Mexico City, Mexico 

Liao et al. 2004 

Period: 1996–1998 

Location: Various U.S. cities 

Park et al. 2005b 

Period: 2000–2003 

Location: Boston,
 

Massachusetts
 

Outcome: HRV
 

Design: Panel
 

Sample: 83 patients, age 43–
 

75 years
 

Outcome: HRV
 

Design: Panel
 

Sample: 36 subjects with 

preexisting CAD, age 51–
 

88 years
 

Outcome: HR and HRV
 

Design: Panel/cohort
 

Sample: n=21, age 53–87 years
 

Outcome: HRV
 

Design: Panel
 

Sample: n=34, age 60–90 years
 

Outcome: HR HRV.
 

Design: Cohort
 

Sample: n=6,784, age 45–
 

64 years
 

Outcome: HRV
 

Design: Panel/cohort
 

Sample: n=497 males, age 21–
 

81 years
 

Avg time: 1 hour 

Mean 1.1 ppm 

Range: 0.1–7.7 ppm 

Avg time: 24 hours 

Mean 95th%: 2.40 ppm 

Range: 0.4–16.5 ppm 

Avg time: 24 hours 

Mean: 0.47 ppm 

Range: 0.12–0.82 ppm 

Avg time: 24 hours 

Mean: 3.3 ppm 

Range: 1.8–4.8 ppm 

Avg time: 24 hours 

Mean: 0.65 ppm 

SD: 0.44 ppm 

Avg time: 24 hours 

Mean: 0.50 ppm 

Range: 0.13–1.8 ppm 

No statistically significant effect on SDNN,
 

rMSSD, LFV, or HFV 

Increment: NR 

Regression coefficient (95% CI):
 

SDNN (not taking β-blockers): 0.0111 (0.002, 

0.020, p=0.02)
 

No statistically significant effect on HRV among 

those taking β-blockers
 

Increment: 0.6 ppm
 

% Change (lag 2 days): 

No significant effect of CO on HR or HRV
 

Increment: 10 ppm
 

Regression coefficients (95% CI), lag 0 days: 

HFV: 0.003 (-0.004, 0.001)
 

LFV: 0.001 (-0.006, 0.008)
 

LFV/HFV: 0.001 (-0.005, 0.002)
 

Increment: 0.44 ppm
 

Regression coefficient, lag 1 day:
 

HR (bpm): 0.404 (p<0.05)
 

HFV (log transformed): -0.033 

LFV (log transformed): 0.006 

SDNN: -0.274 

Increment: 0.24 ppm
 

% Change in HRV (95% CI), 4-hour moving avg: 

SDNN (log10): 2.0 (-2.9, 7.3)
 

HFV (log10): 8.8 (-4.6, 24.1)
 

LFV(log10): 3.2 (-7.0, 14.6)
 

LFV:HFV(log10): -5.1 (-13.5, 4.1)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 73
 

 

 

 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Peters et al. 1999 

Study: 1984–1985 

Location: Augsburg, Germany 

Riojas-Rodriguez et al. 2006 

Period: 2001–2002 

Location: Mexico City, Mexico 

Schwartz et al. 2005 

Period: 1999 

Location: Boston, 

Massachusetts 

Tarkiainen et al. 2003 

Period: 1997–1998 

Location: Kuopio, Finland 

Timonen et al. 2006 

Period: 1998–1999 

Location: Amsterdam, 

Netherlands; Erfert, Germany; 

Helsinki, Finland 

Outcome: HR 

Design: Cohort 

Sample: n=2,681, age 25– 

64 years 

Outcome: HRV 

Design: Panel 

Sample: n=30, age 25–76 years 

Outcome: HRV 

Design: Panel 

Sample: n=28, age 61–89 years 

Outcome: HRV 

Design: Panel 

Sample: n=6 males, age 55– 

68 years 

Outcome: HRV 

Design: Panel 

Sample: n=131, age 64– 

72 years 

Avg time: 24 hours 

Mean: 3.9 ppm 

Range: 0.8–10.0 ppm 

Avg time: 24 hours 

Mean: 2.9 ppm 

Range: 0.1–18.0 ppm 

Avg time: 24 hours 

Median: 0.45 ppm 

25th–75th%: 0.38–0.54 ppm 

Avg time: 24 hours 

Mean: 4.6 ppm 

Range: 0.5–27.4 ppm 

Avg time: 24 hours 

Mean: 0.3–0.5 ppm 

Range: 0.1–2.2 ppm 

Increment: 6.6 mg/m3
 

Mean change in HR, bpm (95% CI), lag 0 days: 

All: 0.97 (0.02, 1.91)
 

Male: 0.95 (-0.37, 2.27)
 

Female: 0.98 (-0.37, 2.34)
 

Increment: 1 ppm
 

Regression coefficients (95% CI), lag 5 minutes: 

HFV: -0.006 (-0.023, 0.010)
 

LFV: -0.024 (-0.041, -0.007)
 

VLFV: -0.034 (-0.061, -0.007)
 

Increment: 0.16 ppm
 

% Change in HRV (95% CI), lag 1 day: 

SDNN: -4.2 (-0.6, -7.7)
 

rMSSD: -10.2 (-2.4, -17.4)
 

PNN50: -14.8 (-3.0, -25.2)
 

LFV/HFV: 6.2 (-0.6, 13.4)
 

Increment: NR
 

RR (95% CI), lag 5 minutes:
 

CO >2.7 ppm: Significant increase in rMSSD
 

(2.4 ms, p=0.034) 

CO <27 ppm: No significant association between 

CO and NN, SDNN, or rMSSD 

Increment: 1 mg/m3
 

β coefficient (95% CI), lag 2 days
 

SDNN: -5.96 (-10.7, -0.72)
 

HFV: -30.7 (-59.8, -1.5)
 

LHV/HFV: -10.1 (-36.9, 16.7)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 74
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Cardiac arrhythmia 

Berger et al. 2006 

Period: 2000–2001 

Location: Erfurt, Germany 

Dockery et al. 2005 

Period: 1995–2002 

Location: Boston,
 

Massachusetts
 

Gold et al. 2005
 

Period: 1999
 

Location: Boston,
 

Massachusetts
 

Metzger et al. 2007 

Period: 1993–2002 

Location: Atlanta, Georgia 

Peters et al. 2000b 

Period: 1995–1997 

Location: Eastern 

Massachusetts
 

Rich et al. 2004 

Period: 2000 

Location: Vancouver, Canada 

Rich et al. 2005
 

Period: 1995–1999 

Location: Boston,
 

Massachusetts
 

Outcome: SVT and VT 24-hour 

EKG 

Design: Panel 

Sample: 57 males with CHD, 

age 52–76 years 

Outcome: Tachycardia 

Design: Panel 

Sample: n=203 with ICDs, age 

19–90 years 

Outcome: ST-segment 

Design: Panel 

Sample: n=24, age 61–68 years 

Outcome: CAR, VT 

Design: Panel 

Sample: n=518 with ICDs, with 

≥1 VT event, age 15–88 years 

Outcome: VT or fibrillation 

Design: Panel 

Sample: n=100 with ICDs, mean 

age 62 years 

Outcome: CAR 

Design: Case-crossover 

Sample: n=34 with ≥1 ICD 

discharge, age 15–85 years 

Outcome: VAR 

Design: Panel/case-crossover 

Sample: n=203 with implanted 

ICDs 

Avg time: 24 hours 

Mean: 0.45 ppm 

Range: 0.10–1.68 ppm 

Avg time: 24 hours 

Median: 0.8 ppm 

25th–75th%: 0.53–1.02 ppm 

Avg time: 5 hours 

Median: 0.52 ppm 

10th–90th%: 0.20–1.08 ppm 

Avg time: 1 hour 

Mean: 1.7 ppm 

Range: 0.1–7.7 ppm 

Avg time: 24 hours 

Mean: 0.58 ppm 

25th–75th%: 0.66 ppm 

Avg time: 24 hours 

Mean: 0.553 ppm 

Interquartile range: 0.162 ppm 

Avg time: 24 hours 

Median: 0.78 ppm 

25th–75th%: 0.52–1.03 

Increment: 0.22 mg/m3
 

RR for SVT (95% CI), 5-day avg:
 

1.18 (1.04, 1.35) 

Increment: 0.48 ppm
 

OR for VT (95% CI), lag 2 days:
 

All: 1.14 (0.95, 1.29)
 

AR ≤3 days prior: 1.65 (1.17, 2.33)
 

Significant association between CO and 

ST-segment depression did not persist in multiple 

pollutant models
 

Increment: 1 ppm
 

OR for VT (95% CI), lag 0 days: 

All: 0.999 (0.970, 1.028)
 

Increment: 0.65 ppm
 

OR for ≥10 defibrillated discharges (95% CI):
 

Lag 3: 1.98 (1.05, 3.72)
 

Lag 5-day avg: 1.94 (1.01, 0.75)
 

No significant effect of CO (quantitative results
 

not reported)
 

Increment: 0.5 ppm
 

OR: (95% CI), lag 0–2 days: 1.11 (0.88, 1.40)
 

(also not significant at other lags)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 75
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Rich et al. 2006b 

Period: 2001 and 2002 

Location: St. Louis, Missouri 

Rich et al. 2006a
 

Period: 1995–1999 

Location: Boston,
 

Massachusetts
 

Sarnat et al. 2006 

Period: 2000 

Location: Steubenville, Ohio 

Vedal et al. 2004 

Period: 1997–2000 

Location: Vancouver, Canada 

Cardiac arrest 

Dennekamp et al. 2010 

Period: 2003–2006 

Location: Melbourne, Australia 

Levy et al. 2001 

Period: 1988–1994 

Location: Seattle, Washington 

Outcome: VAR 

Design: Case-crossover 

Sample: n=60 with ≥1 ICD CAR 

recorded 

Outcome: AF 

Design: Panel/case-crossover 

Sample: n=203 with ICDs 

Outcome: CAR 

Design: Panel 

Sample: 32 nonsmoking, age 

53–90 years 

Outcome: CAR 

Design: Panel 

Sample: n=50 with ICDs and 

≥1 CAR event/4 years, age 12– 

77 years 

Outcome: Cardiac arrest 

Design: Case-crossover 

Sample: 8,434 cases, age >35– 

103 years 

Outcome: Cardiac arrest 

Design: Case-crossover 

Sample: 362 cases, age 25– 

75 years 

Avg time: 24 hours 

Median: 0.5 ppm 

25th–75th%: 0.6 ppm 

Avg time: 24 hours 

Median: 0.78 ppm 

25th–75th%: 0.52–1.03 ppm 

Avg time: 24 hours 

Mean: 0.02 ppm 

Range 0–1.5 ppm 

Avg time: 24 hours 

Mean: 0.6 ppm 

Range: 0.3–1.6 ppm 

Avg time: 24 hours 

Mean: 0.44 ppm 

25th–75th%: 0.27–0.52 ppm 

Avg time: 24 hours 

Mean: 1.79 ppm 

Range: 0.52–5.92 ppm 

Increment: 0.2 ppm
 

OR for VAR (95% CI), lag 0–1 day: 0.99 (0.80, 

1.21)
 

Increment: 0: 0.58 ppm
 

OR for AF (95% CI):
 

Lag 0: 0.87 (0.56, 1.37)
 

Lag 0–23 hours: 0.71 (0.39, 1.28)
 

Increment: 0.2 ppm
 

RR (95% CI), 5-day moving avg:
 

SVE: 0.99 (0.76, 1.29)
 

VE: 1.05 (0.75, 1.46)
 

Increment: 0.2 ppm
 

No significant effect for CO (results shown in 

plots)
 

Increment: 0.25 ppm
 

RR % change (95% CI):
 

Lag 0–1: 3.09 (0.25, 4.58)
 

Lag 0: 2.09 (-0.33, 4.58) 

Lag 1: 2.38 (-0.54, 5.39) 

Lag 2: -0.09 (-2.96, 2.86)
 

Lag 3: 1.61 (-1.31, 4.62)
 

RR (95% CI), lag 1 day:
 

0.99 (0.83, 1.18) 

CARBON MONOXIDE 3. HEALTH EFFECTS 76
 

 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Silverman et al. 2010 

Period: 2002–2006 

Location: New York, New York 

Sullivan et al. 2003 

Period: 1985–1994 

Location: Washington State 

Myocardial infarction 

Peters et al. 2001 

Period: 1995–1996 

Location: Boston,
 

Massachusetts
 

Rosenlund et al. 2006 

Period: 1992–1994 

Location: Stockholm, Sweden 

Outcome: Cardiac arrest 

Design: Case-crossover 

Sample: 8,216 cases, mean age 

>65.6 years 

Outcome: Cardiac arrest 

Design: Case-crossover 

Sample: 1,542 cases, median 

age 69 years 

Outcome: Onset of MI 

Design: Case-crossover 

Sample: 772 cases 

Outcome: MI 

Design: Case-control 

Sample: 1,397 cases, 

1,870 controls, age range 45– 

70 years 

Avg time: 24 hours 

Median: 0.9 ppm 

5th–95th%: 0.6–1.5 ppm 

Avg time: 24 hours 

Mean: 1.92 ppm 

Range: 0.52–7.21 ppm 

Avg time: 24 hours 

Mean: 1.09 ppm 

5th–95th%: 0.49–1.78 ppm 

Avg time: 30 years 

Mean: 0.058 ppm 

5th–95th%: 0.012–0.258 ppm 

Increment: 0.3 ppm
 

RR (95% CI):
 

Lag 0–1: ~0.99 (0.96, 1.03)
 

(estimated from Figure 2)
 

Increment: 1.02 ppm
 

OR (95% CI): 

Lag 0: 0.95 (0.85, 1.05)
 

Lag 1: 0.97 (0.87, 1.08)
 

Lag 2: 0.99 (0.89, 1.11)
 

Increment: 1 or 0.6 ppm
 

OR (95% CI):
 

2 hours: 1.22 (0.89, 1.67) per 1 ppm
 

24 hours: 0.98 (0.70, 1.36) per 0.6 ppm
 

Increment: 300 μg/m3
 

OR: (95% CI): 

All cases: 1.04 (0.89, 1.21)
 

Nonfatal: 0.98 (0.82, 1.16)
 

Fatal: 1.22 (0.98, 1.52)
 

Fatal, in-hospital: 1.16 (0.89, 1.51)
 

Fatal, out-hospital: 1.36 (1.01, 1.84)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 77
 

 

 

 

 

 

 

 

 

Table 3-6. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Blood pressure 

Ibald-Mulli et al. 2001 Outcome: SBP Avg time: 24 hours Increment: 5.6 mg/m3 

Period: 1984–1985 Design: Cohort Mean: 3.6 ppm Mean change in SBP, mmHg (95% CI): 

Location: Augsburg, Germany Sample: n=2,607 men and Range: 1.5–7.2 ppm All: 0.53 (-0.66, 1.72) 

women age 25–64 years Males: 0.68 (-0.94, 2.31) 

Females: 0.51 (-1.31, 2.19) 

Zanobetti et al. 2004b Outcome: BP Avg time: 120 hours Increment: NR 

Period: 1999–2001 

Location: Boston, 

Design: Cohort/panel 

Sample description: n=62, age 

Mean: 0.66 ppm 

10th–90th%: 0.48–0.86 ppm 

RR: No significant effect of CO on BP 

Massachusetts 39–90 years 

CARBON MONOXIDE

AF = atrial fibrillation; AR = arrhythmia; Avg = average; BP = blood pressure; CAD = coronary artery disease; CAR = cardiac arrhythmia; CHD = coronary heart disease; 

CI = confidence interval; CO = carbon monoxide; EKG = electrocardiogram; HFV = high frequency (HR) variability; HR = heart rate; HRV = heart rate variability;
 

ICD = implantable cardioverter defibrillator; LFV = low frequency (HR) variability; MI = myocardial infarction; NR = not reported; OR = odds ratio; PNN50 = proportion of
 

interval differences of successive normal-beat intervals >50 ms in EKG; rMSSD = root mean squared differences between adjacent RR intervals; RR = relative risk;
 

SBP = systolic blood pressure; SD = standard deviation; SDNN = standard deviation normal-to-normal (NN or RR) time interval between each QRS complex in the EKG;
 

SVE = supraventricular ectopy; SVT = supraventricular tachycardia; VAR = ventricular arrhythmia; VLFV = very low frequency (HR) variability; VE = ventricular ectopy;
 

VT = ventricular tachycardia
 

3. HEALTH EFFECTS 78
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 79 

3. HEALTH EFFECTS 

study did not find significance between carbon monoxide exposure levels and HRV end points assessed 

(SDNN, low frequency [LF], high frequency [HF], LF/HF). A study conducted in Augsburg, Germany 

evaluated possible associations between exposures to total suspended particles (TSP), SO2, and carbon 

monoxide (mean: 4.5 mg/m3 [3.9 ppm], range: 2.4–6.8 mg/m3 [2.1–5.9 ppm) and HR in 2,681 adults (age 

range: 25–64 years; Peters et al. 1999). A 6.6 mg/m3

 (5.8 ppm) increase in 24-hour average carbon 

monoxide concentration was associated with a small but significant increase in HR of approximately 

1 beat per minute (0.97 beats/minute, 95% CI: 0.02, 1.91); however, carbon monoxide exposure was not 

significantly associated with HR when based on a 5-day average exposure concentration (0.7 per 

3.3 mg/m3 [2.9 ppm], 95% CI: -0.09, 1.58). A subsample of 6,232 adults (age range: 45–64 years) from 

the Atherosclerosis Risk in Communities study (Washington County, Maryland; Forsyth County, North 

Carolina; and selected suburbs of Minneapolis, Minnesota and Jackson, Mississippi) examined possible 

associations between exposure to carbon monoxide (mean: 0.65 ppm, standard deviation [SD]: 0.44) and 

HR and HRV, as well as to other air pollutants (PM10, O3, NO2, SO2; Liao et al. 2004). An increase in 

carbon monoxide exposure concentration of 0.44 ppm was associated with a small but significant increase 

in HR of 0.4 beats per minute (standard error [SE]: 0.16, 95% CI: 0.09, 0.7 [calculated from SE]). 

Carbon monoxide exposure was not significantly associated with HRV. 

Studies of Arrhythmia. Studies of associations between exposure to carbon monoxide and cardiac 

arrhythmia (e.g., fibrillation, tachycardia) have yielded mixed results (Table 3-6). Mean values of carbon 

monoxide exposure concentrations (i.e., averages over 1–5 days prior to the end point assessment) ranged 

from 0.2 to 1.7 ppm, with the highest values ≤8 ppm. Significant associations between increasing carbon 

monoxide exposure and arrhythmia episode incidence were found in some studies, particularly when the 

analysis was restricted to subjects with prior recent arrhythmia (Berger et al. 2006; Dockery et al. 2005; 

Peters et al. 2000a), but not in other studies (Metzger et al. 2007; Rich et al. 2004, 2005; Sarnat et al. 

2006; Vedal et al. 2004). One of the larger studies examined associations between exposures to carbon 

monoxide (median: 0.8 ppm; 95th percentile: 1.37 ppm) and other air pollutants (e.g., PM10, PM2.5, O3, 

NO2, SO2) and ventricular arrhythmia episodes in 203 patients who were monitored with implanted 

defibrillators (ICDs) and who had prior episodes of ventricular tachycardia (Dockery et al. 2005; Rich et 

al. 2005). In the total sample, exposure to carbon monoxide was not significantly associated with 

ventricular arrhythmia; however, when restricted to patients who had experienced arrhythmias within the 

3 days of the exposure assessment, increasing carbon monoxide exposure of 0.48 ppm was significantly 

associated ventricular arrhythmia (odds ratio: 1.65; 96% CI: 1.17, 2.33). A larger study examined 

512 patients (age range: 15–88 years) exposed to a mean carbon monoxide concentration of 1.7 ppm 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 80 

3. HEALTH EFFECTS 

(range: 0.1–7.7 ppm) and did not find a significant association with defibrillator discharges and carbon 

monoxide exposure concentration (Metzger et al. 2007). 

Studies that have assessed arrhythmias from EKG measurements have also yielded mixed results (Berger 

et al. 2006; Sarnat et al. 2006). A study of 57 coronary heart disease patients (age range: 52–76 years) 

found a significant association between increasing carbon monoxide exposure and risk of supraventricular 

tachycardia (Berger et al. 2006). Mean carbon monoxide exposure concentration was 0.52 mg/m3 

(0.45 ppm; range: 0.11–1.93 mg/m3 [0.10–1.68 ppm]). The relative risk for a 0.27 mg/m3

 (0.24 ppm) 

increase in carbon monoxide was 1.18 (95% CI: 1.04, 1.35). A significant association between carbon 

monoxide exposure and ventricular tachycardia was not evident. Sarnat et al. (2006) did not find a 

significant association between carbon monoxide exposure concentrations (mean: 0.2 ppm, range: 0.1– 

1.5) and arrhythmia in a sample of 32 adults (age range: 53–90 years). The study did find significant 

associations between increased blood pressure and other air pollutants (e.g., PM2.5, SO2, O3, back carbon). 

Studies of Ischemic Heart Disease. Numerous studies have examined possible associations between 

carbon monoxide exposure and ischemic heart disease (Tables 3-6 and 3-7). Although results have been 

mixed, most studies, in particular those that examined hospital admissions or emergency room visits as 

the health outcome, have found increased risk association with increased ambient air carbon monoxide 

concentrations. A case-control study of myocardial infarction (1,397 cases, 1,870 controls) conducted in 

Sweden did not find a significant association with carbon monoxide exposure (Rosenlund et al. 2006). 

Exposure concentrations were estimated from emissions data and air dispersion modeling; the mean was 

61.8 μg/m3

 (0.067 ppm; 5th–95th percentile range: 14–296 μg/m3; predicted steady-state COHb%: <0.3). 

The odds ratio for myocardial infarct for a 300 μg/m3

 (0.3 ppm) increase in 30-year average carbon 

monoxide concentration was 1.04 (95% CI: 0.89, 1.21). When restricted to out-of-hospital deaths, the 

odds ratio was 1.36 (95% CI: 1.01, 1.84). A smaller case-crossover study (772 cases) conducted in 

Boston, Massachusetts did not find a significant association between carbon monoxide exposure and 

myocardial infarction (Peters et al. 2001). The odds ratio for a 1 ppm increment in carbon monoxide 

exposure concentration, for a 2-hour period prior to infarct, was 1.22 (95% CI: 0.89, 1.67); the mean 

carbon monoxide exposure concentration was 1.09 (5th–95th percentile range: 0.49–1.78 ppm, predicted 

steady-state COHb%: ≤0.55). 

Possible associations between carbon monoxide exposure (and other air pollutants; e.g., PM, NO2, O3) 

and ischemic heart disease have also been explored in studies of hospital admissions and/or hospital 

emergency department visits (D’Ippoliti et al. 2003; Hosseinpoor et al. 2005; Lanki et al. 2006; Lee et al. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Ischemic heart disease 

D’Ippoliti et al. 2003 

Period: 1995–1997 

Location: Rome, Italy 

Hosseinpoor et al. 2005 

Period: 1996–2001 

Location: Tehran, Iran 

Lanki et al. 2006 

Period: 1994–2000 

Location: Helsinki, Rome, 

Stockholm 

Lee et al. 2003b 

Period: 1997–1999 

Location: Seoul, Korea 

Maheswaran et al. 2005b 

Period: 1994–1998 

Location: Sheffield, United 

Kingdom 

Mann et al. 2002 

Period: 1988–1995 

Location: California 

Outcome: MI HAs 

Design: Case-crossover 

Sample: n=6,531, age ≥18 years 

Outcome: AP HAs 

Design: Time series 

Sample: n=1,826 

Outcome: MI HAs 

Design: Time series 

Sample: 26,854 admissions, 

age ≥35 years 

Outcome: IHD, MI, AP HAs 

Design: Time series 

Sample: ~10,000 HAs 

Outcome: IHD HAs 

Design: Ecological 

Subjects: 11,407 admissions, age 

≥45 years 

Outcome: IHD, MI HAs 

Design: Time series 

Sample: 54,863 HAs 

Avg time: 24 hours 

Mean: 3.8 ppm 

25th–75th%: 2.4–3.8 ppm 

Avg time: 24 hours 

Mean: 9.4 ppm 

Range: 1.4–50.5 ppm 

Avg time: 24 hours 

Median: 0.4–2.3 ppm 

75th% Range: 0.5–2.9 ppm 

Avg time: Daily maximum 

Mean: 1.8 ppm 

25th–75th%: 1.2–2.2 ppm 

Avg time: NR 

20th–80th%: 0.34–0.40 ppm 

Avg time: 8 hours 

Mean: 2.07 ppm 

Range: 0.30–11.8 ppm 

Increment: 1 mg/m3
 

OR (95% CI), lag 0–2 days:
 

CO alone: 1.044 (1.000, 0.089)
 

CO with TSP: not significant
 

Increment: 1 mg/m3 (0.87 ppm)
 

RR (95% CI), lag 1 day:
 

CO alone: 1.0096 (1.0060, 1.0132)
 

CO with NO2, O3, and PM10: 1.0093 (1.0036, 

1.0151)
 

Increment: 0.2 mg/m3 

RR (95% CI), lag 0 days: 

All: 1.007 (1.001, 1.012) 

Fatal (≤75 years): 1.027 (1.006, 1.048)
 

Increment: 1 ppm
 

RR (95% CI), lag 5 days:
 

All year, all ages: 0.94 (0.91, 0.98)
 

All year, ≥64 years: 1.07 (1.01, 1.13)
 

Summer, all ages: 1.19 (1.02, 1.38)
 

Summer, ≥64 years: 1.60 (1.27, 2.03)
 

All year, ≥64 years (with PM10): 1.04 (0.98, 1.11)
 

Increment: 5th vs. 1st quintile
 

RR, adjusted for sex, age, deprivation, smoking 

(95% CI):
 

0.88 (0.79, 0.98) 

Increment: 1 ppm
 

% Change (95% CI), lag 0 days: 

with arrhythmia: 2.99 (1.80, 4.99)
 

with CHF: 3.60 (1.620, 5.63)
 

without secondary diagnosis: 1.62 (0.65, 2.59)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 81
 

 

 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Szyszkowicz 2007 

Period: 1997–2003 

Location: Montreal 

von Klot et al. 2005 

Period: 1992–2001 

Location: 5 European cities 

Stroke 

Chan et al. 2006 

Period: 1997–2002 

Location: Taipei, Taiwan 

Henrotin et al. 2007 

Period: 1994–2004 

Location: Dijon, France 

Maheswaran et al. 2005b 

Period: 1994–1998 

Location: Sheffield, United 

Kingdom 

Outcome: IHD EDVs 

Design: Time series 

Sample: 4,979 EDVs 

Outcome: MI, AP, CAR, HF, HAs 

Design: Prospective cohort 

Sample: 22,006 survivors of first 

MI 

Outcome: Stroke EDVs 

Design: Time series 

Sample: 7,341 EDVs, age 50– 

100 years 

Outcome: Stroke HAs 

Design: Case-crossover 

Sample: 1,707 cases, age: 

≥40 years 

Outcome Stroke HAs 

Design: Ecological 

Sample: 11,407 HAs, age 

≥45 years 

Avg time: 24 hours 

Mean: 0.5 ppm 

Range: 0.1–3.1 ppm 

Avg time: 24 hours 

Mean: 0.37–0.87 ppm 

Avg time: 8 hours 

Mean: 1.7 ppm 

Range: 0.6–4.4 ppm 

Avg time: 24 hours 

Mean: 0.60 ppm 

Range: 0–3.5 ppm 

Avg time: NR 

20th–80th%: 0.34–0.40 ppm 

Increment: 0.2 ppm
 

% Change (95% CI), lag 0 days: 

All: 5.4 (2.3, 8.5)
 

Males: 7.5 (3.6, 11.6)
 

Females: 2.7 (-2.0, 7.6)
 

All: ≥64 years: 4.9 (1.3, 8.7)
 

Males: ≥64 years: 7.5 (2.6, 12.6)
 

Females: ≥64 years: 0: 2.4 (-3.0, 0.0) 

Increment: 0.2 mg/m3
 

RR (95% CI), lag 0 days: 

MI: 1.022 (0.998, 0.047)
 

AP: 1.009 (0.992, 0.02)
 

Any cardiac: 1.014 (1.001, 0.026)
 

Increment: 0.8 ppm
 

OR (95% CI), lag 2 days: 

All: 1.03 (1.01, 1.06)
 

Stroke: 1.03 (1.01, 1.05)
 

Significant after adjustment for O3, PM2.5, PM10
 

Increment: 10 μg/m3 

OR (95% CI), lag 0 days:
 

Ischemic: 0.999 (0.997, 1.001)
 

Hemorrhagic: 1.000 (0.996, 1.004)
 

Other lags not significant
 

Increment: 5th vs. 1st quintile
 

RR (95% CI) adjusted for sex, age, deprivation,
 

smoking: 1.11 (0.99, 1.25)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 82
 

 

 

 

 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Tsai et al. 2003 

Period: 1997–2000 

Location: Kaohsiung, Taiwan 

Villeneuve et al. 2006a 

Period: 1992–2002 

Location: Edmonton, Canada 

Wellenius et al. 2005a 

Period: NR 

Location: 9 U.S. cities 

Heart failure 

Lee et al. 2007a 

Period: 1996–2004 

Location: Kaohsiung, Taiwan 

Symons et al. 2006 

Period: 2002 

Location: Baltimore, Maryland 

Wellenius et al. 2005b 

Period: 1987–1999 

Location: Pennsylvania 

Outcome: Stroke HAs 

Design: Case-crossover 

Statistical analyses: NR 

Sample: 23,192 HAs 

Outcome: Stroke EDVs 

Design: Case-crossover 

Sample: 12,422 EDVs, age 

≥65 years 

Outcome: Stroke EDVs 

Design: Time series 

Sample: 155,503 EDVs, age 

≥65 years 

Outcome: CHF HAs 

Design: Case-crossover 

Sample description: 13,475 HAs 

Outcome: CHF HAs, symptom 

exacerbation 

Design: Case-crossover 

Sample: 125 cases, median age 

70 years 

Outcome: CHF HAs 

Design: Case-crossover 

Sample: 54,019 HAs, age 

≥65 years 

Avg time: 24 hours 

Mean 0.79 ppm 

Range: 0.24–1.72 ppm 

Avg time: 24 hours 

Mean: 0.8 ppm 

25th–75th%: 0.5–1.0 ppm 

Avg time: NR 

Median: 1.02 ppm 

25th–75th%: 0.73–1.44 ppm 

Avg time: 24 hours 

Mean: 0.76 ppm 

Range: 0.14–1.72 ppm 

Avg time: 24 hours 

Mean: 0.4 ppm 

Range: 0.1–1.0 ppm 

Avg time: 24 hours 

Mean: 1.03 ppm 

25th–75th%: 0.68–1.23 ppm 

Increment: 0.8 ppm
 

OR (95% CI), lag 0–2 days:
 

>20 °C: 1.21 (1.14, 1.28)
 

<20 °C: 1.77 (1.31, 2.39)
 

Significant OR when adjusted for PM10, SO2, or
 

O3
 

Increment: 0.5 ppm
 

OR (95% CI), lag 0–2 days:
 

April–September: 1.32 (1.09, 1.60) (not
 

significant for all seasons)
 

Increment: 0.71 ppm
 

% Change (95% CI) lag 0 days:
 

Ischemic: 2.83 (1.23, 4.46)
 

Hemorrhagic: -1.61 (-4.79, 1.68)
 

Increment: 0.31 ppm
 

OR (lag 0–2 days):
 

≥25 °C: 1.19 (1.09–1.31)
 

<25 °C: 1.39 (1.24–1.54)
 

Significant when adjusted for PM10, NO2, SO2, or
 

O3
 

Increment: 0.2 ppm
 

OR (95% CI), lag 1 day:
 

Avg: 0.90 (0.70, 1.17)
 

Cumulative: 0.82 (0.60, 1.13)
 

Other lags not significant
 

Increment: 0.55 ppm
 

% Change (85% CI), lag 0 days: 

4.55 (3.33, 5.79)
 

Significant when adjusted for NO2 PM10, NO2, 

SO2, or O3
 

CARBON MONOXIDE 3. HEALTH EFFECTS 83
 

 

 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Miscellaneous cardiovascular disease 

CARBON MONOXIDE

Ballester et al. 2001 

Period: 1994–1996 

Location: Valencia, Spain 

Ballester et al. 2006 

Period: 1995–1999 

Location: 14 cities in Spain 

Barnett et al. 2006 

Period: 1998–2001 

Location: Australia, 

Auckland, New Zealand 

Bell et al. 2009 

Period: 1999–2005 

Location: 126 urban U.S. 

counties 

Chang et al. 2005 

Period: 1997–2001 

Location: Taipei, Taiwan 

Outcome: HD, CBVD EDVs 

Design: Time series 

Sample: >9,000 EDVs 

Outcome: HD, CVD HAs 

Design: Time series 

Sample: >250,000 HAs 

Outcome: CVD HAs 

Design: Case-crossover 

Sample: age ≥15 years 

Outcome: CVD HAs 

Design: Time series 

Sample: >9.3 million HAs, 

age >65 years 

Outcome: CVD HAs 

Design: Case-crossover 

Sample 74,509 HAs 

Avg time: 1 hour
 

Mean: 5.4 ppm
 

Range: 0.5–15.5 ppm
 

Avg time: 8 hours
 

Mean: 1.2–2.4 ppm
 

10th% Range: 0.3–1.5 ppm
 

90th% Range: 1.7–3.4 ppm
 

Avg time: 8 hours
 

Mean: 0.5–2.1 ppm
 

Range: 0.0–7.9 ppm
 

Avg time: 1 hour
 

Median (daily maximum): 

1.3 ppm 

25th–75th%: 0.9–1.9 ppm 

Avg time: 24 hours 

Mean: 1.37 ppm 

Range: 0.37–3.66 ppm 

Increment: 1 mg/m3
 

RR (95% CI):
 

All, lag 2: 1.0077 (0.9912, 1.0138)
 

HD, lag 1: 1.0092 (0.9945, 1.0242)
 

CBVD, lag 1: 0.9874 (0.9646, 1.0107)
 

Increment: 1 mg/m3
 

% Change (95% CI), lag 0–1 day: 

CVD: 2.06 (0.65, 3.48)
 

HD: 4.15 (1.31, 7.08)
 

Increment: 0.9 ppm
 

% Change (95% CI) lag 0–1 day: 

Lags examined (days): 0–1 

15–64 years
 

CVD, <65 years: 1.2 (0.3, 2.1)
 

CVD, ≥65 years: 2.2 (0.9, 3.4)
 

Significant when adjusted for NO2 or PM10
 

Increment: 1 ppm
 

RR % Change (95% CI) lag 0 days: 

CO: 0.96 (0.79, 1.12)
 

CO+NO2: 0.55 (0.36, 0.74)
 

CO+PM2.5: 0.76 (0.57, 0.96)
 

CO+NO2+PM2.5: 0.52 (0.29, 0.75)
 

Increment: 0.49 ppm
 

OR (95% CI) lag 0–2 days:
 

≥20 °C: 1.090 (1.064, 1.118)
 

<20 °C: 0.984 (0.927, 1.044)
 

Significant when adjusted for PM10, NO2, SO2, or
 

O3
 

3. HEALTH EFFECTS 84
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Fung et al. 2005 Outcome: CVD HAs 

Period: 1995–2000 Design: Time series 

Location: Windsor, Ontario, Sample: 11,632 HAs 

Canada 

Jalaludin et al. 2006 Outcome: CVD EDVs 

Period: 1997–2001 Design: Time series 

Location: Sydney, Australia Sample: >100,000 EDVs, age 

≥65 years 

Koken et al. 2003 Outcome: CVD HAs 

Period: 1993–1997 Design: Time series 

Location: Denver, Colorado Sample: >4,000 HAs, age 

65 years 

Linn et al. 2000 Outcome: CVD, CBVD HAs 

Period: 1992–1995 Design: Time series 

Location: Los Angeles, Sample: >500,000 HAs, age 

California >30 years 

Metzger et al. 2004 Outcome: Cardiovascular: CVD 

Study: 1993–2000 EDVs 

Location: Atlanta, Georgia Design: Time series 

Sample: 4,407,535 EDVs 

Peel et al. 2007 Outcome: CVD EDVs 

Period: 1993–2000 Design: Case-crossover 

Location: Atlanta, Georgia Sample: 4,407,535 EDVs 

Avg time: 24 hours 

Mean: 1.3 ppm 

Range: 0.0–11.8 ppm 

Avg time: 8 hours 

Mean 0.82 ppm 

Range: 0.02–4.63 ppm 

Avg time: 24 hours 

Mean: 0.9 ppm 

Range: 0.3, 1.6 ppm 

Avg time: 24 hours 

Mean 1.0–2.0 ppm 

Range: 0.2–5.3 ppm 

Avg time: 1 hour 

Median: 1.5 ppm 

10th–90th%: 0.5–3.4 ppm 

Avg time: 1 hour 

Mean: 1.8 ppm 

SD: 1.2 ppm 

Increment: 1.2 ppm
 

% Change (95% CI), lag 0–2 days: 

<65 years: -0.5 (-6.7, 6.0)
 

≥65 years: 2.8 (-1.1, 7.0)
 

Increment: 0.69 ppm
 

% Change (95% CI), lag 0–1 days: 

2.35 (1.39, 3.32) 

Significant when adjusted for PM10, NO2, SO2, or 

O3 

Increment: 0.3 ppm
 

% Change (95% CI) lag 3 days: 

CHF: 10.5 (0.1, 22.0)
 

CO not significantly associated with other CVD
 

categories.
 

Increment: 1 ppm
 

Poisson regression coefficient (SE), lag 0 days: 

CVD, all: 0.032 (0.003) (p<0.05)
 

Significant for AR, CBVD, CHF, MI, stroke p<0.05 

Increment: 1 ppm
 

RR (95% CI), lag 0–2 days:
 

All CVD: 1.017 (1.008, 1.027)
 

PVD/CBVD: 1.031 (1.010, 1.052)
 

Not significant for AR, CHF, IHD categories
 

Increment: 1.2 ppm
 

OR (95% CI), lag 0–2 days:
 

1.020 (1.010, 10.030)
 

ORs for specific CVD categories tended to
 

increase with co-diagnoses of HT, AR, CHF, 

COPD 

CARBON MONOXIDE 3. HEALTH EFFECTS 85
 

 

 

 

 

 

 

Table 3-7. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Hospital Admissions and Emergency Department Visits Related to Cardiovascular Disease
	

Study Design features CO exposure Effect size 

Yang et al. 2004a 

Period: 1997–2000 

Location: Kaohsiung, Taiwan 

Outcome: CVD HAs 

Design: Case-crossover 

Sample: 29,661 HAs 

Avg time: 24 hours 

Mean: 0.79 ppm 

Range 0.24–1.72 ppm 

Increment: 0.28 ppm 

OR (95% CI), lag 0–2 days: 

≥25 °C: 1.264 (1.205, 1.326) 

<25 °C: 1.448 (1.357, 1.545) 

Significant when adjusted for PM10, NO2, SO2, or 

O3 

CARBON MONOXIDE

AP = angina pectoris; AR = arrhythmia; Avg = average; CAR = cardiac arrhythmia; CBVD = cerebrovascular disease; CHF = congestive heart failure; CI = confidence 

interval; CO = carbon monoxide; COPD = chronic obstructive pulmonary disease; CVD = cardiovascular disease; EDV = emergency department visit; HA = hospital 

admission; HD = heart disease; HF = heart failure; HT = hypertension; IHD = ischemic heart disease; MI = myocardial infarction; NR = not reported; OR = odds ratio; 

PVD = peripheral vascular disease; RR = relative risk; SD = standard deviation; SE = standard error; TSP = total suspended particles 

3. HEALTH EFFECTS 86
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 87 

3. HEALTH EFFECTS 

2003b; Maheswaran et al. 2005b; Mann et al. 2002; Szyszkowicz 2007; von Klot et al. 2005). Although 

results have been mixed, most studies found significant associations between increasing carbon monoxide 

exposure concentration and ischemic heart disease-related admissions or emergency room visits 

(Table 3-7). These included increased odds (or relative risk) for hospital admissions for angina pectoris, 

myocardial infarction, and aggregated ischemic heart disease categories (D’Ippoliti et al. 2003; 

Hosseinpoor et al. 2005; Lanki et al. 2006; Lee et al. 2003b; Mann et al. 2002; Szyszkowicz 2007; von 

Klot et al. 2005). Mean air carbon monoxide concentrations in these studies ranged from approximately 

0.4 to 2 ppm, with the upper percentiles (i.e., ≥75th) ranging from approximately 1 to 5 ppm, although one 

study reported a mean of 10.8 mg/m3

 (9.40 ppm) and a maximum of 57.9 mg/m3 (approximately 50 ppm; 

Hosseinpoor et al. 2005). Associations with carbon monoxide tended to be stronger for more elderly 

males than for females or other age strata (e.g., Lee et al. 2003b; Szyszkowicz 2007). Risks were higher 

when ischemic heart disease was accompanied by a diagnosis of arrhythmia or congestive heart failure 

(Mann et al. 2002; see further discussion of carbon monoxide associations with congestive heart failure, 

below). Lee et al. (2003b) found a significant association (1997–1999) between ischemic heart diseaserelated hospital admissions in Seoul, Korea and carbon monoxide exposure concentrations among males 

≥64 years of age, but not for females or other age strata. A 1 ppm increase in carbon monoxide 

concentration was associated with a relative risk of 1.07 (95% CI: 1.01, 1.1) for hospital admission. The 

mean daily 1-hour maximum carbon monoxide concentration was 1.8 ppm (25th–75th percentile range: 

1.2–2.2 ppm). The association with carbon monoxide exposure was not significant after adjustment for 

exposure to PM10 in a two-pollutant model (1.04. 95% CI: 0.98, 1.11). Two-pollutant models with 

carbon monoxide and other gaseous pollutants were not reported, although significant associations were 

found when NO2, O3, or SO2 were considered alone. Szyszkowicz (2007) examined records of 

4,979 emergency room visits in Montreal, Canada for the period 1997–2002. The percent increase in 

visits related to ischemic heart disease for a 0.2 ppm increase in carbon monoxide concentration was 5.4% 

(95% CI: 2.3, 8.5) for all patients, 7.5% (2.6–12.6) for males ≥64 years, and 2.4% (-3.0–0.0) for females 

≥64 years. The mean carbon monoxide exposure concentration was 0.5 ppm (range: 0.1–3.1 ppm). Two 

other studies examined ischemic heart disease end points in multiple-pollutant models. Hosseinpoor et al. 

(2005) found that the relative risk for hospital admissions for angina pectoris (1,826 cases; Tehran, Iran; 

1996–2001) was 1.044 (95% CI: 1.000, 0.089) when air carbon monoxide concentrations were 

considered in a carbon monoxide model and 1.0093 (95% CI: 1.0036, 1.0151) when the model was 

adjusted for PM10, O3, and NO2. Air carbon monoxide concentrations examined in this study were 

relatively high compared to other studies (mean: 10.8 ppm; range: 1.6–58 ppm). A study conducted in 

Rome, Italy examined records of 6,351 hospital admissions (1995–1997) for myocardial infarction and 

found a significant association between increasing air carbon monoxide concentration and increasing odds 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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of hospital admission (odds ratio: 1.004, 95% CI: 1.000, 0.089), which did not persist when adjusted for 

total suspended solids (D’Ippoliti et al. 2003). The mean air carbon monoxide concentration was 3.8 ppm 

(25th–75th percentile range: 2.4–3.7 ppm). 

Studies of Stroke. Possible associations between ambient air carbon monoxide concentrations and stroke 

have been examined in studies of hospital admissions and emergency room visits (Chan et al. 2006; 

Henrotin et al. 2007; Maheswaran et al. 2005b; Tsai et al. 2003b; Villeneuve et al. 2006a; Wellenius et al. 

2005a; Table 3-7). Although results of these studies have been mixed, several studies have found 

significant associations between stroke admissions and/or emergency room visits and increasing air 

carbon monoxide concentrations (Chan et al. 2006; Tsai et al. 2003b; Villeneuve et al. 2006a; Wellenius 

et al. 2005a). Studies that explored two-pollutant models found that the associations persisted after 

adjustment for PM10, SO2, or O3 (Chan et al. 2006; Tsai et al. 2003b). Mean air carbon monoxide 

concentrations in these studies ranged from 0.4 to 1.7 ppm, and the highest reported values were ≤5 ppm. 

The largest study was a time-series analysis of ambient air carbon monoxide concentrations and 

155,503 records of stroke-related emergency room visits in nine U.S. cities (Wellenius et al. 2005a). The 

study found that a 0.71 ppm increase in ambient air carbon monoxide concentration was associated with a 

2.83% (95% CI: 1.23, 4.46) increase in daily rate of emergency room visits for ischemic stroke. Chan et 

al. (2006) conducted a time-series analysis of ambient air carbon monoxide concentrations in Taipei, 

Taiwan (1997–2002) and emergency room visits related to cerebrovascular disease, including stroke 

(n=7,341) and found a significant odds ratio for a 0.8 ppm increase in air carbon monoxide concentration 

for all cerebrovascular disease (1.03, 95% CI: 1.01, 1.06) and stroke (1.03, 95% CI: 1.01, 1.05), which 

remained significant after adjusting for O3, PM2.5 and PM10, or PM2.5 (1.034, 95% CI: 1.001, 1.067). A 

larger study conducted in Kaohsiung, Taiwan (1997–2000) examined records of 23,192 hospital visits for 

stroke in a case-crossover design and found significant odds ratios for a 0.8 ppm increase in carbon 

monoxide concentration (1.77, 95% CI: 1.31, 2.39), which also persisted after adjustment for SO2, O3, or 

PM10 (Tsai et al. 2003b). 

Studies of Other Cardiovascular Outcomes. Case-crossover studies examining possible associations 

between ambient carbon monoxide concentrations and cardiac arrest have either not found significant 

associations or found associations that were relatively small in magnitude (Dennekamp et al. 2010; Levy 

et al. 2001; Silverman et al. 2010; Sullivan et al. 2003; Table 3-6). In two studies that were conducted in 

Seattle, Washington, the mean carbon monoxide exposure concentration (both studies) was 1.7 ppm, with 

the highest value reported as 5.9 ppm. The study reported by Levy et al. (2001) included 362 cases outof-hospital cardiac arrests (1988–1994); the relative risk for a 1-day lag between exposure estimate and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 89 

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outcome was 0.88 (95% CI: 0.83, 1.18). The Sullivan et al. (2003) study examined 1,542 cases of outof-hospital cardiac arrest cases (1985–1994); the odds ratio for a 1.02 ppm increase in carbon monoxide 

concentration (1-day lag) was 0.97 (95% CI: 0.87, 1.08). The Silverman et al. (2010) study examined 

8,216 cases of out-of-hospital cardiac arrests in New York City (2002–2006) and did not find a significant 

association; the relative risk for a 0.3-ppm increment in carbon monoxide was approximately 0.99 (95% 

CI: 0.96, 1.03). The Dennekamp et al. (2010) study examined 8,434 cases of out-of-hospital cardiac 

arrests in Melbourne, Australia (2003–2006) and found a small association; the relative risk was 

1.031 (95% CI: 1.002, 1.046) per 0.25-ppm increase in carbon monoxide concentration. 

Possible associations between air carbon monoxide concentrations and cardiac failure (primarily, 

congestive heart failure) have also been examined in studies of hospital admissions (Lee et al. 2007a; 

Symons et al. 2006; Wellenius et al. 2005b; Table 3-6). The larger of the these studies (Lee et al. 2007a) 

examined 13,475 hospital admissions for congestive heart failure in Kaohsiung, Taiwan (1996–2004) and 

found a significant odds ratios for hospital admission associated with a 0.31 ppm increase in air carbon 

monoxide concentration (odds ratio: 1.39, 95% CI: 1.24, 1.54). The odds ratio remained significant in 

two-pollutant models that adjusted for PM10, NO2, SO2, or O3. 

Studies of possible associations between carbon monoxide exposure and abnormal blood pressure have 

not found significant associations (Ibald-Mulli et al. 2001; Zanobetti et al. 2004b; Table 3-6). The IbaldMulli et al. (2001) study included 2,607 men and women (age range 25–64 years) in the Augsburg, 

Germany area; the mean carbon monoxide exposure concentration was approximately 3.6 ppm and the 

upper end of the range was 7.2 ppm. The estimated increment in systolic blood pressure for a 4.9 ppm 

increase in carbon monoxide concentration was 1.06 (95% CI: -0.17, 2.29). The Zanobetti et al. (2004b) 

study measured blood pressure in repeated examinations of 62 subjects, and found no association between 

blood pressure and carbon monoxide exposure concentrations (90th percentile concentration <1.2 ppm). 

Several studies have evaluated more generic cardiovascular disease outcomes, for example, hospital 

admissions or emergency room visits for any cardiovascular disease (Ballester et al. 2001, 2006; Barnett 

et al. 2006; Bell et al. 2009; Chang et al. 2005; Fung et al. 2005; Jalaludin et al. 2006; Koken et al. 2003; 

Linn et al. 2000; Metzger et al. 2004; Peel et al. 2007; Yang et al. 2004a; Table 3-7). Here again, 

although results have been mixed, most studies found significant associations between increased rate of 

hospital admissions or emergency room visits and increased air carbon monoxide concentrations. The 

association was stronger for older subjects (e.g., ≥64 years, Barnett et al. 2006), and in several studies that 

examined multi-pollutant models, the association persisted after adjustment for PM10, NO2, SO2, or O3 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 90 

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(Bell et al. 2009; Chang et al. 2005; Jalaludin et al. 2006; Yang et al. 2004a). The mean air carbon 

monoxide concentrations in these studies ranged from 0.8 to 6 ppm, with the highest values ≤18 ppm. 

Animal Studies. Although clinical studies in patients with coronary artery disease provide compelling 

evidence of adverse cardiovascular effects of acute-duration exposure to carbon monoxide, these studies 

are limited with respect to exposure conditions and outcomes assessed. Studies in animals, however, have 

investigated adverse cardiovascular effects of carbon monoxide exposure over a much wider range of 

exposure conditions (e.g., exposure concentration and duration) and have evaluated additional outcome 

measures that are not possible to assess in humans. In general, animal studies evaluated carbon monoxide 

exposures resulting in higher COHb levels than those evaluated in clinical studies in patients and healthy 

volunteers. Results of animal studies provide evidence of adverse cardiovascular effects of carbon 

monoxide exposure, including compensatory alterations in hemodynamics, cardiac hypertrophy, cardiac 

arrhythmias, and possibly atherosclerosis (EPA 1991, 2000). For most outcomes evaluated in animal 

studies, conflicting evidence has been reported. Although the reasons for different results have not been 

established, differences in species sensitivity, exposure regimens, and experimental protocols are possible 

factors. Animal studies published prior to 2000 have been reviewed in detail by EPA (1991, 2000); 

therefore, these reviews largely form the basis of the following discussions for animals studies published 

prior to 2000. 

Studies investigating the effects of acute-duration carbon monoxide exposure on hemodynamics have 

been conducted in several animal species, including monkeys, dogs, rats, and rabbits, under exposure 

conditions producing blood COHb levels ranging from 6.2 to 70% (EPA 1991, 2000). Results show that 

brief exposure (from a few minutes to approximately 3 hours) to carbon monoxide at concentrations of 

80–20,000 ppm produces alterations in hemodynamics that are consistent with COHb-induced hypoxia 

and responsive compensatory mechanisms (e.g., vasodilation and increased cardiovascular output), 

including increased coronary blood flow, decreased myocardial O2 consumption, increased heart rate, and 

alterations in blood flow to various vascular beds (e.g., cerebral, limb muscular). Generally, carbon 

monoxide-induced effects on hemodynamics were observed at blood COHb levels ≥7.5%. With longer 

exposure durations at these same concentrations, COHb-induced tissue hypoxia and subsequent 

compensatory increases in heart rate and cardiac workload lead to the development of cardiomyopathy. 

Several studies confirm carbon monoxide-induced cardiomegaly in rats and rabbits exposed to 160– 

11,000 ppm carbon monoxide (COHb 12–58%) for intermediate durations (14 days to ~6 months) (EPA 

1991, 2000). Cardiac remodeling, including left ventricular fibrosis of interstitial and perivascular tissue, 

was observed in rats exposed to 30 ppm, with five daily spikes of 100 ppm, for 12 hours/day for 4 weeks 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 91 

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(Andre et al. 2010). Under these same exposure conditions, carbon monoxide reduced myocardial 

perfusion reserved under β-adrenergic stress and alterations in contractile function (Meyer et al. 2011). In 

rats exposed chronically to 200 ppm carbon monoxide (COHb 14.7%) for 20 hours/day for 72 weeks, left 

and right ventricle weights increased by 20% (p<0.001) and 14% (p<0.001), respectively (Sørhaug et al. 

2006). Studies evaluating developmental cardiovascular effects are reviewed in Section 3.2.6 

(Developmental Effects). 

Alterations in cardiac rhythm, possibly due to disturbances in cardiac conduction, have been observed in 

animals exposed to carbon monoxide for acute to intermediate durations (EPA 1991, 2000). Under 

conditions of simulated myocardial ischemia (i.e., coronary artery ligation), acute exposure (up to 

15 minutes) of dogs to up to 5,000 ppm carbon monoxide (COHb 4.9–15%) enhanced myocardial 

ischemia, as indicated by ST-segment alterations, and severity of myocardial injury. Results of a recent 

study in rats exposed to 50 ppm carbon monoxide (COHb not reported) for 1 week indicate that rats with 

pulmonary hypertension may be more sensitive to carbon monoxide-induced myocardial ischemia 

(Gautier et al. 2007). However, in other studies simulating myocardial injury in dogs exposed to 100– 

500 ppm carbon monoxide for 6–120 minutes (COHb 5.1–20%), cardiac arrhythmias or alterations in 

cardiac conduction speed were not observed. In studies evaluating intermediate-duration (6–24 weeks) 

exposure of dogs and monkeys, 100 ppm carbon monoxide (COHb 2.6–12%) induced cardiac 

arrhythmias, including R-wave depression, ST-segment elevation, increased T-wave, preventricular 

contractions, and reduced threshold for stimulus-induced ventricular fibrillation. In contrast, no evidence 

of cardiac arrhythmias was observed in dogs exposed continuously to 50 ppm carbon monoxide (COHb 

7.3%) for 3 months or in monkeys exposed intermittently to 500 ppm (COHb 21.6%) for 14 months. 

Conflicting evidence has been reported regarding the potential for carbon monoxide exposure to induce or 

enhance atherosclerosis (EPA 1991, 2000). Results of most studies in animals (monkeys, baboons, 

rabbits, and pigs) fed normal diets were negative for inducing or enhancing atherosclerosis at carbon 

monoxide concentrations of 50–400 ppm (COHb ~20%) for exposure durations up to 14 months. 

However, atherosclerosis was increased in monkeys continuously exposed to 200 ppm carbon monoxide 

(COHb 20.6%) for 2 weeks (Thomsen 1974) and in rabbits and monkeys fed high cholesterol diets 

exposed to 100–300 ppm carbon monoxide (COHb 9–33%) for 2–7 months. Based on the weight of 

evidence, EPA (1991, 2000) concluded that the available data do not strongly support a relationship 

between atherogenic effects and carbon monoxide exposure. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 92 

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Gastrointestinal Effects. Studies evaluating gastrointestinal effects of exposure to low levels of 

carbon monoxide (i.e., producing blood COHb levels <20%) were not identified. Although the 

gastrointestinal tract has not been identified as a specific target organ for carbon monoxide-induced 

toxicity, exposure to carbon monoxide at levels producing hypoxia would be expected to affect any tissue, 

in particular those tissues with high O2 utilization requirements (e.g., brain, liver, kidney, heart, small 

intestine). 

Hematological Effects. Hematological effects of carbon monoxide include compensatory responses 

to tissue hypoxia resulting from binding of carbon monoxide to Hb (e.g., increased blood volume, Hb, 

hematocrit, and erythrocyte count and volume). Possible associations between ambient air carbon 

monoxide concentrations and hematologic biomarkers of coagulation and inflammation have been 

examined in epidemiological studies. Collectively, these studies provide some evidence for associations 

that may reflect effects of carbon monoxide in modulating these systems. 

Hypoxia and Related Compensatory Responses. Inhalation exposure to carbon monoxide results in the 

formation of COHb, a stable complex between carbon monoxide and Hb. Because carbon monoxide has 

a much higher affinity for Hb than O2 (equilibrium constant for carbon monoxide is >200 times that of 

O2), O2 is displaced from Hb by relatively low partial pressures of carbon monoxide. Binding of carbon 

monoxide to Hb has two effects that contribute to impaired O2 delivery to tissues: (1) in the presence to 

carbon monoxide, the amount of O2 that can be stored on Hb for delivery to tissues decreases; and 

(2) binding of carbon monoxide to Hb impairs release of O2 from Hb for its diffusion into tissues (see 

Section 3.4.3 for further discussion of effects of carbon monoxide on O2 dissociation from Hb). At 

sufficient levels of COHb, the combined effects of impaired O2 storage and transport results in tissue 

hypoxia, the principal mechanism of many adverse effects of carbon monoxide exposure. 

To maintain O2 delivery to tissues under conditions of hypoxia, compensatory hematological responses 

(e.g., increased erythrocyte count, hematocrit, and Hb) occur. The dose-response relationship for carbon 

monoxide-induced compensatory hematological responses in humans has not been established. Studies in 

animals show that compensatory hematological effects occur in response to the COHb-induced reduction 

in O2 delivery to tissues. Compensatory hematological effects, including increased blood volume, Hb, 

hematocrit, and erythrocyte count and volume, have been observed following acute- and intermediateduration carbon monoxide exposure (Davidson and Penney 1988; Penney 1988; Penney et al. 1974a, 

1974b; WHO 1999). Continuous exposure of rats to 500 ppm carbon monoxide (COHb 40%) for 5– 

42 days produced duration-dependent increases in hematocrit, blood Hb, erythrocyte count, and mean cell 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 93 

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Hb concentration; mean cell volume was increased after 42 days of exposure (Davidson and Penney 

1988). The largest increases (approximately 45–55%) were observed for hematocrit, blood Hb, and 

erythrocyte count, with increases reaching maximum levels after 30 and 42 days of exposure. Similarly, 

blood Hb concentration increased by 70% in rats exposed continuously to 500 ppm carbon monoxide 

(COHb approximately 12% after 42 days) for up to 42 days, with the most rapid increase occurring within 

the first 21 days of exposure (Penney et al. 1974b). A small, but statistically significant increase in Hb 

concentration (6.0%; p<0.001) was observed in rats exposed to 100 ppm carbon monoxide (COHb 

9.25%) for 30 days (Penney et al. 1974b). In rats exposed to 200–1,300 ppm carbon monoxide (COHb 

not reported) for 10–17 days, dose-related increases in hematocrit and blood volume were observed 

(Penney et al. 1988). 

Epidemiological Studies of Blood Markers Related to Coagulation. Studies of carbon monoxide 

mechanisms of action have provided evidence that carbon monoxide may participate in the regulation of 

vascular thrombi formation and inflammation (see Section 3.5.2, Mechanisms of Toxicity). Possible 

associations between ambient air carbon monoxide concentrations and biomarkers of coagulation and 

inflammation have been examined in epidemiological studies (Baccarelli et al. 2007; Liao et al. 2005; 

Pekkanen et al. 2000; Rückerl et al. 2006, 2007; Steinvil et al. 2008). Biomarkers that have been 

examined include inflammation markers, C-reactive protein (CRP), serum amyloid A (SAA), and WBC 

count; cell adhesion markers, E-selectin, von Willebrand factor, antigen (vWF), ICAM-1; and 

coagulation markers, fibrinogen, factor VII (FVII), prothrombin fragment 1+2, prothrombin time (PT), 

and activated partial thromboplastin time (APTT). Collectively, these studies provide some evidence for 

associations between ambient air carbon monoxide concentration and changes in hematological 

indicators of inflammation and coagulation. However, interpretation of the results of these studies, in 

particular quantitative estimates of the effect magnitudes on outcomes, is limited by several factors: 

(1) reliance on area monitoring for estimating exposure levels; (2) uncertainty in knowledge of temporal 

correspondence between monitored exposure levels and outcomes; (3) relatively strong correlations 

between ambient air carbon monoxide concentrations and other air quality variables that can affect 

respiratory function; and (4) relatively low carbon monoxide exposures studied. The mean values of 

carbon monoxide exposure concentrations have ranged from 0.3 to 3 ppm, with the highest values 

≤12 ppm. 

Major findings from the body of reported epidemiological studies of hematological outcomes are 

summarized below. Although most of the studies explored various time lags between monitored air 

carbon monoxide concentrations and outcomes, as well as various sample strata, for the sake of brevity, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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only those indicative of the strongest associations to carbon monoxide are presented. Where co-pollutant 

models have been explored, these results are also presented. 

A cohort study conducted in London, United Kingdom (1991–1993) examined plasma fibrinogen 

concentrations in adult office workers (n=7,205) and found a significant association between increasing 

air carbon monoxide concentrations (mean 1.4 mg/m3 [1.2 ppm], maximum: 9 mg/m3 [8 ppm]) and 

increasing plasma fibrinogen concentrations (Pekkanen et al. 2000). For a 3-day lag between measured 

carbon monoxide concentration and fibrinogen assessment, the odds ratio for a plasma fibrinogen 

exceeding 3.19 g/L was 1.22 (p<0.02) per 1.6 mg/m3

 (1.4 ppm) increase in air carbon monoxide 

concentration. Increasing air concentration of NO2 was also associated with increasing plasma fibrinogen 

concentration (odds ratio: 1.22, p<0.01), and when both were considered in two-pollutant models, the 

associations were no longer significant, reflecting the relative high correlation between air carbon 

monoxide and NO2 concentrations (r=0.81). When stratified by gender, the carbon monoxide association 

for a 1-day lag (3-day lag data not reported) was significant in males, but not in females. 

In contrast to the Pekkanen et al. (2000) study, a smaller cohort study conducted in Tel-Aviv, Israel 

(2003–2006, n=3,659, mean age: 46 years) found a significant association between increases in air 

carbon monoxide concentration and decreasing plasma fibrinogen concentration among males, but not 

among females (Steinvil et al. 2008). The largest effect was estimated for the 1-week air carbon 

monoxide average (mean: 0.8 ppm, 75th percentile: 1 ppm), for which a 0.3 ppm increase in air carbon 

monoxide concentration was associated with a 7.7 mg/dL (95% CI: -12.1, -3.3) decrease in plasma 

fibrinogen in males, with no association among females (-1.6 mg/dL, 95% CI: -7.3, 4.1). Increasing air 

carbon monoxide concentration was also associated with a significant decrease in WBCs among males 

(-158 cell/μL, 95% CI: -298, -18), but not females (-182 cell/μL, 95% CI: -281, 61). However, as in the 

Pekkanen et al. (2000) study, the association between air NO2 and fibrinogen was stronger than that of 

carbon monoxide and when included in two-pollutant models, the association with carbon monoxide was 

no longer significant. Significant associations with air carbon monoxide concentrations were not found 

for CRP. 

A cohort study conducted in three U.S. locations (1996–1998) examined various blood biomarkers of 

coagulation and inflammation (i.e., fibrinogen, factor VIII-C, von Willebrand factor, serum albumin, 

WBC) in subjects enrolled in an Atherosclerosis Risk in Communities study (n=10,208) and found a 

significant association between increasing air carbon monoxide concentrations (mean 1.4 ppm, SD: 0.6) 

and decreasing serum albumin concentrations (Liao et al. 2005). A 0.6 ppm increase in air carbon 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 95 

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monoxide concentration corresponded to a 0.018 g/dL (SE: 0.003, p<0.01) decrease in serum albumin 

concentration. Other blood biomarkers evaluated were not significantly associated with air carbon 

monoxide concentration; results of multi-pollutant models were not reported. 

A panel study conducted in Efert, German (2000–2001) examined air carbon monoxide concentrations 

(mean: 0.52 mg/m3 [0.45 ppm], range: 0.11–1.93 [0.10–1.68 ppm]) and several blood biomarkers of 

coagulation and inflammation in 57 nonsmoking male coronary heart disease patients (age range: 51– 

7 years; Rückerl et al. 2006). Biomarkers evaluated included inflammation markers, CRP and SAA; cell 

adhesion markers, E-selectin, vWF, ICAM-1; and coagulation markers, fibrinogen, FVII, and 

prothrombin fragment 1+2. Odds ratios for increase in air carbon monoxide concentration of 0.27 mg/m3 

(0.23 ppm) (2-day lag) were: increasing CRP, 1.5 (95% CI: 1.1, 2.1); increasing ICAM-1, 1.7 (95% CI: 

1.3, 2.3); and decreasing FVII, 2.8 (95% CI: 5.1, 0.4). Significant associations were not found for other 

blood biomarkers, including fibrinogen. A larger cohort study did not find significant associations 

between ambient air carbon monoxide concentrations (mean range: 0.3–1.48 mg/m3 [0.3–1.29 ppm]) and 

plasma interleukin-6 (IL-6), CRP, or fibrinogen among myocardial infarction survivors (n=1,003, age 

range: 31–87 years) in six European cities (2003–2004, Rückerl et al. 2007). 

A panel study conducted in Milan, Italy (1995–2005) evaluated associations (mean range: 1.14– 

3.11 ppm; highest value: 11.4 ppm) between air carbon monoxide concentrations and several blood 

coagulation parameters, using prothrombin time (PT) and activated partial thromboplastin time (APTT) as 

outcome measures in 1,218 healthy adolescents and adults (age 11–84 years; Baccarelli et al. 2007). 

Increasing ambient air carbon monoxide concentration was associated with a decrease in PT 

(β coefficient: -0.11; 95% CI: -0.18, -0.05). Associations were also significant for PM10 and NO2; 

however, results from multi-pollutant models were not reported. Significant associations with carbon 

monoxide were not found for other blood biomarkers evaluated in the study, including carbon monoxide 

had no effect on fibrinogen, functional antithrombin, functional protein C, protein C antigen, functional 

protein S, or free protein S. 

Musculoskeletal Effects. Studies evaluating effects of exposure to low levels of carbon monoxide 

(i.e., producing blood COHb levels <20%) on bone in humans or animals were not identified. A 26-yearold woman who attempted suicide by inhalation of charcoal smoke developed heterotopic ossification 

(formation of mature lamellar bone within soft tissue) of the femoral joints and proximal thighs within 

3 months of exposure (Chen et al. 2010). Exposure levels of carbon monoxide were not reported; blood 

COHb level at the time of admission to the emergency room was 23.5%, although the time from exposure 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 96 

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to emergency room admission was not reported. The study authors suggested that development of 

heterotopic ossification was secondary to ischemic reperfusion. In mice continuously exposed to 

2,400 ppm for 180 days, increased bone mass was observed in parietal bone, sternum, lumbar vertebrae, 

and ribs (but not femur), and the marrow cavities of ribs, parietal bone, and femurs were expanded (Zebro 

et al. 1983). 

A study of 25 patients with delayed sequelae following exposure to carbon monoxide reported persistent 

muscle weakness, lasting from 1 to 60 months following exposure (Huang et al. 2011). Evaluation by 

computed tomography (CT) imaging showed decreased technetium (99mTc) sestamibi in skeletal muscle. 

99mTc sestamibi, a lipophilic cation used in nuclear medicine imaging, is retained within mitochondria of 

skeletal muscle. Decreased uptake of 99mTc sestamibi is indicative of muscle damage due to altered 

mitochondrial metabolism. Carbon monoxide exposure levels were not reported; blood COHb levels for 

the study cohort were reported as >10%, although COHb range was not reported. Rhabdomyolysis and 

myonecrosis have been reported in cases of carbon monoxide poisoning (Florkowski et al. 1992; Herman 

et al. 1988; Kuska et al. 1980; Wolff 1994). Damage to muscle tissue is consistent with hypoxia due to 

binding of carbon monoxide to Hb and myoglobin and with inhibition of cellular aerobic metabolism due 

to binding of carbon monoxide to intracellular cytochrome oxidases (Wolff 1994). 

Hepatic Effects. Studies evaluating hepatic effects of exposure to low levels of carbon monoxide 

(i.e., producing blood COHb levels <20%) were not identified. Although the liver has not been identified 

as a specific target organ for carbon monoxide-induced toxicity, exposure to carbon monoxide at levels 

producing hypoxia would be expected to affect any tissue, in particular those tissues with high O2 

utilization requirements (e.g., brain, liver, kidney, heart, small intestine). 

Renal Effects. Studies evaluating renal effects of exposure to low levels of carbon monoxide (i.e., 

producing blood COHb levels <20%) were not identified. Although the kidney has not been identified as 

a specific target organ for carbon monoxide-induced toxicity, exposure to carbon monoxide at levels 

producing hypoxia would be expected to affect any tissue, in particular those tissues with high O2 

utilization requirements (e.g., brain, liver, kidney, heart, small intestine). The kidney is the site of active 

transport processes involved in maintaining blood homeostasis and, next to the brain, is the greatest 

contributor to basal metabolic rate due to use of ATP-dependent active transport processes. Carbon 

monoxide-induced hypoxia would decrease the availability of oxygen to produce ATP in renal 

mitochondria, which would produce adverse effects to the kidneys. Acute renal failure secondary to 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 97 

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rhabdomyolysis has been observed in cases of acute carbon monoxide poisoning (Florkowski et al. 1992; 

Kuska et al. 1980; WHO 1999; Wolff 1994). 

Endocrine Effects. Studies evaluating endocrine effects of exposure to low levels of carbon 

monoxide (i.e., producing blood COHb levels <20%) were not identified. Although the endocrine system 

has not been identified as a specific target for carbon monoxide-induced toxicity, exposure to carbon 

monoxide at levels producing hypoxia would be expected to affect any tissue. 

Dermal Effects. Studies evaluating dermal effects of exposure to low levels of carbon monoxide (i.e., 

producing blood COHb levels <20%) were not identified. Skin lesions have been observed in patients 

with severe carbon monoxide poisoning (Myers et al. 1985; Torne et al. 1991). Lesions are primarily 

observed in pressure areas and are characterized by blisters, subepidermal vesicles, and sweat gland 

necrosis. 

Ocular Effects. Visual field deficits, temporary or permanent blindness, retinal venous congestion, 

retinal hemorrhage, papilledema, and optic atrophy have been associated with severe carbon monoxide 

poisoning in humans (Choi 2001). Numerous clinical studies have investigated the potential for carbon 

monoxide to induce visual effects (decreased visual tracking, visual vigilance, visual perception) at COHb 

levels <20% (Benignus et al. 1990; EPA 1991, 2000; Raub and Benignus 2002; Raub et al. 2000). 

Interpretation of results from most of these clinical studies is complicated by poor study design (singleblind or unblinded designs, small number of study subjects), inadequate reporting, inconsistent results, 

and inability to duplicate positive findings (Benignus et al. 1990; EPA 1991, 2000; Raub and Benignus 

2002; Raub et al. 2000). No information was identified to indicate that carbon monoxide is an ocular 

irritant in humans or animals. 

3.2.3 Immunological and Lymphoreticular Effects 

Little information is available regarding the potential of carbon monoxide exposure to produce adverse 

immunological effects. Epidemiological studies regarding blood biomarkers of immunological status are 

summarized in the section on Hematologic Effects. Immunological biomarkers examined in these studies 

have included CRP, SAA, and WBC; however, other markers that can be influenced by the immune 

system have also been evaluated, including cell adhesion markers such as E-selectin, vWF, and ICAM-1; 

and coagulation markers such as fibrinogen, FVII, prothrombin fragment 1+2, PT, and APTT. Although 

results of these studies have been mixed, collectively, they provide some evidence for associations 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 98 

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between ambient air carbon monoxide concentration and changes in hematological indicators of 

inflammation and coagulation. However, these studies do not distinguish between possible effects of 

carbon monoxide and/or other air pollutants on the immune system from indirect effects of carbon 

monoxide on blood biomarkers. Mechanistic studies have revealed evidence that carbon monoxide may 

participate in the regulation of immune function (see Section 3.5.2, Mechanisms of Toxicity). 

Exposure of male Sprague-Dawley rats to 2,000 ppm carbon monoxide for 40 minutes followed by 

exposure to 3,000 ppm for 20 minutes activated and induced proliferation of microglia, immune effector 

cells, in the brain (Wang et al. 2011). In addition, expression of several immune makers, including 

MHCII, CD-4, VCAM-1, INF-γ, and OC-42, were increased in the hippocampus and cortex of the brain. 

Results of a study in guinea pigs investigating the effects of repeated brief bursts of carbon monoxide on 

systemic immune function were equivocal (Snella and Rylander 1979). Exposure of guinea pigs to 

3-minute bursts of 10,000 ppm carbon monoxide 12 times/day for 4 weeks resulted in an 88% reduction 

in the number of splenic plaque-forming cells, compared to unexposed controls; however, the reduction 

did not reach statistical significance. Studies evaluating effects of gestational exposure on the developing 

immune system function are reviewed in Section 3.2.6 (Developmental Effects) (Giustino et al. 1993, 

1994). 

3.2.4 Neurological Effects 

The literature reporting adverse nervous system effects, specifically central nervous system effects, of 

acute exposure of humans to carbon monoxide is extensive. This literature includes case studies of 

carbon monoxide poisoning, clinical studies of neurobehavioral effects of controlled exposures in 

humans, and experimental studies in a variety of animal models (e.g., dogs, rodents, nonhuman primates). 

Much of this literature has been summarized and analyzed in recent reviews and meta-analyses (Benignus 

et al. 1990; EPA 1991, 2000; Kao and Nañagas 2006; Raub and Benignus 2002; Raub et al. 2000; WHO 

1999). This section summarizes the major findings from these analyses. Although the literature on 

central nervous system effects of acute experimental and accidental exposures of humans to carbon 

monoxide is extensive, reports of effects of longer-duration exposure of humans are not available. Effects 

of gestational and perinatal exposure on the developing nervous system are discussed in Section 3.2.6 

(Developmental Effects). 

Acute exposure to high levels of carbon monoxide produces symptoms of central nervous system toxicity 

(EPA 1991, 2000; Ernst and Zibrak 1998; Raub and Benignus 2002; WHO 1999). Symptoms of central 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 99 

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nervous system toxicity include headache, dizziness, drowsiness, weakness, nausea, vomiting, confusion, 

disorientation, irritability, visual disturbances, convulsions, and coma. Symptoms vary depending upon 

the degree of exposure; headache and dizziness are the most commonly reported symptoms (Dolan 1985; 

Ernst and Zibrak 1998). Neuroimaging evaluations of patients with acute carbon monoxide poisoning 

show lesions of the basal ganglia (primarily of the globus pallidus) and white matter (Hopkins et al. 2006; 

Kao and Nañagas 2006; Lo et al. 2007; Parkinson et al. 2002). Following acute-onset effects, delayed 

development of neuropsychiatric impairment may occur within 1–4 weeks of exposure, with symptoms 

including inappropriate euphoria, impaired judgment, poor concentration, memory loss, cognitive and 

personality changes, and psychosis. Delayed neuropsychiatric impairment has been estimated to occur in 

up to 68% of patients with acute carbon monoxide poisoning (Ernst and Zibrak 1998; Kao and Nañagas 

2006; Raub and Benignus 2002; Raub et al. 2000; WHO 1999; Wolf et al. 2008). The relationship 

between initial symptom severity and the likelihood of developing delayed neuropsychiatric impairment 

has not been established. A cohort analysis of 256 patients with carbon monoxide poisoning suggests that 

initial symptom severity does not correlate to delayed-onset effects (Chambers et al. 2008). However, 

based on a review of available data, Kao and Nañagas (2006) concluded that patients with more severe 

initial symptoms are more likely to develop delayed neuropsychiatric impairment. 

Mechanisms of acute and delayed adverse nervous system effects produced by carbon monoxide have not 

been conclusively established. Tissue hypoxia secondary to COHb formation may be a contributing 

factor, particularly in association with high levels of blood COHb (>60%); however, direct cellular effects 

of carbon monoxide (e.g., ATP depletion, excitotoxicity, oxidative stress, immunological responses) and 

postischemic reperfusion injury may also contribute to neurotoxicity (see Section 3.5.2, Mechanisms of 

Toxicity) (Ernst and Zibrak 1998; Gorman et al. 2003; Kao and Nañagas 2006). Under conditions of 

hypoxia, including that induced by COHb formation, cerebrovascular vasodilation and increased cardiac 

output occur as compensatory mechanisms to maintain O2 delivery to the brain (Gorman et al. 2003; 

Helfaer and Traystman 1996; Raub and Benignus 2002; WHO 1999). In healthy individuals, 

cardiovascular compensation effectively maintains whole brain O2 delivery up to COHb levels of 

approximately 60% (EPA 2000). However, based on studies conducted in animals, the elevated cerebral 

blood flow during carbon monoxide exposure is heterogeneous among different brain regions and may 

not be sufficient to satisfy O2 demand in all brain regions (Okeda et al. 1987; Sinha et al. 1991). 

However, despite these compensatory cardiovascular actions, cerebral O2 consumption declines as blood 

COHb levels increase, with statistically significant decreases at COHb levels of 30–50% (Raub and 

Benignus 2002). Results of an analysis conducted by EPA (2000) of data obtained in goats (Doblar et al. 

1977) and sheep (Langston et al. 1996) show that the cerebral metabolic rate for O2 (CMRO2) decreased 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 100 

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10% at a blood COHb of approximately 23%. These results are consistent with data obtained from 

humans showing no statistically significant decline in CMRO2 at COHb levels up to 20% (Paulson et al. 

1973). 

Based on an extensive database of acute carbon monoxide poisoning, it is generally accepted that central 

nervous system symptoms are associated with acute exposures that produce blood COHb levels ≥20% 

(EPA 1991, 2000; Raub and Benignus 2002; Raub et al. 2000; WHO 1999). However, results of clinical 

studies of associations between carbon monoxide exposure and carbon monoxide-induced nervous system 

effects at blood COHb levels between 5 and 20% are more difficult to interpret (EPA 1991, 2000; Raub 

and Benignus 2002; Raub et al. 2000; WHO 1999). Numerous clinical studies have investigated the 

potential for carbon monoxide to induce adverse nervous system effects at COHb levels <20%, including 

visual and auditory sensory effects (decreased visual tracking, visual and auditory vigilance, visual 

perception), fine and sensorimotor performance, cognitive effects (altered time discrimination, learning, 

attention level, driving performance), and brain electrical activity (Benignus et al. 1990; EPA 1991, 2000; 

Raub and Benignus 2002; Raub et al. 2000). Interpretation of results from most of these clinical studies 

is complicated by poor study design (single-blind or unblinded designs, small number of study subjects), 

inadequate reporting, inconsistent results, and inability to duplicate positive findings (Benignus et al. 

1990; EPA 1991, 2000; Raub and Benignus 2002; Raub et al. 2000). Therefore, although evidence has 

been provided for central nervous system effects in humans in association with carbon monoxide 

exposures that result in COHb levels <20%, dose-response relationships for these effects have not been 

firmly established. Effects of exposure to ambient environmental levels of carbon monoxide on 

neurological function and behavior have not been investigated in epidemiological studies. 

Benignus (1994) conducted a meta-analysis of the clinical literature on carbon monoxide-induced 

behavioral effects (also see Benignus et al. 1990; EPA 2000; Raub and Benignus 2002). To minimize the 

introduction of bias from poorly designed studies, the Benignus analysis included only studies conducted 

using a double-blind design. The primary goal of these analyses was to compare the dose-response 

relationship of carbon monoxide-induced effects in humans to other extrapolated data, specifically, the 

dose-response functions for COHb-induced behavioral effects in rats and hypoxic hypoxia (HH)-induced 

behavioral effects in humans. Rat COHb dose-response data were converted to human COHb equivalents 

using a modification of the CFK human model, adjusted to predict exposure-COHb relationships in rats 

(Benignus and Annau 1994). Data on behavioral effects were also adjusted to account for carbon 

monoxide-Hb-related hypothermia that occurs in rats (Gordon 1990), but not in humans, assuming 

response additivity of hypothermia and hypoxia (Benignus 1994). Dose-response data for HH-induced 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 101 

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behavioral effects were converted to COHb equivalents (COHb% that yields the equivalent arterial O2 

content as a given level of HH) and were corrected for hyperventilation that occurs in HH and resulting 

changes in alveolar ventilation rate, based on estimates of blood CO2 (i.e., hypocapnia-induced by HH). 

For all data sets (i.e., carbon monoxide human, carbon monoxide rat, HH human), behavioral responses 

were transformed to percent of baseline response. Dose-response curves were fit to the extrapolated 

carbon monoxide rat and HH human data; curve-fitting was not conducted for carbon monoxide human 

data, due to the small effect level and low COHb levels. Comparison of the extrapolated carbon 

monoxide rat and HH human data showed very close agreement, with nearly superimposable doseresponse curves (Figure 3-1); comparison of dose-response data from carbon monoxide in humans to 

extrapolated data from HH humans is shown in Figure 3-2. The dose-response relationship from this 

meta-analysis predicts a 10% decrement in behavioral outcomes in humans in association with COHb 

levels of approximately ≥20% (range: approximately 18–25%, based on 90% confidence limits) in 

healthy, sedentary individuals. As discussed by Benignus (1994) and others (Benignus et al. 1990; EPA 

1991; Raub and Benignus 2002), the magnitude of behavioral effects that may occur at blood COHb 

levels ≤20% is expected to be small. Although most task performances are not likely to be affected, it is 

possible that even small effects (i.e., <10% decrement) could interfere with successful task performance 

for more difficult or demanding tasks. Therefore, potential minimal behavioral changes occurring at 

COHb levels ≤20% may be important under certain conditions or in sensitive individuals (e.g., 

individuals with compromised cardiovascular or central nervous system function). 

Clinical studies evaluating exposure to low levels of carbon monoxide (i.e., producing blood COHb levels 

<20%) have focused on the potential for carbon monoxide to induce behavioral effects; however, very 

little information is available on the effects of carbon monoxide on sensory system function in humans. 

Results of clinical studies in evaluating the effects of low carbon monoxide exposures on alterations in 

sensory perception (i.e., visual and auditory) are equivocal (EPA 1991, 2000). Epidemiological studies 

have not assessed the potential for carbon monoxide to produce alterations in sensory system function. 

Studies conducted in mature rats provide evidence that acute exposure (<10 hours) to higher levels of 

carbon monoxide (500–1,500 ppm) potentiates noise-induced hearing loss, including noise-induced 

elevation of compound action potential threshold (Chen and Fechter 1999) and auditory threshold shifts 

(Fechter et al. 1988; Young et al. 1987). In mature rabbits, exposure to 700 ppm for 9.5 hours/day for 

5 days potentiated noise-induced increases in the auditory brainstem response threshold (Mortazavi et al. 

2010). In these studies, exposure to carbon monoxide alone did not produce changes in auditory function. 

Noise-induced hearing loss was partially reversed within 4 weeks following exposure to noise alone, but 
 

 

CARBON MONOXIDE 102 

3. HEALTH EFFECTS 

Figure 3-1. Hypoxic Hypoxia Human and Carbon Monoxide Rat Curves* 

*Behavioral decrements in rats with elevated carboxyhemoglobin (COHb; dashed line) compared to behavioral 

effects in hypoxic humans (solid line) in which hypoxia has been expressed in equivalence to COHb. 

Source: Raub and Benignus 2002 
 

 

 

CARBON MONOXIDE 103 

3. HEALTH EFFECTS 

Figure 3-2. Hypoxic Hypoxia Human and Carbon Monoxide Human Curves*
	

*Behavioral decrements in humans (circles) with elevated carboxyhemoglobin (COHb) compared to behavioral 

effects in hypoxic humans (solid and dotted lines) in which hypoxia has been expressed in equivalence to COHb. 

Closed and open circles were the mean values for studies reporting statistically and non-significant results, 

respectively. 

Source: Raub and Benignus 2002 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 104 

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not following exposure to noise and carbon monoxide (Chen and Fechter 1999). Results are consistent 

with carbon monoxide-induced impairment of mechanisms that repair noise-induced damage to outer hair 

cells. In marked contrast to results observed in adult rats, developmental studies in animals show that 

gestational and early postnatal exposure to low levels of carbon monoxide (i.e., 12–25 ppm carbon 

monoxide) may lead to altered development of the auditory system (Beltran-Parrazal et al. 2010; Lopez et 

al. 2003, 2008, 2010; Stockard-Sullivan et al. 2003; Webber et al. 2003). These data are discussed in 

Section 3.2.6. 

Additional evidence for effects of carbon monoxide on depressed auditory thresholds and increased 

cochlear blood flow have been provided from studies in which adult rats received parenteral doses of 

carbon monoxide (Fechter et al. 1987b). However, in these studies, auditory thresholds assessed by 

measurement of the compound action potential recorded at the round window remained stable up to 

COHb levels of at least 30%. Transient impairments of the compound action potential threshold were 

observed among subjects that attained COHb levels of approximately 50%. Cochlear blood flow 

measured using laser Doppler flowmetry also increased following carbon monoxide exposure, reaching a 

maximum of 140% of control values at approximately 50% COHb. In those instances of high COHb 

production that did produce impairment of auditory threshold, recovery of function was observed as 

COHb levels declined. 

3.2.5 Reproductive Effects 

Fetal death in humans has been reported in cases of maternal carbon monoxide poisoning during 

pregnancy. Epidemiological studies have examined possible relationships between exposures to ambient 

air concentrations of carbon monoxide and fetal mortality (see Section 3.2.6). Studies in animals provide 

further evidence that maternal exposure during pregnancy can result in fetal death. 

Case Reports. Several case reports have evaluated pregnancy outcomes following acute carbon 

monoxide poisoning (Brown et al. 1992; Caravati et al. 1988; Cramer 1982; Elkharrat et al. 1991; Farrow 

et al. 1990; Greingor et al. 2001; Hollander et al. 1987; Margulies 1986; Norman and Halton 1990; 

Silverman and Montano 1997; Yildiz et al. 2010). In all cases, the severity of carbon monoxide 

poisoning required emergency room treatment or hospitalization, suggesting that maternal COHb levels 

exceeded 20%. Pregnancy outcomes varied widely, from delivery of healthy infants at term to fetal death 

within first few days of exposure. Pregnancy outcome is most likely related to fetal age at time of 

exposure, with sensitivity increasing with fetal age, and severity of maternal poisoning, although maternal 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 105 

3. HEALTH EFFECTS 

COHb levels are not a good indicator of fetal outcome (Greingor et al. 2001). Fetal death may be 

secondary to maternal hypoxia and/or fetal hypoxia. The available information from these cases is not 

adequate to define dose-response relationships for acute carbon monoxide exposure and pregnancy 

outcomes. 

Animal Studies. Few animal studies have assessed the effects of carbon monoxide exposure on 

reproductive function. Continuous exposure of male mice to 50 ppm carbon monoxide for 2 weeks prior 

to mating with unexposed females or of male and female mice to 50 ppm carbon monoxide for 2 weeks 

prior to mating had no effect on pregnancy rate or live or dead fetuses/dam (Stupfel and Bouley 1970). 

Exposure of pregnant rats to carbon monoxide concentrations up to 200 ppm over the entire gestational 

period had no effect on number of liters, fetuses per litter, or number of live/dead pups per litter (Fechter 

and Annau 1977; Penney et al. 1983). In contrast, increased fetal death during the first 24 hours of the 

postnatal period was observed in rabbits following maternal exposure to 90 and 180 ppm carbon 

monoxide during pregnancy (9.9 and 35% mortality) (Astrup et al. 1972). 

3.2.6 Developmental Effects 

Epidemiological studies have examined possible associations between exposure to ambient air carbon 

monoxide concentrations and various developmental outcomes, including pre-term birth, birth weight, 

congenital anomalies, neonatal and infant death, and neurodevelopment. Results of these studies have 

been mixed and, collectively, do not provide strong evidence for developmental effects in association 

with exposures to ambient levels of carbon monoxide. Studies conducted in animals provide evidence of 

adverse developmental effects of gestational and early postnatal carbon monoxide exposure, including 

decreased fetal weight, adverse central nervous system development, altered peripheral nervous system 

development, cardiac effects, altered sexual behavior, immunological effects, and hematological effects. 

In addition, some studies showed that developmental effects persisted beyond the postnatal period. 

Epidemiological Studies. Interpretation of the results of epidemiological studies of developmental effects 

of carbon monoxide, and in particular, quantitative estimates of the effect magnitudes on outcomes, is 

limited by several factors: (1) reliance on area monitoring for estimating exposure level that may not 

represent exposures that occurred in individuals during any particular period of gestation; (2) uncertainty 

in knowledge of temporal correspondence between monitored exposure levels and outcomes; 

(3) relatively strong correlations between ambient air carbon monoxide concentrations and other air 

quality variables that may affect developmental outcomes; and (4) relatively low carbon monoxide 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 106 

3. HEALTH EFFECTS 

exposures studied. In general, these studies examined relatively low air carbon monoxide concentrations, 

typical of ambient levels (e.g., mean concentrations ranging from 0.5 to 3 ppm, with the highest reported 

values ≤10 ppm). The presentation of the epidemiological studies is organized by major categories of 

birth and neonatal outcomes. Study conclusions are presented in the text, with selected supporting details 

presented in tabular form (Table 3-8). Although most studies explored various time lags between 

monitored air carbon monoxide concentrations and outcomes, as well as various sample strata, for the 

sake of brevity, only selected representative time lags (usually those indicative of the strongest 

associations to carbon monoxide) are presented in the tables. Where co-pollutant models have been 

explored, these results are also presented. 

Studies of Neurodevelopment. A prospective birth cohort study conducted in Guatemala (2002–2010), 

where exposure to wood smoke is common, examined cognitive development in a sample of 39 children 

(Dix-Cooper et al. 2011). Various cognitive and motor function tests were performed at age 6–7 years, 

and associations between test scores and maternal exposures to carbon monoxide during the third 

trimester were evaluated. Carbon monoxide exposures were measured with passive personal air monitors 

worn at the breathing zone during pregnancy. The weekly mean concentration during the third trimester 

was 3.8 ppm (range: 0.62–12.52 ppm). Cognitive and motor function tests performed at age 6–7 years 

included assessments of information processing speed, visual-spatial integration, short- and long-term 

memory, attention, fine motor speed, and coordination. In 4 of 11 tests administered, decreasing 

performance was associated with increasing third trimester maternal exposures. These included visualspatial integration (β: -4.4 per log10 ppm, 95% CI: -9.5, 0.07), immediate recall (β: -0.3 per log10 ppm, 

95% CI: -0.6, 0.01), delayed recall (β: -4.48 per log10 ppm, 95% CI: -9.8, 0.1), and finger tapping 

(β: -5.7 per log10 ppm, 95% CI: -9.7, -1.7). Significant associations were not found for carbon monoxide 

exposure measured with passive personal monitors worn by the infants during the first 9 postnatal 

months. 

Studies of Pre-term Birth. Several epidemiological studies have examined possible associations between 

ambient air carbon monoxide concentrations and risk of pre-term birth (Huynh et al. 2006; Jalaludin et al. 

2007; Leem et al. 2006; Liu et al. 2003; Ritz et al. 2000, 2007; Rudra et al. 2011; Wilhelm and Ritz 

2005). Results of these studies have been mixed and have included estimates of significantly elevated 

risk or lower risks of pre-term birth (Jalaludin et al. 2007). Mean air carbon monoxide concentrations 

evaluated in these studies ranged from 0.8 to 2.7 ppm, with the highest values ≤10 ppm (Ritz et al. 2000). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Bell et al. 2007 Outcome: BW, LBW Avg time: 24 hours 

Period: 1999–2002 Design: Retrospective cohort Mean: 0.65 ppm 

Location: Connecticut and Sample: n=358,504 live full-term SD: 0.2 ppm 

Massachusetts singleton births 

Brauer et al. 2008 Outcome: PTB, LBW, SGA Avg time: 24 hours 

Period: 1999–2004 Design: Retrospective cohort Mean: 0.55 ppm 

Location: Vancouver, Canada Sample: n=70,249 live singleton Range: 0.11–1.23 ppm 

births 

Chen et al. 2002 Outcome: BW, LBW Avg time: 8 hours 

Period: 1991–1999 Design: Retrospective cohort Mean: 0.86 ppm 

Location: Nevada Sample: n=39,338 live singleton Range: 0.42–4.25 ppm 

births 

Dadvand et al. 2011 Outcome: CA (heart) Avg time: 1 week 

Period: 1993–2003 Design: Case-control Mean: 0.48 ppm OR (95% CI) 

Location: England Sample: n=2,769 cases, Range: 0.37–1.21 ppm 

14,256 controls 

Dix-Cooper et al. 2011 Outcome: Cognitive development Avg time: 48 hours 

malformations 

Period: 2002–2010 

Location: San Marcos, 

Design: Prospective birth cohort 

Sample: n=39 children, assessed 

(personal monitor) 

Maternal (3rd TM) 

Guatemala. at age 6–7 years Mean: 3.83 ppm 

Range: 0.62–12.52 ppm 

CARBON MONOXIDE

Increment: 0.30 ppm
 

β coefficient (95% CI) BW (g), total gestation:
 

CO: -16.2 (-19.7, -12.6)
 

Significant negative β persisted after adjustment
 

for NO2, SO2, PM2.5, or PM10
 

OR (90% CI) LBW, total gestation:
 

CO: 1.028 (0.983, 1.074)
 

Increment: 0.1 mg/m3
 

OR (95% CI), total gestation:
 

SGA: 1.06 (1.03, 1.08)
 

LBW: 1.02 (0.96, 1.09)
 

PTB: 1.16 (1.01, 1.33)
 

Increment: 1 ppm
 

β coefficient (SE), BW (g):
 

TM 1: -1.02 (6.68)
 

TM 2: -0.07 (6.58)
 

TM 3: -3.95 (6.76)
 

Not significant when adjusted for PM10 or O3
 

ORs not significant for LBW
 

Increment: 1 mg/m3
 

Cardiac septa: 2.330 (1.748, 3.102)
 

Pulmonary valve stenosis: 2.682 (1.298, 5.534)
 

Ventricular septa: 2.634 (1.871, 3.707)
 

CO not associated with other cardiac
 

Increment: log10 ppm
 

β coefficient (95% CI)
 

Visual-spatial integration: -4.4 (-9.5, 0.07)
 

Immediate recall: -0.3 (-0.6, 0.01)
 

Delayed recall: -4.8 (-9.8, 0.1)
 

Finger tapping: -5.7 (-9.7, -1.7)
 

3. HEALTH EFFECTS 107
 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study 

Gilboa et al. 2005 

Period: 1997–2000 

Location: Texas 

Design features CO exposure Effect size 

Outcome: CA (heart, orofacial) 

Design: Case-control 

Sample: n=4,594 cases 

Avg time: 24 hours 

Mean: NR 

25th–75th%: 0.4–0.7 ppm 

Gouveia et al. 2004 

Period: 1997 

Location: San Paulo, Brazil 

Outcome: BW, LBW 

Design: Retrospective cohort 

Sample: n=179,460 live full-term 

singleton births 

Avg time: 8 hours 

Mean: 3.7 ppm 

Range: 1.1–11.4 

Ha et al. 2001 

Period: 1996–1997 

Location: Seoul, South Korea 

Ha et al. 2003 

Period: 1995–1999 

Location: Seoul, South Korea 

Outcome: LBW 

Design: Retrospective cohort 

Sample: n=276,763 live full-term 

singleton births 

Outcome: Post-neonatal mortality 

(1–12 months) 

Design: Time series 

Sample: n=1,045 deaths 

Avg time: 8 hours 

Median: 1.7 ppm 

25th–75th%: 0.99–1.41 

Avg time: 24 hours 

Median: 1.2 ppm 

Range: 0.39–3.38 ppm 

RR (95% CI): 

Increment: <0.4 ppm (reference), 0.4–0.5 (L),
 

0.5–0.7 (M), >0.7 (H)
 

OR (95% CI), 3–8 weeks of gestation:
 

Conotruncal defect: (L) 1.38 (0.97, 1.97); (M) 1.17 

(0.81, 1.70); (H) 1.46 (1.03, 2.08)
 

Teratology of Fallot: (L) 0.92 (0.52, 1.62); (M)
 

1.17 (0.75, 2.14); (H) 2.04 (1.16, 3.29) 

CO not associated with other heart defects or 

orofacial defects 

Increment: 1 ppm
 

β coefficient (95% CI), BW (g):
 

TM 1: -23.1 (-41.3, -4.9)
 

TM 2: 3.2 (-18.2, 24.5)
 

TM 3: 1.9 (-18.2, 22.0)
 

Significant negative β did not persist after
 

adjustment for SO2 or PM10
 

OR (95% CI), LBW: 4th vs. 1st quartile exposure: 

TM 1: 1.02 (0.82, 1.27);
 

TM 2: 1.07 (0.88, 1.30)
 

TM 3: 0.93 (0.76, 1.12)
 

Increment: 0.42 ppm 

TM 1: 1.08 (1.04, 1.12)
 

TM 3: 0.91 (0.87, 0.96)
 

Increment: 0.57 ppm
 

RR (95% CI), lag 0 days:
 

All causes: 1.020 (0.976, 1.067)
 

Respiratory: 1.388 (1.009, 1.911)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 108
 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Huynh et al. 2006 

Period: 1999–2000 

Location: California 

Hwang and Jaakkola 2008 

Period: 2001–2003 

Location: Taiwan 

Outcome: PTB
 

Design: Case-control
 

Sample: n=10,673 cases (24–
 

36 weeks), 32,119 controls (39–
 

44 weeks)
 

Outcome: CA (oral cleft)
 

Design: Case-control
 

Sample: n=653 cases
 

Avg time: 24 hours 

Mean: 0.8 ppm 

SD: 0.2 ppm 

Avg time: 8 hours 

Mean: 0.69 ppm 

Range: 0.25–2.7 ppm 

Increment: 1 ppm 

OR (95% CI) 

Month 1 (of gestation): 

CO: 1.10 (0.999, 1.20) 

CO+PM2.5: 1.03 (0.93, 1.13) 

Last 2 weeks: 

CO: 1.00 (0.93, 1.09) 

CO+PM2.5: 0.97 (0.90, 1.06) 

Total gestation: 

CO: 1.06 (0.95, 1.18) 

CO+PM2.4: 0.98 (0.87, 1.10) 

No significant trend in OR with exposure quartile 

Increment: 0.1 ppm 

RR (95% CI), oral cleft 

Cleft lip: 

Month 1: 1.00 (0.96, 1.04) 

Month 2: 1.00 (0.96, 1.03) 

Month 3: 1.00 (0.96, 1.03) 

Cleft lip with or without cleft palate: 

Month 1: 1.00 (0.97, 1.04) 

Month 2: 1.00 (0.97, 1.05) 

Month 3: 1.00 (0.96, 1.04) 

No significant ORs after adjustment for NO2, O3, or 

PM10 

CARBON MONOXIDE 3. HEALTH EFFECTS 109
 

 

 

 

 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Jalaludin et al. 2007 

Period: 1998–2000 

Location: Sydney, Australia 

Lee et al. 2003a 

Period: 1996–1998 

Location: Seoul, Korea 

Leem et al. 2006 

Period: 2001–2002 

Location: Incheon, Korea 

Lin et al. 2004a 

Period: 1998–2000 

Location: Sao Paulo, Brazil 

Outcome: PTB (<37 or <42 weeks) 

Design: Retrospective cohort 

Sample: n=721,289 full-term 

singleton births 

Outcome: LBW 

Design: Retrospective cohort 

Sample: n=388,105 live full-term 

singleton births 

Outcome: PTB 

Design: Retrospective cohort 

Sample: n=52,113 live singleton 

births 

Outcome: Neonatal mortality 

(<28 days) 

Design: Time series 

Sample: n=6,700 deaths 

Avg time: 8 hours 

Mean: 0.9 ppm 

SD: 0.68 ppm 

Avg time: 24 hours 

Mean: 1.2 ppm 

Range: 0.4–3.4 ppm 

Avg time: 24 hours 

Mean: NR 

Range: 0.3–1.4 ppm 

Avg time: 24 hours 

Median: 2.83 ppm 

Range: 0.54–10.25 ppm 

Increment: 1 ppm 

RR (95% CI) <5 km of monitoring site or city-wide: 

Month 1, <5 km: 1.03 (0.68, 1.54) 

Month 1, city-wide: 0.89 (0.84, 0.95) 

TM 1, <5 km): 1.24 (0.81, 1.91) 

TM 1, city-wide: 0.77 (0.71, 0.83) 

Last month, <5 km: 1.00 (0.86, 1.15) 

Last month, city-wide: 0.96 (0.88, 1.04) 

TM 3, <5 km: 1.11 (0.94, 1.31) 

TM 3, city-wide: 0.99 (0.90, 1.09) 

Increment: 0.5 ppm 

OR (95% CI): 

TM 1: 1.04 (1.01, 1.07) 

TM 2: 1.03 (1.00, 1.06) 

TM 3: 0.96 (0.93, 0.99) 

Total gestation: 1.05 (1.01, 1.09) 

Increment: quartiles (mg/m3): 1st 0.47–0.63; 2nd 

0.6–0.77, 3rd 0.78-0.90, 4th 0.91–1.27 

OR (95% CI): 

TM 1: 2nd, 0.92 (0.81, 1.05); 3rd, 1.14 (1.01, 1.29); 

4th, 1.26 (1.11, 1.44) 

TM 3: 2nd , 1.07 (0.95, 1.21); 3rd, 1.07 (0.94, 1.22); 

4th , 1.16 (1.01, 1.34) 

Increment: 0.57 ppm 

β coefficient (SE), deaths/day, lag 0 days: 

0.0061 (0.0110) 

CARBON MONOXIDE 3. HEALTH EFFECTS 110
 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study 

Lin et al. 2004b 

Period: 1995–1997 

Location: Taiwan 

Design features CO exposure Effect size 

Outcome: LBW 

Design: Retrospective cohort 

Sample: n=92,288 live full-term 

singleton births 

Avg time: 24 hours 

Mean: Taipei, 0.84– 

1.31 ppm; Kaohsiun, 5.56– 

10.05 ppm 

Range: NR 

>14.2 (H) p

OR (95% C

pm 

I): 

Liu et al. 2003 

Period: 1985–1998 

Location: Vancouver, Canada 

Outcome: PTB, LBW, IUGR 

Design: Retrospective cohort 

Sample: n=386,202 live singleton 

births 

Avg time: 24 hours 

Mean: 1.0 ppm 

25th–75th%: 0.7–1.2 ppm 

(0.63–0.94) 

OR (95% CI): 

Liu et al. 2007 

Period: 1995–2007 

Location: Canada 

Outcome: IUGR 

Design: Retrospective cohort 

Sample: n=386,202 live singleton 

births 

Avg time: 24 hours 

Mean: 1.1 ppm 

25th–75th%: 0.6–1.3 ppm 

RR (95% C

TM 1: 

I): 

Increment: <1.1 (reference),1.1–14.2 (L) vs.
 

TM 1: (L) 1.01 (0.89, 1.16); (H) 0.90 (0.75, 1.09)
 

TM 2: (L) 1.02 (0.90, 1.16); (H) 1.00 (0.82, 1.22)
 

TM 3: (L) 0.88 (0.77, 1.00); (H) 0.86 (0.71, 1.03)
 

Total gestation: (L) 0.89 (0.77, 1.01); (H) 0.77
 

Increment: 1 ppm
 

PTB, first month: 0.95 (0.89, 1.01)
 

PTB, last month: 1.08 (1.01, 1.15)
 

LBW, first month: 1.01 (0.93, 1.09)
 

LBW, last month: 0.96 (0.88, 1.04)
 

IUGR, first month:1.06 (1.01, 1.10)
 

IUGR, last month: 0.98 (0.94, 1.03)
 

IUGR, TM 1: 1.05 (1.00, 1.10)
 

IUGR, TM 2: 0.97 (0.92, 1.01)
 

IUGR, TM 3: 0.97 (0.93, 1.02)
 

Increment: 1 ppm
 

CO:1.18 (1.14, 1.23)
 

CO+NO2+O3: 1.18 (1.12, 1.24)
 

TM 2:
 

CO:1.14 (1.10, 1.18)
 

CO+NO2+O3: 1.15 (1.08, 1.21)
 

TM 3:
 

CO:1.09 (1.24, 1.14)
 

CO+NO2+O3: 1.20 (1.14, 1.26)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 111
 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Maisonet et al. 2001 Outcome: BW Avg time: 24 hours 

Period: 1994–1996 Design: Retrospective cohort Mean: 1.1 ppm OR (95% CI): 

Location: Northeast United Sample: n=89,557 live full-term 25th–75th%: 0.9–1.5 ppm 

States singleton births 

Mannes et al. 2005 Outcome: BW, SGA Avg time: 8 hours 

Period: 1998–2000 Design: Retrospective cohort Mean: 0.8 ppm 

Location: Sydney, Australia Sample: n=136,056 live full-term 25th–75th%: 0–4.6 ppm monitoring site: 

singleton births 

Medeiros and Gouveia 2005 Outcome: BW, LBW Avg time: 24 hours 

Period: 1998–2000 Design: Retrospective cohort Mean: ~2–3 ppm 

Location: Sao Paulo, Brazil Sample: n=311,735 live full-term Range: ~1–12 ppm 

singleton births (37–41 weeks) 

Increment: 1 ppm 

TM 1: 1.08 (0.91, 1.28) 

TM 2: 1.14 (0.83, 1.58) 

TM 3: 1.31 (1.06, 1.62) 

African-Americans: 

TM 1: 1.43 (1.18, 1.74) 

TM 2: 1.27 (0.87, 1.86) 

TM 3: 1.75 (1.50, 2.04) 

CO had no effect on strata for whites or Hispanics
 

Increment: 1 ppm
 

β coefficient (95% CI) BW (g), TM 2, <5 km from
 

CO: -29.87 (-50.98, -6.76)
 

CO+NO2: -20.17 (-43.12, 2.78)
 

CO+ PM10: -27.31 (-55.30, 0.68)
 

OR (95% CI) SGA <5 km from monitoring site:
 

TM 1: 0.99 (0.86, 1.14)
 

TM 2: 1.06 (0.90, 1.25)
 

TM 3: 1.05 (0.90, 1.23)
 

One month prior to birth: 1.10 (9.96, 1.27)
 

Increment: 1 ppm
 

β coefficient (95% CI) BW:
 

TM 1: -11.9 (-15.5, -8.2)
 

TM 2 4.9 (0.5, 9.3)
 

TM 3: 12.1 (7.6, 16.6)
 

OR (95% CI) LBW (75th % vs. 25th %):
 

TM 1: 0.98 (0.91, 1.06);
 

TM 2: 0.97 (0.90, 1.05)
 

TM 3: 1.03 (0.96, 1.11
 

CARBON MONOXIDE 3. HEALTH EFFECTS 112
 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study 

Morello-Frosch et al. 2010 

Period: 1996–2006 

Location: California 

Design features CO exposure Effect size 

Outcome: BW, LBW 

Design: Retrospective cohort 

Sample: n=3.5 million live full-term 

singleton births (37–44 weeks) 

Avg time: 24 hours 

Mean: 0.87 ppm 

25th–95th%: 0.56–1.09 ppm 

Parker et al. 2005 

Period: 2000 

Location: California 

Outcome: BW, SGA 

Design: Retrospective cohort 

Sample: n=18,247 live full-term 

singleton births 

Avg time: 24 hours 

Mean: 0.78 ppm 

25th–95th%: 0.57–0.93 ppm 

Ritz and Yu 1999 

Period: 1989–1993 

Location: California 

Outcome: LBW 

Design: Retrospective cohort 

Sample: n=125,275 live full-term 

singleton births 

Avg time: 6–9 AM 

Mean: 2.59 ppm 

95th%: 5.5 ppm 

>5.5 (H) 

OR (95% CI): 

Increment: 1 ppm 

β coefficient (95% CI) BW: 

CO, TM 1–3: -5.4 (-6.8, -4.1)
 

(remained significant when adjusted for O3 and 

SO2, but not when adjusted for PM10 or PM2.5)
 

OR (95% CI) LBW:
 

CO, TM 1–3: 1.04 (1.02, 1.06)
 

Increment (ppm): <0.57 (reference), 0.57–0.76 

(L), 0.76–0.93 (M), >0.93 (H)
 

OR (95% CI) for total gestation:
 

CO, L: 0.93 (0.80, 1.09)
 

CO, M: 0.91 (0.78, 1.06)
 

CO, H: 0.95 (0.81, 1.12)
 

CO (L)+PM2.5: 0.90 (0.77, 1.06)
 

CO (M)+PM2.5: 0.91 (0.77, 1.07)
 

CO (H)+PM2.5: 0.82 (0.68, 0.99)
 

Increment (ppm): <2.2 (reference), 2.2–<5.5 (L),
 

CO (L): 1.04 (0.96, 1.13)
 

CO, (H): 1.22 (1.03, 1.44)
 

CO (L)+NO2+O3_PM10: 1.10 (0.91, 1.32)
 

CO (H)+NO2+O3_PM10: 1.38 (0.86, 2.22)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 113
 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Ritz et al. 2000 Outcome: PTB Avg time: 6–9 AM 

Period: 1989–1993 Design: Retrospective cohort Mean: 2.70 ppm RR (95% CI): 

Location: California Sample: n=97,518 live singleton Range: 0.36–9,12 ppm 

births 

conception: 

Ritz et al. 2002 Outcome: CA (heart, orofacial) Avg time: 24 hours 

Period: 1987–1993 Design: Case-control Mean: NR 

Location: California Sample: n=3,549 cases 25th–75th%: 1.4–2.46 ppm 

Ritz et al. 2006 Outcome: Post-neonatal mortality Avg time: 24 hours 

Period: 1989–2000 (28 days–1 year) Mean: 1.63 ppm 

Location: California Design: Case-control Range: 0.38–3.44 ppm death: 

Sample: n=13,146 cases 

Increment: 3 ppm
 

Adjusted for risk factors:
 

Last 6 weeks: 1.06 (1.02, 1.10)
 

First month: 1.01 (0.97, 1.04)
 

Adjusted for risk factors and season of birth and
 

Last 6 weeks: 1.04 (0.99, 1.10)
 

First month: 1.04 (0.99, 1.09)
 

Adjusted for risk factors, NO2, O3, and PM10:
 

Last 6 weeks: 1.05 (0.97, 1.12)
 

First month: 1.03 (0.96, 1.10)
 

Increment: <1.4 ppm (reference), 1.14–1.57 (L),
 

1.57–2.39 (M), >2.39 (H)
 

OR (95% CI), month 2 of gestation:
 

Ventricular septal: 

CO: (L) 1.62 (1.05, 2.48); (M) 2.09 (1.19, 3.67);
 

(H) 2.95 (1.44, 6.05) 

CO+NO2+O3+PM10: (L) 1.63 (1.00, 2.66); (M) 1.97 

(1.0, 3.91); (H) 2.84 (1.15, 6.99) 

CO not associated with conotruncal, aortic artery 

and valve, or pulmonary artery and valve defects 

Increment: 1 ppm 

OR (95% CI), exposure period 2 months prior to 

All causes: 1.11 (1.06, 1.16)
 

SIDS: 1/19 (1.10, 1.28)
 

OR not significant after adjustment for NO2, O3, 

and PM10
 

CARBON MONOXIDE 3. HEALTH EFFECTS 114
 

 

 

 

 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study 

Ritz et al. 2007 

Period: 2003 

Location: California 

Design features CO exposure Effect size 

Outcome: PTB 

Design: Nested case-control 

Sample: n=2,543 cases, 

2,543 controls from 58,316 births in 

registry 

Avg time: 24 hours 

Mean: NR 

Range: NR 

Rudra et al. 2011 

Period: 1996–2006\ 

Location: Seattle and Tacoma, 

Washington 

Outcome: PTB, PEC 

Design: Prospective cohort 

Sample: n=3,509 pregnant women 

Avg time: 1 month 

Median: 1.08 ppm 

25th–75th%: 0.80–1.38 ppm 

Salam et al. 2005 

Period: 1975–1987 

Location: California 

Outcome: BW, LBW, IUGR 

Design: Retrospective cohort 

Sample: n=3,901 births (37– 

44 weeks) 

Avg time: 24 hours 

Mean: 1.8 ppm 

SD: 0.9 ppm 

OR (95% C

TM 1: 

TM 1: 

I): 

Tsai et al. 2006a 

Period: 1994–2000 

Location: Taiwan 

Outcome: Post-neonatal mortality 

(27 days–1 year) 

Design: Case-crossover 

Sample: n=206 cases 

Avg time: 24 hours 

Mean: 0.83 ppm 

Range: 0.23–1.77 ppm 

CO + O3: 

Increment (ppm): <0.58 (reference), 0.59– 

0.91 (L), 0.92–1.25 (M), >1.25 (H)
 

OR (95% CI), adjusted for risk factors:
 

TM 1: L: 1.17 (1.08, 1.26); M: 1.15 (1.05, 1.26);
 

H: 1.25 (1.12, 1.38)
 

Last 6 weeks: L: 1.00 (0.93, 1.08); M: 1.08 (0.98, 

120); H: 1.03 (0.93, 1.14)
 

Total gestation: L: 0.76 (0.70, 0.82); M: 0.84
 

(0.77, 0.91); H: 1.03 (0.91, 1.17)
 

Increment (ppm): 0.1 ppm
 

OR (95% CI), adjusted for risk factors:
 

PTB: 0.98 (0.94, 1.01)
 

PEC: 1.07 (1.02, 1.13)
 

PEC: 0.98 (0.91, 1.06) (adjusted for year of birth)
 

Increment: 1.4 ppm
 

LBW, CO: 1.0 (0.7, 1.5)
 

IUGR, CO: 1.2 (1.0, 1.4)
 

β coefficient (95% CI) for IUGR
 

CO: -21.7 (-42,3, -1.1)
 

-28.6 (-50.4, -6.9) 

Increment: 0.31 ppm 

OR (95% CI), lag 0–2 days: 

All causes: 1.051 (0.304, 3.630) 

CARBON MONOXIDE 3. HEALTH EFFECTS 115
 

 

 

 

 

 

 

 

Table 3-8. Selected Epidemiological Studies of Associations Between Ambient Carbon Monoxide Concentrations and 

Developmental Outcomes
	

Study Design features CO exposure Effect size 

Wilhelm and Ritz 2005 

Period: 1994–2000 

Location: California 

Outcome: LBW, PTB 

Design: Retrospective cohort 

Sample: n=106,483 births for PTB 

outcome, 136,134 births for LBW 

Avg time: 24 hours 

Mean: 1.2–1.4 ppm 

Range: 0.2–5.9 ppm 

Increment: 1 ppm (≤1 mile from monitoring 

station) 

RR (95% CI), adjusted for risk factors: 

PTB, TM 1: 

outcome CO: 1.06 (1.00, 1.12) 

CO+NO3+O3: 1.10 (1.01, 1.20) 

CO+NO3+O3+PM10: 0.99 (0.83, 1.18) 

PTB, last 6 weeks: 

CO: 1.04 (0.98, 1.09) 

CO+NO3+O3: 1.10 (1.03, 1.18) 

CO+NO3+O3+PM10: 0.98 (0.83, 1.16) 

LBW, TM 3: 

CO: 1.10 (0.98, 1.23) 

CO+NO3+O3: 1.15 (0.98, 1.35) 

CO+NO3+O3+PM10: 1.21 (0.85, 1.74) 

Woodruff et al. 2008 

Period: 1999–2002 

Location: U.S. counties with 

>250,000 residents 

Outcome: Post-neonatal mortality 

(28 days–1 year) 

Design: Retrospective cohort 

Sample: n=6,639 deaths of 

3,583,495 births 

Avg time: 24 hours 

Median: 0.70 ppm 

25th–75th%: 0.48–0.87 ppm 

Increment: 0.39 ppm 

OR (95% CI), exposure during age 0–2 months: 

All causes: 1.01 (0.95, 1.07) 

Respiratory: 

CO: 1.14 (0.93, 1.40) 

CO+O3+PM10+SO2: 1.02 (0.89, 1.15) 

SIDS: CO: 0.88 (0.76, 1.03) 

SIDS, CO+O3+PM10+SO2:.0.96 (0.87, 1.06) 

Yang et al. 2006 

Period: 1994–2000 

Location: Taiwan 

Outcome: Post-neonatal mortality 

(27 days–1 year) 

Design: Case-crossover 

Sample: n=471 cases 

Avg time: 24 hours 

Mean: 1.158 ppm 

Range: 0.32–4.84 ppm 

Increment: 0.55 ppm 

OR (95% CI), lag 0–2 days: 

All causes: 1.038 (0.663, 1.624) 

CARBON MONOXIDE 3. HEALTH EFFECTS 116

Avg = average; BW = birth weight; CA = congenital anomalies; CI = confidence interval; CO = carbon monoxide; IUGR = intrauterine growth rate (BW <10th percentile of 

birth cohort when adjusted for gestational age); LBW = low birth weight (<2,500 g); OR = odds ratio; PTB = pre-term birth (<37 weeks); PEC = preeclampsia; RR = relative 

risk; SD = standard deviation; SE = standard error; SGA = small for gestational age (BW <10th percentile of birth cohort when adjusted for gestational age); SIDS = sudden 

infant death syndrome; TM = trimester 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 117 

3. HEALTH EFFECTS 

A prospective cohort study conducted in the Seattle and Tacoma areas of Washington (1996–2006) 

examined possible associations between air carbon monoxide concentrations and pre-term birth and 

preeclampsia in 3,509 pregnancies (Rudra et al. 2011). Pre-term birth was not significantly associated 

with air carbon monoxide concentrations; the odds ratio was 0.98 (95% CI: 0.94, 1.01) per 0.1 ppm 

increase in carbon monoxide concentration. This study did find an association between carbon monoxide 

and preeclampsia (odds ratio: 1.07, 95% CI: 1.02, 1.13). However, the association was not significant 

when year of pregnancy was included in the model (0.98, 95% CI: 0.91, 1.06). A retrospective cohort 

study (n=97,158 births) conducted in southern California (1989–1993) found a significant association 

between increasing air carbon monoxide concentration (mean: 2.7 ppm, range: 0.6–9.12) and pre-term 

birth (Ritz et al. 2000). After adjustment for other risk factors as well as ambient air concentrations of 

NO2, O3, and PM10, the relative risk of pre-term birth was estimated to be 1.12 (95% CI: 1.04, 1.21) per 

3 ppm increase in air carbon monoxide concentration during the last 6 weeks of pregnancy. Subjects 

were matched to ambient carbon monoxide measurements made at monitors that were <2 miles from the 

residence. In a follow-up study (1994–2000) that included 106,483 births, relative risk (adjusted for NO2 

and O3) was estimated to be 1.10 (95% CI: 1.03, 1.08) per 1 ppm increment in air carbon monoxide 

concentration during the last 6 weeks of pregnancy (Wilhelm and Ritz 2005). The association was not 

significant when PM10 was included in the model along with NO2 and O3 (relative risk: 0.98; 95% CI: 

0.83, 1.18). A subsequent analysis of southern California data included a nested case-control study 

consisting of a subset of 2,543 cases of pre-term birth (<37 weeks of gestation) or low birth weight 

(<2,500 g) and an equal number of randomly selected controls for a larger cohort of 58,316 births (Ritz et 

al. 2007). Detailed individual data on potential co-variables were obtained, including maternal age, race, 

education, marriage status, birth season, parity, active and passive smoking, and alcohol use during 

pregnancy. The adjusted odds ratio in the case-control study for pre-term birth (exposure to >1.25 ppm in 

first trimester compared to <0.58 ppm) was 1.21 (95% CI: 0.88, 1.65; adjusted for co-variables other than 

co-pollutants). The odds ratio in the larger cohort (n=58,316) was similar (odds ratio: 1.25, 95% CI: 

1.12, 1.38; adjusted for maternal age, race, education, birth season, and parity). Results of multi-pollutant 

models were not reported. A larger case-control study, also conducted in southern California (1999– 

2000), did not find a significant association between ambient air carbon monoxide concentration and preterm birth (Huynh et al. 2006). This study examined 10,673 cases of pre-term births (<37 weeks of 

gestation) and 32,119 full-term controls (matched for last menstrual period date within 2 weeks of cases). 

The adjusted odds ratios for pre-term birth were not significant when adjusted for maternal age, maternal 

race/ethnicity, maternal education, marital status, and parity (with or without inclusion of PM2.5 

exposure). A 1 ppm increase in ambient carbon monoxide concentration during the first month of 

pregnancy was associated with an odds ratio of 1.10 (95% CI: 0.99, 1.20) when CO was considered alone, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 118 

3. HEALTH EFFECTS 

and 1.03 (95% CI: 0.83, 1.13) after adjustment for PM10. This study matched ambient carbon monoxide 

measurements to subjects whose residence was <5 miles of the monitoring station, whereas the Ritz et al. 

(2000, 2007) and Wilhelm and Ritz (2005) studies matched subjects to <2 miles from the monitoring 

station. 

Other large retrospective cohort studies have examined pre-term births in association with ambient air 

carbon monoxide concentrations. Liu et al. (2003) examined a cohort of 229,085 births in Vancouver, 

Canada (1985–1998). The odds ratio for pre-term birth for a 1 ppm increase in ambient air carbon 

monoxide concentration measured during the first month of pregnancy was 1.08 (95% CI: 1.01, 1.15; 

adjusted for maternal age, parity, infant sex, birth weight, and season of birth) and remained elevated after 

adjustment for NO2 and O3 (1.08, 95% CI: 1.00, 1.20). The mean air carbon monoxide concentration in 

the study was 1 ppm, and the highest value was 12.8 ppm. A cohort study of 52,113 births in Incheon, 

Korea (2001–2002) also estimated elevated risks of pre-term birth in association with increasing ambient 

air carbon monoxide concentrations during the first trimester. The relative risk increased with increasing 

estimated exposure concentration and was 1.26 (95% CI: 1.11, 1.44) for the strata 0.91–1.27 mg/m3 

(0.79–1.10 ppm) compared to the reference, >0.47–0.63 mg/m3

 (0.40–0.55 ppm) (adjusted for maternal 

age, parity, sex, season of birth, and education level of father and mother; Leem et al. 2006). Results of 

multi-pollutant models were not reported. The ambient air carbon monoxide concentrations ranged from 

approximately 0.35 to 1.4 ppm and were matched to subjects by spatial kriging (a spatial statistical 

method for interpolating exposure levels between sampling locations), with spatial averaging on a scale of 

approximately 3.5 km2

. A cohort study of 123,840 births in Sydney, Australia (1998–2000) did not find a 

significant association between ambient air carbon monoxide concentration and pre-term birth (Jalaludin 

et al. 2007). The highest odds ratio estimated was 1.24 (95% CI: 0.81, 1.91) or a 1 ppm increase in 

8-hour maximum carbon monoxide concentration measured during first trimester, based on residence 

<5 km of the monitoring station. When exposure estimates were based on city-wide monitoring, the odds 

ratio was significantly less than 1 (0.89, 95% CI: 0.84, 0.95), suggesting that risk of pre-term birth 

decreased with a 1 ppm increase in air carbon monoxide concentration. The city-wide mean 8-hour 

maximum air carbon monoxide concentration was 0.9 ppm (SD: 0.68). 

Studies of Low Birth Weight. Results of studies of low birth weight (i.e., <2,500 g or <10th percentile 

weight for gestation age) have been mixed, with most studies finding associations between increasing 

ambient air carbon monoxide concentrations and decreasing birth weight (Bell et al. 2007; Gouveia et al. 

2004; Ha et al. 2001; Lee et al. 2003a; Liu et al. 2003, 2007; Maisonet et al. 2001; Mannes et al. 2005; 

Medeiros and Gouveia 2005; Morello-Frosch et al. 2010; Parker et al. 2005; Ritz and Yu 1999; Salam et 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 119 

3. HEALTH EFFECTS 

al. 2005; Wilhelm and Ritz 2005). In some studies that found significant regression coefficients (i.e., 

β coefficients) relating air carbon monoxide concentration to birth weight (g), magnitudes of the changes 

in birth weight were not sufficient to produce elevated risk of low birth weight, where low birth weight is 

defined categorically as a birth weight <2,500 g. Furthermore, the relative contribution of co-exposures 

to other air pollutants has not been completely elucidated in epidemiology studies. In many, but not all, 

studies showing significant associations with birth weight, these associations were not significant after 

adjustments for exposures to other co-pollutants (e.g., NO2, O3, PM10). All of these studies described 

below estimated risks after adjustment for typical co-variables that are thought to affect birth weight (e.g., 

infant sex, maternal age, race/ethnicity, and education, interval since previous live birth, previous low 

birth weight or preterm infant, level of prenatal care, birth season, parity, and gestational age). 

Collectively, the reported studies of birth weight outcomes provide supportive evidence for an association 

between ambient air carbon monoxide concentrations and low birth weight. 

A series of studies conducted in California found that such associations were stronger when carbon 

monoxide was the only pollutant considered in the model and attenuated when adjustments were made for 

co-pollutants (Morello-Frosch et al. 2010; Parker et al. 2005; Ritz and Yu 1999; Salam et al. 2005; 

Wilhelm and Ritz 2005). Mean air carbon monoxide concentrations in these studies ranged from 0.75 to 

2.4 ppm and the highest value reported was 6.70 ppm (Wilhelm and Ritz 2005). Morello-Frosch et al. 

(2010) found significant associations between increasing carbon monoxide concentrations and decreasing 

birth weight and elevated risk of low birth weight in a sample of 3.5 million births (1996–2006). The 

β coefficient for birth weight was -5.4 g (95% CI: -6.8, -4.1) per 1 ppm increase in carbon monoxide 

concentration for the entire period of pregnancy and was also significant for exposures during the first or 

third trimesters. The odds ratio for low birth weight was 1.04 (95% CI: 1.02, 1.06). The association 

between exposure to carbon monoxide and birth weight persisted when adjusted for exposures to ozone 

and SO2, but was no longer significant when adjusted for PM10 or PM2.5. The Ritz and Yu (1999) study 

found elevated risk of low birth weight in a sample of 125,573 births (1989–1993). The odds ratio 

(>5.5 vs. <2.2 ppm during third trimester) was 1.22 (95% CI: 1.03, 1.44) when carbon monoxide alone 

was the only air pollutant considered and 1.38 (95% CI: 0.86, 2.22) when NO2, O3, and PM10 were 

included in the model. The odds ratios remained significant after adjustment for NO2, O3, and PM10, 

when the analysis was restricted to women <20 years of age (multi-pollutant model: 5.08, 95% CI: 1.77, 

16.63; carbon monoxide alone: 1.54, 95% CI: 1.07, 2.22). In a follow-up study (Wilhelm and Ritz 2005; 

1994–2000) that included 136,134 births, the odds ratio (>1.84 vs. <0.96 ppm) was estimated to be 

1.36 (95% CI: 1.04, 1.76) for women who resided ≤1 mile from an air monitoring station; however, risk 

was no longer significant when NO2 and O3 (1.29, 95% CI: 0.92, 1.81) or NO2, O3, and PM10 (1.39, 95% 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 120 

3. HEALTH EFFECTS 

CI: 0.77, 2.49) were included in the model. A smaller cohort study (1975–1987) of 3,901 births found 

significant associations between ambient air carbon monoxide concentrations and low birth weight and 

intrauterine growth retardation (IUGR, <15th percentile of weight at gestational age; Salam et al. 2005). 

The estimated odds ratio for IUGR was 1.2 (95% CI: 1.0, 1.4) for a 1.4 ppm increase in air carbon 

monoxide concentration in the first trimester (carbon monoxide considered alone). Although the odds 

ratio for low birth weight was not significant (1.0, 95% CI: 0.7, 1.5), a significant association between 

increasing air carbon monoxide concentration and lower birth weight was observed when birth weight 

was treated as a continuous variable (β coefficient: -21.7 g, 95% CI: -42.3, -1.1), which persisted when 

O3 was included in the model (-28.6, 95% CI: -50.4, -6.9). A cohort study of 18,247 full-term births in 

California (2000) did not find a significant association between ambient air carbon monoxide 

concentration and risk of SGA (i.e., small for gestational age, <10th percentile of weight for gestational 

age; Parker et al. 2005). The SGA odds ratio (>0.97 vs. <0.57 ppm for entire pregnancy) was 0.95 (95% 

CI: 0.81, 1.12) when carbon monoxide was considered alone and 0.82 (95% CI: 0.68, 0.99) when 

adjusted for PM2.5. When treated as a continuous variable, a significant association between increasing air 

carbon monoxide concentration and lower birth weight was found when carbon monoxide was modeled 

alone (β coefficient: -20.5 g, 95% CI: -40.1, -0.8); however, the association was not significant when 

adjusted for PM2.5 (2.6, 95% CI: -20.6, 25.8). 

Other studies of low birth weight conducted in the United States have yielded mixed results. A cohort 

study of 89,557 full-term births conducted in five northeastern cities (1994–1996) estimated the odds ratio 

for low birth weight to be 1.31 (95% CI: 1.06, 1.62) for a 1 ppm increase in air carbon monoxide 

concentration during the third trimester (Maisonet et al. 2001). When stratified by race, the effect was 

only significant among African Americans for the first trimester (odds ratio: 1.43, 95% CI: 1.18, 1.74) 

and third trimester (odds ratio: 1.75, 95% CI: 1.50, 2.04). Results of multi-pollutant models were not 

reported. A cohort study of 358,504 births in Connecticut and Massachusetts found a significant 

association between increasing ambient air carbon monoxide concentration (for entire pregnancy) and 

reduced birth weight (β coefficient: -16.2, 95% CI: -19.7, -12.6), which persisted when adjusted for NO2, 

O3, PM10, PM2.5, or SO2 (Bell et al. 2007). However, the magnitude of the change in birth weight did not 

result in a significant odds ratio (odds ratio: 1.028, 95% CI: 0.983, 1.074). Mean air carbon monoxide 

concentrations in the above studies ranged from 0.65 to 0.95 ppm. 

Two studies examined low birth weight or IUGR in Canada (Liu et al. 2003, 2007). The Liu et al. (2003) 

study included 229,085 births in the Vancouver area (1985–1998) and found a significant association 

between ambient air carbon monoxide concentration (during fist month of pregnancy) and IUGR risk per 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 121 

3. HEALTH EFFECTS 

1 ppm increase in carbon monoxide (odds ratio: 1.06, 95% CI: 1.01, 1.10), which persisted when 

adjusted for NO2, O3, or SO2 (OR estimates not reported). In a larger area study (Liu et al. 2007) that 

included 386,202 births (1995–2000), odds ratios were significant for IUGR when ambient air carbon 

monoxide concentrations were considered during the first trimester (1.18, 95% CI: 1.14, 1.22), second 

trimester(1.14, 95% CI: 1.10, 1.18), or third trimester (1.19, 95% CI: 1.14, 1.24). The odd ratios 

remained significant after adjustment for exposures to NO2 and PM2.5. The mean air carbon monoxide 

concentration in both studies was 1 ppm and the highest value reported was 5.6 ppm. 

Two studies conducted in Seoul, South Korea (1996–1997, 1996–1998) found significantly increased risk 

of low birth weight in cohorts of 276,763 births (Ha et al. 2001) and 388,105 births (Lee et al. 2003a). In 

the Ha et al. (2001) study, the relative risk of low birth weight for a 0.42 ppm increase in ambient air 

carbon monoxide concentration during the first trimesters was 1.08 (95% CI: 1.04, 1.12). In the Lee et 

al. (2003a) study, the odds ratios for a 0.5 ppm increase in carbon monoxide concentration were 

1.04 (95% CI: 1.01, 1.07) for the first trimester, 1.03 (1.00–1.06) for the second trimester carbon 

monoxide, 0.96 (0.93–0.99) for the third trimester carbon monoxide, and 1.05 (1.01–1.09) for carbon 

monoxide concentration during the entire pregnancy. Results of multi-pollutant models were not 

reported. The mean air carbon monoxide concentration was 1.2 ppm (range: 0.4–3.4 ppm). 

A cohort study conducted in Sydney, Australia (1998–2000) included 138,056 births and found a 

significant association between increasing ambient air carbon monoxide concentration and decreasing 

birth weight (Mannes et al. 2005). For carbon monoxide exposure during the second trimester, an 

increase of 1 ppm was associated with a 28.7 g reduction birth weight (95% CI: 7.76, 50.98). The 

association did not persist when the regression models were adjusted for exposure to NO2 or PM10 in twopollutant models. Furthermore, the magnitude of the effect did not result in a significant risk of SGA 

(<2 SD of mean weight for gestational age). The mean ambient carbon monoxide concentration was 

0.8 ppm (range: 0–4.6). 

Two cohort studies conducted in Sao Paulo, Brazil also found a significant association between increasing 

ambient air carbon monoxide concentration and decreasing birth weight (Gouveia et al. 2004; Medeiros 

and Gouveia 2005). In the Gouveia et al. (2004) study, in a cohort of 179,460 births (1997), a 1 ppm 

increase in ambient air carbon monoxide concentration during the first trimester was associated with a 

23.1 g reduction in birth weight (95% CI: 4.9, 41.3); however, the effect was not of sufficient magnitude 

to result in elevated risk of low birth weight. The Medeiros and Gouveia (2005) study included 

311,735 births (1998–2000) and estimated a reduction in birth weight of 11.9 g (95% CI: 8.2, 15.5) per 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 122 

3. HEALTH EFFECTS 

1 ppm increase in first trimester carbon monoxide concentration. Here again, odds ratios for low birth 

weight were not significant. The ambient carbon monoxide concentrations in these studies ranged from 

approximately 1 to 11 ppm. 

Studies of Congenital Anomalies. Possible associations between exposures to carbon monoxide and 

developmental anomalies have been evaluated in four case-control studies (Dadvand et al. 2011; Gilboa et 

al. 2005; Hwang and Jaakkola 2008; Ritz et al. 2002). Three of the studies found significant associations 

between carbon monoxide and heart anomalies (i.e., ventricular septic defect (Ritz et al. 2002), 

conotruncal defects (Gilboa et al. 2005), malformation of cardiac septa (Dadvand et al. 2011), and 

pulmonary valve stenosis (Dadvand et al. 2011). The evaluation in the Hwang and Jaakkola (2008) study 

was limited to cleft lip and palate and found no association with carbon monoxide, consistent with the 

Ritz et al. (2002) study. Collectively, these studies do not provide convincing evidence for associations 

between exposure to carbon monoxide and congenital anomalies. 

The Dadvand et al. (2011) study included 2,769 cases and 14,256 controls born during the period 1993– 

2003 in northeast England. The study examined heart anomalies, including malformations of the cardiac 

chambers and connections, cardiac septa, aortic and mitral valves, and great arteries and vein; atrial septal 

defect; coarctation of aorta; congenital pulmonary stenosis; tetralogy of Fallot; and ventricular septal 

defect. Of these, significant associations with carbon monoxide concentrations (odds ratio per 1 mg/m3 

[0.87 ppm] increase in carbon monoxide concentration) were observed for malformation of cardiac septa 

(2.330, 95% CI: 1.748, 3.102), pulmonary valve stenosis (2.682, 95% CI: 2.682, 5.534), and ventricular 

septal defect (2.634, 95% CI: 1.871, 3.707). The Ritz et al. (2002) study included 3,549 cases and 

10,649 controls born during the period 1987–1993 in southern California. The study included various 

categories of anomalies including heart and pulmonary, conotruncal, cleft lip and palate, and 

chromosomal defects. Of these, significant odds ratios were found for ventricular septal defects with 

increasing ambient air carbon monoxide concentration during the second month of pregnancy. Odds 

ratios increased with increasing ambient air carbon monoxide concentration during the second month of 

pregnancy (<1.14 ppm reference): 1.14–1.60 ppm, odds ratio 1.62 (95% CI: 1.05, 2.48); 1.60– 

<2.47 ppm, odds ratio 2.09 (95% CI: 1.19, 3.67); and ≥2.47 ppm, odds ratio 2.95 (95% CI: 1.44, 6.05). 

Significant odds ratios for ventricular septal defects persisted in multi-pollutant models. 

A case-control study conducted in Texas (1996–2000) included 4,594 cases and 3,667 controls (Gilboa et 

al. 2005). Anomalies considered in the study included heart and pulmonary, conotruncal, and cleft lip and 

palate. Of these, a significant dose trend was evident for tetralogy of Fallot (a conotruncal anomaly of the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 123 

3. HEALTH EFFECTS 

heart), with a significant odds ratio (>0.7 vs. <0.4 ppm) for ambient air carbon monoxide concentration 

during the 3rd–8th week of pregnancy (2.04, 95% CI: 1.26, 3.29). The odds ratio for any conotruncal 

anomaly was also significant at the highest exposure category (>0.7 vs. <0.4 ppm) (1.46, 95% CI: 1.03, 

2.08). Results of multi-pollutant models were not reported. 

A case-control study conducted in Taiwan (2001–2003) included 653 cases of cleft lip and/or palate and 

6,530 controls and examined associations with ambient air carbon monoxide concentrations measured 

during the first trimester of pregnancy (Hwang and Jaakkola 2008). Air carbon monoxide concentration 

was not associated with odds ratio for either anomaly in single- or multiple-pollutant models (O3, PM10, 

or SO2). 

Studies of Neonatal and Infant Mortality. Studies of possible associations between ambient air carbon 

monoxide concentrations and neonatal and infant mortality have yielded mixed results (Ha et al. 2003; 

Lin et al. 2004a; Ritz et al. 2006; Tsai et al. 2006a; Woodruff et al. 2008; Yang et al. 2006). Although 

increased risk of infant mortality in association with increasing ambient air carbon monoxide 

concentrations has been reported (Ha et al. 2003; Ritz et al. 2006), these outcomes have not been 

rigorously examined for the possible confounding by birth weight and/or gestational age, two relatively 

influential variables in predicting infant mortality. In one study that did examine the effect of 

stratification by gestational age or birth weight, the association between air carbon monoxide 

concentration and mortality from all causes or sudden infant death syndrome (SIDS) persisted in singlepollutant models, but not in models that adjusted for NO2, PM10, and O3 (Ritz et al. 2006). Collectively, 

these studies do not provide convincing evidence for an association between ambient air carbon monoxide 

concentrations and neonatal or infant mortality. 

A time-series analysis conducted in Sao Paulo, Brazil (1998–2000) did not find a significant association 

between ambient air carbon monoxide concentrations and neonatal mortality (age 1–28 days; Lin et al. 

2004a). The mean air carbon monoxide concentration was 2.8 ppm (range: 0.5–10 ppm). A case-control 

study conducted in California (1989–2000) included 13,146 cases of infant death (age 28 days–1 year) 

and 151,015 controls (Ritz et al. 2006). Results varied depending on the temporal window for averaging 

air carbon monoxide concentration. The odds ratio for infant death for a 1 ppm increase in ambient air 

carbon monoxide concentration, averaged for 2 months prior to death, was 1.11 (95% CI: 1.06, 1.16), 

with higher risk for deaths attributable to SIDS (odds ratio: 1.19; 95% CI: 1.10, 1.28). However, risks 

were not significant after adjustment for co-pollutants (NO2, PM10, and O3). For an averaging period of 

2 weeks prior to death, risks were significant for all respiratory-related deaths that occurred between 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 124 

3. HEALTH EFFECTS 

28 days and 1 year (odds ratio: 1.14, 95% CI: 1.03, 1.25) or from age 28 days to 3 months (odds ratio: 

1.20, 95% CI: 1.02, 1.40). Significant respiratory deaths persisted in multi-pollutant models. The 

association between air carbon monoxide concentration and SIDS mortality risk was persistent when the 

data were stratified by gestational age and birth weight; however, in these strata, the associations were not 

significant after adjustment for exposure to NO2, PM10, and O3. The mean air carbon monoxide 

concentration in the study was 1.6 ppm (range: 0.4–3.4 ppm). 

A retrospective cohort study analyzed deaths that occurred between age 28 days and 1 year in a cohort of 

3,590,134 births (6,939 deaths) across U.S. counties having a population >250,000 residents (1989–2000; 

Woodruff et al. 2008). Ambient air carbon monoxide concentration (median: 0.70 ppm, 25th–75th 

percentile range: 0.48–0.87 ppm) during the first 2 months postpartum was not associated with infant 

death of any category, including all causes (odds ratio: 1.01, 95% CI: 0.95, 1.07), respiratory (odds ratio: 

1.14, 95% CI: 0.93, 1.40), or SIDS (odds ratio: 0.88, 95% CI: 0.76, 1.03). The latter values were 

estimated from single-pollutant models; however, similar results were obtained in multi-pollutant models 

that adjusted for O3 and SO2. 

A time-series study conducted in Seoul, South Korea (1995–1999) found a significant risk of respiratoryrelated mortality (age 1 month–1 year) in association with increasing ambient air carbon monoxide 

concentration measured on the day of death (odds ratio: 1.388, 95% CI: 1.009, 1.911, per 0.57 ppm 

increase in carbon monoxide concentration), but not for deaths from all causes (Ha et al. 2003). Two 

case-crossover studies conducted in Taiwan (1994–2000) did not find a significant association between 

ambient air carbon monoxide concentration and infant mortality (Tsai et al. 2006a; Yang et al. 2006). 

The Tsai et al. (2006a) study included 206 cases (age 28 days–1 year), and the mean ambient air carbon 

monoxide concentration was 0.83 ppm (range: 0.23–1.77 ppm). The Yang et al. (2006) study included 

471 cases (age 27 days–1 year); the mean ambient air carbon monoxide concentration was 1.58 ppm 

(range: 0.3–4.8 ppm). 

Animal Studies. Numerous studies on developmental effects of gestational and early postnatal exposure 

to carbon monoxide have been conducted in animals. Study details are summarized in Table 3-9. In 

general, most studies evaluated effects of relatively low carbon monoxide concentrations (i.e., ≤300 ppm), 

with exposure concentrations selected to produce maternal COHb levels typically associated with 

smoking; however, studies did not consistently report maternal or fetal COHb levels. Studies in animals 

have examined effects of carbon monoxide exposure on numerous developmental outcomes, including 

several outcomes that have not been assessed in epidemiological studies (e.g., auditory and immune 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Effects on birth weight 

Astrup et al. 1972 

Carmines and 

Rajendran 2008 

Fechter and Annau 

1977 

Fechter and Annau 

1980 

Fechter et al. 1987a 

Rabbits 

Rats 

Rats 

Rats 

Rats 

Continuous exposure 

to 0, 90, or 180 ppm 

CO throughout 

gestation 

2 hours/day to 

600 ppm CO on 

GDs 6–19 (nose-only 

exposure) 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–21 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 0, 75, 150, or 

300 ppm CO from 

GD 0 through 

PND 10 

mCOHb: 8–9% in 90 ppm 

CO group; 16–18% in 

180 ppm CO group 

fCOHb: NR 

mCOHb: ~30% (measured 

on GD 20) 

fCOHb: NR 

mCOHb: 15% 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

mCOHb: 11, 18, and 27% 

in the 75, 150, or 300 ppm 

CO, respectively 

fCOHb: NR 

Birth weight: Fetal weight decreased by 11 and 20% in the 90 

and 180 ppm CO groups, respectively. 

NOAEL (birth weight): Not established
 

LOAEL (birth weight): 90 ppm CO (mCOHb 8–9%)
 

Birth weight: Significantly decreased by 11%, compared to 

control.
 

NOAEL (birth weight): Not established
 

LOAEL (birth weight): 600 ppm CO (mCOHb ~30%)
 

Birth weight: Decreased by 4.8%, compared to controls (not
 

statistically significant).
 

Pre-weanling weight: Pre-weanling weight significantly 

decreased, compared to control, on PNDs 4–21 (decreased 

by 16 and 27% on PNDs 4 and 21, respectively). 

NOAEL (pre-weanling weight): Not established
 

LOAEL (pre-weanling weight): 60 ppm CO (mCOHb 15%)
 

Birth weight: Decreased by 7.6%, compared to controls.
 

NOAEL (pre-weanling weight): Not established 

LOAEL (pre-weanling weight): 150 ppm CO 

Birth weight: Fetal weight decreased by 8.9 and 13.8% in 

150 and 300 ppm CO groups, respectively, compared to 

control; by PND 21, no effects of CO treatment on pup weight. 

NOAEL (birth weight): 75 ppm CO (mCOHb 11%) 

LOAEL (birth weight): 150 ppm CO (mCOHb 18%) 

CARBON MONOXIDE 3. HEALTH EFFECTS 125
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb	 Results 

Penney et al. 1983 Rats Continuous exposure 

to 0, 157, 166, or 

200 ppm CO on 

GDs 5–22 

Prigge and Hochrainer Rats Continuous exposure 

1977 to 0, 60, 125, 250, or 

500 ppm CO on 

GDs 0–21 

Storm and Fechter Rats Continuous exposure 

1985b to 0, 75, 150, or 

300 ppm CO for 

entire gestational 

period 

Tolcos et al. 2000b Guinea pigs 10 hours/day 0 or 

200 ppm CO from 

GDs 23 or 25 to 

GD 68 

Effects on CNS (central control of respiratory function) 

McGregor et al. 1998 Guinea pigs	 10 hours/day 0 or 

200 ppm CO from 

GDs 23 or 25 to 

GD 68 

mCOHb: 24.9% (in dams
 

exposed to 200 CO,
 

measured over period of
 

PNDs 1–6)
 

fCOHb: 21.8, 24.9, and 

3.10–33.5% at 157, 166,
 

and 200 ppm CO,
 

respectively (at birth)
 

mCOHb: NR 

fCOHb: NR 

mCOHb: 11.5, 18.5, and 

26.8% in the 75, 150, and 

300 ppm CO groups, 

respectively 

fCOHb: NR 

mCOHb: 8.5% 

fCOHb: 13% 

mCOHb: 8.5% 

fCOHb: 13% 

Birth weight: Statistically significant decrease (~10%) in all 

CO groups, compared to control. 

NOAEL (birth weight): Not established
 

LOAEL (birth weight): 157 ppm CO (fCOHb 21.8%)
 

Birth weight: Dose-related, statistically significant decrease 

(7.5–36.7%) in fetal weight at ≥125 ppm, compared to control.
	

NOAEL (birth weight): 60 ppm CO 

LOAEL (birth weight): 125 ppm CO 

Birth weight: Fetal weight decreased by 12.5% in 300 ppm 

CO group, compared to control. 

NOAEL (birth weight): 150 ppm CO (mCOHb 18.5%) 

LOAEL (birth weight): 300 ppm CO (mCOHb 27%) 

Birth weight: Fetal weight decreased by 9.6% in CO group, 

compared to control. 

NOAEL (birth weight): Not established
 

LOAEL (birth weight): 200 ppm CO (mCOHb 8.5%)
 

CNS development (function): On PND 4, pups from COexposed dams exhibited abnormal respiratory responses to 

asphyxia and hypercapnia; responses consistent with 

developmental alterations in brain stem.
 

NOAEL (CNS function): Not established
 

LOAEL (CNS function): 200 ppm CO (mCOHb 8.5%)
 

CARBON MONOXIDE 3. HEALTH EFFECTS 126
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Effects on CNS (behavioral) 

De Salvia et al. 1995 Rats 

Fechter and Annau 

1977 

Rats 

Fechter and Annau 

1980 

Rats 

Giustino et al. 1999 Rats 

0, 75, or 150 ppm 

CO on GDs 0–20 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–21 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 75 and 150 ppm 

CO on GDs 0–20 

mCOHb: ~15% for 

150 ppm CO (NR for 

75 ppm CO) 

fCOHb: NR 

mCOHb: 15% 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

mCOHb: 7.3 and 16.1% in 

75 and 150 ppm CO 

groups, respectively 

fCOHb: NR 

CNS development (behavioral effects): Significant 

impairment of acquisition (at 3 and 18 months) and 

reacquisition (at 18 months) of conditioned avoidance 

behavior following gestational exposure of pups to 150 ppm 

CO. 

NOAEL (CNS behavioral): 75 ppm CO 

LOAEL (CNS behavioral): 150 ppm CO 

CNS development (behavioral effects): During the 

preweaning period, CO pups were less active and showed 

decreased response to L-DOPA-induced movement 

stimulation. 

NOAEL (CNS behavioral): Not established
 

LOAEL (CNS behavioral): 60 ppm CO (mCOHb 15%)
 

CNS development (behavioral effects): Pups of exposed 

dams showed impaired righting reflexes, impaired negative 

geotaxis, and delayed homing behavior.
 

NOAEL (CNS behavioral): Not established 

LOAEL (CNS behavioral): 150 ppm CO 

CNS development (behavioral effects): Alterations in 

habituation and working memory in young adult male 

offspring at PND 40, including decreased time of exploration 

of novel objects (75 and 150 ppm CO) and lack of habituation 

after the second exposure to a previously viewed object 

(150 ppm CO); decreased spontaneous motor activity in open 

field test (75 and 150 ppm CO). 

NOAEL (CNS behavioral): Not established 

LOAEL (CNS behavioral): 75 ppm CO 

CARBON MONOXIDE 3. HEALTH EFFECTS 127
 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

CARBON MONOXIDE 3. HEALTH EFFECTS 128

Reference Species Exposure COHb Results 

Mactutus and Fechter 

1985 

Rats Continuous exposure 

to 150 ppm CO over 

entire gestational 

period 

mCOHb: 15.6% 

fCOHb: NR 

CNS development (behavioral effects): Prenatal CO 

exposure induced learning and memory deficits in male and 

female offspring, as indicated by impairments in reacquisition 

performance, an index of retention, on PND 31 and 

decrements in two-way conditioned avoidance behavior 

(flashing light warnings followed by mild foot shock) on 

PND 120. 

NOAEL (CNS behavioral): Not established 

LOAEL (CNS behavioral): 150 ppm CO (mCOHb 15.6%) 

Singh 1986 Mice Continuous exposure 

to 0, 65, or 135 ppm 

CO on GDs 7–18 

mCOHb: NR 

fCOHb: NR 

CNS development (behavioral effects): On PNDs 1–10, pups 

of exposed dams showed impaired righting reflexes (125 ppm 

CO), geotaxis (125 ppm CO), and aerial righting reflex (65 

and 125 ppm CO). 

NOAEL (CNS behavioral): Not established 

LOAEL (CNS behavioral): 65 ppm CO 

Tattoli et al. 1999 Rats Continuous exposure 

to 0, 75, or 150 ppm 

CO on PNDs 1–10 

COHb in pups: NR CNS development (behavioral effects): Assessed at 3 and 

18 months of age, no effects of early postnatal exposure on 

acquisition and reacquisition of an active avoidance task in 

either adult or aged rats. 

NOAEL: 150 ppm CO 

LOAEL: Not established 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Effects on CNS (neurotransmitter) 

Cagiano et al. 1998 Rats 

Fechter and Annau 

1977 

Rats 

Fechter and Annau 

1980 

Rats 

Fechter et al. 1987a Rats 

Storm and Fechter 

1985a 

Rats 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–21 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 0, 75, 150, or 

300 ppm CO from 

GD 0 through 

PND 10 

Continuous exposure 

to 0 or 150 ppm for 

entire gestational 

period 

mCOHb: ~16% 

fCOHb: NR 

mCOHb: 15% 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

mCOHb: 11, 18, and 27% 

In the 75, 150, or 300 ppm 

CO, respectively 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

CNS development (neurotransmitter changes): On PND 80, 

no CO effect on basal extracellular levels of dopamine in the 

nucleus accumbens; however, the amphetamine-induced 

dopamine release was decreased in pups of CO-exposed 

dams. 

NOAEL (CNS neurotransmitter): Not established
 

LOAEL (CNS neurotransmitter): 150 ppm CO (mCOHb 16%)
 

CNS development (neurotransmitter changes): Brain 

dopamine content decreased by 45 and 25% on PNDs 1 and
 

4, respectively.
 

NOAEL (CNS neurotransmitter): Not established
 

LOAEL (CNS neurotransmitter): 60 ppm CO (mCOHb 15%)
 

CNS development (neurotransmitter changes): On PND 1, no 

effect of CO exposure on forebrain and hindbrain levels of
 

dopamine or norepinephrine.
 

NOAEL (CNS neurotransmitter): 150 ppm CO 

LOAEL (CNS neurotransmitter): Not established 

CNS development (neurotransmitter changes): On PND 21, 

pups of CO-exposed dams showed elevated dopamine levels 

in neostriatum (150 and 300 ppm CO). 

NOAEL (CNS neurotransmitter): 75 ppm CO (mCOHb 11%) 

LOAEL (CNS neurotransmitter): 150 ppm CO (mCOHb 18%) 

CNS development (neurotransmitter changes): 

Norepinephrine levels (amount and concentration) in 

cerebellum (but not cortex) elevated from PND 14 to 42, 

compared to controls. 

NOAEL (CNS neurotransmitter): Not established 

LOAEL (CNS neurotransmitter): 150 ppm CO 

CARBON MONOXIDE 3. HEALTH EFFECTS 129
 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

CARBON MONOXIDE 3. HEALTH EFFECTS 130

Reference Species Exposure COHb Results 

Storm and Fechter 

1985b 

Rats Continuous exposure 

to 0, 75, 150, or 

300 ppm CO for 

entire gestational 

period 

mCOHb: 11.5, 18.5, and 

26.8% in the 75, 150, and 

300 ppm CO groups, 

respectively 

fCOHb: NR 

CNS development (neurotransmitter changes): On PND 21, 

weight of cerebellum decreased by 8.5 and 11.4% in 150 and 

300 ppm CO groups, respectively; dose-related trend for 

decreased norepinephrine concentration in pons/medulla (but 

not neocortex, hippocampus, or cerebellum; decreased 

serotonin concentration in pons/medulla in 150 and 300 ppm 

CO groups. On PND 42, weight of cerebellum decreased by 

8.3% in 300 ppm CO group; dose-related trend for increased 

norepinephrine concentration neocortex and hippocampus 

(but not pons/medulla or cerebellum). 

NOAEL (CNS neurotransmitter): 75 ppm CO (mCOHb 

11.5%) 

LOAEL (CNS neurotransmitter): 150 ppm CO (mCOHb 

18.5%) 

Tolcos et al. 2000b Guinea pigs 10 hours/day 0 or 

200 ppm CO from 

GDs 23 or 25 to 

GD 68 

mCOHb: 8.5% 

fCOHb: 13% 

CNS development (neurotransmitter changes): Effects on 

cholinergic and catecholaminergic pathways in the medulla, 

including significant decrease in tyrosine hydroxylaseimmunoreactivity in the nucleus tractus solitarius, dorsal 

motor nucleus of the vagus, area postrema, intermediate 

reticular nucleus, and ventrolateral medulla; significant 

increase in choline acetyltransferase-immunoreactivity in the 

dorsal motor nucleus of the vagus and hypoglossal nucleus, 

compared with controls. 

NOAEL (CNS neurotransmitter): Not established 

LOAEL (CNS neurotransmitter): 200 ppm CO (mCOHb 8.5%) 
 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb	 Results 

Effects on CNS (auditory system) 

Lopez et al. 2003 Rats	 Continuous exposure mCOHb: NR 

to 0, 12, or 25 ppm fCOHb: NR 

CO on PNDs 8–22 

Lopez et al. 2008 Rats	 10–18 hours/day to mCOHb: NR 

25 ppm CO on fCOHb: NR 

GDs 5–20 or on 

GDs 5–20 plus 

PNDs 5–20 

CNS development (auditory system): Pups examined on 

PND 27, nerve terminals innervating inner hair cells were 

swollen, with cytoplasmic vacuolization and atrophy (25 ppm 

CO); in the 8th cranial nerve at the level of the internal 

auditory canal, fibers showed “distorted myelin” with 

vacuolization (25 ppm CO); in spiral ganglion neurons of the 

organ of corti, decreased immunoreactivity of enzymes 

cytochrome oxidase, NADH-TR, and calcium-mediated 

myosin ATPase (25 ppm CO); in organ of corti, decreased 

immunostaining of neurofilament and myelin basic protein 

(25 ppm CO). 

NOAEL (CNS auditory): 12 ppm CO 

LOAEL (CNS auditory): 25 ppm CO 

CNS development (auditory system): Similar effects in pups 

exposed during gestation only and during gestation and 

PNDs 5–20. On PND 3, no morphological deterioration or 

loss of inner or outer hair cells; on PND 20, vacuolization on 

the afferent terminals at the basal portion of the cochlea; 

type I spiral ganglia neurons and afferent nerve fibers showed 

decreased neurofilament-immunoreactivity. 

NOAEL (CNS auditory): Not established 

LOAEL (CNS auditory): 25 ppm CO 

CARBON MONOXIDE 3. HEALTH EFFECTS 131
 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb	 Results 

Stockard-Sullivan Rats 22 hour/day to 12, 

2003 25, 50, or 100 ppm 

CO on PNDs 6–22 

Webber et al. 2003 Rats	 Continuous exposure 

to 0, 12.5, 25, or 

50 ppm CO on 

GDs 8 through 20– 

22 

COHb in pups: 5–7% in 

100 ppm CO group (not 

measured in other groups) 

mCOHb: NR 

fCOHb: NR 

CNS development (auditory system): Decreased in 

otoacoustic emissions at 50 and 100 ppm CO, measured at 

age 22–24 days; attenuation of the amplitude of the 8th nerve 

action potential in all CO groups, measured at age 22– 

24 days, with effects persisting though age 73 days in the 

50 and 100 ppm CO group (not examined at later ages in 

other groups); no effect on auditory brain stem conduction 

times in any CO group, measured at ages 22, 30, or 51– 

52 days. 

NOAEL (CNS auditory): Not established 

LOAEL (CNS auditory): 12 ppm CO 

CNS development (auditory system): Examined effects of CO 

exposed on central inferior colliculus (an area of the mid-brain 

with auditory integrative functions) during period of 

synaptogenesis/auditory development. Immunostaining of 

c-Fos (marker of neuronal activation in the nervous system) 

showed significant decrease in C-Fos immunoreactivity in the 

central inferior colliculus on PNDs 27 and 75–77 in all CO 

groups. Results indicate that gestational exposure to CO can 

produce changes in the auditory system of rats that persist 

into adulthood. 

NOAEL (CNS auditory): Not established 

LOAEL (CNS auditory): 12.5 ppm CO 

CARBON MONOXIDE 3. HEALTH EFFECTS 132
 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Effect on peripheral nervous system 

Carratu et al. 1993 Rats 

Carratu et al. 2000a Rats 

Carratu et al. 2000b Rats 

Effects on cardiovascular system
 

Penney et al. 1982 Rats
 

Continuous exposure 

to 0, 75, or 100 ppm 

CO on GDs 0–20 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 0, 75, or 100 ppm 

CO on GDs 0–20 

Continuous exposure 

to 0 or 500 ppm CO 

on PNDs 1–32 

mCOHb: ~15% for 

150 ppm CO (NR for 

75 ppm CO) 

fCOHb: NR 

mCOHb: 16.02% 

fCOHb: NR 

mCOHb: 7.34 and 16.08% 

in the 75 and 150 ppm CO 

groups, respectively 

fCOHb: NR 

COHb in pups: 38–42% 

PNS development (electrophysiological changes): In sciatic 

nerves isolated on PND 40, inactivation kinetics of inactive 

sodium channels were significantly slowed and negative shift 

in sodium equilibrium potential was observed in both CO 

groups; on PND 270, sciatic nerves showed negative shift in 

sodium equilibrium potential both CO groups. 

NOAEL (PNS development): Not established 

LOAEL (PNS development): 75 ppm CO 

PNS development (neuronal development): Altered 

sphingomyelin composition of sciatic nerve, but no effect on 

motor activity in pups at PND 90. 

NOAEL (PNS development): Not established 

LOAEL (PNS development): 150 ppm CO 

PNS development (neuronal development): Exposure of 

dams produced decreased myelin sheath thickness of nerve 

fibers (75 and 100 ppm CO) but not axon diameter or motor 

activity in pups at PNDs 40 and 90. 

NOAEL (PNS development): Not established 

LOAEL (PNS development): 75 ppm CO 

CVS (heart weight): Relative heart weight increased on 

PND 14 and remained above normal through PND 104. 

NOAEL (developmental heart weight): Not established 

LOAEL (developmental heart weight): 500 ppm CO (COHb 

38–42%) 

CARBON MONOXIDE 3. HEALTH EFFECTS 133
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Penney et al. 1983 Rats 

Prigge and Hochrainer Rats 

1977 

Sartiani et al. 2004 Rats 

Effects on sexual behavior 

Cagiano et al. 1998 Rats 

Continuous exposure 

to 0, 157, 166, or 

200 ppm CO on 

GDs 5–22 

Continuous exposure 

to 0, 60, 125, 250, or 

500 ppm CO on 

GDs 0–21 

Continuous exposure 

to 0 or 150 ppm CO 

on GDs 0–20 

Continuous exposure 

to 0, 75, or 150 ppm 

CO on GDs 0–20 

mCOHb: 24.9% (in dams
 

exposed to 200 CO,
 

measured over period of
 

PNDs 1–6)
 

fCOHb: 21.8, 24.9, and 

3.10–33.5% at 157, 166,
 

and 200 ppm CO,
 

respectively (at birth)
 

mCOHb: NR 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

mCOHb: ~7.5 and ~16% in 

75 and 150 ppm CO 

groups, respectively 

fCOHb: NR 

CVS (heart weight): Dose-related, statistically significant 

increased in relative heart weight (10–108%) in all CO 

groups, compared to control. 

NOAEL (developmental heart weight): Not established 

LOAEL (developmental heart weight): 157 ppm CO (fCOHb 

21.8%) 

CVS (heart weight): Dose-related, statistically significant 

increase in relative heart weight (10–52%) in all CO groups, 

compared to control. 

NOAEL (developmental heart weight): Not established 

LOAEL (developmental heart weight): 60 ppm CO 

CVS (myocardial electrophysiological changes): In ventricular 

cardiocytes isolated from pups on PNDs 1–60, delayed 

development of age-related action potential duration 

shortening was observed. Delay was maximum at 4 weeks of 

age. 

NOAEL (CVS function): Not established 

LOAEL (CVS function): 150 ppm CO 

Development of sexual behavior: On PND 80, in pups of 

dams exposed to 150 ppm CO (but not 75 ppm CO), 

alterations in sexual behavior, including increase in mount to 

intromission latency, decrease in mount to intromission 

frequency, and decrease in ejaculation frequency. 

NOAEL (developmental sexual behavior): 75 ppm CO 

LOAEL (developmental sexual behavior): 150 ppm CO 

CARBON MONOXIDE 3. HEALTH EFFECTS 134
 

 

 

 

 

 

 

 

 

 

Table 3-9. Effects of Gestational or Perinatal Exposure on Developmental Outcomes in Animals
	

Reference Species Exposure COHb Results 

Effects on immunological system
 

Giustino et al. 1993 Rats
 

Giustino et al. 1994 Rats
 

Effects on hematological system 

Prigge and Hochrainer Rats 

1977 

Continuous exposure 

to 75 and 150 ppm 

CO on GDs 0–20 

Continuous exposure 

to 75 and 150 ppm 

CO on GDs 0–20 

Continuous exposure 

to 0, 60, 125, 250, or 

500 ppm CO on 

GDs 0–21 

mCOHb: ~15% in 150 ppm 

CO group (NR in 75 ppm 

CO group) 

fCOHb: NR 

mCOHb: ~15% in 150 ppm 

CO group (NR in 75 ppm 

CO group) 

fCOHb: NR 

mCOHb: NR 

fCOHb: NR 

Immunological effects: On PNDs 15 and 21, decreased 

splenic macrophage phagocytosis of Candida albicans 

(150 ppm CO); on PND 15, decreased splenic macrophage 

killing (75 and 150 ppm CO); no effects observed on PND 60. 

NOAEL (immunological): Not established 

LOAEL (immunological): 75 ppm CO 

Immunological effects: On PND 21, significant decreased in 

number of leukocyte common antigen cells in 150 ppm CO 

group; no effects observed on PND 540. 

NOAEL (immunological): 75 ppm CO
 

LOAEL (immunological): 150 ppm CO (mCOHb ~15%)
 

Hematological effects: Dose-related, statistically significant
 

decrease in hematocrit (14.8–34.2%) and hemoglobin (12.5–
 

28.4%) at ≥250 ppm, compared to control.
 

NOAEL (hematological): 125 ppm CO
 

LOAEL (hematological): 250 ppm CO
 

CARBON MONOXIDE 3. HEALTH EFFECTS 135

CNS = central nervous system; CO = carbon monoxide; COHb = carboxyhemoglobin; CVS = cardiovascular system; fCOHb = fetal COHb; GD = gestation day;
 

LOAEL = lowest-observed-adverse-effect level; mCOHb = maternal COHb; NOAEL = no-observed-adverse-effect level; NR = not reported; PND = postnatal day
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 136 

3. HEALTH EFFECTS 

system development). Results of animal studies show adverse developmental effects of gestational and 

early postnatal carbon monoxide exposure, including decreased fetal weight, adverse central nervous 

system development, altered peripheral nervous system development, cardiac effects, altered sexual 

behavior, immunological effects, and hematological effects. In addition, some studies showed that 

developmental effects persisted beyond the postnatal period (Carratu et al. 1993, 2000a, 2000b; De Salvia 

et al. 1995; Mactutus and Fechter 1985; Stockard-Sullivan et al. 2003; Webber et al. 2003), although 

persistence of effects was not examined in all studies. The lowest LOAEL values for developmental 

effects were obtained in studies evaluating effects of carbon monoxide on the developing auditory system 

(i.e., LOAEL 12–25 ppm carbon monoxide); however, since other developmental outcomes were not 

assessed at this range of low carbon monoxide concentrations, it is not possible to determine if the 

developing auditory system is more sensitive to carbon monoxide exposure than other systems, or to 

identify a biological basis for such susceptibility. 

Birth Weight. Several studies have evaluated effects of gestational exposure to carbon monoxide on birth 

weight in rats (Carmines and Rajendran 2008; Fechter and Annau 1977, 1980; Fechter et al. 1980, 1987a; 

Penney et al. 1983; Prigge and Hochrainer 1977; Singh 2008; Storm and Fechter 1985b), rabbits (Astrup 

et al. 1972), and guinea pigs (Tolcos et al. 2000b). Results consistently show that gestational exposure to 

carbon monoxide significantly decreased birth weight and/or pre-weanling weight, with LOAEL values 

ranging from 60 ppm carbon monoxide (maternal COHb 15%) for continuous exposure during gestation 

(Fechter and Annau 1977) to 600 ppm (maternal COHb approximately 30%) for intermittent 

(2 hours/day) exposure (Carmines and Rajendran 2008). Decreases in birth weight exhibited exposure 

concentration-dependence (Astrup et al. 1972; Fechter et al. 1987a; Prigge and Hochrainer 1977) and 

were exacerbated when dams were fed protein-deficient diets (Singh 2008). 

Central Nervous System Development. Several studies have observed adverse effects on the developing 

central nervous system, including altered control of respiratory function, behavioral effects, changes in 

brain neurotransmitters levels, alteration of the cerebellum, and auditory development. Gestational 

exposure of guinea pigs to 200 ppm carbon monoxide produced abnormal respiratory responses to 

asphyxia and hypercapnia, indicative of altered brain stem development (McGregor et al. 1998). In rat or 

mouse pups exposed to 60–150 ppm carbon monoxide during gestation, behavioral changes included 

decreased motor activity and response to stimulation (Fechter and Annau 1977, 1980), impaired righting 

reflexes (Fechter and Annau 1980; Singh 1986), and impaired homing and memory acquisition behaviors 

(Giustino et al. 1999; Mactutus and Fechter 1985). Effects on acquisition and reacquisition behavior 

persisted up to 18 months of age in rats exposed to 150 ppm carbon monoxide during gestation (De Salvia 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 137 

3. HEALTH EFFECTS 

et al. 1995; Mactutus and Fechter 1985), although similar effects were not observed in pups exposed to 

150 ppm carbon monoxide during the early postnatal period (Tattoli et al. 1999). Gestational exposure of 

rats or guinea pigs to 60–300 ppm carbon monoxide produced altered levels of dopamine and 

norepinephrine in several regions of the brain (Cagiano et al. 1998; Fechter and Annau 1977; Fechter et 

al. 1987a; Storm and Fechter 1985a, 1985b; Tolcos et al. 2000b). Gestational and postnatal exposure of 

rat pups to low levels of carbon monoxide (25 ppm) produced changes consistent with oxidative stress in 

the cerebellum, including increased expression of neuroglobin and cytoglobin and up-regulation of genes 

related to generation of ROS and lipid metabolism; changes were more pronounced in pups exposed 

during gestation compared to those exposed only during the postnatal period (Beltran-Parrazal et al. 2010; 

Lopez et al. 2009). Gestational or postnatal exposure to low levels of carbon monoxide (i.e., 12–25 ppm) 

has been shown to have effects on the developing auditory system. Gestational and/or early postnatal 

exposure of artificially-reared rat pups (i.e., reared on formula to allow exposure to the pups without 

exposure to the dams during nursing) to 25 ppm carbon monoxide produced morphological changes in the 

developing auditory system, including swelling, cytoplasmic vacuolization and atrophy of nerve terminals 

innervating inner hair cells, “distorted myelin” with vacuolization in the 8th cranial nerve at the level of 

the internal auditory canal, decreased immunoreactivity of the enzymes cytochrome oxidase, NADH-TR, 

and calcium-mediated myosin ATPase, and decreased immunostaining of neurofilament and myelin basic 

protein in the organ of corti (Lopez et al. 2003, 2008). Limited physiological and acoustic testing of pups 

suggested potential functional impairment in the auditory system. Neuroglobin was decreased in spiral 

ligament cells and spiral ganglia neuron of the cochlea of rat pups exposed to 25 ppm carbon monoxide 

during gestation (Lopez et al. 2010). The study authors suggested that decreased cochlear neuroglobin 

could result in development of auditory deficits. Exposure of artificially-reared rat pups during the early 

postnatal period decreased action potential amplitude of the 8th cranial nerve at ≥12 ppm carbon 

monoxide, although the magnitude of the effect was not dose-dependent. Otoacoustic emissions showed 

a small reduction in amplitude (3 dB at two of three frequencies tested and one loudness level) at 

≥50 ppm carbon monoxide, with effects on action potential amplitude of the 8th nerve persisting through 

age 73 days (Stockard-Sullivan et al. 2003). The reduction in amplitude of otoacoustic emissions 

observed in this study was relatively small. Larger effects are more typically associated with hearing loss 

(e.g., 10–29 dB across five or more frequencies). Gestational exposure on gestation days (GDs) 8–20 of 

dam-reared rat pups to ≥12.5 ppm carbon monoxide significantly decreased neuronal activation of the 

central inferior colliculus (the area or the brain with auditory integrative function), with effects observed 

through postnatal days 75–77 (Webber et al. 2003). Results indicate that carbon monoxide-induced 

effects on brain auditory integrative neurons can persist into adulthood. 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 138 

3. HEALTH EFFECTS 

Peripheral Nervous System Development. Gestational exposure to carbon monoxide produced effects on 

peripheral nervous system development. In sciatic nerves of pups exposed during gestation, myelin 

sheath thickness was decreased and sphingomyelin composition was altered at 75–150 ppm carbon 

monoxide, with changes persisting through age 90 days (Carratu et al. 2000a, 2000b). Altered nerve 

transmission, indicative of slowed inactivation kinetics of inactive sodium channels, was observed in 

sciatic nerves from pups exposed to 75 ppm carbon monoxide during gestation, with changes persisting to 

age 270 days (Carratu et al. 1993). 

Cardiac Effects. Dose-related increases in heart weight were observed in rat pups exposed to 60– 

157 ppm carbon monoxide during gestation (Penney et al. 1983; Prigge and Hochrainer 1977) or to 

500 ppm carbon monoxide during the early postnatal period (Penney et al. 1982). The development of 

cardiomyopathy is consistent with a pathophysiological compensatory response to hypoxia. In ventricular 

cells isolated from pups exposed to 150 ppm carbon monoxide (but not 75 ppm) during gestation, agerelated decreases in action potential duration were seen (Sartiani et al. 2004). Maturation of cardiac cells 

was impaired, as indicated by decreased expression of sarcomeric proteins (actin, myosin, and troponin I), 

Ca2+ transporters (Ca2+ transporting ATPase), and enzymes (aldolase), in rat pups exposed to 150 ppm 

carbon monoxide during gestation (Sartiani et al. 2010) 

Sexual Behavior. In male pups exposed to 150 ppm carbon monoxide during gestation, altered 

development of sexual behavior was observed at age 80 days (Cagiano et al. 1998). Effects included 

increased mount to intromission latency, decreased mount to intromission frequency, and decreased 

ejaculation frequency. 

Immune System Effects. In studies conducted by Giustino et al. (1993, 1994), gestational exposure 

produced reversible alterations in immune system function. Decreases in splenic macrophage 

phagocytosis of Candida albicans was observed in pups exposed to 150 ppm carbon monoxide, and 

decreased splenic macrophage killing was observed in pups exposed to 75 and 150 ppm carbon monoxide 

(Giustino et al. 1993); effects did not persist at age 60 days. Rats exposed to 150 ppm carbon monoxide, 

but not 75 ppm, showed an alteration in splenic immune cell populations, with a significant decrease in 

leukocyte common antigen cells; effects did not persist to age 540 days (Giustino et al. 1994). 

Hematological Effects. Dose-related decreases in hematocrit and Hb were observed in pups exposed to 

250 and 500 ppm carbon monoxide during gestation (Prigge and Hochrainer 1977). Effects are consistent 

with physiological compensatory responses to COHb-induced hypoxia. 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 139 

3. HEALTH EFFECTS 

3.2.7 Cancer 

Epidemiological studies have examined possible associations between exposure to ambient air 

concentration of carbon monoxide and cancer mortality (described in Section 3.2.1, Death). A 

prospective study examined mortality in a cohort of 552,138 adults in 151 U.S. metropolitan areas 

enrolled in the study in 1982 and followed through 1998 (Jerrett et al. 2003; Pope et al. 1995, 2002). 

Based on estimates of average ambient air carbon monoxide concentration during the period 1982–1998, 

relative risk for mortality from lung cancer was approximately 0.90 (95% CI: 0.83, 0.96) per 1 ppm 

increase in carbon monoxide concentration (estimated from Figure 5 of Pope et al. 2002). A time-series 

analysis conducted in New York City, New York (1985–1994) evaluated data on cancer deaths with or 

without contributing respiratory diseases (De Leon et al. 2003). Estimates of cancer mortality risk were 

significant only in the strata with contributing respiratory disease (risk ratio was approximately 1.18, the 

95% lower confidence limit >1) and did not persist when estimates were adjusted for ambient 

concentrations of PM10 (risk ratio approximately 1.06, 95% CI: ~0.97, 1.17). Collectively, the 

epidemiological data do not show an increase in cancer risk in association with exposure to carbon 

monoxide. 

Carbon monoxide has not been assessed for carcinogenicity using animal models. 

3.3 GENOTOXICITY 

Few studies have evaluated the genotoxic effects of carbon monoxide exposure. Results of available 

studies are summarized in Table 3-10. An in vitro bacterial replication assay in Escherichia coli reported 

that exposure to carbon monoxide inhibited deoxyribonucleic acid (DNA) synthesis (Cairns and Denhardt 

1968); however, interpretation of study results is compromised by poor reporting of experimental and 

analytical methods (e.g., carbon monoxide concentration, exposure conditions, and statistical analyses). 

Exposure of pregnant mice to carbon monoxide during gestation produced dose-related increases in 

micronuclei and sister chromatid exchanges in maternal bone marrow and fetal blood (Kwak et al. 1986). 

Pregnant mice were exposed to 0, 1,500, 2,500, or 3,500 ppm carbon monoxide for 10 minutes on GDs 5, 

11, or 15 or to 0 or 500 ppm carbon monoxide for 1 hour on GDs 0–6, 7–13, or 14–20; maternal bone 

marrow and fetal blood were examined for micronuclei formation and sister chromatid exchanges on 

GD 21. Increases in micronuclei and sister chromatid exchanges in maternal bone marrow and fetal 

blood were observed under all carbon monoxide exposure conditions, compared to unexposed controls. 
 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 140 

3. HEALTH EFFECTS 

Table 3-10. Genotoxicity of Carbon Monoxide 

Species (test 

system) Exposure End point Results Reference 

Prokaryotic organisms: 

Escherichia coli, CO concentration not DNA + Cairns and Denhardt 

TAMT reported replication 1968 

Mammalian cells: 

Mice (ICR strain, 0, 1,500, 2,500, or Sister Maternal bone Kwak et al. 1986 

pregnant females, 3,500 ppm CO for chromatid marrow: + 

64/dose) 10 minutes on GD 5, 11, exchange Fetal blood: + 

or 16; fetal blood and 

maternal bone marrow 

examined on GD 21 

Mice (ICR strain, 0 or 500 ppm CO for Sister Maternal bone Kwak et al. 1986 

pregnant females, 1 hour on GDs 0–6, 7–13, chromatid marrow: + 

50/dose) or 14–20; fetal blood and exchange Fetal blood: + 

maternal bone marrow 

examined on GD 21 

Mice (ICR strain, 0, 1,500, 2,500, or Chromosomal Maternal bone Kwak et al. 1986 

pregnant females, 3,500 ppm CO for aberrations, marrow: + 

64/dose) 10 minutes on GD 5, 11, micronucleus Fetal blood: + 

or 16; fetal blood and assay 

maternal bone marrow 

examined on GD 21 

Mice (ICR strain, 0 or 500 ppm CO for Chromosomal Maternal bone Kwak et al. 1986 

pregnant females, 1 hour on GDs 0–6, 7–13, aberrations, marrow: + 

50/dose) or 14–20; fetal blood and micronucleus Fetal blood: + 

maternal bone marrow assay 

examined on GD 21 

+ = positive result; CO = carbon monoxide; DNA = deoxyribonucleic acid; GD = gestation day 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 141 

3. HEALTH EFFECTS 

The magnitude of effect was similar in dams and fetuses. Although blood COHb levels were not 

measured in this study, a 1-hour exposure to 500 ppm carbon monoxide would be expected to produce a 

maternal blood COHb concentration of approximately 20–25% (based on CFK model prediction for rats). 

3.4 TOXICOKINETICS 

Carbon monoxide exists in the environment as a gas (Henry’s law constant >50,000 atm/mol fraction, 

25 °C, see Table 4-2). As a result, humans can be exposed to carbon monoxide from breathing and/or 

skin contact with carbon monoxide in air. No information is available on the dermal absorption of carbon 

monoxide resulting from exposures to gaseous carbon monoxide. However, as is the case for other gases 

that are avidly absorbed from the lung (e.g., O2), dermal absorption of carbon monoxide through intact 

skin would be expected to make a minor contribution to absorbed carbon monoxide, relative to inhalation. 

Although carbon monoxide can dissolve in water (23 mL CO/L water, 20 °C), appreciable concentrations 

in drinking water would occur only at very high partial pressures of carbon monoxide in air, conditions in 

which inhalation would be the dominant absorption pathway. Since the only relevant pathway of 

exposure to humans is the inhalation pathway, oral and dermal exposures are not considered further in the 

discussion of the toxicokinetics of carbon monoxide, 

3.4.1 Absorption 

Inhaled carbon monoxide is rapidly and extensively absorbed into blood (Benignus et al. 1994; Burge and 

Skinner 1995; Peterson and Stewart 1970, 1975; Tikuisis et al. 1987b). Inhaled carbon monoxide is 

transported to lung alveoli as a result of convective forces in the respiratory tract and diffusion. At the 

alveolar gas-blood interface, carbon monoxide dissolves into pulmonary capillary plasma and, from 

plasma, diffuses into erythrocytes and other tissues (Figure 3-3). Binding of carbon monoxide by 

erythrocyte Hb (to form COHb) contributes to maintaining relatively low concentrations of dissolved 

carbon monoxide in erythrocyte cytosol and a partial pressure gradient to drive carbon monoxide transfer 

from alveolar air to blood. Diffusion of carbon monoxide into erythrocytes and binding of carbon 

monoxide to Hb is sufficiently rapid that near equilibrium is achieved between carbon monoxide partial 

pressures in alveolar air and alveolar end capillary (arterial) blood (Chakraborty et al. 2004). Continued 

uptake of carbon monoxide results from systemic elimination processes that lower mixed venous blood 

carbon monoxide concentrations returned to alveolar capillaries (Benignus et al. 1994). The primary 

elimination processes include diffusive transfer of carbon monoxide to extravascular tissues and binding 

of carbon monoxide to intracellular heme proteins (e.g., muscle myoglobin), and oxidative metabolism of 

carbon monoxide to CO2. Seconds after initiating inhalation exposures to carbon monoxide, COHb is 
 

 

CARBON MONOXIDE 142 

3. HEALTH EFFECTS 

Figure 3-3. Summary of Carbon Monoxide Uptake, Distribution, and Elimination 

Pathways
	

Alveolar Air 

Plasma 

RBC 

Hemoglobin 

Endogenous 

Production 

Metabolism to 

CO2 

Intravascular 

Extravascular 

Myoglobin 

Intracellular 

Enzymes 
 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 143 

3. HEALTH EFFECTS 

detected in arterial blood. During 2–6 minutes of exposure, arterial COHb concentrations were 

approximately twice venous COHb concentrations and approached unity within 3–5 minutes of cessation 

of exposure (Benignus et al. 1994). With continued exposure to a constant air carbon monoxide 

concentration, a steady-state would be achieved within 200–500 minutes (Figure 3-4; Bruce and Bruce 

2003; Peterson and Stewart 1970, 1975). At that point, net absorption diminishes to a value determined 

primarily by metabolic elimination of carbon monoxide (see Section 3.4.3, Metabolism). 

Major factors that control absorption of carbon monoxide include those that affect delivery of inhaled air 

to the alveolar region of the lung and those that affect lung carbon monoxide diffusion capacity. Lung 

diffusion capacity refers to the driving force for diffusion of carbon monoxide across the alveolar airblood interface and is reflected in the carbon monoxide partial pressure difference between inspired and 

exhaled air. In general, factors that increase alveolar ventilation, cardiac output, and gas diffusing 

capacity of the lung, while maintaining alveolar ventilation perfusion matching (i.e., proportional 

increases in alveolar ventilation rate and cardiac output) tend to increase absorption of inhaled carbon 

monoxide. Factors that may increase net carbon monoxide absorption include exercise, supine position, 

age (increased in infancy and childhood and declines in adults with age), altitude, increasing blood Hb 

concentration, and decreasing partial pressure of O2 in inhaled air or blood (Castillo et al. 2006; Horvath 

et al. 1988; Joumard et al. 1991; McGrath et al. 1993; Peterson and Stewart 1975; Tikuisis et al. 1992). 

3.4.2 Distribution 

Inhaled carbon monoxide distributes to blood and extravascular tissues. In blood, carbon monoxide 

rapidly distributes into erythrocytes where is exists primarily as a complex with Hb (COHb). The binding 

equilibrium constant for COHb is approximately 750 μM-1 (Chakraborty et al. 2004; see further 

discussion in Section 3.4.3, Metabolism). At a blood Hb concentration of 150 g/L (approximately 

2.3 mM), the molar concentration ratio of COHb would be approximately 1.7x106 times greater than the 

molar concentration of dissolved carbon monoxide. The relative affinity of Hb for carbon monoxide and 

O2 greatly favors binding of carbon monoxide to Hb over O2. The CO/O2 affinity ratio (Haldane 

constant) is approximately 234 (Chakraborty et al. 2004). This means that a partial pressure of O2 (pO2) 

approximately 234 times that of pCO is needed to achieve an equilibrium in which equal amounts of O2 

and carbon monoxide are bound to Hb (i.e., %COHb = % oxyhemoglobin [O2Hb]; Engel et al. 1969; 

Rodkey et al. 1969; Roughton 1970). In general, typical levels of COHb in nonsmokers are <2% (Adams 

et al. 1988; Allred et al. 1991; Anderson et al. 1973; Hinderliter et al. 1989; Kleinman et al. 1989, 1998; 

Sheps et al. 1987, 1990). Of this, COHb levels of approximately 0.2–1.0% are thought to be derived from 
 

 

 

 

CARBON MONOXIDE 144 

3. HEALTH EFFECTS 

Figure 3-4. Temporal Profile of Blood Carboxyhemoglobin (%) for Hypothetical
	

Continuous Exposures to Air Carbon Monoxide at Concentrations of 25, 200,
	

or 1,000 ppm
	

Source: Peterson and Stewart 1975
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 145 

3. HEALTH EFFECTS 

endogenous production of carbon monoxide (Coburn et al. 1963; Delivoria-Papadopoulos et al. 1974; 

Longo 1977). Levels of COHb can (rarely) achieve 10% immediately following cigarette smoking (Kao 

and Nañagas 2006; Landaw 1973). 

Although bound extensively to Hb in blood, distribution of dissolved carbon monoxide out of the 

vasculature can occur in response to diffusion gradients for carbon monoxide created by binding of 

carbon monoxide to Hb, myoglobin, and other heme proteins in extravascular tissues (e.g., muscle, 

spleen), as well as removal of carbon monoxide from extravascular tissues by oxidative metabolism 

(Bruce and Bruce 2006; Bruce et al. 2008; Luomanmäki and Coburn 1969). Myoglobin, the dominant 

binding protein for carbon monoxide in cardiac and skeletal muscle, has a lower affinity for carbon 

monoxide than Hb (COMb equilibrium constant of ≈20 μM-1 and Haldane constant of approximately 23) 

and a single binding site for carbon monoxide (Gibson et al. 1986); however, its abundance in muscle can 

result in transfer of substantial amounts of inhaled carbon monoxide into muscle tissue. At a skeletal 

muscle myoglobin concentration of 4.7 g/kg muscle (approximately 0.26 mmole/kg; Moller and Sylven 

1981), the molar concentration ratio of COMb would be approximately 7.4x103 times greater than the 

molar concentration of dissolved carbon monoxide. Binding of carbon monoxide to Hb in blood and 

myoglobin in muscle decreases the concentrations of dissolved carbon monoxide in both tissues and 

limits the concentration gradient for diffusion of carbon monoxide into muscle (Bruce and Bruce 2006; 

Bruce et al. 2008). Exercise can increase the rate of transfer of carbon monoxide from blood to skeletal 

muscle (Richardson et al. 2002; Werner and Lindahl 1980). The effect of exercise is thought to be 

related, in part, to increased O2 consumption and lower pO2 in muscle, which favors binding of carbon 

monoxide to myoglobin, and increased muscle blood flow. These effects a more pronounced at low 

COHb concentrations (≤2%) than at higher concentrations (20% COHb; Richardson et al. 2002). 

Hypoxia appears to increase transfer of carbon monoxide from blood to muscle (Coburn and Mayers 

1971; Richardson et al. 2002). 

Binding of carbon monoxide to intracellular proteins, in particular, heme proteins, contributes to 

maintaining a favorable gradient for carbon monoxide diffusion from plasma into cells. Measurements of 

total carbon monoxide concentrations in tissues obtained from human autopsies showed the highest 

concentrations in blood, spleen, lung, kidney, and skeletal muscle, with detectable levels also in brain and 

adipose tissue (Table 3-11, Vreman et al. 2006). Higher concentrations of carbon monoxide in blood, 

heart, skeletal muscle, and spleen observed in human autopsy studies reflect the abundance of the major 

carbon monoxide binding proteins in these tissue, Hb in erythrocytes and spleen (site of destruction and 

storage of erythrocytes), and myoglobin in cardiac and skeletal muscle. If the values presented in 
 

 

 

CARBON MONOXIDE 146 

3. HEALTH EFFECTS 

Table 3-11. Post-Mortem Tissue Distribution of Carbon Monoxide in Humansa 

Exposure Adipose Brain Muscle Heart Kidney Lung Spleen Blood 

Concentration (pmol/100 g) 

Background 2 3 15 31 23 57 79 165 

Fire 5 7 24 54 27 131 95 286 

Fire + carbon 18 17 168 128 721 1,097 2,290 3,623 

monoxide 

Carbon monoxide 25 72 265 527 885 2,694 3,455 5,196 

asphyxiation 

Tissue/blood carbon monoxide concentration ratio 

Background 0.012 0.018 0.091 0.188 0.139 0.345 0.479 1.000 

Fire 0.017 0.024 0.084 0.189 0.094 0.458 0.332 1.000 

Fire + carbon 0.005 0.005 0.046 0.035 0.199 0.303 0.632 1.000 

monoxide 

Carbon monoxide 0.005 0.014 0.051 0.101 0.170 0.518 0.665 1.000 

asphyxiation 

Body weight (kg) 70 70 70 70 70 70 70 70 

Tissue mass 200 2.0 40.0 0.5 0.4 1.4 0.3 7.4 

(percent) 

Tissue carbon monoxide burden (nmol) 

Background 0.28 0.04 4.20 0.10 0.07 0.57 0.14 8.55 

Fire 0.70 0.10 6.72 0.18 0.08 1.31 0.17 14.81 

Fire + carbon 2.52 0.24 47.04 0.42 2.22 10.97 4.12 187.67 

monoxide 

Carbon monoxide 3.50 1.01 74.20 1.73 2.73 26.95 6.22 269.15 

asphyxiation 

Tissue carbon monoxide burden (percent of total) 

Background 2.0 0.3 30.1 0.7 0.5 4.1 1.0 61.3 

Fire 2.9 0.4 27.9 0.7 0.3 5.4 0.7 61.5 

Fire + carbon 1.0 0.1 18.4 0.2 0.9 4.3 1.6 73.5 

monoxide 

Carbon monoxide 0.9 0.3 19.2 0.4 0.7 7.0 1.6 69.8 

asphyxiation 

a

Carbon monoxide concentrations based on Vreman et al. (2006). Tissue masses based on Davies and Morris 

(1993) and ILSI (1994). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 147 

3. HEALTH EFFECTS 

Table 3-11 are converted to tissue carbon monoxide mass (pmol), based on assumed tissue masses for a 

70-kg adult (Davies and Morris 1993; ILSI 1994), carbon monoxide in blood and muscle accounted for 

approximately 60–70 and 20–30% of total body carbon monoxide burden, respectively. Relatively large 

contributions of blood and skeletal muscle to total body carbon monoxide content is consistent with the 

contributions that these tissues make to total body Hb and muscle myoglobin (Bruce and Bruce 2003). In 

a typical adult, blood contains approximately 12 mmoles of Hb with a total binding capacity of 

approximately 48 mmole carbon monoxide when completely saturated and muscle contains 

approximately 8 mmoles of myoglobin with a total binding capacity of 8 mmole carbon monoxide when 

completely saturated. 

The distribution of carbon monoxide residues observed in human autopsy studies is similar to that 

observed in rodents. In mice and rats that had not been intentionally exposed to air carbon monoxide (i.e., 

sacrificed during steady-state conditions), blood and muscle accounted for most the total body carbon 

monoxide burden (Vreman et al. 2005). Following 30-minute exposures to carbon monoxide 

(5,000 ppm), blood made a much larger contribution (approximately 90%) to carbon monoxide body 

burden, reflecting the longer period needed for carbon monoxide to distribute from blood to extravascular 

tissues (Vreman et al. 2005). 

Carbon monoxide in the maternal system distributes to fetal tissues. Measurements of steady-state COHb 

concentrations in fetal and maternal blood of nonsmoking women have found fetal COHb concentrations 

to be approximately 10–15% higher than maternal blood (fetal/maternal ratio=1.1–1.15; Longo 1977). 

Carbon monoxide binding to fetal Hb is analogously similar to maternal Hb. Both Hbs have the same 

binding capacity of 4 moles CO/mole Hb and both exhibit cooperative binding of carbon monoxide, 

whereby binding affinity increases as carbon monoxide molecules are successively added to Hb (see 

Section 3.4.3, Metabolism). However, the binding affinity of fetal Hb is approximately twice that of 

maternal Hb (Di Cera et al. 1989). The Haldane coefficient, reflecting the relative affinities of carbon 

monoxide and O2 (CO/O2) for fetal Hb, appears to be approximately 20% lower than adult Hb (Di Cera et 

al. 1989; Engel et al. 1969; Hill et al. 1977). The higher binding affinity of fetal Hb as well as the 

relatively small diffusion gradients for carbon monoxide between maternal and fetal blood contribute to 

slower kinetics of COHb in fetal blood compared to maternal blood. This has been experimentally 

verified in studies conducted in pregnant sheep (Longo and Hill 1977). The half-time for approach to 

steady-state in the human fetus has been predicted (from modeling) to be approximately 7.5 hours in the 

fetus, compared to approximately 4 hours in maternal blood (Hill et al. 1977). As a result, with 

continuous exposure to a constant level of carbon monoxide in air, fetal blood COHb concentration would 
 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 148 

3. HEALTH EFFECTS 

be expected to lag behind maternal levels and reach a steady-state that is approximately 10–15% higher 

than maternal (Longo 1977). Similarly, following cessation of exposure, elimination kinetics of carbon 

monoxide from fetal blood would be expected to lag behind that of maternal blood (Hill et al. 1977). 

3.4.3 Metabolism 

Metabolism of carbon monoxide consists of three major processes: (1) metabolic production of carbon 

monoxide from endogenous and exogenous precursors; (2) binding of carbon monoxide to heme proteins 

(e.g., Hb, myoglobin, cytochromes); and (3) oxidative metabolism of carbon monoxide to CO2. 

Metabolic Production of Carbon Monoxide. Carbon monoxide is produced from the enzymatic 

degradation of endogenous and exogenous precursors. The major endogenous source of carbon monoxide 

production is the oxidative metabolism of heme by the enzyme heme oxygenase (HO). The net rate of 

endogenous production of carbon monoxide (i.e., total production minus metabolism) has been estimated 

in healthy adults to be approximately 0.42 mL CO/hour (16.4 μmole/hour) or approximately 

400 μmole/day (Coburn et al. 1963). Of this, approximately 75–80% is thought to be derived from Hb 

metabolism, and the remaining portion from metabolism of other heme proteins, such as myoglobin, 

cytochromes, peroxidases, and catalase (Berk et al. 1976). Endogenous carbon monoxide production 

contributes to a blood COHb concentration of approximately 0.4–0.7% (Benignus 1995; Coburn et al. 

1965). Carbon monoxide is produced in all tissues that express HO; however, the major tissues 

contributing to carbon monoxide production are also major sites of heme metabolism, including liver, 

spleen, and reticuloendothelial system (Berk et al. 1974). 

Numerous physiological and disease factors affect the rate of endogenous production of carbon 

monoxide. Carbon monoxide production increases by approximately 2-fold during the post-ovulatory 

(progesterone) phase of the menstrual cycle (Delivoria-Papadopoulos et al. 1974; Mercke and Lundh 

1976). Carbon monoxide production also increases during pregnancy, reaching values that are 2–5 times 

that of the estrogen phase of the menstrual cycle at partum and returning to pre-pregnancy levels within 

4 days following delivery (Longo 1977). Contributing factors to the increase in carbon monoxide 

production during pregnancy include the contribution of the growing fetus to carbon monoxide 

production, as well as the increase in maternal erythrocyte production and related changes in Hb 

metabolism (Longo 1977). The rate of production of carbon monoxide is accelerated in conditions that 

increase catabolism of Hb or other heme proteins, including hemolysis, hematomas, hemolytic anemias, 

thalassemia, and Gilbert’s syndrome (Berk et al. 1974; Coburn et al. 1964, 1965; Hampson 2007; Meyer 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 149 

3. HEALTH EFFECTS 

et al. 1998; Solanki et al. 1988). Carbon monoxide production was estimated to be 2–3 times higher in 

patients with hemolytic anemia compared with healthy individuals (Coburn et al. 1965). 

HO is the rate-limiting step in heme degradation, and its expression and activity are modulated by 

numerous factors. The HO-1 isozyme (one of three isozymes) and expression of the enzyme is induced 

by heme and heme derivatives, oxidative stress, hypoxia (including altitude-induced hypoxia), various 

metals, various cytokines, and exogenous carbon monoxide (Wu and Wang 2005). These factors would 

tend to promote endogenous carbon monoxide production. 

In addition to endogenous carbon monoxide production from metabolism of heme, carbon monoxide is 

produced from oxidative metabolism of certain exogenous hydrocarbons, including dichloromethane 

(DCM) and other dihalomethanes, and carbon tetrachloride (Agency for Toxic Substances and Disease 

Registry 2000, 2005; Stevens et al. 1980). The oxidative metabolism of DCM by isoform CYP2E1 of 

cytochrome P450 results in the production of carbon monoxide and increased blood COHb concentrations 

in blood (Andersen et al. 1991). Elevated blood COHb levels have been observed following DCM 

poisoning (Leikin et al. 1990). Other sources of exogenous carbon monoxide production include the 

heme oxidase catalysis of products of auto-oxidation of phenols, photo-oxidation of organic compounds, 

and lipid peroxidation of cell membrane lipids (Rodgers et al. 1994). 

Binding of Carbon Monoxide to Heme Proteins. Carbon monoxide binds to heme and competes for 

binding of O2. Binding of carbon monoxide to heme proteins (e.g., blood Hb, muscle myoglobin) has 

profound effects on the kinetics of distribution and elimination kinetics of both carbon monoxide and O2. 

Affinities of heme for carbon monoxide for Hb and myoglobin are sufficiently high to result in 

concentrations of dissolved carbon monoxide being 103

–106 times lower than the concentrations of COHb 

or COMb. This substantially lowers the concentration of dissolved carbon monoxide in blood and tissues, 

decreases the diffusion gradients for carbon monoxide movement of carbon monoxide from tissues and 

blood to the lungs, and substantially prolongs the elimination time for carbon monoxide than would 

otherwise occur in the absence of binding. Furthermore, the rates of dissociation of carbon monoxide 

from Hb and myoglobin are substantially slower than that of O2 and sufficiently slow, relative to 

erythrocyte capillary transit times, to limit rates of exchange of carbon monoxide between tissues and 

capillary blood. Binding of carbon monoxide to Hb also increases the affinity of Hb for O2, decreasing 

the availability of O2 to tissues. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 150 

3. HEALTH EFFECTS 

Although carbon monoxide binds to many different heme proteins (see Section 3.5.2), the affinities and 

abundance of Hb and myoglobin in the body results in most of the body stores of carbon monoxide being 

associated with these two heme proteins. Estimated kinetics and equilibrium parameters for carbon 

monoxide and O2 binding to Hb and myoglobin are presented in Table 3-12. Each of the four heme 

moieties in Hb can bind O2 or carbon monoxide. The overall affinity (i.e., equilibrium constant, Keq) is 

substantially higher for carbon monoxide (≈750 μM-1) compared to that of O2 (≈3.2 μM-1). As a result, at 

similar partial pressures of the two gases (pCO=PO2), binding of carbon monoxide will occur at the 

expense of binding of O2, and the O2 carrying capacity of blood will be compromised. The ratio of the 

Keq values (CO/O2) is referred to as the Haldane constant (≈234). This value gives the partial pressure 

ratio (pO2/pCO) needed to achieve equal amounts of bound COHb and O2Hb (i.e., %COHb = %O2Hb). 

At an ambient air pO2 of approximately 160 Torr (21% O2), the equilibrium condition of equal %COHb = 

%O2Hb would be achieved at a carbon monoxide exposure concentration of approximately 900 ppm. The 

affinity of Hb for carbon monoxide results in an equilibrium condition in which nearly all carbon 

monoxide in blood is bound to Hb. For example, based on the value of Keq of 750 μM-1, at a blood Hb 

concentration of 150 g/L (≈2.3 mM), the equilibrium ratio of bound carbon monoxide to dissolved carbon 

monoxide in blood would be approximately 1.7x106

 (i.e., > 106 times as much carbon monoxide is bound 

to Hb than is circulating in blood as dissolved carbon monoxide). The carbon monoxide dissociation rate 

from Hb (kd≈0.008 s-1; t1/2≈87 s) is slower than from O2 (ke≈20 s-1, t1/2≈0.035 s). As a result, exchange of 

O2 bound to Hb in blood with alveolar air and tissues is much more efficient than carbon monoxide 

exchange (i.e., fast vs. slow dissociation relative to erythrocyte transit times in capillaries). These two 

characteristics (high affinity and slow dissociation) contribute to relatively long retention times of carbon 

monoxide in blood following exposures to carbon monoxide. 

Binding of O2 to the four heme moieties of Hb is cooperative (Alcantara et al. 2007; Roughton 1970). 

The associative reaction rate (ka) becomes faster with successive additions of O2, increasing the affinity 

(Keq) of Hb for O2 (values for ka shown in Table 3-12 are for the high affinity, R, state of fully loaded 

Hb). Cooperative binding of O2 to Hb serves an important physiological function. Under conditions of 

relatively high pO2 in arterial blood entering the lung (pO2=100 mmHg), cooperative binding promotes 

the loading of Hb with O2; with successive binding of O2 molecules, the associative rate and affinity 

increases, promoting binding of a subsequent molecule of O2. Conversely, at lower pO2 in venous blood 

(pO2≈20 mmHg), cooperative binding promotes unloading of O2 for utilization; dissociation of a 

molecule of O2 decreases the affinity of Hb for O2, promoting the dissociation of a subsequent molecule 
 

 

CARBON MONOXIDE 151 

3. HEALTH EFFECTS 

Table 3-12. Hemoglobin and Myoglobin Binding Kinetics and Equilibrium
	

Constants for Oxygen and Carbon Monoxide
	

Ligand 

ka 

(μM-1·s-1) 

kd 

(s-1) 

KEq 

(μM-1) M 

Hemoglobina 

Oxygen 66 20 3.2 1 

Carbon monoxide 6 0.008 750 234 

Myoglobinb 

Oxygen 14 12 1.2 1 

Carbon monoxide 0.51 0.019 26.8 23 

a

Based on Chakraborty et al. 2004

b

Based on Gibson et al. 1986 

ka = association rate constant; kb = dissociation rate constant; KEq = equilibrium constant; M = Haldane constant 

(KEq CO/KEq O2) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 152 

3. HEALTH EFFECTS 

of O2. Cooperative binding contributes to the sigmoid shape of the O2 dissociation curve for Hb 

(Figure 3-5). 

Binding of carbon monoxide to Hb is also cooperative. Binding of carbon monoxide increases the 

associative rate of binding and affinity of both carbon monoxide and O2. As a result, the presence of 

carbon monoxide has several effects on the dissociation curve for O2 (Figure 3-5): (1) decreases the 

partial pressure of O2 in blood and tissues (i.e., by an amount equal to pCO), shifting the pO2 axis 

downscale at each point in the arterial-venous circuit; (2) displaces O2 from Hb, decreasing the maximum 

%COHb achieved in arterial blood; and (3) shifts the O2 dissociation curve downscale so that less O2 

dissociates O2 from Hb (more will remain bound, %O2Hb will be higher) at the lower pO2 values in 

venous blood. The combined result of these changes is that less O2 in blood is available for utilization in 

tissues. 

The binding affinities of carbon monoxide and O2 to myoglobin are lower than that for Hb; however, the 

higher affinity for carbon monoxide (Haldane constant ≈23), results in preferential binding of carbon 

monoxide over O2 and displacement of O2 of myoglobin at similar partial pressures of both gasses 

(Table 3-12). In addition to displacing O2 from myoglobin, binding of carbon monoxide to myoglobin 

has a pronounced effect on the distribution of carbon monoxide in the body by limiting the dissolved 

carbon monoxide concentration in muscle and, thereby, the rates of diffusion of carbon monoxide from 

muscle to blood. The affinity of myoglobin (Keq≈27) results in an equilibrium condition in which 

dissolved carbon monoxide concentrations in muscle are very low relative to COMb concentrations. For 

example, based on a value for Keq of 27 μM-1, at a muscle myoglobin content of approximately 4.7 g/kg 

(≈0.28 mM), the equilibrium ratio of bound carbon monoxide to dissolved carbon monoxide in muscle 

would be approximately 7.4x103

 (approximately 104 times as much carbon monoxide is bound to 

myoglobin than is dissolved muscle tissue). Furthermore, the carbon monoxide dissociation rate from 

myoglobin (kd≈0.019 s-1; t1/2≈36 s) is slower than O2 (ke≈12 s-1, t1/2≈0.06 s). As a result exchange of 

carbon monoxide bound to myoglobin in muscle with blood is much less efficient than O2 exchange (i.e., 

slow vs. fast dissociation relative to erythrocyte transit times in capillaries). These two characteristics 

(high affinity and slow dissociation) contribute to relatively long retention times of carbon monoxide in 

muscle following exposures to carbon monoxide. 

Oxidative Metabolism of Carbon Monoxide. Carbon monoxide can be oxidized to CO2. The rate of 

oxidation has been estimated in human subjects who inhaled 14CO to be approximately 0.015 mL 

CO/hour, which corresponds to approximately 0.6 μmol/hour; 14 μmol/day, and approximately 3% of 
 

 

 

CARBON MONOXIDE 153 

3. HEALTH EFFECTS 

Figure 3-5. Oxyhemoglobin Dissociation Curve for Normal Human Blood 

Containing 50% Carboxyhemoglobin and for Blood of an Anemic Human
	

Source: EPA 2000 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 154 

3. HEALTH EFFECTS 

endogenous carbon monoxide production (Luomanmaki and Coburn 1969). Similar measurements made 

in dogs yielded estimates for carbon monoxide metabolism that were approximately 8% of endogenous 

production (Luomanmaki and Coburn 1969). The major pathway for metabolism of carbon monoxide to 

CO2 is oxidation by mitochondrial cytochrome oxidase (Fenn 1970; Young and Caughey 1986). 

3.4.4 Elimination and Excretion 

Absorbed carbon monoxide is eliminated from the body by exhalation and oxidative metabolism. 

Oxidative metabolism of carbon monoxide has been estimated to be a relatively small fraction (<10%) of 

endogenous carbon monoxide production (Luomanmaki and Coburn 1969). Under most conditions, the 

dominant route of elimination of absorbed carbon monoxide is exhalation. Rates of elimination of carbon 

monoxide in humans who have experienced inhalation exposures to carbon monoxide have been 

estimated from kinetic analyses of the time course of blood %COHb (Bruce and Bruce 2006; Joumard et 

al. 1991; Landaw 1973; Levasseur et al. 1996; Peterson and Stewart 1970; Shimazu et al. 2000; Weaver et 

al. 2000). The decline in blood %COHb following cessation of an inhalation exposure to carbon 

monoxide exhibits at least two kinetic phases (Bruce and Bruce 2006; Shimazu et al. 2000). The fast 

phase is thought to reflect a combination of exhalation of carbon monoxide along with slower distribution 

of blood carbon monoxide to tissues that continues after cessation of exposure (Bruce and Bruce 2006). 

The elimination half-times for both phases appear to increase with exposure intensity and/or duration; a 

contributing factor to this effect may be the amount of carbon monoxide accumulated in extravascular 

stores. In human subjects exposed to 2% carbon monoxide for 1–3 minutes (peak COHb%=30–40), 

values for elimination half-lives were 5.7±1.5 and 103±20.5 minutes for the fast and slow phases, 

respectively (Shimazu et al. 2000). The fast phase rate increased when subjects were exposed to 500 ppm 

for 5–10 hours (peak %COHb=34–37): 21.5±2.1 and 118±11.2 minutes, respectively (Shimazu et al. 

2000). Rates have been reported for the slow phase of elimination. In subjects whose peak %COHb 

ranged from 2 to 15, the half-life was 320 minutes (range: 128–409 minutes, Peterson and Stewart 1970). 

Bruce and Bruce (2006) measured the time to achieve one-half of peak %COHb in subjects whose peak 

%COHb values ranged from 15 to 20 and estimated a half-life of 248 minutes (range: 206–328). Clinical 

studies conducted on healthy individuals exposed to ambient air carbon monoxide concentrations have 

found that elimination half-time increases with age, with the most pronounced increase occurring from 

age 2 to 20 years, and is approximately 6% longer in males compared to females (Joumard et al. 1991). 

The gender effect may be related to relative differences in body size and/or muscle mass. Exercise 

decreases carbon monoxide elimination half-time (Joumard et al. 1991). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 155 

3. HEALTH EFFECTS 

The rate of elimination of absorbed carbon monoxide is accelerated by inhaling high concentrations of O2 

(Landaw 1973; Peterson and Stewart 1970; Weaver et al. 2000). Elimination half-lives of approximately 

20 minutes have been observed in subjects who inhaled 100% O2 following cessation of exposure to 

carbon monoxide. An analysis of elimination rates observed in 93 acute carbon monoxide poisoning 

patients who were treated with 100% O2 did not find significant associations between elimination halflives and age, gender (<40 years, ≥40 years), smoke inhalation, history of loss of consciousness, 

concurrent tobacco smoking, degree of initial metabolic acidosis (base excess), or initial %COHb level 

(Weaver et al. 2000). 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 156 

3. HEALTH EFFECTS 

specific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-6 shows a conceptualized representation of a PBPK model. 

If PBPK models for carbon monoxide exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

The first physiologically-based mechanistic model of carbon monoxide kinetics was reported in Coburn et 

al. (1965). This model, which subsequently became known as the Coburn-Forster-Kane (CFK) model, 

was developed to predict relationships between inhalation exposures to carbon monoxide and blood 

COHb levels in humans. Numerous modifications and extensions of the original CFK model have been 

reported that more rigorously address nonlinearities resulting from interdependence of COHb and O2Hb 

levels in blood (Tikuisis et al. 1987b), simulation of arterial and venous blood compartments (Smith et al. 

1994), simulation of maternal-fetal transfer of carbon monoxide (Hill et al. 1977), extrapolation to 

nonhuman species (Benignus and Annau 1994; Hill et al. 1977; Longo and Hill 1977), linkage of the CFK 

model to more complex respiratory gas exchange models (Abram et al. 2007; Benignus 1995), and use in 

simulating the elimination kinetics of carbon monoxide produced from exogenous precursors (Andersen 
 

 

 

 

CARBON MONOXIDE 157 

3. HEALTH EFFECTS 

Figure 3-6. Conceptual Representation of a Physiologically Based
	

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
	

Inhaled chemical Exhaled chemical 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km 

Ingestion 

GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 158 

3. HEALTH EFFECTS 

et al. 1991). A multi-compartment model was also developed that simulates carbon monoxide absorption 

and distribution kinetics in muscle (Bruce and Bruce 2003; Bruce et al. 2008). 

Coburn-Forster-Kane Model 

The CFK model, as originally described in Coburn et al. (1965), is a single-compartment model of 

instantaneous equilibrium between carbon monoxide, O2, and blood Hb, and assumes that blood O2Hb 

concentration is constant (i.e., independent of COHb concentration). This linear form of the CFK model 

is expressed in the following differential equation which is integrated over time to solve for COHb 

concentration (Equation 1): 

Eq. (1) 

where t represents time at the end of the integration time step and t-1 represents the time at the beginning 

of the time step; Vb is blood volume in mL; [COHb] is the COHb concentration in mL carbon monoxide 

per mL blood (STPD); VCO is the endogenous carbon monoxide production rate in mL/minute (STPD); 

[O2Hb] is the oxyhemoglobin concentration in mL O2 per mL blood (STPD); PcO2 is the average partial 

pressure of O2 in lung capillaries in Torr; M is the Haldane constant; VA is the alveolar ventilation in 

mL/minute (STPD); DLCO is the lung diffusing capacity of carbon monoxide in mL/minute-Torr (STPD); 

and PICO is the carbon monoxide partial pressure in inhaled air in Torr. 

The linear form of the CFK model is acceptable for simulating low COHb concentrations (<6%; Smith 

1990). However, at higher COHb levels, appreciable errors are introduced into the simulation by ignoring 

the interdependence of COHb and O2Hb levels that result from limited binding capacity of Hb. This 

interdependence can be introduced into the CFK model by replacing the constant term for [O2Hb] with 

the following expression relating COHb and O2Hb (Tikuisis et al. 1987b; Equation 2):

where 1.38·Hb represents the maximum binding capacity of Hb for O2 or carbon monoxide in mL O2/mL 

blood (STPD). The resulting nonlinear form of the CFK model is expressed in Equations 3 and 4: 

 Eq. (2) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 159 

3. HEALTH EFFECTS

 Eq. (3)

 Eq. (4) 

where PB is the barometric pressure (Torr) and the value 47 represents the partial pressure of water in 

water saturated air (Torr). Typical parameters values used in the CFK model are presented in Table 3-13. 

Parameter values for application of the nonlinear CFK model for predicting COHb levels in rats were 

reported by Benignus and Annau (1994) and are also shown in Table 3-13. 

Validation of the model. Numerous studies have examined the accuracy of exposure-blood COHb 

relationships predicted from the CFK model (Benignus et al. 1994; Coburn et al. 1965; Hauck and 

Neuberger 1984; Joumard et al. 1991; Peterson and Stewart 1970, 1975; Stewart et al. 1970, 1973; 

Tikuisis et al. 1987a, 1987b). In general, the model performs well for predicting near equilibrium 

conditions; however, it performs less well in predicting the early uptake phase of carbon monoxide 

kinetics and COHb levels associated with rapidly changing exposures (Benignus et al. 1994; Tikuisis et 

al. 1987a, 1987b). The model also underestimates the arterial blood COHb level and overestimates the 

venous blood COHb level, an expected outcome of the simplistic assumption of a single well-mixed 

blood compartment. Nevertheless, the model predicts quasi-steady-state blood COHb levels that agree 

closely with observations (Benignus et al. 1994; Bruce and Bruce 2003; Tikuisis et al. 1987a, 1987b). 

McCartney (1990) reported a sensitivity analysis of the CFK model and found that parameter value 

sensitivities varied considerably in magnitude at different points in the exposure simulation (Figure 3-7). 

At steady-state, the model is most sensitive to the values assigned to the parameters representing the input 

value, the inhaled carbon monoxide concentration (PICO), as well as the total Hb level (Hb) and the 

Haldane coefficient (M). Increases in values for any of these parameters result in higher predicted COHb 

levels. However, during the accumulation phase of the simulation, the predicted COHb level is also 

highly sensitive to alveolar ventilation rate (VA) and the lung carbon monoxide diffusing capacity (DLCO), 

with increases in these parameters resulting in higher COHb levels, and to the value assigned to the blood 

volume (Vb), with increases in the parameter value resulting in lower predicted COHb levels. 
 

 

 

 

 

CARBON MONOXIDE 160 

3. HEALTH EFFECTS 

Table 3-13. Parameter Values for the Coburn-Forster-Kane (CFK) Model 

Value 

Parameter Definition Unit Humana Ratb 

BW Body weight kg 70 0.250 

COHb0 Blood COHb level at start of mL CO/mL blood 0.00155 0.00155 

simulation (STPD) 

DLCO Lung CO diffusing capacity mL CO/minute-Torr 30 0.027·0.563·BW 

(STPD) 

Hb Blood Hb concentration g/mL 0.144 0.158 

M Haldane coefficient unitless 218 207 

O2HbMAX Maximum blood O2Hb mL O2/mL blood 1.38 1.38 

concentration (STPD) 

PCO2 Average partial pressure of O2 in Torr (STPD) 49 49 

alveolar air 

PICO Partial pressure of inhaled CO Torr (STPD) Input Input 

VA Alveolar ventilation rate L/hourc (15·BW0.74) (15·BW0.74) 

VB Blood volume Ld 0.074·BW 0.074·BW 

VCO Endogenous CO production rate mL/minute (STPD) 0.007 0.000333·BW 

a

Based on Tikuisis et al. (1992)

b

Based on Benignus and Annau (1994)
 c

Must be converted to mL/minute by multiplying 1,000/60 d

Must be converted to mL by multiplying by 1,000
 

BW = body weight; CO = carbon monoxide; COHb = carboxyhemoglobin; Hb = hemoglobin; STPD = standard 

temperature and pressure, dry (i.e., adjusted for partial pressure of water vapor in saturated air [47 Torr STP])
 
 

 

 

 

 

 

CARBON MONOXIDE 161 

3. HEALTH EFFECTS 

Figure 3-7. Plot of Standardized Sensitivity Coefficients for Carboxyhemoglobin 

(COHb) Levels Predicted from the Coburn-Forster-Kane (CFK) Model for a
	

100 ppm Exposure to an Individual Engaged in Vigorous Exercise
	

(Alveolar Ventilation Rate=30 L/Minute)*
	

*Each curve represents the time trend of sensitivity coefficients for a given parameter during the simulation. Time 

trends for six model parameters are shown: DLCO, lung carbon monoxide diffusion capacity; FICO, fractional air 

carbon monoxide concentration (ppm); M, Haldane coefficient; THb, blood hemoglobin concentration; VA, alveolar 

ventilation rate; and VB, blood volume. Sensitivity coefficients and central coefficients are for 1% upward and 

downward perturbation of each parameter. Coefficients >0 indicate an increase in predicted COHb in association 

with an increase in the parameter value; coefficients that are <0 indicate that COHb decreased in association with an 

increase in the parameter value. 

Source: EPA (2009g) based on McCartney (1990) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 162 

3. HEALTH EFFECTS 

Risk assessment. The CFK model has been used in establishing the National Ambient Air Quality 

Standard for carbon monoxide (EPA 2000) and has been used in analyses that have supported 

development of Threshold Limit Values for occupational safety (Tikuisis et al. 1987b). 

Target tissues. The CFK model predicts COHb levels in blood. 

Species extrapolation. Although originally developed to simulate blood COHb levels in humans, 

the model can be used to predict COHb levels in other mammalian species if physiological and chemicalspecific parameter values are available for the species of interest. The latter include the Haldane 

coefficient (M), the binding capacity of Hb, and the lung carbon monoxide diffusing capacity (DLCO). 

Parameter values for the rat have been reported by Benignus and Annau (1994; Table 3-13). 

Interroute extrapolation. The CFK model simulates inhalation exposures. 

Smith et al. (1994) Multi-compartment Model 

The nonlinear CFK model, described above, represents blood as a well-mixed compartment, an 

acceptable assumption for simulating near equilibrium conditions. However, during uptake and 

elimination phases of carbon monoxide kinetics, appreciable differences have been observed between 

arterial and venous blood (Benignus et al. 1994). Improved prediction of arterial COHb levels was 

achieved with an expansion of the CFK model to include slowly and rapidly perfused compartments and 

an arm compartment (representing vascular sampling sites) that includes compartments representing the 

major arterial and venous vasculature (Smith et al. 1994, Table 3-14; Figure 3-8). 

Validation of the model. The Smith et al. (1994) models was evaluated with data collected from 

15 healthy adults subjects who inhaled carbon monoxide under controlled conditions (Benignus et al. 

1994). Each subject (15 adult males) inhaled for approximately 5 minutes from a bag that had an initial 

carbon monoxide concentration of approximately 7,000 ppm. The exposures achieved end exposure 

blood COHb concentrations ranging from 10 to 15%. The Smith et al. (1994) model provided improved 

predictions of COHb levels in samples taken from radial artery and antecubital vein. 

Risk assessment. Risk assessment applications of the Smith et al. (1994) were not identified in the 

available literature. 
 

 

 

 

CARBON MONOXIDE 163 

3. HEALTH EFFECTS 

Table 3-14. Parameter Values for the Smith et al. (1994) Model 

Parameter Definition Unit Value 

Chemical parametersa 

COHb0 Blood COHb level at start of simulation mL CO/mL blood 0.00155 

(STPD) 

DLCO Lung CO diffusing capacity mL CO/minute-Torr 30 

(STPD) 

Hb Blood Hb concentration g/mL 0.144 

M Haldane coefficient unitless 218 

O2HbMAX Maximum blood O2Hb concentration mL O2/mL blood 1.38 

(STPD)
 

PCO2 Average partial pressure of O2 in alveolar Torr (STPD) 49
 

air 

PICO Partial pressure of inhaled CO Torr (STPD) Input 

VCO Endogenous CO production rate mL/minute (STPD) 0.007 

Compartment volumesb 

BW Body weight kg 70 

VB Blood volume L 0.074·BW 

V1 Volumes of pulmonary capillaries and veins L 0.1·VB 

and 1⁄2 heart 

V2 Volume of rapidly perfused compartment L 0.11·VB 

V3 volume of slowly perfused compartment L 0.652·VB 

V4 Volume of major arteries in arms L 0.0069·VB 

V5, V6 Volume of small vessels in arms L 0.0076·VB 

V7 Volume of intermediate veins in arms L 0.0025·VB 

V8 Volume of large veins in arms L 0.0361·VB 

V9 Volume of 1⁄2 heart and pulmonary arteries L 0.085·VB 

Compartment flowsc 

VA Alveolar ventilation rate L/hour (15·BW0.74) 

QC Cardiac output L/hour (15·BW0.74) 

Q12 Flow to rapidly perfused tissue L/hour 0.6·QC 

Q13 Flow to slowly perfused tissue L/hour 0.35·QC 

Q14 Flow to arteries of arms L/hour 0.05·QC 

Q45 Flow to small vessels in arms L/hour 0.005·QC 

a

Based on Tikuisis et al. (1992) b

Must be converted to mL/minute by multiplying 1,000/60 

c

Must be converted to mL by multiplying by 1,000 

BW = body weight; CO = carbon monoxide; COHb = carboxyhemoglobin; Hb = hemoglobin; STPD = standard 

temperature and pressure, dry (i.e., adjusted for partial pressure of water vapor in saturated air [47 Torr STP]) 
 

 

CARBON MONOXIDE 164 

3. HEALTH EFFECTS 

Figure 3-8. Structure of the Smith et al. (1994) Model* 

CO O2 

Rapidly Perfused 

(2) 

Slowly Perfused 

(3) 

1⁄2 Heart 

Pulmonary Arteries 

(9) 

Major Arteries 

(4) 

Small Vessels 

(5) 

Small Vessels 

(6) 

Antecubital Vein 

(7) 

Large Veins 

(8) 

Pulmonary Capillaries 

Pulmonary Veins 

1⁄2 Heart 

(1) 

ARMS 

OTHER 

QC 

*Diffusive exchange carbon monoxide (CO) and oxygen (O2) occurs between lung alveolar space alveolar capillary 

blood. Instantaneous equilibrium is assumed between gases and blood hemoglobin, governed by the Haldane 

coefficient. Blood carboxyhemoglobin (COHb) is apportioned to various blood subcompartments according to 

subcompartment blood flows and volumes. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 165 

3. HEALTH EFFECTS 

Target tissues. The Smith et al. (1994) model predicts COHb levels in arterial and venous blood. 

Species extrapolation. Although originally developed to simulate blood COHb levels in humans, 

the model could be used to predict COHb levels in other mammalian species provided that physiological 

and chemical-specific parameter values are available for the species of interest. 

Interroute extrapolation. The Smith et al. (1994) model simulates inhalation exposures. 

Hill et al. (1977) Maternal-Fetal Model 

Hill et al. (1977) developed a multi-compartment model for simulating maternal-fetal transfer of carbon 

monoxide. This model includes simulations of maternal, placental, and fetal compartments, as well as 

maternal and fetal contributions to endogenous production of carbon monoxide (Table 3-15; Figure 3-9). 

The model assumes instantaneous equilibrium of O2 and carbon monoxide with Hb in maternal, placental, 

and fetal tissues, with delivery to placental and fetal tissues governed by blood flow rates. 

Validation of the model. The Hill et al. (1977) model was evaluated with data collected in 

experiments conducted in pregnant sheep (Longo 1977; Longo and Hill 1977). Pregnant sheep were 

exposed to 30, 50, or 100 ppm carbon monoxide for 24 hours or to 300 ppm for 4 hours, and maternal and 

fetal arterial blood was sampled from indwelling catheters for measurement of COHb levels. These 

exposures achieved maternal blood COHb levels ranging from approximately 4 to 24% (300 ppm). 

Steady-state blood COHb levels in the fetus, achieved during the exposures to 30–100 ppm, were 

approximately 70% higher than maternal levels. The model predicted maternal and fetal arterial blood 

COHb levels that agreed with observations (e.g., were within ±1 SD of observations). The model predicts 

slower accumulation and elimination of COHb in the human fetus compared to the maternal system, with 

steady-state values in fetal blood that are approximately 10–12% higher in than maternal blood. The 

latter prediction agrees with observations made in cord blood (Longo 1977). 

Risk assessment. Risk assessment applications of the Hill et al. (1977) model were not identified in 

the available literature. However, Hill et al. (1977) present and discuss predictions made with the model 

regarding effects of various factors on maternal and fetal blood COHb levels, including air carbon 

monoxide concentration, air O2 concentration, altitude, exercise, fetal O2 utilization, and fetal blood flow. 
 

 

CARBON MONOXIDE 166 

3. HEALTH EFFECTS 

Table 3-15. Parameter Values for the Hill et al. (1977) Model 

Parameter Definition Unit Value 

Chemical parameters 

DMCO Lung membrane diffusing capacity mL CO/minute-Torr 50, 60 

DLCO Lung CO diffusing capacity mL CO/minute-Torr 30, 28 

DPCO Placental CO diffusing capacity mL CO/minute-Torr 1.5, 2.7 

HbM Maternal blood Hb concentration g/mL 0.125 

HbF Fetal blood Hb concentration g/mL 0.155 

capM Maternal blood O2 capacity mL O2/mL 0.168 

capF Fetal blood O2 capacity mL O2/mL 0.208 

MM Haldane coefficient for maternal Hb unitless 223 

MF Haldane coefficient for fetal Hb unitless 181 

PB Atmospheric pressure Torr 760 

PHOH Partial pressure of water vapor (STP) Torr 47 

(PO2/O2Hb)L Average ratio of partial pressure of O2 to O2Hb Torr/% 1.029 

concentration in lung capillaries (at PICO=0) 

(PO2/O2Hb)M Average ratio of partial pressure of O2 to O2Hb Torr/% 0.5609 

concentration in maternal placental capillaries (at PICO=0) 

(PO2/O2Hb)F Average ratio of partial pressure of O2 to O2Hb Torr/% 0.4128 

concentration in fetal placental capillaries (at PICO=0) 

PAO2 Partial pressure of O2 in alveolar air Torr 108 

PACO2 Partial pressure of CO2 in alveolar air Torr 32 

PVO2 Partial pressure of O2 in mixed venous blood in Torr 38 

pulmonary artery 

PVCO2 Partial pressure of CO2 in mixed venous blood in Torr 38 

pulmonary artery 

PFO2 Partial pressure of O2 in umbilical artery Torr 20 

PFCO2 Partial pressure of CO2 in umbilical artery Torr 48 

PMO2 Partial pressure of O2 in uterine artery Torr 95 

PMCO2 Partial pressure of CO2 in uterine artery Torr 32 

P50,M Partial pressure of O2 at half O2 saturation in Torr 26.4 

maternal blood 

P50,F Partial pressure of O2 at half O2 saturation in fetal Torr 20.0 

blood 

pHM pH of uterine artery blood M 7.40 

pHF pH of umbilical artery blood M 7.34 

pHM pH of mixed venous blood M 7.37 

PICO Partial pressure of inhaled CO Torr Input 

VCO,M Maternal endogenous CO production rate mL/minute 0.0153 

VCO,F Fetal endogenous CO production rate mL/minute 0.0006 

VO2M Total maternal O2 consumption rate mL/minute 271 

VO2F Fetal O2 consumption rate mL/minute 22 
 

 

CARBON MONOXIDE 167 

3. HEALTH EFFECTS 

Table 3-15. Parameter Values for the Hill et al. (1977) Model 

Parameter Definition Unit Value 

Compartment volumes 

volM Maternal blood volume mL 5,000 

volF Fetal blood volume mL 400 

Compartment flows 

VA Alveolar ventilation rate mL/minute 6,000 

QM Maternal placental blood flow mL/minute 350 

QF Fetal placental blood flow mL/minute 350 

QL Lung blood flow mL/minute 5,600 

CO = carbon monoxide; Hb = hemoglobin; STP = standard temperature and pressure 
 

 

 

 

CARBON MONOXIDE 168 

3. HEALTH EFFECTS 

Figure 3-9. Structure of the Hill et al. (1977) Maternal-Fetal Model* 

P ICO VCO,M VCO,F 

Body Gas-Hb 

Equilibration 

Model 

Lung Placenta 

Fetal 

Tissues 

Maternal 

Tissues 

Umbilical 

Artery PO2 

Fetal 

VO2 

Maternal 

VO2 

Uterine 

Artery PO2 

(PO2/O2Hb)F 

COHbF 

(PO2/O2Hb)M 

COHbM 

*Average blood carboxyhemoglobin (COHb) levels in maternal and fetal tissues are calculated in the Body Gas 

Equilibration Model, based on inputs of PO2/O2Hb from lung, maternal tissue, placental tissue, and fetal placental 

capillary models. 

PICO = inhaled carbon monoxide partial pressure; VCO,M = maternal endogenous carbon monoxide production; 

VCO,F = fetal endogenous carbon monoxide production; VO2 = oxygen consumption 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 169 

3. HEALTH EFFECTS 

Of particular relevance to risk assessment is the prediction of slower accumulation and elimination of 

COHb in the human fetus compared to the maternal system. Based on model predictions, the elimination 

half-times were approximately 4 hours for maternal and 7.5 hours for fetal. Furthermore, the model 

predicted a more pronounced effect of breathing 100% O2 on carbon monoxide elimination from the 

maternal system (5-fold decrease in half-time) compared to the effect on fetal half-time (2-fold decrease). 

Target tissues. The Hill et al. (1977) model predicts COHb levels in maternal and fetal blood. 

Species extrapolation. The Hill et al. (1977) model has been applied to predicting maternal and 

fetal blood COHb levels in humans and sheep (Hill et al. 1977; Longo 1977; Longo and Hill 1977). 

Interroute extrapolation. The Hill et al. (1977) model simulates inhalation exposures. 

Bruce et al. (2008) Blood-Muscle Model 

Bruce et al. (Bruce and Bruce 2003; Bruce et al. 2008) developed a multi-compartment model that 

simulates kinetics of carbon monoxide, blood COHb, and muscle COMb (Table 3-16; Figure 3-10). The 

model includes compartments for blood, muscle, and other non-vascular tissues. In blood, carbon 

monoxide exists as dissolved carbon monoxide in equilibrium with COHb. Binding of carbon monoxide 

and O2 to Hb is assumed to achieve instantaneous equilibrium of carbon monoxide with Hb, defined by 

the Haldane equation, with adjustment for cooperative binding of carbon monoxide and O2 to Hb and 

myoglobin. Simulation of arterial and venous blood includes a time delay to account for the time required 

to achieve mixing of arterial blood leaving the lung and mixed venous blood. The muscle compartment 

consists of two subcompartments, between which dissolved carbon monoxide exchanges by diffusion. 

Subcompartment 1 represents tissue that exchanges dissolved carbon monoxide with the arterial and 

venous vasculature (representing arterial-venous shunting). Subcompartment 2 represents tissue that 

exchanges with capillary blood. Dissolved carbon monoxide in muscle is in equilibrium with myoglobin, 

with the equilibrium defined by the Haldane equation adjusted for cooperative binding of O2. Carbon 

monoxide in the other tissue compartment is assumed to consist entirely of dissolved carbon monoxide. 

Validation of the model. The Bruce et al. (2008) model was evaluated with data collected in 

experiments various experiments conducted in volunteers (Benignus et al. 1994; Burge and Skinner 1995; 

Peterson and Stewart 1975; Tikuisis et al. 1987a). The evaluations are reported in Bruce and Bruce 

(2003, 2006) and Bruce et al. (2008). The model predicted observed arterial and venous blood COHb 
 

 

CARBON MONOXIDE 170 

3. HEALTH EFFECTS 

Table 3-16. Parameter Values for the Bruce et al. (2008) Modela 

Parameter Definition Unit Value 

Chemical parameters 

DLCO Lung CO diffusion capacity mL CO/minute-Torr 30 

DMCO Muscle CO diffusion capacity mL CO/minute-Torr 1.75 

DTO2 Within tissue diffusion coefficient for O2 mL/minute-Torr 0.00060 

DTCO Within tissue diffusion coefficient for O2 mL/minute-Torr 0.00045 

Hb Blood Hb concentration g/mL 0.14 

HbF Fetal blood Hb concentration g/mL 0.155 

MHb Haldane coefficient for Hb unitless 218 

MMb Haldane coefficient for Mb unitless 36 

n Hill equation exponent unitless variablea 

O2HbMax O2 capacity of Hb mL O2/g Hb 1.381 

PB Barometric pressure Torr 760 

PAO2 Partial pressure of O2 in arterial blood Torr 100 

PMO2 Partial pressure of O2 in muscle Torr 20 

P50Hb Partial pressure at 50% Hb saturation Torr variablea 

P50Mb Partial pressure at 50% Mb saturation Torr 2.32 

MRO2 B Whole body O2 consumption mL/minute/g 0.0032 

MRO2 M Muscle O2 consumption mL/minute/g 0.021–0.03 

SO2 Solubility of O2 in plasma mL/Torr 3.14·10-5 

SCO Solubility of CO in plasma mL/Torr 2.35·10-5 

VO2 Total body O2 consumption mL/minute 225 

VCO Endogenous CO production ml/minute 0.007 

Volumes 

VM Volume of muscle L 29.1 

VM1F Volume of muscle subcompartment 1 L 0.4·VM 

VM2F Volume of muscle subcompartment 1 L 0.6·VM 

VOT Volume of other tissue L 9.6 
 

 

CARBON MONOXIDE 171 

3. HEALTH EFFECTS 

Table 3-16. Parameter Values for the Bruce et al. (2008) Modela 

Parameter Definition Unit Value 

Flows 

QC Cardiac output mL/minute 5,800 

QMf Blood flow fraction to muscles unitless 0.40 

QOTf Blood flow fraction to other tissue unitless 0.25 

VA Alveolar ventilation rate mL/minute 5,500 

a

Estimated from Hill equation: 

(PO / P )

n 

O Hb = O Hb ⋅ 2 50 

2 2 max n 1 + (PO2 / P50 ) 

Values for n ranged from approximately 2.34 at COHb=0% to 1.8 at COHb=100%. Values for P50Hb ranged from 

25 at COHb=0% to 0 at COHb=100% 

CO = carbon monoxide; COHb = carboxyhemoglobin; Hb = hemoglobin 
 

 

CARBON MONOXIDE 172 

3. HEALTH EFFECTS 

Figure 3-10. Structure of the Bruce et al. (2008) Model* 

CO 

O2 

Mixed 

Venous 

Blood 

(Hb) 

Other Tissue 

Muscle 2 

Muscle 1 

Lung 

Blood 

Blood 

Blood 

Mb 

Mb 

Hb 

Hb 

Hb 

CO 

O2 

Arterial 

Blood 

(Hb) 

*The model simulates diffusive exchange of carbon monoxide (CO) and oxygen (O2) between alveolar space and 

capillaries and tissue capillary blood and tissues. Competitive cooperative binding of carbon monoxide and O2 with 

hemoglobin (Hb) occurs in blood and to myoglobin (Mb) in muscle. No binding is assumed in the other tissue 

compartments. In muscle, diffusive exchange is assumed to occur between blood and both muscle 

subcompartments, as well as between muscle compartments. 

Sources: Adapted from Bruce and Bruce (2003); Bruce et al. (2008) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 173 

3. HEALTH EFFECTS 

differences and kinetics during and following single or multiple brief exposures to carbon monoxide 

(Benignus et al. 1994). The model predicted continued uptake of carbon monoxide into muscle during the 

first 300 minutes following cessation of exposure, with subsequent return of muscle carbon monoxide to 

blood (Bruce and Bruce 2006). Blood-muscle carbon monoxide exchange, in combination with 

elimination of carbon monoxide from blood to exhaled air, resulted in multi-phase blood elimination 

kinetics, with the early faster phase dominated by transfer of carbon monoxide from blood to muscle, and 

the later slower phase contributed by return of carbon monoxide from muscle to blood and elimination 

from blood to exhaled air. The multi-phase kinetics predicted from the model agreed with post-exposure 

elimination kinetics of carbon monoxide from blood observed in Benignus et al. (1994). The model also 

predicted blood COHb kinetics observed in 1- and 5-minute exposures observed in Tikuisis et al. (1987a). 

Model predictions match the CFK model when muscle diffusion is set to zero, and the model predicts 

lower blood COHb levels than the CFK model when the muscle carbon monoxide diffusion is enabled. 

This difference reflects the blood-muscle kinetics and storage of carbon monoxide in muscle myoglobin 

that is not accounted for in the CFK model. 

Risk assessment. Risk assessment applications of the Bruce et al. (2008) model were not identified 

in the available literature. However, the model has been applied to predicting the outcome of breathing 

100% O2 on blood COHb and muscle COMb kinetics (Bruce and Bruce 2006). The model predicted a 

decrease in blood and muscle elimination half-times. Of particular relevance to risk assessment is the 

prediction of continued uptake of carbon monoxide from blood to muscle that occurs for several hours 

after cessation of exposure, which contributes to slowing the elimination kinetics of carbon monoxide 

from the body. 

Target tissues. The Bruce et al. (2008) model predicts blood COHb and muscle COMb levels and 

can also be used to predict blood and muscle carbon monoxide burden. 

Species extrapolation. The Bruce et al. (2008) model has been applied only to predicting blood 

COHb and muscle COMb levels in humans. The model could be applied to other mammalian species 

providing that physiological and chemical-specific parameter values are available for species of interest. 

Interroute extrapolation. The Bruce et al. (2008) model simulates inhalation exposures. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 174 

3. HEALTH EFFECTS 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Pharmacokinetic mechanisms of carbon monoxide action are related to its binding to heme proteins. 

Kinetics and equilibria of binding to the major heme proteins that have the greatest influence on carbon 

monoxide pharmacokinetics (Hb and myoglobin) are discussed in the Section 3.4, Toxicokinetics. 

Absorption. Inhaled carbon monoxide is rapidly and extensively absorbed into blood (Benignus et al. 

1994; Burge and Skinner 1995; Peterson and Stewart 1970, 1975; Tikuisis et al. 1987b). Inhaled carbon 

monoxide is transported to lung alveoli as result of convective forces in the respiratory tract and diffusion. 

At the alveolar gas-blood interface, carbon monoxide dissolves into pulmonary capillary plasma and, 

from plasma, diffuses into erythrocytes and other tissues. Binding of carbon monoxide by erythrocyte Hb 

(to form COHb) contributes to maintaining relatively low concentrations of dissolved carbon monoxide in 

erythrocyte cytosol and a partial pressure gradient to drive carbon monoxide transfer from alveolar air to 

blood. Diffusion of carbon monoxide into erythrocytes and binding of carbon monoxide to Hb is 

sufficiently rapid that near-equilibrium is achieved between carbon monoxide partial pressures in alveolar 

air and alveolar end capillary (arterial) blood (Chakraborty et al. 2004). Continued uptake of carbon 

monoxide results from systemic elimination processes that lower mixed venous blood carbon monoxide 

concentrations returned to alveolar capillaries (Benignus et al. 1994). 

Distribution. The distribution of absorbed carbon monoxide is determined, in large part, by its affinity 

for binding to heme. Binding of carbon monoxide to intracellular heme proteins contributes to 

maintaining gradients for carbon monoxide diffusion from plasma into erythrocytes and extravascular 

tissues. The dominant heme proteins that influence carbon monoxide distribution are erythrocyte Hb and 

muscle myoglobin. The distribution of carbon monoxide in the body is largely a reflection of the 

distribution of Hb and myoglobin, with the largest carbon monoxide burden found in blood, heart, 

skeletal muscle, and spleen (Vreman et al. 2005, 2006). Relatively large contributions of blood and 

skeletal muscle to total body carbon monoxide content is consistent with the contributions that these 

tissues make to total body Hb and muscle myoglobin (Bruce and Bruce 2003). In a typical adult, blood 

contains approximately 12 mmoles of Hb, with a total binding capacity of approximately 48 mmole 

carbon monoxide when completely saturated, and muscle contains approximately 8 mmoles of 

myoglobin, with a total binding capacity of 8 mmole carbon monoxide when completely saturated. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 175 

3. HEALTH EFFECTS 

Metabolism. Metabolism of carbon monoxide consists of three major processes: (1) metabolic 

production of carbon monoxide from endogenous and exogenous precursors; (2) binding of carbon 

monoxide to heme proteins; and (3) oxidative metabolism of carbon monoxide to CO2. 

Metabolic Production of Carbon Monoxide. Endogenous carbon monoxide is produced primarily from 

the enzymatic degradation of heme by the enzyme HO. Carbon monoxide is produced in all tissues that 

express HO; however, the major tissues contributing to carbon monoxide production are also major sites 

of heme metabolism, including liver, spleen, and reticuloendothelial system (Berk et al. 1974). Three 

isoforms of HO have been identified, of which HO-1 is inducible, whereas HO-2 and HO-3 are 

constitutive. In general, factors that induce HO-1 increase carbon monoxide production, whereas 

inhibition of HO activity or expression of HO decreases carbon monoxide production. Numerous stimuli 

have been shown to up-regulate HO-1 expression (Wu and Wang 2005): (1) those related to heme 

metabolism (e.g., heme and heme derivatives, endogenous carbon monoxide); (2) stimuli that produce or 

are associated with physiological or oxidative stress such as hyperoxia, heat shock factors, oxidized 

lipids, lipopolysaccharides, hydrogen peroxide, radiation (including ultraviolet light), endotoxin, heavy 

metals and arsenite, and various cytokines (e.g., interleukins, TNF-α); (3) substances that are mediators of 

vascular resistance (NO, angiotensin II); and (4) mitogens and other factors that regulate cell growth (e.g., 

growth factors, phorbol ester). Expression of the constitutive isoform, HO-2, is increased by estrogen, 

glucocorticoids, stimuli that inhibit HO, and stimuli that down-regulate NO production (e.g., inhibition of 

NO synthase). In human cells (e.g., grown in culture), expression of HO-1 is down-regulated during 

hypoxia, heat shock factors, and interferon-γ. The response to the above factors is not uniform across 

species. For example, hypoxia and heat shock have been shown to induce HO in rodents, whereas the 

dominant effect in human tissues is down-regulation (Nakayama et al. 2000; Shibahara et al. 2003; Wu 

and Wang 2005). 

Carbon monoxide can be produced from oxidative metabolism of certain exogenous hydrocarbons (e.g., 

DCM) by isoform CYP2E1 of cytochrome P450 (Andersen et al. 1991) and from heme oxidase catalysis 

of products of auto-oxidation of phenols, photo-oxidation of organic compounds, and lipid peroxidation 

of cell membrane lipids (Rodgers et al. 1994). 

Carbon Monoxide Binding to Heme Proteins. Carbon monoxide competes for O2 for binding to the iron 

site in heme. Kinetic constants and equilibrium constants for the binding of O2 and carbon monoxide to 

Hb and myoglobin are provided in Table 3-12. 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 176 

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Oxidative Metabolism of Carbon Monoxide. The mechanism of oxidative metabolism of carbon 

monoxide to CO2 is thought involve catalysis by cytrochrome c oxidase (Fenn 1970; Young and Caughey 

1986). 

Excretion. Absorbed carbon monoxide is eliminated from the body by exhalation and oxidative 

metabolism. Oxidative metabolism of carbon monoxide has been estimated to be a relatively small 

fraction (<10%) of endogenous carbon monoxide production (Luomanmaki and Coburn 1969). Under 

most conditions, the dominant route of elimination of absorbed carbon monoxide is exhalation. The 

mechanism of elimination of carbon monoxide by exhalation is diffusion, with the driving forces at the 

alveolar interface being the partial pressure difference between carbon monoxide in alveolar air and in 

alveolar capillary blood. The latter is maintained at a relatively low level by binding of carbon monoxide 

to Hb. Diffusion is also the mechanism of release of carbon monoxide from intracellular stores to blood, 

with the driving forces influenced by binding of carbon monoxide to extravascular heme proteins (e.g., 

myoglobin) and blood Hb. 

3.5.2 Mechanisms of Toxicity 

Carbon monoxide exerts effects on cell metabolism through both hypoxic and non-hypoxic mechanisms. 

Both types of effects are thought to be largely (if not entirely) the result of the ability of carbon monoxide 

to bind to heme and alter function and/or metabolism of heme proteins. Carbon monoxide may also act 

through mechanisms unrelated to heme binding, although evidence for this is currently more contentious. 

Hypoxic Mechanisms. Carbon monoxide produces tissue hypoxia by binding to, and displacing O2 from, 

Hb. The formation of COHb decreases the O2 carrying capacity of blood and impairs release of O2 from 

Hb for its utilization in tissues (see Section 3.4.3, Metabolism for further discussion of kinetics of binding 

of carbon monoxide and O2 to Hb). Through similar mechanisms, carbon monoxide decreases O2 storage 

in muscle cells by binding to, and displacing O2 from, myoglobin. The principal mechanisms underlying 

the hypoxic mechanism of carbon monoxide are: (1) higher affinity of carbon monoxide for Hb than O2 

and (2) increased binding affinity for O2 from COHb. The overall affinity of Hb for carbon monoxide is 

approximately 230 times greater than that for O2 (Chakraborty et al. 2004). As a result, at a partial 

pressure of carbon monoxide that is approximately 230-fold lower than ambient O2 concentration 

(21%/230≈900 ppm), O2 and carbon monoxide will bind to Hb in an equimolar ratio (i.e., COHb≈50%). 

Binding of carbon monoxide and O2 to the four heme moieties of Hb is cooperative (Alcantara et al. 

2007; Perrella and Di Cera 1999; Roughton 1970). The associative reaction rate (ka) becomes faster with 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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successive additions of carbon monoxide or O2, increasing the affinity (Ka) of Hb for O2 and impairing 

the release of O2 from Hb for utilization in tissues. Overall, the affinity increase is 588-fold due to 

cooperative events as more carbon monoxide binds to hemoglobin; however, this is not a monotonic 

function with each ligation. Once the first hemoglobin chain binds a carbon monoxide molecule, the 

affinity increases 16.5-fold when the second carbon monoxide molecule binds, 4.6-fold at the third 

ligation step, and 7.7-fold in the fourth ligation step (Perrella and Di Cera 1999). 

Although all tissues are vulnerable to carbon monoxide-induced hypoxic injury, those having the highest 

O2 demand are particularly vulnerable, including the brain and heart. Carbon monoxide-induced hypoxia 

triggers compensatory cardiovascular responses that include increased cardiac output (heart rate and 

stroke volume) and dilation of cardiac and cerebral vasculature. During exercise, cardiac work and O2 

consumption increase and the vulnerability of the heart to carbon monoxide-induced hypoxic injury 

increases. In patients who have underlying coronary artery or myocardial disease, the increased O2 

demand of exercise, in combination with decreased O2 carrying capacity of blood and impaired release of 

O2 from Hb, can produce cardiac toxicity (e.g., myocardial ischemia, exertional angina, arrhythmia) at 

lower carbon monoxide exposure levels than experienced in healthy individuals (Adams et al. 1988; 

Allred et al. 1989, 1991; Anderson et al. 1973; Kleinman et al. 1989, 1998; Leaf and Kleinman 1996b). 

Brain hypoxia induced by carbon monoxide can result in various symptoms of impaired central nervous 

system function, including headache, dizziness, drowsiness, weakness, nausea, vomiting, confusion, 

disorientation, irritability, visual disturbances, convulsions, and coma (Dolan 1985; Ernst and Zibrak 

1998). Delayed development of neuropsychiatric and neurological impairment may occur within 1– 

4 weeks of exposure, with symptoms including inappropriate euphoria, impaired judgment, poor 

concentration, memory loss, cognitive and personality changes, psychosis, and Parkinsonism (Choi 2002; 

Ernst and Zibrak 1998; Kao and Nañagas 2006; Klawans et al. 1982; Raub and Benignus 2002; Raub et 

al. 2000; Ringel and Klawans 1972; WHO 1999; Wolf et al. 2008). 

Non-Hypoxic Mechanisms. Most of the non-hypoxic mechanisms of action of carbon monoxide have 

been attributed to binding of carbon monoxide to heme in proteins other than Hb. A list of heme proteins 

that have been shown to undergo functional modification in response to carbon monoxide is presented in 

Table 3-17. Notable targets of carbon monoxide include components of several important physiological 

regulatory systems, including brain and muscle O2 storage and utilization (myoglobin, neuroglobin), nitric 

oxide NO cell signaling pathway (e.g., nitric oxide synthase [NOS], guanylyl cyclase [GC]), 

prostaglandin cell signaling pathway (cyclooxygenase, prostaglandin H synthase), energy metabolism and 
 

 

 

 

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Table 3-17. Heme Proteins Modulated by Carbon Monoxide 

Effects or carbon monoxide or 

Name of protein heme oxygenase up-regulation Reference 

Catalase Inhibition Hu and Kincaid 1992 

Cyclooxygenase Inhibition Alcaraz et al. 2003 

Activation Lee et al. 2001 

Cytochrome c Binding Bhuyan and Kumar 2002 

Cytochrome P450 Inhibition Estabrook et al. 1980 

Cytochrome c oxidase Inhibition Wohlrab and Ogunmola 1971 

Guanylyl cyclase Activation Stone and Marletta 1994 

Hemoglobin Inhibition Forster 1970 

Neuroglobin Inhibition Burmester et al. 2000 

Myoglobin Inhibition Coburn and Mayers 1971 

Cytoglobin Inhibition Geuens et al. 2003; Sawai et al. 2003 

NADPH oxidase Inhibition Taille et al. 2004 

NO synthases Inhibition Thorup et al. 1999; Willis et al. 1995 

Peroxidases Binding Carlsson et al. 2005 

Prostaglandin H synthase Binding Lou et al. 2000 

Tryptophan dioxygenase Inhibition Piantadosi 2002 

NPAS2 Inhibition Dioum et al. 2002 

Source: Wu and Wang 2005 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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mitochondrial respiration (cytochrome c oxidase, cytochrome c, NADPH oxidase), steroid and drug 

metabolism (cytochrome P450), cellular redox balance and ROS (catalase, peroxidases), and various 

transcription factors (e.g., neuronal PAS domain protein, NPAS2, implicated in regulation of circadian 

rhythm). 

Endogenously produced carbon monoxide may participate in the physiological regulation of some, if not 

all, of these systems. This has potentially important implications for the understanding of carbon 

monoxide toxicology and dose-response relationships for the following reasons: (1) carbon monoxide 

modulation of physiological processes may underlie some aspects of the toxicity of exogenous carbon 

monoxide; (2) exogenous carbon monoxide may disrupt physiological regulation of those systems that are 

responsive to endogenous carbon monoxide (e.g., vascular resistance); and (3) exposures to exogenous 

carbon monoxide may affect carbon monoxide-mediated physiological responses at levels that approach 

those resulting from endogenous production. Whole-body endogenous carbon monoxide production rate 

has been estimated to be approximately 16.4 μmol/hour (0.007 mL/minute STPD; Coburn 1970a). Local 

rates of production of carbon monoxide in tissues are influenced by many tissue-specific factors, 

including those that regulate intracellular heme oxygenase activity (e.g., some areas of brain have 

relatively high HO-2 activities). A similar whole-body rate of delivery of carbon monoxide to the 

alveolar region of the lung would be achieved by inhaling air at a carbon monoxide concentration of 

approximately 1–2 ppm (i.e., assuming that alveolar ventilation rate is approximately 4,000 mL/minute; 

0.007 mL/minute/4,000 mL/minute=1.75·10–6 mL CO/mL air, STPD=1.75 ppm). Such levels are only 

modestly above national average ambient air carbon monoxide concentrations in the United States 

(approximately 0.5 ppm, see Chapter 6) and well within variability observed in measurements made with 

personnel air monitors (Chang et al. 2000). One implication of this is that, if a dose threshold for effects 

of exogenous carbon monoxide exists at all, it may lie near or below ambient air carbon monoxide 

concentrations. Although currently available toxicology and epidemiological studies provide evidence for 

increasing severity of adverse carbon monoxide effects in association with increasing levels of exposure, 

these studies do not provide strong evidence supporting or refuting a dose threshold for adverse effects. 

Of the many physiological systems that may contribute to non-hypoxic mechanisms of carbon monoxide 

action, the following are thought to be particularly important and are the subject on ongoing intense 

research interests: modulation of cell signaling pathways and generation of ROS. 

Carbon Monoxide Modulation of Cell Signaling and Ion Channel Activity. Cell signaling pathways 

that are thought to be modulated by carbon monoxide are depicted in Figure 3-11. These pathways 
 

 

 

 

 

 

CARBON MONOXIDE 180 

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Figure 3-11. Potential Signaling Pathways Modulated by Carbon Monoxide
	

CO 

NO•

sGC 

cGMP 

NOS COX CYP450 

PGs 20 HETE 

MAPK 

SJNK1/2 p38 ERK1/2 

HSF1 

HSP70 

IL-6 TNFα, IL-1, MIP1α

cytokines 

cGMP-activated 

PK, PDE, Ion channels 

(+) 

(-) 

(+) 

(-) 

(-) (-) 

(-) (-) (-) 

(+) 

Anti-inflammation Anti-apoptosis Anti-proliferation Anti-thrombosis Smooth NANC 

Muscle Synaptic 

Tone Transmission 

+ = stimulates pathway; – = inhibits pathway; cGMP = cyclic guanosine monophosphate; CO = carbon monoxide; 

COX = cylcooxygenase; CRF = corticotropin releasing factor; CNS = central nervous system; CYPP40 = cytochrome 

P450; ERK = extracellular signal regulated kinase; 20-HETE = 20-hydroxyeicostetraenoic acid; HSF = heat shock 

factor; HSP = heat shock protein; IL = interleukin; JNK = a stress activate protein kinase; MAPK = mitogen activate 

protein kinase; MIP = macrophage inflammatory protein; NANC = non-noradrenergic non-cholinergic; NO• = nitric 

oxide radical; NOS = nitrogen oxide synthase; PDE = phosphodiesterase; PG = prostaglandins; PK = protein kinase; 

sGC = soluble guanylate cyclase; TNF = tumor necrosis factor 

Adapted from Ryter et al. 2006; Volti et al. 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 181 

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contribute to the regulation of various physiological process, including inflammatory responses, 

apoptosis, cell proliferation, thrombosis (i.e., platelet aggregation), smooth muscle tone (including 

vasodilation and relaxation of extravascular smooth muscle), and synaptic neurotransmission in the 

central and peripheral nervous systems (e.g., glutamate). The nitric oxide radical (NO•) plays an 

important signal transduction role in regulating smooth muscle relaxation, synaptic neurotransmission 

(e.g., glutamate), platelet function, and other physiological processes (Denninger and Marletta 1999). 

One of the major transduction pathways mediated by NO• is the NO•-cGMP pathway, in which NO• 

produced by the enzyme NOS binds to the heme moiety of soluble guanylate cyclase (sGC), which 

catalyzes conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The 

latter (cGMP) activates various downstream signaling cascades that regulate cell function (e.g., cGMPdependent protein kinase, cGMP-regulated cation channels, and cGMP-regulated phosphodiesterase). 

Carbon monoxide binds to the heme moieties of both NOS and sGC, and in doing so, inhibits NOS 

activity and activates sGC activity (Stone and Marletta 1994; Thorup et al. 1999). The potency of carbon 

monoxide for activating sGC is approximately 20-fold less than that of NO•; as a result, in the presence of 

NO•, carbon monoxide may modulate sGC activity downward by displacing NO• from sGC (Stone and 

Marletta 1994). The NO•-cGMP signaling pathway has been implicated in the mechanism by which 

carbon monoxide produces relaxation of smooth muscle (Ny et al. 1996) and inhibition of platelet 

homotypic aggregation (Brune and Ullrich 1987). Carbon monoxide increases platelet-neutrophil 

interactions (heterotypic aggregation) through a free-radical mechanism (Thom et al. 2006). 

Carbon monoxide modulates mitogen activated protein kinase (MAPK) signaling pathways, either 

through its interaction with sGC (Ryter et al. 2006) or through secondary effects on ROS generation (see 

below). MAPK pathways are important regulators of cytokine production and release in inflammatory 

responses and in regulating apoptosis and proliferation. 

Carbon monoxide exposure can perturb heme protein binding by nitric oxide; induce a variety of proteins 

including heme oxygenase (HO), superoxide dismutase, and nitric oxide synthase; alter mitochondrial 

function; and modify production of ATP and ROS (Brown and Piantadosi 1992; Davutoglu et al. 2006; 

Kim et al. 2007; Lee et al. 2006; Maulik et al. 1996; Nakao et al. 2008; Piantadosi et al.1997; Thom et al. 

1994, 1997, 2000; Zuckerbraun et al. 2003). Carbon monoxide increases production of ROS from 

mitochondria and also some non-mitochondrial sources, which can activate one or more protein kinases 

(e.g., p38 MAPK, c-Jun N-terminal kinase, ERK), signal transducers (e.g., peroxisome proliferatoractivated receptor-γ), and transcriptional regulators (e.g., nuclear factor-κB, AP-1), as well as guanylate 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 182 

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cyclase, and lead to secondary events such as vasodilation and fibrinolysis (Arruda et al. 2004; Fujita et 

al. 2001; Mishra et al. 2006; Ryter and Otterbein 2004; Soares et al. 2004; Wijayanti et al. 2004). 

Carbon monoxide also binds to the heme moieties and inhibits cytochrome P450 and cyclooxygenase 

(COX) and, thereby, can modify physiological processes regulated by products of these enzyme systems. 

Inhibition of cytochrome P450 catalyzed production of eciosanoids (e.g., 20-hydroxyeicostetraenoic acid, 

[20-HETE]) and COX-mediated production of prostaglandins have been postulated as a potential 

mechanisms by which carbon monoxide may contribute to the regulation of vascular smooth muscle tone 

and vasodilation (Botros et al. 2002; Volti et al. 2008). 

Carbon monoxide has been shown to modulate activity of several ion channels, including calciumsensitive and voltage-gated K+ channels, cardiac L-type and intestinal smooth muscle L-type Ca2+ 

channels, and epithelial Na+

 channels (Peers 2011; Peers and Steel 2011; Peers et al. 2009). Carbon 

monoxide may augment or inhibit channel activity, depending on ion channel type and carbon monoxide 

concentration. Several mechanisms for ion channel modulation have been proposed, including increased 

production of ROS (cardiac L-type Ca2+ channels and voltage-gated K+

 channels), protein kinase G 

activation (K+ channels), and increased nitric oxide and cGMP (intestinal smooth muscle L-type Ca2+ 

channels). 

Carbon Monoxide Modulation of ROS Generation. Carbon monoxide may promote and/or modify ROS 

generation through several different mechanisms. Binding to the heme moiety and inhibition of 

mitochondrial cytochrome c oxidase disrupts mitochondrial respiration and promotes ROS generation 

(Alonso et al. 2003; D'Amico et al. 2006; Favory et al. 2006a; Iheagwara et al. 2007; Zuckerbraun et al. 

2007). Carbon monoxide also appears to promote a more general disruption of the regulation of iron and 

ferritin levels, at least in part through promotion of heme protein degradation (Cronje et al. 2004; Ghio et 

al. 2008; Iheagwara et al. 2007). 

3.5.3 Animal-to-Human Extrapolations 

Studies conducted in nonhuman primates, dogs, and various rodent species have demonstrated the major 

health effects of carbon monoxide that have been observed in humans, including COHb-related hypoxia, 

cardiovascular responses, and neurological effects (Benignus 1994; Benignus et al. 1990; EPA 1991, 

2000; Raub and Benignus 2002). These studies also provide support for the concept of non-hypoxic 

modes of action of carbon monoxide that operate on a variety of physiological systems (e.g., Wu and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Wang 2005; also, see Section 3.5.2 for discussion and relevant references). These systems include 

physiological regulatory systems that function in all mammalian species, such as brain and muscle 

oxygen storage and utilization; nitric oxide cell signaling pathway; prostaglandin cell signaling pathway; 

energy metabolism and mitochondrial respiration; steroid and drug metabolism; cellular redox balance 

and ROS; and various transcription factors. Therefore, results from mechanistic studies conducted in 

typical laboratory animal models are likely to be directly relevant to understanding mechanisms of action 

of carbon monoxide in humans. Manifestations of these various modes of action may differ qualitatively 

and quantitatively across species. For example, rats exhibit pronounced hypothermia in response to 

exposures to carbon monoxide, whereas at low levels of exposure (e.g., COHb <20%), this response is not 

evident in humans (Benignus 1994; Gordon 1990). Differences in dose-response relationships between 

humans and animal models can also be expected, in part due to differences in physiological and chemical 

determinants of carbon monoxide uptake, elimination, and binding kinetics with major heme proteins, 

(Benignus and Annau 1994; Longo and Hill 1977) as well as interspecies differences in physiological 

regulation of systems that are non-hypoxic targets of carbon monoxide. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

No studies were located regarding endocrine disruption in humans and/or animals after exposure to 

carbon monoxide. Several cell signaling pathways that are thought to be modulated by endogenous 

carbon monoxide that could play a role in the regulation of activity of the hypothalamic-pituitary-adrenal 

(HPA) axis include cGMP and NO• signaling (Mancuso et al. 1997, 2010; Snyder et al. 1998; Wu and 

Wang 2005). Modulation of endogenous carbon monoxide levels and/or production has been shown to 

modify various HPA axis processes, including release of arginine vasopressin (AVP), gonadotropin, and 

corticotropin releasing hormone from the hypothalamus, release of adrenocorticotropic hormone (ACTH) 

from the pituitary, and response of the adrenal gland to ACTH (Wu and Wang 2005). The toxicological 

significance of these various actions of carbon monoxide has not been established. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 185 

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susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

The fetus may be particularly vulnerable to maternal carbon monoxide exposure. Carbon monoxide in the 

maternal system distributes to fetal tissues. Measurements of steady-state fetal COHb concentrations in 

fetal and maternal blood of nonsmoking women have found fetal COHb concentrations to be 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 186 

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approximately 10–15% higher than maternal blood (fetal/maternal ratio=1.1–1.15; Longo 1977). Binding 

affinity of fetal Hb is approximately twice that of maternal Hb (Di Cera et al. 1989). The higher binding 

affinity of fetal Hb, as well as the relatively small diffusion gradients for carbon monoxide between 

maternal and fetal blood, contribute to slower kinetics of COHb in fetal blood compared to maternal 

blood. As a result, with continuous exposure to a constant level of carbon monoxide in air, the kinetics of 

fetal blood COHb concentration would be expected to lag behind maternal kinetics and to reach a steadystate that is approximately 10–15% higher than maternal (Longo 1977). Similarly, following cessation of 

exposure, elimination kinetics of carbon monoxide from fetal blood would be expected to lag behind that 

of maternal blood (Hill et al. 1977). 

Epidemiological studies have examined possible associations between exposure to ambient air carbon 

monoxide concentrations and various developmental outcomes, including pre-term birth, reduced birth 

weight, congenital anomalies, and neonatal and infant death (see Section 3.2.6, Table 3-8). Results of 

these studies have been mixed and, collectively, do not provide strong evidence for developmental 

effects, including neonatal or infant mortality in association with exposures to ambient levels of carbon 

monoxide (<10 ppm). However, studies conducted in animals provide evidence of adverse 

developmental effects of gestational and early postnatal carbon monoxide in association with maternal 

exposure concentrations as low as 12–25 ppm. Observed effects have included decreased fetal weight, 

adverse central nervous system development, altered peripheral nervous system development, cardiac 

effects, altered sexual behavior, immunological effects, and hematological effects (see Table 3-9). In 

addition, some studies showed that developmental effects persisted beyond the postnatal period (Carratu 

et al. 1993, 2000a, 2000b; De Salvia et al. 1995; Lopez et al. 2003, 2008; Stockard-Sullivan et al. 2003; 

Webber et al. 2003). 

Although no studies have directly compared the sensitivity of adults and children to the effects of carbon 

monoxide, several epidemiological studies have examined pulmonary function, asthma morbidity, and 

exacerbation of asthma symptoms in children (Chen et al. 1999; Fischer et al. 2002; Mortimer et al. 2008; 

Yu et al. 2000). Although results have been mixed, these studies provide some evidence for increased 

vulnerability of asthmatic children to carbon monoxide-associated respiratory effects (see Section 3.2.2, 

Respiratory Effects). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 187 

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3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

The National Report on Human Exposure to Environmental Chemicals provides an ongoing assessment 

of the exposure of the U.S. population to environmental chemicals using biomonitoring. This report is 

available at http://www.cdc.gov/exposurereport/. The biomonitoring data for carbon monoxide from this 

report is discussed in Section 6.5. A biomarker of exposure is a xenobiotic substance or its metabolite(s) 

or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is 

measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure 

are generally the substance itself, substance-specific metabolites in readily obtainable body fluid(s), or 

excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. 

The body burden of a substance may be the result of exposures from more than one source. The 

substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels 

of phenol can result from exposure to several different aromatic compounds). Depending on the 

properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route 

of exposure), the substance and all of its metabolites may have left the body by the time samples can be 

taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly 

found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). 

Biomarkers of exposure to carbon monoxide are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by carbon monoxide are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 188 

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other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Carbon Monoxide 

Measurement of blood COHb is the principal biomarker for identifying exposure to carbon monoxide. 

Nearly all carbon monoxide in the body exists as complexes with Hb and other heme proteins. 

Approximately 60–70% of the body burden exists as blood COHb (Bruce and Bruce 2003; Vreman et al. 

2006). Therefore, measurement of COHb provides a useful indicator of the elevated carbon monoxide 

body burden, although the utility for blood COHb measurements for large-scale screening for elevated 

exposures or poisoning is questionable (Heckerling et al. 1990). The relationship between COHb levels 

and exposure is more complex because of the numerous physiological factors that influence carbon 

monoxide uptake and elimination. The elimination half-time of absorbed carbon monoxide has been 

estimated to be approximately 300 minutes (Bruce and Bruce 2006; Peterson and Stewart 1970); 

therefore, a value for COHb measured at a given time following exposure will reflect both the exposure 

and elimination rate of carbon monoxide. Several pharmacokinetic models have been developed that can 

be used to predict blood COHb levels that would correspond to a given exposure concentration and 

duration in a typical adult and in the fetus resulting from maternal exposures (see Section 3.4.5). These 

models can be used to reconstruct possible carbon monoxide exposure scenarios (e.g., concentrations, 

duration and gap between measurement of COHb and cessation of exposure) that could result in a given 

measured COHb level. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Carbon Monoxide 

Although blood COHb reflects current carbon monoxide body burden, measurement of blood COHb has 

not been shown to be a reliable predictor of severity of acute toxicity (Hampson and Hauff 2008). 

Furthermore, due to the time elapsed between cessation of CO exposure to measurement of COHb, 

coupled with effects of medical intervention (see Section 3.11, Methods Reducing Toxic Effects), blood 

COHb does not provide reliable estimates of the level of CO exposure. Typical levels of COHb in 

nonsmokers are <2% (Adams et al. 1988; Allred et al. 1991; Anderson et al. 1973; Hinderliter et al. 1989; 

Kleinman et al. 1989, 1998; Sheps et al. 1987, 1990). Levels of ≥10% can be observed immediately after 

smoking a cigarette (Kao and Nañagas 2006). In general, signs and symptoms of acute carbon monoxide 

poisoning can present at COHb levels ranging from 3 to 24% (Hampson and Hauff 2008; Kao and 

Nañagas 2006). Levels ranging from 2 to 6% have been shown to exacerbate underlying cardiovascular 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 189 

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disease, including enhanced myocardial ischemia and increased cardiac arrhythmias (Adams et al. 1988; 

Allred et al. 1989, 1991; Anderson et al. 1973; Kleinman et al. 1989, 1998; Leaf and Kleinman 1996b). 

More severe signs of carbon monoxide poisoning are poorly correlated with blood COHb, with loss of 

consciousness occurring at mean levels of 24.3% (range: 2–70%) and fatality at mean levels of 32.1% 

(range: 3.0–60%; Hampson and Hauff 2008). Exposures that result in COHb levels >50% are usually 

fatal (Kao and Nañagas 2006). 

Diagnosis and characterization of carbon monoxide toxicity include both the measurement of blood 

COHb and assessment of signs. In order of increasing severity, these include: (1) headache, nausea, 

dilation of cutaneous vasculature, vomiting, dizziness, and blurred vision; (2) confusion, syncope, chest 

pain, dyspnea, weakness, tachycardia, and tachynea rhabdomyolysis; and (3) palpitations, cardiac 

dysrhythmias, hypotension, myocardial ischemia, cardiac arrest, respiratory arrest, pulmonary edema, 

seizures, and coma (Kao and Nañagas 2006). Neuropsychological testing and neuroimaging have been 

considered for evaluating central nervous system effects (Tomaszewski 2006). 

Cardiac enzyme markers are associated with myocardial dysfunction and an elevated risk for long-term 

cardiac mortality following carbon monoxide poisoning; biochemical markers for brain injury, such as 

neuron-specific enolase and S-100 beta protein, have not been found to reliably correlate with severity of 

poisoning or clinical outcome (Brvar et al. 2004; Davutoglu et al. 2006; Kalay et al. 2007; Rasmussen et 

al. 2004; Satran et al. 2005). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

The effects of combined exposure of carbon monoxide with other chemicals (e.g., pollutants, drugs) were 

reviewed by the EPA (1991, 2000). In general, research has mainly focused on effects of combined 

chemical exposures on the cardiovascular, respiratory, and central nervous systems. As discussed in 

Section 3.10 (Populations that Are Unusually Susceptible), in addition to interactions with other 

chemicals, exposure to carbon monoxide at a higher altitude may result in higher body burdens of carbon 

monoxide and, therefore, there may be higher vulnerability to carbon monoxide at higher altitudes than at 

lower altitudes (McGrath et al. 1993), in particular for people who have not physiologically adapted to 

higher altitudes (Horvath et al. 1988; Hsia 2002). 

Oxygen. The chemical interaction of highest toxicological and clinical significance is that between 

carbon monoxide and O2. Carbon monoxide and O2 compete for binding to heme (Chakraborty et al. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 190 

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2004; Gibson et al. 1986). Binding to, and displacing O2 from, heme proteins, including blood Hb and 

muscle myoglobin, has profound effects on the kinetics of distribution and elimination kinetics of both 

carbon monoxide and O2, and is also the principal mechanism underling the hypoxic effects of carbon 

monoxide (Bruce and Bruce 2006; Bruce et al. 2008; Vreman et al. 2005, 2006). Decreasing levels of O2 

in inspired air facilitates carbon monoxide binding to Hb and myoglobin and exacerbates carbon 

monoxide-induced hypoxia. This interaction can contribute to a higher vulnerability to carbon monoxide 

toxicity at lower O2 pressures that occur at higher altitudes (Horvath et al. 1988; Hsia 2002; McGrath et 

al. 1993). Increasing levels of O2 in inspired air facilitates displacement of carbon monoxide from Hb 

and myoglobin, increases the rate of carbon monoxide elimination from the body, and increases O2 

availability to tissues (Landaw 1973; Peterson and Stewart 1970; Weaver et al. 2000). These actions of 

O2 form the basis for the use of 100% O2 and hyperbaric O2 therapy in the treatment of carbon monoxide 

poisoning (Lavonas 2007; Tomaszewki 2006). 

Chemicals that Bind to Hemoglobin. Several nitrate compounds, including dinitrotoluenes (Ellis et al. 

1985; U.S. Army 1979) and nitroanilines (NTP 1993), bind to hemoglobin and induce anemia. Although 

studies evaluating the interaction between CO and other chemicals that bind hemoglobin were not 

identified, any chemical that binds to hemoglobin, and thereby reduces the oxygen carrying capacity of 

the blood, could potentiate the effects of CO. 

Cyanide. Carbon monoxide and cyanide poisonings can occur concomitantly in victims of smoke 

inhalation (Lundquist et al. 1989; Shusterman et al. 1996; Wetherell 1966). Experimental studies 

conducted in animal models provide evidence that carbon monoxide and cyanide can produce synergistic 

toxicity (Moore et al. 1987; Norris et al. 1986; Pitt et al. 1979). 

Drugs Affecting the Central Nervous System. Due to effects of carbon monoxide on the central nervous 

system, it is anticipated that combined exposure to drugs with activity in the central nervous system, 

including therapeutic agents and drugs of abuse, could enhance the central nervous system toxicity of 

carbon monoxide (EPA 1991, 2000). However, the available data are not sufficient to determine if effects 

of combined exposures are additive or exhibit other types of interaction relationships (e.g., synergistic). 

Enhanced carbon monoxide-induced central nervous system toxicity has been reported to occur with 

concomitant exposures to alcohol, barbiturates, amphetamine, chlorpromazine, nicotine, diazepam, and 

morphine (EPA 1991). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 191 

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Drugs Affecting the Cardiovascular System. In response to carbon monoxide-induced tissue hypoxia, 

alterations in hemodynamics and responsive compensatory mechanisms (e.g., vasodilation and increased 

cardiovascular output) occur, including increased coronary blood flow, decreased myocardial O2 

consumption, increased heart rate, and alterations in blood flow to various vascular beds (e.g., cerebral, 

limb muscular). Thus, drugs used to treat patients with coronary artery disease (e.g., beta-blockers, 

calcium-channel blockers, nitrates) potentially may affect susceptibility to carbon monoxide. This is of 

particular concern, as patients with cardiovascular disease are more susceptible to carbon monoxideinduced cardiovascular toxicity than are healthy individuals. However, little data evaluating potential 

interactions with therapeutic agents used to treat cardiovascular disease are available (EPA 1991, 2000). 

Air Pollution. Numerous epidemiological studies have examined associations between exposure to 

carbon monoxide and other air pollutants (e.g., NO2, O3, particular matter, SO2). In general, these studies 

have found evidence for multiple air pollutant contributors to outcomes observed, including 

cardiovascular, respiratory, and mortality end points (see discussion of epidemiology in Section 3.2). The 

interactive aspects of these associations have not been fully explored or elucidated. However, evidence is 

provided from several studies of increased risks of adverse cardiovascular and respiratory outcomes in the 

context of ongoing cardiovascular disease (e.g., ischemic heart disease) and respiratory diseases (e.g., 

asthma). These studies suggest that it is both plausible and likely that interactions contribute to outcomes 

observed in populations that experience co-exposures to carbon monoxide, NO2, O3, particular matter, and 

SO2. 

Tobacco Smoke. In addition to exposures to carbon monoxide, tobacco smoking results in exposures to a 

variety of agents that act directly on the heart to increase cardiac O2 demand (e.g., nicotine) (Benowitz 

1997) and that contribute to respiratory and coronary vascular disease, both of which can render people 

more vulnerable to carbon monoxide toxicity (see Section 3.10, Populations that are Unusually 

Susceptible). 

Noise. Studies conducted in animals provide evidence that acute exposure to carbon monoxide 

potentiates noise-induced hearing loss, including noise-induced elevation of compound action potential 

threshold (Chen and Fechter 1999; Mortazavi et al. 2010) and auditory threshold shifts (Fechter et al. 

1988; Young et al. 1987). However, in these studies, exposure to carbon monoxide alone did not produce 

changes in auditory function. Additional details are provided in Section 3.2.4. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 192 

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3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to carbon monoxide than will most 

persons exposed to the same level of carbon monoxide in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters result in reduced detoxification or excretion of carbon monoxide, or compromised 

function of organs affected by carbon monoxide. Populations who are at greater risk due to their 

unusually high exposure to carbon monoxide are discussed in Section 6.7, Populations with Potentially 

High Exposures. 

Cardiovascular Disease. Studies of the cardiovascular effects of inhalation exposures to carbon 

monoxide conducted in controlled human clinical studies, epidemiology studies, and various animal 

models (monkeys, dogs, rats, and rabbits) provide convincing evidence for adverse cardiovascular effects 

in association with carbon monoxide exposures that result in blood COHb levels of ≥2.4%, with effects 

occurring at the lowest levels in subjects who have compromised cardiovascular function (e.g., coronary 

artery disease). Therefore, exposure to carbon monoxide appears to exacerbate underlying cardiovascular 

disease, and people with cardiovascular disease that renders them vulnerable to myocardial ischemia (e.g., 

coronary artery disease) represent a population that would be unusually susceptible to carbon monoxide. 

Epidemiological studies of exposure to ambient concentrations of carbon monoxide and cardiovascular 

outcomes also provide supporting evidence for higher vulnerability of people with pre-existing heart 

conditions, such as ischemic heart disease, people with a history of cardiac arrhythmia, and the elderly 

(Barnett et al. 2006; D’Ippoliti et al. 2003; Dockery et al. 2005; Hosseinpoor et al. 2005; Lanki et al. 

2006; Lee et al. 2003b; Mann et al. 2002; Rich et al. 2005; Szyszkowicz 2007; von Klot et al. 2005). 

Asthma and COPD. Several studies have examined possible associations between ambient air carbon 

monoxide concentrations and pulmonary function in subjects who had ongoing lung disease (e.g., asthma, 

chronic obstructive lung disease) and who might be more sensitive to agents that affect pulmonary 

function (Rabinovitch et al. 2004; Silkoff et al. 2005; Timonen et al. 2002), as well as asthma morbidity 

and exacerbation of asthma symptoms (Park et al. 2005a; Rabinovitch et al. 2004; Schildcrout et al. 2006; 

Silkoff et al. 2005; Slaughter et al. 2003; von Klot et al. 2002; Yu et al. 2000). Results of these studies 

have been mixed; however, collectively, these studies provide evidence for higher vulnerability of people 

who have ongoing respiratory disease, including asthma and COPD. This subpopulation may also 

include a subpopulation of former tobacco smokers (Silkoff et al. 2005). As noted in Section 3.7, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Children’s Susceptibility, the fetus may be particularly vulnerable to exposures that occur during 

pregnancy. 

Anemia. Conditions that produce anemia (e.g., hemolysis, hemorrhage, reduced hematopoiesis, or iron, 

vitamin B-6, folate, and/or vitamin B-12 deficiency) decrease the oxygen carrying capacity of blood. 

Hemolytic anemia increases heme metabolism and endogenous carbon monoxide production. These 

factors would be expected to render individuals more vulnerable to hypoxic effects of carbon monoxide. 

Environmental and Behavioral Factors. In addition to ongoing diseases, other environmental and/or 

behavior factors may increase vulnerability to carbon monoxide toxicity. In general, factors that increase 

alveolar ventilation and cardiac output, while maintaining alveolar ventilation perfusion matching (i.e., 

proportional increases in alveolar ventilation rate and cardiac output), tend to increase absorption of 

inhaled carbon monoxide. Factors that increase carbon monoxide absorption include moderate exercise, 

supine position, age (increased in infancy and childhood and declines in adults with age), altitude, 

increasing blood Hb concentration, and decreasing partial pressure of O2 in inhaled air or blood. 

These factors could contribute to higher body burdens of carbon monoxide and, therefore, higher 

vulnerability to carbon monoxide at higher altitudes than at lower altitudes (McGrath et al. 1993), in 

particular for people who have not physiologically adapted to higher altitudes (Horvath et al. 1988; Hsia 

2002). Exercise increases oxygen demand, absorption of carbon monoxide, and transfer of carbon 

monoxide from blood to muscle, and decreases elimination of carbon monoxide (Joumard et al. 1991; 

Richardson et al. 2002; Werner and Lindahl 1980); these factors may contribute to higher vulnerability 

during strenuous exercise. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section describes clinical practice and research concerning methods for reducing toxic effects of 

exposure to carbon monoxide. However, because some of the treatments discussed may be experimental 

and unproven, this section should not be used as a guide for treatment of exposures to carbon monoxide. 

When specific exposures have occurred, poison control centers and medical toxicologists should be 

consulted for medical advice. The following texts provide specific information about treatment following 

exposures to carbon monoxide: 

Dart RC, ed. 2004. Medical toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 

1208. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 194 

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Lavonas EJ. 2007. Carbon monoxide poisoning. In: Haddad and Winchester's clinical management of 

poisoning and drug overdose. 4th ed. Philadelphia, PA: Saunders, 1297-1307 

Tomaszewski C. 2006. Carbon monoxide. In: Goldfrank's toxicologic emergencies. New York, NY: 

McGraw-Hill, 1689-1704. 

3.11.1 Reducing Peak Absorption Following Exposure 

Human exposure to carbon monoxide occurs by the inhalation route. General recommendations for 

reducing absorption of carbon monoxide following acute high-level inhalation exposure have included 

immediate removal of the exposed individual from the contaminated area and administering 100% 

oxygen through a face mask that does not allow rebreathing of expired air or by endotracheal tube for a 

minimum of 4 hours. For patients with life-threatening carbon monoxide exposure, hyperbaric oxygen 

therapy has also been suggested, although this remains a controversial method for treatment (Buckley et 

al. 2011; Dart 2004; Lavonas 2007; Tomaszewski 2002; Weaver et al. 2000, 2009; Wolf et al. 2008). 

Hyperbaric oxygen treatment is optimal within 6 hours of exposure, as patients treated after 6 hours have 

displayed a higher percent of delayed sequelae (30 vs. 19%) and mortality (30 vs. 14%) compared with 

patients treated within 6 hours of carbon monoxide exposure (Tomaszewski 2006). 

Studies conducted in animal models have provided evidence for a potential influence of isocapnia or 

hypercapnia (i.e., normal or elevated CO2 levels) in the effect of O2 therapy in promoting the reduction in 

carbon monoxide body burden. Studies utilizing laboratory animals (dogs and sheep) exposed to carbon 

monoxide have demonstrated that the carbon monoxide washout time can be significantly reduced if the 

subjects receive a mixture of oxygen and carbon dioxide gas designed to maintain normal PCO2 values 

(Fisher et al. 1999; Kreck et al. 2001). This outcome has been replicated in experimental trials using 

volunteers exposed to carbon monoxide concentrations producing COHb levels of 10–12%. As compared 

to the subjects treated with hyperoxia alone, those treated with hyperoxia and carbon dioxide who 

maintained isocapnia showed accelerated clearance of carbon monoxide (Rucker et al. 2002; Takeuchi et 

al. 2000). These studies identify a potential means to enhance the treatment of acute carbon monoxide 

poisoning. 

3.11.2 Reducing Body Burden 

Absorbed carbon monoxide binds to, and displaces oxygen (O2) from, blood Hb and other heme proteins 

(e.g., muscle myoglobin). Nearly all of carbon monoxide in the body exists as complexes with Hb or 

other heme proteins. Binding to heme proteins limits diffusion of carbon monoxide from tissues to blood 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 195 

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and elimination of carbon monoxide from blood to exhaled air. At ambient oxygen pressures of 

approximately 0.2 atm, elimination of carbon monoxide occurs with a half-time of approximately 100– 

300 minutes (Bruce and Bruce 2006; Peterson and Stewart 1970). However, the elimination rate can be 

increased substantially by administering 100% oxygen (Tomaszewski 2006; Weaver et al. 2000). As 

noted above, the general recommendation for reducing the body burden of carbon monoxide is 

administration of 100% oxygen through a face mask that does not allow rebreathing of expired air, at 

ambient pressure, and/or hyperbaric oxygen therapy. The longer time period required for the elimination 

of carbon monoxide in the fetus (Hill et al. 1977; Longo 1977) has prompted a concern about the 

premature cessation of oxygen therapy to a pregnant woman based upon her COHb level. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Binding of carbon monoxide to Hb impairs transfer of oxygen to tissues and can produce tissue hypoxia. 

Tissues that have a high oxygen utilization rate, including brain and heart, are particularly vulnerable to 

hypoxia. Carbon monoxide-induced hypoxia is treated by administering 100% oxygen, which increases 

the dissolved concentration of oxygen in blood, facilitates displacement of carbon monoxide from Hb, 

and increases the rate of elimination of carbon monoxide from the body. Hyperbaric oxygen therapy may 

further reduce the risk of brain and heart injury from hypoxia. Intravenous fluids and inotropic agents 

may be administered to alleviate hypotension and myocardial depression (Lavonas 2007; Tomaszewski 

2006). 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of carbon monoxide is available. Where adequate information 

is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to 

assure the initiation of a program of research designed to determine the health effects (and techniques for 

developing methods to determine such health effects) of carbon monoxide. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 196 

3. HEALTH EFFECTS 

3.12.1 Existing Information on Health Effects of Carbon Monoxide 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

carbon monoxide are summarized in Figure 3-12. The purpose of this figure is to illustrate the existing 

information concerning the health effects of carbon monoxide. Each dot in the figure indicates that one or 

more studies provide information associated with that particular effect. The dot does not necessarily 

imply anything about the quality of the study or studies, nor should missing information in this figure be 

interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying 

Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and 

Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature. 

Human clinical studies of acute exposures have investigated cardiovascular, respiratory, and 

neurobehavioral end points. Human epidemiology studies have examined possible associations between 

ambient air carbon monoxide concentrations and various health end points, including mortality, 

cardiovascular, respiratory, blood biomarkers of coagulation and inflammation, and developmental (preterm birth, birth weight, congenital anomalies, neonatal and infant mortality). Studies conducted in 

animals have included acute, intermediate, and chronic exposures that have largely focused on 

cardiovascular, respiratory, and reproductive (e.g., fetal mortality) end points. Bioassays of 

carcinogenicity of carbon monoxide have not been reported. Carbon monoxide has been assessed for 

genotoxicity in an in vivo mouse model of micronuclei formation and sister chromatid exchange. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Most information on effects of acute exposures to carbon monoxide 

derive from clinical case studies of carbon monoxide poisoning, in which blood COHb levels were >20%. 

Although these studies provide information on effects resulting from severe carbon monoxide-induced 

toxicity, they do not provide information on low dose-response relationships for carbon monoxide. 

Experimental clinical studies providing low dose-response information have focused on evaluating organ 

systems that are expected to be vulnerable to or contribute to hypoxia (e.g., brain, heart, respiratory tract). 

Effects of acute exposures to carbon monoxide on other organ systems have been studied far less 

thoroughly. Studies of low-dose carbon monoxide exposure in humans or animals have not identified 

NOAELs for sensitive organ systems and have not provided data that would enable low-dose response 
 

 

CARBON MONOXIDE 197 

3. HEALTH EFFECTS 

Figure 3-12. Existing Information on Health Effects of Carbon Monoxide 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human
	

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal
	

Existing Studies 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 198 

3. HEALTH EFFECTS 

modeling (e.g., benchmark dose). Such studies would be beneficial for analyses in support of deriving 

MRLs. 

Experimental clinical studies have examined cardiovascular effects in humans, including a major 

vulnerable subpopulation, people with ongoing heart disease; however, these studies have not identified 

NOAELs in cardiovascular disease patients (Adams et al. 1988; Allred et al. 1989, 1991; Anderson et al. 

1973; Kleinman et al. 1989, 1998; Leaf and Kleinman 1996b). Studies investigating the effects of acuteduration carbon monoxide exposure on hemodynamics have been conducted in several animal species, 

including monkeys, dogs, rats, and rabbits, under exposure conditions producing blood COHb levels 

ranging from 6.2 to 70% (EPA 1991, 2000). These studies have shown that brief exposure (from a few 

minutes to approximately 3 hours) to carbon monoxide at concentrations of 80–20,000 ppm produces 

alterations in hemodynamics that are consistent with COHb-induced hypoxia and responsive 

compensatory mechanisms (e.g., vasodilation and increased cardiovascular output), including increased 

coronary blood flow, decreased myocardial O2 consumption, increased heart rate, and alterations in blood 

flow to various vascular beds (e.g., cerebral, limb muscular). 

A few clinical experimental studies have evaluated adverse respiratory effects of carbon monoxide 

exposure in relatively small numbers of healthy subjects (Chevalier et al. 1966; Fisher et al. 1969; Koike 

et al. 1991; Ren et al. 2001; Vesely et al. 2004). Results of these studies indicate that brief exposure to 

relatively higher levels (e.g., ≥500 ppm) of carbon monoxide may decrease ventilatory performance. No 

studies were identified that examined effects of carbon monoxide on respiratory function in patients with 

underlying respiratory diseases, who would be expected to have a higher sensitivity to hypoxic effects of 

carbon monoxide. Studies of dose-response relationships of respiratory function at low levels of carbon 

monoxide exposure (e.g., COHb <20%) in patients with respiratory disease (e.g., asthma) would be 

beneficial for quantifying vulnerability of this subpopulation to carbon monoxide toxicity. 

Intermediate-Duration Exposure. Controlled experimental studies in humans of effects of 

intermediate-duration exposures to carbon monoxide were not identified. Intermediate-duration studies 

have examined cardiovascular and respiratory effects of exposure to carbon monoxide in various animal 

models, including monkeys, dogs, and rodents (EPA 2000). The observation of cardiomegaly in rats 

exposed chronically to carbon monoxide (Sørhaug et al. 2006) suggests that prolonged exposure to carbon 

monoxide may produce effects on the heart that might not be observed with acute exposures. Additional 

intermediate-duration exposure studies in animals that provide dose-response relationships for 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 199 

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cardiovascular effects and other end points (e.g., respiratory, neurological) would be beneficial for 

analyses in support of deriving MRLs. 

Chronic-Duration Exposure and Cancer. Epidemiological studies have examined health 

outcomes in the context of chronic exposures or acute variations in exposure concentrations that occur 

during chronic exposures. Outcomes that have been assessed include mortality, including cancer 

mortality, cardiovascular effects, respiratory effects, effects on blood biomarkers of coagulation and 

inflammation, and developmental effects (pre-term birth, birth weight, congenital anomalies, neonatal and 

infant mortality). A chronic study conducted in rats found cardiomegaly, which may have represented 

long-term adaptive changes to carbon monoxide-induced hypoxia (Sørhaug et al. 2006). This finding 

suggests that prolonged exposure to carbon monoxide may produce effects on the heart that might not be 

evident from acute- or intermediate-duration studies. Additional chronic-duration exposure studies in 

animals would that provide dose-response relationships for cardiovascular effects and other end points 

(e.g., respiratory, neurological) would be beneficial for analyses in support of deriving MRLs. 

Carbon monoxide has not been assessed for carcinogenicity using animal models. Cancer bioassays in 

animals would provide a more confident basis for establishing whether or not carbon monoxide has 

carcinogenic potential in humans. 

Genotoxicity. In a bacterial replication assay with Escherichia coli, exposure to carbon monoxide 

inhibited DNA synthesis (Cairns and Denhardt 1968). Gestational exposure of mice to carbon monoxide 

increased micronuclei formation and sister chromatid exchange in dams (bone marrow) and fetuses 

(blood) (Kwak et al. 1986). Additional studies conducted on the mechanisms of genotoxicity in 

mammalian cells would provide a more confident basis for establishing whether or not carbon monoxide 

has carcinogenic potential in humans. 

Reproductive Toxicity. Pregnancy outcomes, including fetal death in humans, have been reported in 

cases of maternal carbon monoxide poisoning during pregnancy (Brown et al. 1992; Caravati et al. 1988; 

Cramer 1982; Elkharrat et al. 1991; Farrow et al. 1990; Greingor et al. 2001; Hollander et al. 1987; 

Margulies 1986; Norman and Halton 1990; Silverman and Montano 1997). Epidemiological studies have 

examined possible relationships between exposures to ambient air concentrations of carbon monoxide and 

fetal mortality (see Table 3-8). Few studies of reproductive effects in animals were identified, and these 

have been limited to assessments of effects of maternal exposure during pregnancy on fetal mortality 

(Astrup et al. 1972; Fechter and Annau 1977; Penney et al. 1983; Stupfel and Bouley 1970). The 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 200 

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available data do not allow a confident determination of the relative sensitivity of reproductive systems to 

carbon monoxide. Greater confidence would be achieved from studies that examine more comprehensive 

end points of reproductive toxicity in females and males, in association with exposures prior to mating 

and pregnancy and during pregnancy. 

Developmental Toxicity. Epidemiological studies have examined developmental outcomes in the 

context of chronic exposures or acute variations in exposure concentrations that occur during chronic 

exposures (see Table 3-8). Outcomes that have been assessed include pre-term birth, birth weight, 

congenital anomalies, neonatal, infant mortality, and neurodevelopment. Studies conducted in animals 

provide evidence of adverse developmental effects of gestational and early postnatal carbon monoxide 

exposure, including decreased fetal weight, adverse central nervous system development, altered 

peripheral nervous system development, cardiac effects, altered sexual behavior, immunological effects, 

and hematological effects. In addition, some studies showed that developmental effects persisted beyond 

the postnatal period (see Table 3-9). Two studies found functional impairments in the auditory system of 

rats in association with exposures to ≥12 ppm carbon monoxide during the neonatal periods or during 

gestation (Stockard-Sullivan et al. 2003; Webber et al. 2003). These values are the lowest LOAELs for 

external exposure that have been reported and, as a result, have a substantial impact on analyses 

conducted to derive MRLs. Additional studies to establish greater confidence in the dose-response 

relationship for neurodevelopmental effects on the auditory system would be beneficial for establishing 

MRLs for carbon monoxide based on this end point. Studies conducted to understand the mechanism for 

this effect would provide additional information about the relevance of these effects to humans exposed at 

similar levels. 

Immunotoxicity. Epidemiological studies have examined effects on blood biomarkers of 

inflammation. Biomarkers examined have included been inflammation markers (CRP, SAA, and WBC) 

and cell adhesion markers (E-selectin, vWF, and ICAM-1) (Baccarelli et al. 2007; Liao et al. 2005; 

Pekkanen et al. 2000; Rückerl et al. 2006, 2007; Steinvil et al. 2008). A study conducted in guinea pigs 

examined effects of carbon monoxide exposure on plaque forming cells in spleen (Snella and Rylander 

1979). Effects of gestational exposure on the developing immune system have been studied in rats 

(Giustino et al. 1993, 1994). Studies conducted in cell culture and in vivo models of sepsis have 

examined effects of endogenous and exogenous carbon monoxide on inflammatory responses and 

cytokine and signaling pathways involved in inflammation (Ryter et al. 2006). These studies suggest a 

potential for carbon monoxide to exert effects on the immune system. Additional studies to establish 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 201 

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modes of action and dose-response relationships would be beneficial for determining the sensitivity of the 

immune system to carbon monoxide, relative to other targets of toxicity, and for establishing MRLs. 

Neurotoxicity. Experimental clinical studies (Benignus et al. 1994), clinical case studies (Chambers 

et al. 2008; Dolan 1985; Ernst and Zibrak 1998; Hopkins et al. 2006; Kao and Nañagas 2006; Lo et al. 

2007; Parkinson et al. 2002; Raub and Benignus 2002), and studies conducted in animals (Benignus et al. 

1994; Chambers et al. 2008; Chen and Fechter 1999; Dolan 1985; Ernst and Zibrak 1998; Fechter et al. 

1988; Hopkins et al. 2006; Kao and Nañagas 2006; Lo et al. 2007; Parkinson et al. 2002; Raub and 

Benignus 2002; Young et al. 1987) have examined effects of acute carbon monoxide exposures on 

behavior cognitive function. Although these studies provided strong evidence for impairments in 

association with exposures that result in blood COHb levels >20%, dose-response relationships for lower 

levels remain controversial (Benignus 1994; Benignus et al. 1990; Raub and Benignus 2002). Further 

research on dose-response relationships of neurobehavioral and neurosensory effects at low levels of 

carbon monoxide exposure (e.g., COHb<20%) utilizing double-blind designs would be beneficial for 

analyses in support of deriving MRLs. 

Epidemiological and Human Dosimetry Studies. Epidemiological studies have examined health 

outcomes in the context of chronic exposures or acute variations in exposure concentrations that occur 

during chronic exposures (see Tables 3-3, 3-6, 3-7, and 3-8). Outcomes that have been assessed include 

mortality, including cancer mortality, cardiovascular effects, respiratory effects, blood biomarkers of 

coagulation and inflammation, and developmental effects (pre-term birth, birth weight, congenital 

anomalies, neonatal and infant mortality). Human dosimetry studies have examined relationships 

between carbon monoxide exposure levels and durations and blood COHb levels in resting subjects, 

during exercise, and at various altitudes (see Tables 3-4 and 3-5). Studies of elimination kinetics of 

carbon monoxide in humans have explored effects of exercise, age, gender, and oxygen therapy on 

elimination half-time (Bruce and Bruce 2006; Joumard et al. 1991; Landaw 1973; Levasseur et al. 1996; 

Peterson and Stewart 1970; Shimazu et al. 2000; Weaver et al. 2000). 

Biomarkers of Exposure and Effect. 

Exposure. Measurement of blood COHb is the principal biomarker for identifying exposure to carbon 

monoxide. Several pharmacokinetics models have been developed that can be used to predict blood 

COHb levels that would correspond to a given exposure concentration and duration in a typical adult and 

in the fetus resulting from maternal exposures. These models can be used to reconstruct possible carbon 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 202 

3. HEALTH EFFECTS 

monoxide exposure scenarios (e.g., concentrations, duration, and gap between measurement of COHb and 

cessation of exposure) that could result in a given measured COHb level. 

Effect. Although blood COHb reflects current carbon monoxide body burden, measurement of blood 

COHb has not been shown to be a reliable predictor of severity of acute toxicity (Hampson and Hauff 

2008). Therefore, diagnoses and characterization of toxic effects of carbon monoxide relies on both the 

measurement of blood COHb and the assessment of signs and symptoms of carbon monoxide toxicity. 

Studies conducted to identify biomarkers of non-hypoxic mechanisms of carbon monoxide (those 

unrelated to blood COHb levels) would be beneficial for internal dosimetry in epidemiological and 

clinical experimental studies, for development of PBPK/PD models of non-hypoxic effects of carbon 

monoxide, and for improving diagnosis of carbon monoxide poisoning. 

Absorption, Distribution, Metabolism, and Excretion. Pharmacokinetics of carbon monoxide 

has been extensively studied in humans and in animal models, including nonhuman primates (see 

Section 3.4). Studies conducted in humans have provided information on absorption, metabolism, 

distribution, and elimination kinetics, as well as physiological factors (e.g., age, gender) and 

environmental factors (e.g., altitude, exercise) that affect carbon monoxide kinetics. These studies have 

provided the bases for pharmacokinetic models that simulate carbon monoxide absorption and elimination 

kinetics and blood COHb and muscle COMb levels in humans (see Section 3.4.5). Several studies have 

provided estimates of rates of whole-body endogenous production of carbon monoxide in adult males and 

females during and following pregnancy (Coburn et al. 1963; Delivoria-Papadopoulos et al. 1974; Longo 

1977; Mercke and Lundh 1976). However, measurement of local tissue production rates would also be 

valuable for studying mechanisms by which endogenously produced carbon monoxide modulates cellular 

metabolism and cell signaling pathways, as well as the relative contributions of exogenous carbon 

monoxide and endogenously produced carbon monoxide contribute to these processes. 

Comparative Toxicokinetics. Major physiological and biochemical determinants of blood and 

skeletal muscle carbon monoxide kinetics that would be expected to contribute to interspecies differences 

in carbon monoxide toxicokinetics have been identified. This information provides a basis for 

extrapolating pharmacokinetics models across mammalian species, for which physiological (e.g., 

ventilation rates, blood Hb levels) and chemical-specific parameters are known (e.g., binding affinities 

and capacities of Hb and myoglobin, long carbon monoxide diffusion capacity). Models developed to 

simulate carbon monoxide kinetics in humans have been adapted for applications to animal models (e.g., 

rats; Benignus and Annau 1994) and to simulate maternal-fetal transfer of carbon monoxide during 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 203 

3. HEALTH EFFECTS 

pregnancy in sheep (Longo and Hill 1977). Adaptation of these models to a wider range of species would 

be facilitated by studies that provide estimates of model parameters in these species (e.g., Haldane 

coefficient, binding coefficients of Hb and Mb, and the lung carbon monoxide diffusing capacity). 

Methods for Reducing Toxic Effects. Efficacies of normobaric and hyperbaric oxygen therapy for 

hastening the elimination of carbon monoxide from the body and for treating carbon monoxide-induced 

hypoxia have been studied. Although hyperbaric oxygen therapy is considered to be a therapeutic option, 

its efficacy, over normobaric therapy, remains controversial (Wolf et al. 2008). Further research 

regarding benefits and limitations of hyperbaric oxygen therapy would improve the clinical management 

of treatment of carbon monoxide poisoning. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

Mechanisms of Toxicity. Although hypoxic mechanisms of action of carbon monoxide are well 

established (i.e., those related to formation of COHb), a better understanding is needed of non-hypoxic 

mechanisms, their contribution to observed adverse health effects of carbon monoxide, and related doseresponse relationships. 

3.12.3 Ongoing Studies 

Ongoing studies pertinent to information of health effects and/or mechanisms of action of carbon 

monoxide are listed in Table 3-18. 
 

 

 

CARBON MONOXIDE 204 

3. HEALTH EFFECTS 

Table 3-18. Ongoing Studies on the Health Effects of Carbon Monoxide 

Investigator Affiliation Research description Sponsor 

Abraham NG New York Medical Heme oxygenase regulation of 

College eicosanoid biosynthesis 

Bauer AJ University of Pittsburgh Protective mechanisms of carbon 

at Pittsburgh Office of monoxide in intestinal inflammation 

Research 

Bauer PM University of Pittsburgh Role of caveolin-1 and eNOS in 

at Pittsburgh Office of mediating the therapeutic effects of 

Research carbon monoxide in polycyclic 

aromatic hydrocarbons 

Choi AM Brigham and Women’s Role of heme oxygenase in hyperoxic 

Hospital Research lung injury 

Administration 

Durante W University of Missouri- Carbon monoxide and vascular cell 

Columbia function 

Fallon MB University of Texas Mediators of pulmonary 

vasodilatation in liver disease 

Fowler AA Virginia Commonwealth Role of hypotoxia inducible factor-1 in 

University inflammation 

Kibbe MR Northwestern University Nitric oxide eluting therapies for 

vascular surgery 

Lefer DJ Yeshiva University Mechanism of myocardial reperfusion 

injury in diabetes 

Leffler CW University of Tennessee Carbon monoxide in newborn 

Health Science Center cerebral circulation 

Leffler CQ University of Tennessee Control of neonatal circulation 

Health Science Center 

Lindahl PA Texas A&M University Bioinorganic chemistry of carbon 

System monoxide dehydrogenase 

Sciences 

Machado RF Clinical Center Effects of inhaled carbon monoxide 

on human lung inflammation 

Mapes JP Rules-Based Medicine, Biomarker profiles for carbon 

Inc. monoxide poisoning 

Sciences 

McCurry KR University of Pittsburgh Cytoprotective effect of carbon 

at Pittsburgh Office of monoxide in lung ischemia/ 

Research reperfusion 

Morse ED University of Pittsburgh Inhibitor of differentiation-1 mediates 

at Pittsburgh Office of antifibrotic effects of carbon 

Research monoxide 

Murase N University of Pittsburgh Protective role of carbon monoxide in 

at Pittsburgh Office of hepatic I/R injury 

Research 

National Institute of 

Diabetes and Digestive 

and Kidney Diseases 

National Institute of 

Diabetes and Digestive 

and Kidney Diseases 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Institute of 

Diabetes and Digestive 

and Kidney Diseases 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Institute of 

General Medical 

Not applicable 

National Institute of 

Environmental Health 

National Heart, Lung, 

and Blood Institute 

National Heart, Lung, 

and Blood Institute 

National Institute of 

Diabetes and Digestive 

and Kidney Diseases 
 

 

 

CARBON MONOXIDE 205 

3. HEALTH EFFECTS 

Table 3-18. Ongoing Studies on the Health Effects of Carbon Monoxide 

Investigator Affiliation Research description Sponsor 

O’Neill MS University of Michigan at 

Ann Arbor 

Air pollution, inflammation, and 

preterm birth: a mechanistic study in 

Mexico City 

National Institute of 

Environmental Health 

Sciences 

Parfenova H University of Tennessee 

Health Science Center 

Heme oxygenase and cerebral 

vascular injury 

National Institute of 

Neurological Disorders 

and Stroke 

Raman CS University of Texas 

Health Science Center, 

Houston 

Structural biology of gaseous 

messenger signaling 

National Institute of 

General Medical 

Sciences 

Roberts GP University of Wisconsin 

Madison 

Sensing mechanisms for carbon 

monoxide and other small molecules 

National Institute of 

General Medical 

Sciences 

Tolbert PE Emory University Air pollution and birth defects in 

Atlanta, 1968–2002 

National Institute of 

Environmental Health 

Sciences 

Tulis DA North Carolina Central 

University 

NO-independent cGMP regulation of 

vascular remodeling 

National Heart, Lung, 

and Blood Institute 

Vitali SH Children’s Hospital 

Boston 

Hypoxic inflammation, pulmonary 

hypertension, and HO-1 

National Heart, Lung, 

and Blood Institute 

Williams MA Swedish Medical 

Center, First Hill 

Ambient air pollution, preeclampsia, 

and preterm delivery 

National Institute of 

Environmental Health 

Sciences 

Xuan U University of Louisville Delayed cardioprotection induced by 

NO and carbon monoxide 

National Heart, Lung, 

and Blood Institute 

Source: FEDRIP 2009 
 

CARBON MONOXIDE 206 

3. HEALTH EFFECTS 

This page is intentionally blank. 
 

 

 

 

 

 

CARBON MONOXIDE 207 

4. CHEMICAL AND PHYSICAL INFORMATION
	

4.1 CHEMICAL IDENTITY
	

The chemical identity of carbon monoxide is shown in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Carbon monoxide is a highly poisonous, odorless, colorless, and tasteless gas. It is very flammable in air 

over a wide range of concentrations (George 2001) and burns in air with a bright blue flame (O’Neil et al. 

2006). It becomes a liquid at 81.62 K (-191.53 °C) and is insoluble in water above 70 °C (George 2001). 

The physical and chemical properties of carbon monoxide are shown in Table 4-2. 
 

 

CARBON MONOXIDE 208 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Carbon Monoxide 

Characteristic Carbon monoxidea 

Synonym(s) Carbon oxide, flue gas, monoxide
 

Registered trade name(s)
 

Chemical formula COb
 

Chemical structure :C O:
 

Identification numbers:
 

CAS registry 630-08-0b
 

NIOSH RTECS FG350000
 

EPA hazardous waste No data
 

OHM/TADS No data
 

DOT/UN/NA/IMDG shipping 1016c; 9202d,e
 

HSDB 903
 

NCI No data
 

a

All information obtained from HSDB 2009, except where noted. b

O’Neil 2006 

c

Compressed

d

NIOSH 2005 

e

Cryogenic liquid 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 
 

CARBON MONOXIDE 209 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Carbon Monoxide 

Property Carbon monoxidea 

Molecular weight 28.01 

Color Colorless 

Physical state Gas 

Melting point -205 °C 

Boiling point -191.5 °C 

Density at 25 °C 1.145 g/L at 25 °C and 1 atm3b 

Odor Odorless 

Odor threshold: 

Water No data 

Air No data 

Solubility: 

Water at 20 °C 2.3 mL/100 mL 

Organic solvents Appreciably soluble in ethyl acetate, chloroform, and acetic acid; 

freely absorbed by a concentrated solution of cuprous chloride in 

hydrochloric acid or ammonium hydroxide; solubility in methanol and 

ethanol about 7 times as great as in water; soluble in benzene 

Partition coefficients: 

Log Kow Not applicable 

Log Koc Not applicable 

Henry's law constant at 25 °C 57,978.5 atm/mol fraction (~1.04 atm-m3/mole)c 

Autoignition temperature 605 °Cd 

Flashpoint Flammable gasd 

Flammability limits Upper limit 74.2%; lower limit 12.5%e 

Conversion factors 1 ppm=1.16 mg/m3 at 20 °C and 1 atm 

Explosive limits No data 

a

All information obtained from HSDB 2009, except where noted. c

Yaws et al. 1999 

b

Lide 2008 

d

IPCS 2008 

e

George 2001 
CARBON MONOXIDE 210 

4. CHEMICAL AND PHYSICAL INFORMATION 

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CARBON MONOXIDE 211 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Carbon monoxide is produced by the incomplete combustion of carbon in liquid, solid, and gaseous fuels 

(George 2001). Commercially, it is produced on an industrial scale by the partial oxidation of 

hydrocarbon gases from natural gas or by the gasification of coal and coke. Laboratory-scale production 

of carbon monoxide is accomplished by heating calcium carbonate with zinc dust (O’Neil et al. 2006). 

Carbon monoxide is also obtained from the dehydration of formic acid (Lewis 2007). The majority of 

carbon monoxide produced is used immediately downstream and at the plant site for chemical synthesis 

or steel manufacturing; consequently, quantitative production volumes are not available (George 2001). 

Carbon monoxide is a co-product along with hydrogen in syn gas (synthetic gas) production, gases are 

then separated and purified by pressure swing adsorption and/or cryogenic distillation. 

Carbon monoxide is a major air pollutant (Lewis 2007). It is a byproduct of highway vehicle exhaust, of 

industrial processes and fuel combustion in boilers and incinerators, and of household appliances fueled 

with gas, oil, kerosene, or wood, and fires. The largest contribution comes from highway motor vehicles. 

Carbon monoxide exceeds all other atmospheric pollutants, combined with the exception of CO2 (George 

2001). 

The major facility within the United States that manufactures or processes carbon monoxide (produced in 

commercial quantities exceeding 5,000 pounds or $10,000 in value annually) is Air Liquide America L.P. 

in Freeport, Texas (SRI 2008). 

5.2 IMPORT/EXPORT 

No data were located on the import or export of carbon monoxide. 

5.3 USE 

Carbon monoxide is used by the chemical industry for the synthesis of many compounds such as acetic 

anhydride, polycarbonates, acetic acid, and polyketones (George 2001). It finds application as a reducing 

agent in metallurgical operations, specifically the Mond process for the recovery of nickel, in the 

manufacture of metal carbonyls, and in organic synthesis, especially for the Fischer-Tropsch process for 
 

 

 

 

 

CARBON MONOXIDE 212 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

petroleum-related products and in the oxo reaction (O’Neil et al. 2006). Carbon monoxide is also used in 

the manufacture of zinc white pigments (Lewis 2007). 

5.4. DISPOSAL 

EPA considers a waste to be hazardous if it exhibits any of the following characteristics: ignitability, 

corrosivity, reactivity, or toxicity as defined in 40 CFR 261.21–261.24. Under the Resource Conservation 

and Recovery Act (RCRA) (40 USC 6901 et seq.), EPA has specifically listed many chemical wastes as 

hazardous. Although carbon monoxide is not specifically listed as a hazardous waste under RCRA, EPA 

requires employers to treat waste as hazardous if it exhibits any of the characteristics discussed above 

(OSHA 2000). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 213 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Carbon monoxide is a colorless, odorless, and tasteless gas that is ubiquitous in the atmosphere (George 

2001). It arises from both natural and anthropogenic (human-made) sources. It is produced as a primary 

pollutant during the incomplete combustion of fossil fuels and biomass, including internal combustion 

engines, wildfires, and controlled burns. Carbon monoxide is also produced indirectly from the 

photochemical oxidation of methane and other VOCs in the atmosphere. Vegetation can emit carbon 

monoxide into the atmosphere as a metabolic byproduct. Photooxidation of organic matter in surface 

waters (lakes, streams, rivers, oceans) and surface soils also results in the formation of carbon monoxide. 

Volcanic activity is another natural source of carbon monoxide in the atmosphere. Carbon monoxide is 

also produced endogenously in humans during the normal catabolism of hemoglobin (Hb). The amount 

of anthropogenic carbon monoxide emissions versus that from natural sources is difficult to quantify since 

both sources of carbon monoxide vary over time. The EPA estimated that 84% of all carbon monoxide 

emissions in 2005 arose as a result of human activity, with biogenic emissions accounting for 16% of the 

total emissions (EPA 2012). However, an analysis of the carbon monoxide budget over North America 

concluded that during the summer months, when natural sources of carbon monoxide precursors such as 

biogenic VOCs and forest fires are high, natural sources of carbon monoxide in the atmosphere are far 

greater than anthropogenic contributions (Miller et al. 2008). Data from the EPA National Emissions 

Inventory (NEI) suggest that as much as 75% of the total point and non-point emissions of carbon 

monoxide are historically associated with on-road automobile use (EPA 2010). 

The background levels of carbon monoxide have changed significantly in the past several decades. 

Concentrations have decreased appreciably due to reduced emissions from automobiles as a consequence 

of advancements in automotive design. The development of catalytic converters for passenger vehicles, 

beginning in the 1970s, resulted in a substantial decrease in carbon monoxide emissions, despite large 

increases in miles traveled (George 2001). In the early 1980s, automakers equipped vehicles with more 

sophisticated catalytic converters and added on-board computers and O2 sensors in order to help optimize 

the efficiency of the converter. The end result is that modern passenger automobiles emit about 90% less 

carbon monoxide over their lifetimes as compared to vehicles designed in previous decades (George 

2001). 

The annual average outdoor carbon monoxide concentrations are roughly 0.12 parts per million by 

volume (ppmv) in the Northern Hemisphere and about 0.04 ppmv in the Southern Hemisphere (EPA 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 214 

6. POTENTIAL FOR HUMAN EXPOSURE 

2000). These levels are variable throughout the course of the year, with seasonal maximum levels 

occurring during late winter in both hemispheres when inversion conditions (in which air pollutants are 

trapped near the ground beneath a layer of warm air) are more frequent. Minimum levels are generally 

observed during late summer. Carbon monoxide concentrations are reported to range from a minimum of 

about 0.03 ppmv during summer in the Southern Hemisphere to about 0.20 ppmv at high latitudes in the 

Northern Hemisphere during winter (EPA 2000). Urban locations with high automobile usage or a high 

volume of stationary emission sources, such as refineries or power plants, typically have greater 

atmospheric levels of carbon monoxide as compared to rural or remote sites. In metropolitan areas in the 

United States, as much as 95% of all carbon monoxide emissions result from on-road vehicle exhaust 

(EPA 2008). The majority of these on-road emissions are derived from gasoline-powered vehicles, since 

diesel vehicles emit less carbon monoxide. There is also a diurnal pattern of atmospheric carbon 

monoxide concentrations in urban areas, with the highest levels occurring during hours with heavy 

vehicular usage (rush hours) and the lowest levels occurring at times that correlate with lower commuting 

activity (Campbell et al. 1995; EPA 2000). Maximum carbon monoxide levels frequently exceed 5 ppmv 

at these locations during the high commute hours. 

Carbon monoxide levels in indoor air are greatly dependent upon the presence of combustion-based 

appliances and whether occupants smoke tobacco products. Unvented kerosene and gas space heaters; 

leaking chimneys and furnaces; back-drafting from furnaces, gas water heaters, wood stoves, and 

fireplaces; gas stoves, generators, and other gasoline-powered equipment; automobile exhaust from 

attached garages; and tobacco smoke all contribute to indoor air levels of carbon monoxide (EPA 2009a). 

Average levels in homes without gas stoves vary from 0.5 to 5 ppmv. Levels near properly adjusted gas 

stoves are often 5–15 ppmv, and those near poorly adjusted stoves may be ≥30 ppmv (EPA 2009a). 

Dangerous levels of carbon monoxide can occur inside boat cabins, partially enclosed cockpits, and 

beneath swim platforms or other enclosed areas (USCG 2008). Most new boats are equipped with carbon 

monoxide monitors; however, the U.S. Coast Guard advises owners of boats built prior to 1998 to have 

the monitors inspected or replaced (USCG 2008). 

The primary degradation pathway of carbon monoxide in the environment occurs through its reaction 

with photochemically-produced hydroxyl radicals. (It should be noted that the production of hydroxyl 

radicals requires ultraviolet [UV] radiation that does not penetrate windows and therefore, photooxidation 

is likely negligible indoors.) In addition, soils and coastal waters may also act as a sink for carbon 

monoxide, since various forms of microorganisms are capable of utilizing carbon monoxide as an energy 

source (Tolli et al. 2006). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 215 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure of the general population to carbon monoxide occurs through inhalation. Populations living in 

urban areas with heavy vehicular traffic or stationary sources such as petroleum refineries, gas and coal 

burning power plants, petrochemical plants, and coke oven plants are more likely to be exposed to higher 

levels of carbon monoxide from ambient outdoor air. Employees in these refineries and plants and 

workers who are subject to high levels of vehicular exhaust (such as taxi cab drivers and toll booth 

workers) may be occupationally exposed to higher levels of carbon monoxide. Members of the public 

who smoke or work in smoke-filled environments such as restaurants, bars, and casinos where smoking is 

allowed are exposed to higher levels of carbon monoxide than members of the population who do not 

smoke and are not frequently exposed to second-hand tobacco smoke. 

6.2 RELEASES TO THE ENVIRONMENT 

6.2.1 Air 

Title I of the Clean Air Act of 1970 establishes carbon monoxide as one of six criteria pollutants and sets 

national air quality standards for carbon monoxide and the other criteria pollutants (EPA 2000). Two 

databases developed by the EPA are particularly useful for monitoring carbon monoxide levels and 

emissions throughout the United States. EPA's National Emission Inventory (NEI) database contains 

detailed information about sources that emit criteria air pollutants and their precursors and hazardous air 

pollutants for the 50 United States, Washington DC, Puerto Rico, and the U.S. Virgin Islands. The Air 

Quality System (AQS) database is EPA's repository of criteria air pollutant monitoring data since the 

1970s. Table 6-1 contains data for carbon monoxide emissions from 1970 to 2008 from the NEI database 

for 13 major emission categories. Detailed carbon monoxide emissions from these sources for individual 

years are available as zipped Microsoft Access® database files that may be accessed directly from the 

EPA website; however, these data are subject to occasional revisions by EPA as emission estimates for a 

specific time period are amended. As indicated in Table 6-1, on-road vehicle use has historically 

accounted for the largest percentage of emissions in the United States as compared to the other emission 

sources; however, the quantity of carbon monoxide emitted from automobiles has been declining 

significantly over the past 4 decades due to the use of emission control devices and catalytic converters. 

Indoor air levels of carbon monoxide are highly dependent upon the smoking habits, the types of 

appliances and heating units that are used in the home or building, and whether or not the home or 

building has an attached garage for automobiles. Carbon monoxide levels from the use of appliances will 
 

 

 

 

CARBON MONOXIDE 216 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Anthropogenic Carbon Monoxide Emissions (Thousands of Short 

Tons) from 1970 to 2008
	

Emissions by categorya 

Yearb 1 2 3 4 5 6 7 8 9 10 11 12 13 Total 

1970 237 770 3,625 3,397 3,644 2,179 620 NA NA 7,059 163,231 11,371 7,909 204,042 

1975 276 763 3,441 2,204 2,496 2,211 630 NA NA 3,230 153,555 14,329 5,263 188,398 

1980 322 750 6,230 2,151 2,246 1,723 830 NA NA 2,300 143,827 16,685 8,344 185,408 

1985 291 670 7,525 1,845 2,223 462 694 2 49 1,941 134,187 19,029 7,927 176,845 

1990 363 879 4,269 1,183 2,640 333 537 5 76 1,079 110,255 21,447 11,122 154,188 

1991 349 920 4,587 1,127 2,571 345 548 5 28 1,116 104,980 21,934 8,618 147,128 

1992 350 955 4,849 1,112 2,496 371 544 5 17 1,138 99,705 22,419 6,934 140,895 

1993 363 1,043 4,181 1,093 2,536 371 594 5 51 1,248 94,431 22,904 7,082 135,902 

1994 370 1,041 4,108 1,171 2,475 338 600 5 24 1,225 89,156 23,389 9,656 133,558 

1995 372 1,056 4,506 1,223 2,380 348 624 6 25 1,185 83,881 23,874 7,298 126,778 

1996 408 1,188 2,741 1,053 1,599 354 561 1 70 2,904 78,606 24,358 15,016 128,859 

1997 423 1,162 2,742 1,071 1,710 367 582 2 71 2,948 75,849 23,668 7,316 117,911 

1998 451 1,151 2,727 1,081 1,702 366 590 2 72 3,121 73,244 23,689 7,184 115,380 

1999 496 1,213 3,829 350 1,255 159 571 52 163 3,019 68,708 23,316 11,410 114,541 

2000 484 1,219 3,081 361 1,295 161 592 51 169 1,849 68,061 24,178 12,964 114,465 

2001 485 1,253 3,088 372 1,380 162 615 50 178 1,851 63,476 24,677 8,676 106,263 

2002 657 1,267 3,550 284 987 357 490 2 118 1,594 60,596 22,662 18,493 111,057 

2003 652 1,229 3,477 259 934 355 504 2 114 1,580 56,579 21,999 17,364 105,078 

2004 647 1,190 3,404 233 882 353 519 2 111 1,567 52,562 21,336 16,235 99,041 

2005 643 1,152 3,331 208 829 351 534 2 107 1,554 48,544 20,672 15,106 93,034 

2006 661 1,173 3,343 227 869 352 522 2 110 1,564 45,318 19,793 13,981 87,915 

2007 680 1,195 3,352 246 908 353 511 2 113 1,574 42,092 18,915 12,856 82,801 

2008 699 1,216 3,369 265 947 355 500 2 115 1,584 38,866 18,036 11,731 77,685 

a

Categories 

1. Fuel combustion electric utilities 

2. Fuel combustion industrial utilities 

3. Fuel combustion other 

4. Chemical allied manufacturing 

5. Metal processing 

6. Petroleum and related categories 

7. Other industrial processes 

8. Solvent utilization 

9. Storage and transport 

10. Waste disposal and recycling 

11. Highway vehicles 

12. Off-highway 

13. Miscellaneous
 b

Emission estimates are subject to updates for subsequent revised versions of the National Emissions Inventory (NEI)
 

database. These numbers may be different than values published for previous versions of the data and may also be 

different than values for subsequent revisions of the data as generated by the Environmental Protection Agency.
 

NA = not available 

Source: EPA 2009h 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 217 

6. POTENTIAL FOR HUMAN EXPOSURE 

depend on several factors, such as the type of fuel used, ventilation, appliance design, fuel consumption 

rate, use pattern, and operating condition (EPA 1991, 2000, 2010). As reported in the EPA Air Quality 

Criteria Reports (1991, 2000), carbon monoxide emissions from ranges, ovens, and pilot lights using 

natural gas were typically greater under yellow tipping flame conditions (characteristic of an improper 

air-fuel ratio) than blue tipping flame conditions (characteristic of properly adjusted stoves). The average 

emission rate (mass of carbon monoxide emitted per energy unit produced) for top burning ovens and 

broilers was 11.9–87.7 micrograms per kilojoule (μg/kJ) under blue flame conditions, as opposed to 53.5– 

156.6 μg/kJ for improperly adjusted ovens and broilers. In separate tests using three different gas ranges 

deliberately adjusted to produce blue tipping or yellow tipping flames, the average emission rate ranged 

from 34.3–70.9 μg/kJ under properly adjusted operation to 108.4–196.9 μg/kJ under improperly adjusted 

conditions (EPA 1991, 2000). 

Quantitative estimates have been made regarding emissions of carbon monoxide from wood-burning 

stoves and fireplaces under normal operating conditions (Houck et al. 2006). Carbon monoxide emission 

factor data were based on 277 tests on 70 fireplace models. The mean emission factor was 64.1 g carbon 

monoxide emitted per kg dry wood (SD of 40.7 g/kg dry wood) (Houck et al. 2006). It has been reported 

that emission rates of carbon monoxide for well-tuned unvented gas appliances range from 0.15 to 

3.2 g/hour, while rates for poorly tuned unvented ones range from 1.5 to 22 g/hour (Dutton et al. 2001). 

6.2.2 Water 

Direct anthropogenic releases of carbon monoxide to water are not expected; however, natural processes 

occur that result in carbon monoxide formation in waters. The photodegradation of dissolved organic 

matter is primarily responsible for producing carbon monoxide in sunlit surface waters (Tolli et al. 2006). 

Emissions from oceans are a minor source of carbon monoxide with estimated ranges from about 10 to 

100 teragrams (Tg) annually (EPA 2000; Liss and Slater 1974). 

6.2.3 Soil 

The formation of carbon monoxide in soils appears to occur by abiotic processes, such as thermal 

decomposition or photodecomposition of organic matter. In general, warm and moist conditions found in 

most soils favor carbon monoxide uptake, whereas hot and dry conditions as found in deserts and some 

savannas favor the release of carbon monoxide from soil to the atmosphere with estimated annual 

emissions of about 30 Tg per year (EPA 2000). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 218 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Carbon monoxide is a gas that will partition to the atmosphere and is distributed globally by the 

horizontal movement of the wind. Wind direction determines the horizontal transport of carbon 

monoxide and what impact emissions from one location will have upon another site (EPA 1991). Carbon 

monoxide levels may be high around local sources, and locations downwind from the source may also be 

elevated. The transport of carbon monoxide in urban locations is complex and can be influenced by the 

geometry of street canyons, topography around roadways, and presence of noise barriers, vegetation, and 

buildings, as well as local meteorological factors. A field study was designed to characterize the air 

quality and flow of pollutants near a highway with and without noise barriers (Baldauf et al. 2008). The 

site also contained an open field and a residential neighborhood with mature vegetation. Time-series 

carbon monoxide levels were collected in an open field with no barrier and an area behind the noise 

barrier. Levels of carbon monoxide were reduced as much as 50% behind the noise barrier as compared 

to measurements taken at the open field, depending upon the direction of the wind. However, when wind 

direction was directly toward the road, carbon monoxide levels behind the barrier were slightly higher 

than in the open field indicating that pollutants can be trapped behind noise barriers depending upon 

meteorological conditions (Baldauf et al. 2008). 

In most urban areas during the winter months, there is often enhanced stability in the atmospheric 

boundary layer, which reduces the vertical mixing of emissions from the ground. This effectively traps 

carbon monoxide at street levels during these periods. Unreacted carbon monoxide in the troposphere is 

slowly transported to the mesosphere and stratosphere, where it reacts with atomic oxygen generated by 

the photodissociation of O2 (Fabian et al. 1979; Pressman and Warneck 1970). 

The surface waters of the world’s oceans are saturated with carbon monoxide with respect to the 

atmosphere and are therefore a net source of atmospheric carbon monoxide. Using a mean atmospheric 

carbon monoxide concentration over the ocean surface of 0.13 ppmv and a surface water concentration of 

6x10-8 cm3

 carbon monoxide per cm3 water, the total annual flux of carbon monoxide to the atmosphere 

from seawater was estimated at approximately 4.3x1013 g/year (43 teragrams (Tg)) (Liss and Slater 1974). 

Other reported estimates based on computed carbon monoxide concentrations in surface waters were 

reported to range from 13 to 165 Tg/year (Ohta 1997). Differences in microbial activity in surface water 

account for the variations in surface water levels and the flux into the atmosphere (Conrad and Seiler 

1988). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 219 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Carbon monoxide is generally stable under environmental conditions. Reactions with molecular oxygen 

(O2) or water vapor are very slow at ambient temperatures and pressure. Carbon monoxide reacts with 

ground-state triplet oxygen atoms, O(3

P), produced by the atmospheric photodegradation of nitrogen 

dioxide and ozone, or atomic oxygen, formed by the photodissociation of molecular O2 in the 

stratosphere, to form CO2 (NRC 1977). However, the primary degradation pathway of carbon monoxide 

in the troposphere is through its reaction with photochemically-produced hydroxyl radicals. This results 

in the formation of CO2 and atomic hydrogen, which rapidly reacts with O2 to form peroxy radicals (EPA 

2000, 2010). The second-order rate constant for the gas-phase reaction of carbon monoxide with 

hydroxyl radicals at atmospheric pressure has been measured as 2.4x10-13 cm3

/molecule-second (EPA 

1991). This corresponds to an estimated tropospheric half-life of approximately 22–67 days, assuming a 

hydroxyl radical concentration of 5.0x105

–1.5x106 hydroxyl radicals per cm3 air. No estimates of the 

half-life of carbon monoxide in indoor air were located. Hydroxyl radicals are formed photochemically 

by sunlight; therefore, their levels in indoor air will be negligible. 

6.3.2.2 Water 

Although oceans and other water bodies are considered a net source of carbon monoxide in the 

environment, evidence suggests that various microorganisms may degrade carbon monoxide in the water 

(Conrad and Seiler 1988). Taxonomically diverse microorganisms isolated from surface waters collected 

off the New England coast readily oxidized carbon monoxide (Tolli et al. 2006). Microbial oxidation rate 

constants for carbon monoxide in coastal waters were reported to range from 0.01 to 0.11 hours-1 , 

corresponding to half-lives on the order of several hours (Tolli et al. 2006). These rates were reported to 

be approximately an order of magnitude greater than in oligotrophic environments, suggesting the 

presence of an active carbon monoxide oxidizing microbial community near shore. 

6.3.2.3 Sediment and Soil 

Soils may act as a source or a sink for carbon monoxide, depending on soil moisture, intensity of sunlight 

reaching the soil surface, and soil temperature (Conrad and Seiler 1985). In general, warm and moist 

conditions found in most soils favor uptake, whereas hot and dry conditions as found in deserts and some 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 220 

6. POTENTIAL FOR HUMAN EXPOSURE 

savannas favor the release of carbon monoxide (EPA 2000). Global estimates of carbon monoxide 

consumption by soil microorganisms ranged from 15 to 640 Tg (from 1.5x1013 to 6.4x1014 g) per year 

(King 1999a). Carbon monoxide oxidation to CO2 has been demonstrated for both aerobic and anaerobic 

microorganisms. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to carbon monoxide depends in part on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of carbon monoxide in unpolluted atmospheres and in pristine surface waters are often so 

low as to be near the limits of current analytical methods. In reviewing data on carbon monoxide levels 

monitored or estimated in the environment, it should also be noted that the amount of chemical identified 

analytically is not necessarily equivalent to the amount that is bioavailable. The analytical methods 

available for monitoring carbon monoxide in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

The concentration of carbon monoxide in air can be represented using various concentration units. Air 

monitoring data for carbon monoxide are usually expressed or reported as either parts per million by 

volume (ppmv) or parts per billion by volume (ppbv). A concentration of 1 ppmv implies that for every 

million molecules of gas in the measured volume, one of them is a carbon monoxide molecule. In order 

to express these concentrations in mass units, the following conversion factors may be used: 

1.00 ppmv=1.16 mg/m3

 (1.00 mg/m3=0.86 ppmv) and 1.00 ppbv=1.16 μg/m3 at 20 °C. 

Annual average outdoor carbon monoxide concentrations are about 0.12 ppmv in the Northern 

Hemisphere and about 0.04 ppmv in the Southern Hemisphere (EPA 2000). In general, the concentration 

of carbon monoxide decreases with altitude in the Northern Hemisphere, but this vertical gradient may be 

reversed in the Southern Hemisphere due to the transport of carbon monoxide from the Northern to the 

Southern Hemisphere (EPA 1991). Annual 24-hour average carbon monoxide concentrations obtained at 

monitoring locations at rural sites in the United States are typically about 0.2 ppmv, compared with an 

annual 24-hour average of 1.2 ppmv across all monitoring sites (EPA 2000). Carbon monoxide levels 

(1- and 8-hour maximum levels) from various cities in the United States for 2008 are provided in 

Table 6-2. These data are derived from measurements submitted to the EPA AQS database, which 

collects data from EPA, state, local, and tribal air pollution control agencies. As indicated by the data 

presented in the table, only one measurement exceeded the EPA 8-hour carbon monoxide level of 9 ppm, 
 

 

CARBON MONOXIDE 221 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

2,169 8.1 6.7 0 3.6 3.5 0 Fairbanks AK 

2,176 6.1 6 0 4.1 3.8 0 Anchorage AK 

1,988 5.1 4.5 0 2.5 2.3 0 Not provided AK 

2,176 5.6 5.5 0 3.1 2.8 0 Anchorage AK 

2,173 5.7 4.5 0 3.3 2.2 0 Fairbanks AK 

2,173 8.3 8 0 4.8 4.7 0 Anchorage AK 

7,500 19.6 15.9 0 10.7 8.1 1 Birmingham AL 

7,563 8 6.1 0 2.3 2.2 0 Fairfield AL 

8,012 3.4 3 0 2.4 2.3 0 Birmingham AL 

8,750 6.8 2.5 0 1.8 1.5 0 North Little AR 

Rock 

5,049 1.5 1.4 0 1 1 0 Surprise AZ 

4,584 0.7 0.7 0 0.5 0.5 0 Not provided AZ 

7,947 3.1 3.1 0 2.5 2.4 0 Phoenix AZ 

8,720 2.2 1.8 0 1.3 1 0 Tucson AZ 

8,736 2.6 2.1 0 1.1 1.1 0 Tucson AZ 

8,696 2.9 2.5 0 1.4 1.3 0 Tucson AZ 

4,369 2.5 2.5 0 1.9 1.5 0 Tucson AZ 

8,157 1.5 1.3 0 1 0.9 0 Tucson AZ 

4,315 2 1.8 0 1.3 1.2 0 Tucson AZ 

5,027 2.4 2.3 0 1.8 1.4 0 Tempe AZ 

5,043 1.8 1.7 0 1.4 1.4 0 Chandler AZ 

5,057 3.7 3.2 0 2.2 2 0 Phoenix AZ 

8,654 3 3 0 2.7 2.4 0 Phoenix AZ 

4,933 2 2 0 1.5 1.4 0 Scottsdale AZ 

5,060 2.1 2 0 1.6 1.5 0 Glendale AZ 

5,038 2.1 2 0 1.3 1.3 0 Phoenix AZ 

5,012 1.7 1.7 0 1.4 1.3 0 Mesa AZ 

8,575 4.7 4.5 0 3.1 3 0 Phoenix AZ 

8,307 3.9 3.6 0 2.8 2.8 0 Phoenix AZ 

8,397 3.6 3.5 0 2.6 2.2 0 Phoenix AZ 

6,905 2.1 1.9 0 1.1 1 0 Lompoc CA 

6,893 1.4 1.2 0 0.6 0.6 0 Goleta CA 

6,097 1.6 1.3 0 0.7 0.6 0 Vandenberg CA 

Air Force Base 

6,177 3.3 3 0 2.1 1.9 0 San Jose CA 

7,046 7.6 3.7 0 1.3 1.1 0 Davenport CA 

6,230 2.7 2.5 0 1.9 1.7 0 Vallejo CA 
 

 

CARBON MONOXIDE 222 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

6,251 0.9 0.9 0 0.7 0.6 0 Benicia CA 

6,244 3.5 1.9 0 1.3 1.1 0 Santa Rosa CA 

5,550 2.8 2.3 0 1.8 1.7 0 Modesto CA 

6,035 1.9 1.9 0 1.2 1.2 0 Turlock CA 

6,270 2.2 2.2 0 1.4 1.4 0 Livermore CA 

6,227 2.9 2.4 0 1.6 1.4 0 Oakland CA 

6,202 1.9 1.8 0 1.3 1.3 0 Fremont CA 

(Centerville) 

6,175 2.1 2 0 1.5 1.5 0 Berkeley CA 

5,576 3.1 3 0 2.4 2.1 0 Chico CA 

6,240 1.5 1.5 0 1 1 0 Concord CA 

6,274 1 0.9 0 0.8 0.8 0 Bethel Island CA 

6,225 2.5 2.1 0 1.3 0.9 0 San Pablo CA 

6,266 2.8 2.2 0 1.4 1.3 0 Pittsburg CA 

5,430 2.6 2.6 0 1.8 1.7 0 Fresno CA 

5,563 3.1 2.8 0 2.3 2.1 0 Fresno CA 

5,519 1.6 1.5 0 1 1 0 Fresno CA 

4,785 2.3 2.2 0 1.5 1.3 0 Clovis CA 

5,768 1.9 1.9 0 1.6 1.4 0 Eureka CA 

5,543 8.2 7 0 5.3 4.1 0 Calexico CA 

5,262 7.3 6.8 0 3.2 3.1 0 Calexico CA 

6,270 2.5 2.3 0 1.7 1.7 0 El Centro CA 

4,139 3.5 2.7 0 2.2 2.1 0 Bakersfield CA 

5,554 2.3 2.1 0 1.4 1.3 0 Azusa CA 

5,552 2.7 2.3 0 1.8 1.7 0 West Los CA 

Angeles 

5,555 3 2.8 0 2.5 2 0 Burbank CA 

5,560 2.9 2.8 0 2 1.9 0 Los Angeles CA 

5,594 3.4 3.3 0 2.3 2.1 0 Reseda CA 

5,579 5.8 5.7 0 4.3 4.1 0 Lynwood CA 

5,281 2.9 2.5 0 1.9 1.8 0 Pico Rivera CA 

5,557 2.6 2.6 0 1.7 1.7 0 Pomona CA 

5,550 2.4 2.4 0 2 1.9 0 Pasadena CA 

5,567 3.3 3 0 2.5 2.4 0 Long Beach CA 

5,315 3.1 2.6 0 1.9 1.8 0 Los Angeles CA 

5,495 1.6 1.5 0 0.9 0.8 0 Santa Clarita CA 

5,538 2.2 1.7 0 0.9 0.8 0 Lancaster CA 

6,208 1.7 1.7 0 1 1 0 San Rafael CA 
 

 

CARBON MONOXIDE 223 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

7,224 4.5 3.9 0 3.4 3.3 0 Ukiah CA 

3,282 1.5 1.4 0 1 0.9 0 Willits CA 

7,177 2.2 1.6 0 0.9 0.8 0 Salinas CA 

6,255 3.2 3.1 0 1.8 1.6 0 Napa CA 

5,560 3.3 3 0 2.4 2.1 0 Anaheim CA 

5,571 3 2.8 0 2 2 0 Costa Mesa CA 

5,524 1.5 1.5 0 1.1 1 0 Mission Viejo CA 

5,567 4.7 4.6 0 2.5 2.4 0 La Habra CA 

5,605 4.7 4.5 0 1.9 1.9 0 Riverside CA 

5,574 1 0.9 0 0.5 0.5 0 Palm Springs CA 

5,546 2.7 2.5 0 1.9 1.7 0 Rubidoux CA 

(West 

Riverside) 

5,564 1.1 1.1 0 0.8 0.8 0 Lake Elsinore CA 

6,390 2.3 2.3 0 1.8 1.8 0 North CA 

Highlands 

7,292 2.9 2.7 0 2.5 1.8 0 Sacramento CA 

8,036 3.1 3.1 0 2.8 2.4 0 Sacramento CA 

4,812 2.7 2.5 0 1.8 1.7 0 Sacramento CA 

5,519 1.4 1.3 0 1.2 1.1 0 Barstow CA 

5,587 1.4 1.4 0 0.9 0.9 0 Victorville CA 

5,491 2.1 1.9 0 1.4 1.2 0 Upland CA 

1,388 1.3 1.1 0 0.8 0.8 0 Fontana CA 

5,556 2.2 2.1 0 1.4 1.4 0 San CA 

Bernardino 

6,212 2 2 0 1.5 1.5 0 Chula Vista CA 

706 2.4 2.2 0 1.8 1.5 0 San Diego CA 

6,006 4.6 4 0 2.8 2.5 0 Escondido CA 

6,130 3.1 3.1 0 2.5 2.5 0 San Diego CA 

5,119 4.3 3.9 0 2.7 2.5 0 Otay Mesa CA 

6,247 2.1 1.9 0 1.5 1.4 0 San Francisco CA 

5,546 2.6 2.5 0 1.6 1.6 0 Stockton CA 

6,214 4.3 3.8 0 1.9 1.8 0 Redwood City CA 

4,811 5.2 3.4 0 1.2 1.2 0 Santa Barbara CA 

5,462 1.5 1.5 0 0.8 0.8 0 Santa Maria CA 

6,182 3.5 2.5 0 1.7 0.9 0 Capitan CA 

6,190 3.1 3.1 0 2.4 1.7 0 Welby CO 

6,505 3.5 3.3 0 2.7 2.4 0 Longmont CO 
 

 

CARBON MONOXIDE 224 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measure- maximum maximum exceeding maximum maximum exceeding 

ments (ppmv) (ppmv) average (ppmv) (ppmv) average City Statea 

6,507 3.4 3.2 0 2.3 2.2 0 Greeley CO 

6,481 2.2 2.1 0 1.4 1.3 0 Grand Junction CO 

6,487 5.1 4.6 0 3 2.2 0 Fort Collins CO 

4,249 0.8 0.8 0 0.7 0.7 0 Not provided CO 

6,420 4 3.5 0 2.6 2.3 0 Colorado CO 

Springs 

6,203 7.1 7 0 3.1 2.3 0 Denver CO 

6,488 4.8 4.5 0 2.4 1.9 0 Denver CO 

6,499 6 5.9 0 3.7 3.1 0 Hartford CT 

6,319 1.6 1.6 0 1.4 1.1 0 Westport CT 

6,305 3.3 3.2 0 2.2 2 0 Bridgeport CT 

6,491 1.2 1.1 0 0.9 0.9 0 Thomaston CT 

6,511 1.8 1.6 0 1.3 1.2 0 East Hartford CT 

3,314 2.2 2.1 0 1.9 1.6 0 New Haven CT 

6,525 6 4 0 2.6 1.8 0 Washington DC 

6,513 3 2.7 0 2.6 2.1 0 Washington DC 

7,030 1.4 1 0 0.9 0.8 0 Not provided DE 

7,171 2 2 0 1.3 1.1 0 Wilmington DE 

6,500 2.1 2 0 1.6 1.6 0 Fort FL 

Lauderdale 

6,513 1.6 1.5 0 1 0.9 0 Clearwater FL 

6,499 2.4 2.1 0 1.6 1.5 0 Hollywood FL 

6,269 8.7 6.2 0 3.3 2.8 0 Jacksonville FL 

6,318 2.5 2.1 0 1.4 1.2 0 Jacksonville FL 

6,250 2.3 2.2 0 1.1 1.1 0 Jacksonville FL 

6,551 2.6 2.5 0 2 1.8 0 Tampa FL 

6,511 1.2 1 0 0.5 0.4 0 Plant City FL 

6,506 2.2 2 0 1.2 1.1 0 Miami FL 

6,515 2.4 2 0 1.7 1.4 0 Not provided FL 

6,329 3.9 3.9 0 2.4 2.1 0 Miami FL 

6,550 2.8 2.6 0 2.1 1.6 0 Miami FL 

6,449 1.1 1 0 1 1 0 Winter Park FL 

2,167 1.5 1.4 0 1.1 1.1 0 Palm Beach FL 

6,280 1.5 1.4 0 1.2 1.1 0 Pompano FL 

Beach 

5,747 2.8 2.1 0 1.8 1.8 0 Decatur GA 

6,435 0.5 0.5 0 0.5 0.5 0 Not provided GA 

5,918 2.2 2.1 0 1.4 1.2 0 Atlanta GA 
 

 

CARBON MONOXIDE 225 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

6,554 2.1 1.7 0 1 1 0 Honolulu HI 

5,268 1.7 1.3 0 0.7 0.7 0 Ewa Beach HI 

2,050 1.5 1.1 0 0.7 0.6 0 Cedar Rapids IA 

5,017 1.6 1.5 0 1.3 1.2 0 Cedar Rapids IA 

7,396 1.9 1.6 0 1 1 0 Des Moines IA 

8,199 1.2 1.2 0 0.7 0.7 0 Davenport IA 

4,609 4.1 3.6 0 1.6 1.5 0 Boise ID 

7,797 2.9 2.7 0 2.3 2.2 0 East Saint IL 

Louis 

7,977 2.5 2.2 0 1.5 1.3 0 Springfield IL 

7,965 5.6 3 0 1.9 1.7 0 Rockford IL 

7,917 3.6 3.2 0 2.9 2.1 0 Peoria IL 

7,960 2.5 2.5 0 2.3 2.2 0 Maywood IL 

8,007 1.9 1.3 0 1.2 0.9 0 Northbrook IL 

7,926 2.4 2.3 0 1.7 1.5 0 Cicero IL 

7,783 2.3 2 0 1.8 1.5 0 Schiller Park IL 

7,982 7.3 4.4 0 2 1.5 0 Chicago IL 

6,380 1.9 1.7 0 1.2 1.2 0 Indianapolis IN 

(Remainder) 

5,972 2 1.8 0 1.5 1.1 0 Evansville IN 

6,538 9.1 7.1 0 3.3 3 0 East Chicago IN 

3,984 0.8 0.8 0 0.7 0.7 0 Pittsboro IN 

6,445 3.9 3.8 0 2.9 2.3 0 Fort Wayne IN 

8,710 3.6 3.5 0 3.2 2.1 0 Indianapolis IN 

6,520 2.8 2.7 0 2 1.2 0 Wichita KS 

6,394 2.7 2.4 0 1.6 1.5 0 Wichita KS 

6,389 2.2 2.2 0 1.8 1.4 0 Kansas City KS 

7,113 6.9 3.4 0 2.8 2.2 0 Louisville KY 

6,937 3.1 3.1 0 2.7 2.1 0 Louisville KY 

7,723 2.9 2.5 0 1.9 1.8 0 Baton Rouge LA 

5,769 0.9 0.7 0 0.4 0.4 0 Lynn MA 

6,586 3.4 3.4 0 3 2.5 0 Springfield MA 

6,835 3.7 3.2 0 2.6 2.1 0 Lowell MA 

6,830 1.7 1.6 0 1.3 1 0 Boston MA 

6,875 1.5 1.5 0 1.1 0.9 0 Boston MA 

6,831 2.8 2.7 0 1.7 1.3 0 Worcester MA 

6,022 2.6 2.4 0 1.6 1.5 0 Essex MD 

6,407 0.4 0.4 0 0.3 0.3 0 Not provided MD 
 

 

CARBON MONOXIDE 226 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measure- maximum maximum exceeding maximum maximum exceeding 

ments (ppmv) (ppmv) average (ppmv) (ppmv) average City Statea 

6,104 2.4 2.2 0 2.1 2 0 Baltimore MD 

6,439 1.4 1 0 0.9 0.8 0 Beltsville MD 

1,211 0.6 0.6 0 0.4 0.4 0 Presque Isle ME 

5,816 1.6 1.4 0 1.3 1 0 Portland ME 

6,351 0.4 0.4 0 0.4 0.3 0 Not provided ME 

4,569 2 1.6 0 1.2 1.1 0 Allen Park MI 

4,218 2 1.8 0 1.1 1 0 Grand Rapids MI 

7,278 2 2 0 0.8 0.7 0 Minneapolis MN 

7,262 0.5 0.5 0 0.3 0.3 0 Inver Grove MN 

Heights 

5,712 0.6 0.6 0 0.4 0.3 0 Rosemount MN 

2,169 1.8 1.5 0 1.2 1.2 0 Fridley MN 

7,022 3.2 3.1 0 2.4 2.4 0 St. Paul MN 

6,975 1.8 1.7 0 1.2 1.2 0 St. Cloud MN 

7,122 4.1 2.2 0 1.8 1.5 0 Duluth MN 

6,533 1.1 1 0 0.7 0.7 0 Sunset Hills MO 

6,536 1.9 1.8 0 1.2 1 0 Springfield MO 

6,528 3.3 2.9 0 2.2 1.6 0 St. Louis MO 

6,469 2.4 2.1 0 1.8 1.4 0 St. Louis MO 

2,083 3.4 3.4 0 2.9 2.7 0 Missoula MT 

2,104 2 1.9 0 0.7 0.7 0 Not provided MT 

6,916 6.7 5.7 0 2.4 2.2 0 West MT 

Yellowstone 

1,542 6.1 4.2 0 1.6 1.1 0 Not provided MT 

7,130 4.8 3.7 0 2.3 2 0 Billings MT 

7,244 7.7 3 0 1.8 1.5 0 Great Falls MT 

5,578 7.2 3.4 0 2.4 1.9 0 Kalispell MT 

2,819 1.5 1.5 0 1.3 1.1 0 Not provided NC 

7,811 1.9 1.8 0 1.5 1.4 0 Charlotte NC 

3,664 3.5 3.1 0 2.2 2.2 0 Raleigh NC 

7,081 4 2.8 0 2.4 1.8 0 Raleigh NC 

7,384 1.6 1.5 0 0.9 0.7 0 Rockwell NC 

2,044 2.2 2.2 0 1.7 1.7 0 Fayetteville NC 

7,927 2.3 2.1 0 1.9 1.6 0 Charlotte NC 

1,985 1.9 1.9 0 1.6 1.5 0 Greensboro NC 

6,531 2.7 2.5 0 2.3 1.9 0 Winston-Salem NC 

2,754 1.9 1.9 0 1.5 1.2 0 Durham NC 

7,930 6.5 1.7 0 1.2 0.7 0 Not provided ND 
 

 

CARBON MONOXIDE 227 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

6,365 3.1 2.9 0 2.5 2 0 Omaha NE 

7,252 6.5 4.5 0 1.8 1.8 0 Lincoln NE 

6,464 9.4 6 0 4.4 3.5 0 Manchester NH 

6,285 1.5 1.4 0 1.1 1.1 0 Fort Lee NJ 

2,188 1.8 1.6 0 1.1 1 0 Elizabeth NJ 

6,544 2.3 1.9 0 1.5 1.3 0 Morristown NJ 

6,508 3.4 3.4 0 2 1.6 0 Freehold NJ 

6,373 2.2 2.1 0 1.2 1.2 0 Camden NJ 

6,522 1 0.9 0 0.7 0.6 0 Not provided NJ 

6,498 2.1 2.1 0 1.7 1.5 0 Jersey City NJ 

6,318 2 1.6 0 1.2 0.9 0 Perth Amboy NJ 

6,484 2.2 2.2 0 1.8 1.6 0 Hackensack NJ 

6,326 3.7 2.7 0 1.8 1.4 0 Burlington NJ 

3,065 3.6 2.8 0 1.8 1.5 0 Albuquerque NM 

6,140 2.6 2.2 0 1.7 1.1 0 Albuquerque NM 

3,130 2.6 2.5 0 1.8 1.7 0 Albuquerque NM 

5,792 6.5 3 0 2.4 2.3 0 Albuquerque NM 

3,057 4.9 3.7 0 1.6 1.3 0 Albuquerque NM 

806 2.4 2.4 0 1.9 1.8 0 South Valley NM 

6,377 4.2 3.9 0 2.1 2 0 Sparks NV 

6,463 2.2 1.9 0 1.5 1.5 0 Lemmon NV 

Valley-Golden 

Valley 

4,243 2.9 2.7 0 2.2 1.7 0 Carson City NV 

5,033 3.5 2.9 0 2.3 2.1 0 Las Vegas NV 

6,217 5.1 4.7 0 4.2 3.7 0 Las Vegas NV 

6,275 4.1 3.9 0 3.1 2.8 0 Las Vegas NV 

6,190 3.2 2.9 0 2.1 2.1 0 Las Vegas NV 

6,271 4.2 3.6 0 2.5 2.4 0 Las Vegas NV 

6,178 5.8 5.3 0 2.6 2.4 0 Stateline NV 

6,476 2.1 2.1 0 1.5 1.5 0 Reno NV 

6,515 1.8 1.7 0 1.3 1.3 0 Reno NV 

6,400 3 2.9 0 2.3 2.2 0 Reno NV 

6,512 1.8 1.7 0 0.8 0.8 0 Reno NV 

6,466 1.8 1.8 0 1.2 0.9 0 Holtsville NY 

7,922 3 2.7 0 1.8 1.8 0 Schenectady NY 

7,445 8.6 2.3 0 1.7 1.6 0 New York NY 

7,956 2 1.9 0 1.7 1.4 0 Syracuse NY 
 

 

CARBON MONOXIDE 228 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measure- maximum maximum exceeding maximum maximum exceeding 

ments (ppmv) (ppmv) average (ppmv) (ppmv) average City Statea 

7,957 1.4 1.3 0 1.2 1 0 Niagara Falls NY 

7,769 1.5 1.2 0 1 0.9 0 Albany NY 

4,245 1.6 1.5 0 1.2 1.2 0 New York NY 

7,429 1.3 1.2 0 1.1 1 0 Rochester NY 

5,757 1.3 1 0 0.7 0.7 0 Tonawanda NY 

7,452 1.6 1.6 0 1.1 1 0 Buffalo NY 

7,962 2.3 2.1 0 1.8 1.7 0 New York NY 

3,419 1.7 1.6 0 1.3 1.2 0 New York NY 

6,967 4.8 4.8 0 2.1 1.5 0 Cleveland OH 

7,023 7.8 6.3 0 3.3 2.4 0 Cleveland OH 

6,948 2 1.5 0 0.9 0.8 0 Akron OH 

7,003 1.7 1.6 0 1.3 1.1 0 Akron OH 

6,158 2.9 2.9 0 2.6 2.5 0 Canton OH 

8,739 2.3 2.3 0 1.6 1.5 0 Dayton OH 

8,720 1.5 1.4 0 1.1 1 0 Dayton OH 

7,259 2.6 2.6 0 2.6 2.3 0 Mentor OH 

6,358 5.9 5.1 0 3.6 2.7 0 Cincinnati OH 

7,183 2.7 2.3 0 1.6 1.4 0 Columbus OH 

7,232 2 1.8 0 1.5 1.3 0 Cleveland OH 

7,252 2 2 0 1.2 1.2 0 Cleveland OH 

7,752 2.5 2.1 0 1.1 1.1 0 Oklahoma City OK 

1,382 0.4 0.4 0 0.3 0.3 0 Cherry Tree OK 

3,185 1.7 0.5 0 0.4 0.3 0 Park Hill OK 

4,625 1.7 0.3 0 0.5 0.3 0 Not provided OK 

2,278 1.7 1.6 0 1.4 1.3 0 Tulsa OK 

7,991 2.1 1.9 0 1.3 1.2 0 Tulsa OK 

5,933 2.7 2.6 0 2.3 2.2 0 Portland OR 

6,541 2.7 2.7 0 1.8 1.6 0 Portland OR 

6,437 3.4 3.4 0 2.6 2.2 0 Medford OR 

6,530 2.2 2.1 0 1.7 1.6 0 Eugene OR 

5,023 0.8 0.8 0 0.5 0.4 0 Not provided PA 

7,048 1.9 1.8 0 1.6 1.5 0 Pittsburgh PA 

7,243 2 2 0 1.3 1.2 0 York PA 

7,211 1.4 1 0 0.8 0.5 0 Greensburg PA 

6,517 1.6 1.6 0 1.3 1.1 0 Pittsburgh PA 

6,523 2.3 2.1 0 1.7 1.4 0 Pittsburgh PA 

7,054 2.6 2 0 1.6 1.3 0 Beaver Falls PA 
 

 

CARBON MONOXIDE 229 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

7,197 1.5 1.3 0 0.9 0.9 0 Not provided PA 

7,206 1.4 1.2 0 0.8 0.7 0 Altoona PA 

7,009 4.3 2.9 0 2 1.9 0 Bristol PA 

7,215 1.7 1.4 0 1.2 1.1 0 Johnstown PA 

7,174 1.4 1.4 0 1.1 1.1 0 Harrisburg PA 

7,152 2.8 1.6 0 1 1 0 Erie PA 

4,958 0.5 0.5 0 0.3 0.3 0 Not provided PA 

7,212 1.8 1.4 0 1.2 1 0 Scranton PA 

6,694 2.6 1.9 0 1.6 1.4 0 Lancaster PA 

7,162 1.2 1.2 0 0.7 0.7 0 New Castle PA 

7,200 2.6 2.4 0 1.9 1.5 0 Wilkes-Barre PA 

7,306 1.1 1.1 0 0.8 0.8 0 Norristown PA 

7,308 2.1 2 0 1.6 1.6 0 Freemansburg PA 

6,160 3.7 2.7 0 1.7 1.3 0 Philadelphia PA 

1,764 1.3 1.1 0 0.7 0.7 0 Philadelphia PA 

7,094 1.3 1.2 0 1.2 1.1 0 Charleroi PA 

3,795 4.2 2.8 0 2.3 2.3 0 Bayamon PR 

5,854 3.8 3.7 0 2.4 2.3 0 San Juan PR 

6,421 3.9 3.3 0 1.7 1.4 0 San Juan PR 

6,420 1.5 1.4 0 1 0.9 0 East RI 

Providence 

8,714 2.3 2 0 1.4 1.3 0 Greenville SC 

8,561 0.9 0.8 0 0.5 0.5 0 Not provided SC 

8,747 3.2 3.2 0 2.4 1.9 0 Nashville TN 

6,248 1.7 1.5 0 1 1 0 Kingsport TN 

8,514 3.2 2.5 0 1.5 1.4 0 Memphis TN 

6,824 1.6 1.5 0 0.8 0.7 0 Brownsville TX 

5,201 1.7 1.7 0 1.4 1.3 0 Dallas TX 

7,170 7 6.1 0 4.9 3.2 0 El Paso TX 

6,895 2.9 2.7 0 1.5 1.5 0 El Paso TX 

7,198 5 4.8 0 3 1.8 0 El Paso TX 

6,712 7.3 6 0 4.2 2.4 0 El Paso TX 

7,202 6.7 6.6 0 4.8 3.9 0 El Paso TX 

6,985 4.3 4 0 3 2.8 0 El Paso TX 

7,040 3.5 3.4 0 1.7 1.7 0 Laredo TX 

7,176 2.5 2.1 0 1.4 1.3 0 El Paso TX 

6,875 2.9 2.7 0 1.7 1.5 0 Not provided TX 

6,310 3.8 3.7 0 2.7 2.3 0 Houston TX 
 

 

CARBON MONOXIDE 230 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

6,258 2.1 1.9 0 1.6 1.3 0 Houston TX 

6,322 8.9 8.1 0 5.9 5.2 0 Houston TX 

5,662 1.4 1.4 0 1 0.8 0 Houston TX 

6,863 1.7 1.5 0 0.9 0.6 0 Deer Park TX 

5,594 1.8 1.7 0 1 0.7 0 Nederland TX 

7,105 0.8 0.3 0 0.3 0.3 0 Waco TX 

7,080 1.7 1.7 0 1.1 1 0 Fort Worth TX 

7,205 1.8 1.4 0 1 0.9 0 Arlington TX 

7,241 0.7 0.6 0 0.4 0.4 0 Austin TX 

6,942 3.2 2.9 0 1.4 1.3 0 Laredo TX 

6,154 0.9 0.9 0 0.5 0.5 0 Not provided TX 

6,309 2.5 2.4 0 1.9 1.4 0 San Antonio TX 

7,199 7.8 4.7 0 2.7 2.6 0 San Antonio TX 

7,235 3.2 2.9 0 1.6 1.6 0 Socorro TX 

6,469 3 2.9 0 2.2 2.1 0 Not provided UT 

6,297 4.1 3.6 0 2.4 2.3 0 Salt Lake City UT 

5,776 27.9 24.2 0 8.8 6.4 0 Ogden UT 

6,333 5 3.9 0 1.6 1.5 0 Provo UT 

5,744 3.3 3.3 0 2 2 0 Ogden UT 

2,125 3.7 3.3 0 1.8 1.8 0 West Valley UT 

5,996 1.1 1 0 0.9 0.8 0 Annandale VA 

6,479 1.3 1.2 0 1 0.8 0 Richmond VA 

6,469 1.7 1.6 0 1.2 1.1 0 Not provided VA 

7,175 1.4 1.4 0 1.2 1 0 Not provided VA 

7,133 1.9 1.9 0 1.9 1.8 0 Franconia VA 

6,489 2 2 0 1.5 1.4 0 Roanoke VA 

7,097 2 2 0 1.5 1.5 0 Mclean VA 

6,365 1.9 1.9 0 1.2 1.2 0 Alexandria VA 

6,439 4.2 4.1 0 1.6 1.3 0 Hampton VA 

6,487 4.7 4.5 0 2.2 1.9 0 Norfolk VA 

6,218 3.1 2.7 0 2.1 1.8 0 Rutland VT 

6,194 1.9 1.8 0 1.2 1.1 0 Burlington VT 

7,232 3.4 3.1 0 2.3 1.9 0 Bellevue WA 

5,468 0.3 0.3 0 0.3 0.3 0 Not provided WA 

6,885 1.4 1.2 0 0.9 0.9 0 Seattle WA 

7,140 4.3 4.1 0 2.4 2.4 0 Spokane WA 

7,674 0.5 0.5 0 0.4 0.4 0 Not provided WI 
 

 

CARBON MONOXIDE 231 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1-Hour and 8-Hour Maximum Carbon Monoxide Levels at Monitoring 

Stations Throughout the United States
	

1-Hour carbon monoxide level 8-Hour carbon monoxide level 

Number of First Second Number First Second Number 

measurements 

maximum 

(ppmv) 

maximum 

(ppmv) 

exceeding 

average 

maximum 

(ppmv) 

maximum 

(ppmv) City 

exceeding 

average Statea 

6,541 3.9 3.5 0 2.3 2.2 0 Weirton WV 

6,532 2.7 2.7 0 1.8 1.7 0 Weirton WV 

6,449 4.5 4.3 0 2.9 2.3 0 Weirton WV 

6,984 0.9 0.8 0 0.6 0.4 0 Not provided WY 

6,361 0.9 0.9 0 0.7 0.7 0 Not provided WY 

a

Post office state abbreviations are used. 

Source: EPA 2009i 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 232 

6. POTENTIAL FOR HUMAN EXPOSURE 

and no measurements exceeded the 1-hour average level of 35 ppm at the 365 different monitoring sites. 

Using data from this nationwide network of monitoring sites, EPA estimated that there has been a 75% 

decrease in the ambient levels of carbon monoxide in the United States from 1980 to 2006 (EPA 2008). 

The EPA Integrated Science Assessment (ISA) on carbon monoxide (2010), used monitoring data from 

2005 to 2007 at 12 remote locations in the United States to estimate policy-relevant background (PRB) 

concentrations of carbon monoxide. These concentrations are defined as levels that would be expected to 

occur in the United States in the absence of anthropogenic emissions in continental North America. 

These remote-site baseline measurements were obtained from The National Oceanic and Atmospheric 

Administration’s (NOAA) Earth System Research Laboratory (ESRL), Global Monitoring Division 

(GMD). The 3-year average carbon monoxide PRBs at remote locations outside the continental United 

States (OCONUS) were 0.13 ppmv (Alaska sites) and 0.0992 ppmv (Hawaii sites). Over the continental 

United States (CONUS) region, the 3-year average carbon monoxide PRB concentration was 0.132 ppmv 

(EPA 2010). The seasonal variability of carbon monoxide levels was observed at each monitoring 

location with minima achieved during the summer and fall months and maxima observed during the 

winter and spring seasons. 

Urban areas with heavy vehicular traffic congestion tend to have high levels of carbon monoxide in 

ambient air. These levels follow a predictable diurnal pattern, which reaches maximum concentrations at 

times of heavy commuting and then decreases during periods of low vehicular traffic. The apex of these 

profiles corresponds to the morning and evening rush hour commutes when vehicle density is at its 

highest. For many locations, the morning peak yields higher carbon monoxide levels than the evening 

peak, because the height of the mixed layer is much lower during the morning, thereby inhibiting vertical 

mixing that helps dissipate the carbon monoxide. In the late afternoon and into early evening, increased 

atmospheric turbulence resulting from solar activity raises the height of the mixed layer, resulting in 

generally lower carbon monoxide concentrations compared with those of the morning (EPA 2000). A 

study conducted by the Toronto (Canada) Public Health Department examined the level of carbon 

monoxide at four sites in Toronto as a function of traffic density (Campbell et al. 1995). The four areas of 

the study were categorized as low, medium, or high in terms of traffic density. Mean hourly carbon 

monoxide levels ranged from 0.63 ppmv at a low traffic density site (average daily vehicle count of 

2,000 vehicles) to 1.54 ppmv at a site in which the vehicular count was about 45,000 per day (Campbell et 

al. 1995). Chen et al. (2008) measured carbon monoxide levels at 10 roadside pollution monitoring sites 

in the city of Leicester, England. A diurnal carbon monoxide concentration pattern was observed in this 

study; however, the carbon monoxide levels during the evening rush hour period generally exceeded the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 233 

6. POTENTIAL FOR HUMAN EXPOSURE 

levels than the morning commute. Maximum carbon monoxide levels at these sites ranged from 0.8 to 

3.1 ppmv during the morning commute, while maximum levels were 1.0–4.0 ppmv during the evening 

rush hour (Chen et al. 2008). 

High levels of carbon monoxide inside vehicles and other transportation sources that use gasoline 

powered engines are frequently observed. Duci et al. (2003) studied the concentration of carbon 

monoxide in vehicles along heavy traffic routes in Athens, Greece. The mean carbon monoxide exposure 

level for trips greater than 30 minutes in duration were 21.4 ppmv for private car versus 10.4, 9.6, 4, and 

11.5 ppmv for bus, trolley, electric train, and pedestrians, respectively, during the winter season (Duci et 

al. 2003). Besides the mode of transportation, the route travelled, the monitoring period, and the season 

of year had significant influences on the measured carbon monoxide concentrations. In-vehicle carbon 

monoxide levels were monitored in a passenger vehicle driven along a heavily traveled route of a 

commercial/residential area of Beirut, Lebanon under several ventilation modes (Abi Esper et al. 2007a). 

Trips were conducted during morning rush hours in spring and summer months. The highest mean 

carbon monoxide levels were observed within vehicles driven with the windows and vents closed 

(37.4 ppmv) and windows closed and air conditioning on recirculation ventilation settings (30.8 ppmv) 

(Abi Esper et al. 2007a). Opening a window or setting the air conditioning unit to fresh air intake 

generally resulted in a reduction of carbon monoxide levels within the vehicle. 

Indoor air levels of carbon monoxide are greatly dependent upon the presence of indoor combustion 

sources such as wood burning stoves, fireplaces, gas space heaters, and gas stoves, as well as the 

operating condition and usage patterns of these appliances or whether the occupants smoke. Dutton et al. 

(2001) studied carbon monoxide levels in two residences located in Boulder, Colorado using unvented 

natural gas fireplaces. Time-averaged carbon monoxide levels were1.5–78 ppmv at one residence and 

1.6–30 ppmv at the other residence while the fireplace operated uninterrupted; however, levels >100 ppm 

were observed at one of the residences on several occasions. Background carbon monoxide levels were 

0–7 ppmv in the homes when the fireplaces were not operating. Attached garages may also be a 

significant source of carbon monoxide to the indoor air of residences. The net increase of carbon 

monoxide levels in 16 homes with attached garages ranged from <1 to 30 ppmv following the cold start 

of an automobile enclosed within the attached garage (Graham et al. 2004). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 234 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.2 Water 

The levels of carbon monoxide in the surface waters of the world’s oceans are supersaturated with respect 

to the partial pressure of carbon monoxide in the atmosphere and are subject to diurnal cycling. Levels 

have been reported to vary from 2x10-8 to 1.3x10-7 cm3

 carbon monoxide per cm3 of water (20–130 

nanoliters per liter [nL/L]) based on measurements in the Pacific Ocean and from 2x10-8 to 1x10-7 cm3 

carbon monoxide per cm3 of water (20–100 nL/L) in the North Atlantic (Liss and Slater 1974). Carbon 

monoxide concentrations in seawater measured in the upwelling region of the equatorial Pacific Ocean 

were reported to range from 42 to 173 nL/L on two consecutive sampling dates and reached a maximum 

value of 246 nL/L on subsequent sampling at a later date (Ohta 1997). These levels showed a marked 

diurnal variation with a maximum and minimum occurring early in the afternoon and morning, 

respectively. The concentrations in the water column decreased as a function of depth from the water 

surface to approximately 10 nL/L at a depth of 70 meters. Tolli et al. (2006) reported a carbon monoxide 

level of 12 nanomoles/L at a coastal sampling location in Vineyard Sound, Massachusetts. 

6.4.3 Sediment and Soil 

In-situ soil-gas carbon monoxide levels were studied in a pine forest soil and cultivated soil as a function 

of depth from the surface (King 1999b). In the pine forest soil, the carbon monoxide concentrations 

remained elevated (250–320 ppbv) and greater than the atmospheric levels through the upper surface soil 

(O-horizon, 0–2 cm depth), but declined to values less than the atmospheric level in the lower depths of 

the soil (A-horizon 2–10 cm depth). In the cultivated soil, carbon monoxide levels decreased rapidly 

from approximately 250 ppbv in the upper 1 cm of the O-horizon to approximately 50 ppbv at a depth of 

3 cm, which was roughly 5-fold less than ambient atmospheric levels. 

6.4.4 Other Environmental Media 

Carbon monoxide is released from tobacco smoke; however, the amount released is a function of the type 

of tobacco product (e.g., cigarette, cigar) and the degree to which tobacco is actively smoked. Moir et al. 

(2008) examined the emissions of carbon monoxide and other compounds under two smoking conditions 

from marijuana and tobacco cigarettes using a mechanical rotary smoking machine. The standard 

conditions employed a puff volume of 35 mL, puff duration of 2 seconds, and a puff interval of 

60 seconds. Conditions more consistent with marijuana smoking employed a puff volume of 70 mL, puff 

duration of 2 seconds, and a 30-second interval between puffs. These conditions were referred to as 

extreme conditions. Under standard conditions, the average±standard deviation (SD) emission of carbon 
 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 235 

6. POTENTIAL FOR HUMAN EXPOSURE 

monoxide in mainstream smoke (n=20) was 20.8±1.9 mg carbon monoxide per tobacco cigarette and 

13.4±1.6 mg carbon monoxide per marijuana cigarette. Under extreme smoking conditions, the levels 

were 41.5±4.0 mg carbon monoxide per tobacco cigarette and 35.3±2.9 mg carbon monoxide per 

marijuana cigarette. These results predict that typical use of marijuana (70 mL puff volume) would result 

in more carbon monoxide being inhaled than during typical cigarette smoking (30 mL puff volume). The 

carbon monoxide emissions in sidestream smoke were 61.7±2.0 and 54.0±3.7 mg carbon monoxide per 

tobacco cigarette and marijuana cigarette, respectively, using the standard conditions. Under extreme 

smoking conditions, the levels were 61.6±2.9 and 50.6±3.9 mg carbon monoxide per cigarette for tobacco 

and marijuana cigarettes, respectively. 

Emissions from plants and biomass burning are reported to contribute approximately 1x1014 g/year to the 

global environment (Khalil and Rasmussen 1990). The direct emission of carbon monoxide from living 

plants increases as a function of solar irradiance. The source of the carbon monoxide likely occurs as a 

result of direct photooxidation of the plant material followed by transport to the stomata; however, the 

exact mechanism is not fully understood (Sanderson 2002). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is exposed to carbon monoxide through the inhalation of indoor and outdoor air. 

Since carbon monoxide is ubiquitous in the environment, all humans are exposed to some level of carbon 

monoxide. The CDC estimated that during 2004–2006, an estimated average of 20,636 emergency room 

visits occurred for nonfatal, unintentional, non-fire-related carbon monoxide exposures annually (CDC 

2008). Approximately 73% of these exposures occurred in residences, 13% occurred in workplace 

settings, and the rest were in other or unknown settings. The greatest number of incidences 

(8,538 incidences representing approximately 41% of the cases) occurred during the winter months of 

December through February. Nearly 70% of the incidences were diagnosed as carbon monoxide 

poisoning. Table 6-3 displays the estimated number of exposure cases categorized by age and gender. 

Weather-related disasters in which large segments of the population have lost power for extended periods 

of time often result in carbon monoxide-related accidents through the improper use of gasoline-powered 

devices. Two major hurricanes struck the Gulf Coast of the United States in 2005 (hurricanes Katrina and 

Rita) resulting in sustained power outages for many residents of the affected states. Multiple carbon 

monoxide poisonings were reported over the period of disrupted power, primarily due to the use of 

improperly vented generators (CDC 2006). Twenty-seven separate incidents of carbon monoxide 
 

 

CARBON MONOXIDE 236 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Average Annual Estimated Non-Fatal Carbon Monoxide Exposure
	

Cases in the United States Emergency Room Visits (2004–2006)
	

Age (years) Number of casesa Percentage of the total 

0–4 2,344 11.4 

5–9 1,407 6.8 

10–14 1,577 7.6 

15–24 3,341 16.2 

25–34 4,183 20.3 

35–44 2,775 13.5 

45–54 2,229 10.8 

55–64 1,444 7.0 

≥65 1,328 6.4 

Gender 

Male 9,770 47.3 

Female 10,866 52.7 

a

Age data were unavailable for eight cases. 

Source: CDC 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 237 

6. POTENTIAL FOR HUMAN EXPOSURE 

poisoning were reported during the dates of August 29–October 19, 2005, in Texas and Alabama, 

resulting in 78 nonfatal cases and 10 deaths. A portable generator was involved in 25 (93%) of the 

27 incidents. Regarding the other two incidents, one involved a fixed generator and one involved a 

portable gas stove (CDC 2006). 

Recreational water craft are a source of accidental carbon monoxide exposures (USCG 2008). A study 

conducted by the National Institute for Occupational Safety and Health (NIOSH) confirmed 176 acute 

boating-related carbon monoxide poisonings over a 15-year period at a lake on the Arizona/Utah border 

(CDC 2005). The findings of this study indicated that occupancy near carbon monoxide sources, failed 

carbon monoxide detectors, water level exhaust from generators on houseboats or cabin cruisers, and 

carbon monoxide from generators or propulsion engines within the airspace formed by an extended rear 

houseboat deck contributed to these accidents (CDC 2005). 

NIOSH (1996) issued a report describing carbon monoxide poisonings that occurred through the use of 

small gasoline-powered engines and tools such as pressure washers, gas-powered saws, and compressors. 

In many cases, dangerous levels of carbon monoxide built up rapidly when using these tools, even in 

relatively open spaces with some ventilation like parking garages or open barns. 

Blood carboxyhemoglobin (COHb) levels were measured on a cross-sectional national probability sample 

of persons representative of the civilian population in the United States aged 3–74 years in the second 

National Health and Nutrition Examination Survey (NHANES II) conducted from February 1976 to 

February 1980 (Radford and Drizd 1982). The statistical analysis of COHb levels in blood of the 

population based on smoking status and age is provided in Table 6-4. Four principal inhalation exposure 

routes were examined (outdoor air, indoor air, occupational exposure, and smoking). Of these four 

exposure routes, it was concluded that COHb levels in the population were most influenced by smoking 

status. Close examination of the data also indicated that COHb levels in the population tended to be 

greater during the winter months as opposed to the summer months, presumably due to the amount of 

time spent indoors where carbon monoxide levels are assumed to be higher than outdoor air. A slightly 

higher proportion of ex-smokers had COHb levels over 2% versus people who never smoked (5.5% 

versus 3.6%). This accounts for the higher mean and standard deviation for ex-smokers than for neversmokers, because the two medians are nearly identical (0.77% COHb versus 0.74% COHb, respectively). 

This difference may be accounted for in part or wholly by the inclusion in the ex-smoking group of 

people who incorrectly reported a history of having stopped smoking (Radford and Drizd 1982). 
 

 

 

 

CARBON MONOXIDE 238 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Carboxyhemoglobin (COHb) Levels in the U.S. Population Based Upon 

Smoking Status
	

Mean 

Age 

(years) N2a N3b 

COHb 

percent 

Standard 

deviation 

Standard 

error 

50th 

percentile 

75th 

percentile 

90th 

percentile 

95th 

percentile 

All smoking status 

3–74 9,365 195,877 1.93 2.236 0.037 0.91 2.38 5.49 6.83 

3–11 2,055 30,066 0.73 0.502 0.019 0.67 0.87 1.12 1.42 

12–74 7,310 165,812 2.14 2.358 0.044 1.01 3.17 5.79 7.05 

Never smokedc 

3–74 5,459 106,042 0.83 0.671 0.021 0.72 0.97 1.33 1.65 

3–11 2,055 30,066 0.73 0.502 0.019 0.67 0.87 1.12 1.42 

12–74 3,404 75,976 0.87 0.726 0.025 0.74 1.01 1.38 1.77 

Ex-smokersc 

12–74 1,366 28,655 0.97 0.999 0.031 0.77 1.04 1.58 2.08 

Current smokersc 

12–74 2,533 61.015 4.30 2.533 0.072 4.15 5.89 7.56 8.68 

a

N2 = unweighted population size b

N3 = population estimate in thousands c

Never-smokers were defined as persons who self-reported that they had smoked fewer than 100 cigarettes in their 

lifetimes and were not current smokers. Ex-smokers were persons who reported that they had smoked more than 

100 cigarettes but were not current smokers. Current smokers were persons reporting that they were current 

cigarette, cigar, or pipe smokers. 

Source: Radford and Drizd 1982 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 239 

6. POTENTIAL FOR HUMAN EXPOSURE 

Additional studies have shown that COHb levels do not differ in ex-smokers versus those who never 

smoked (Yasuda et al. 2004). 

Carbon monoxide exposure to European populations residing in five cities have been investigated through 

the EXPOLIS research project conducted from 1996 to 1998, and the results of this study have been 

summarized in several publications (Bruinen de Bruin et al. 2004a, 2004b; Hanninen et al. 2004). The 

geometric mean 48-hour exposure levels of nonsmoking subjects were 1.68, 0.82, 0.45, 2.17, and 

1.50 mg/m3

 (1.45, 0.71, 0.39, 1.87, and 1.29 ppmv) in Athens, Basle, Helsinki, Milan, and Prague, 

respectively (Hanninen et al. 2004). Bruinen de Bruin et al. (2004a) used data for 50 office workers 

residing in Milan, Italy over a 1-year period to assess the contribution of local sources to exposure and 

microenvironment concentrations. This study examined the time that the subjects spent in 11 different 

microenvironments and three exposure-influencing activities: gas cooking, smoking, and commuting. 

The results of this study indicated that exposures from indoor environments contributed approximately 

82% of the total carbon monoxide exposures, because this is where the study population spent over 90% 

of their time; however, approximately 16% of the total exposure to carbon monoxide occurred from 

commuting activities, even though these activities only accounted for about 7.5% of the population’s 

time. 

Occupations such as toll both workers, gas station attendants, taxi drivers, and traffic or bicycle police are 

potentially exposed to high levels of carbon monoxide due to emissions from automobile exhaust. 

Carbon monoxide levels were monitored continuously during both morning (9 AM–12 PM) and afternoon 

(2–4 PM) hours at seven gas stations located in New York, New Jersey, and Connecticut (API 1994). 

Mean (arithmetic) concentrations of carbon monoxide at the pumping islands ranged from 1.15 to 

5.44 ppmv, with a maximum 1-minute level of 144 ppmv observed at one station. Firefighters and 

rescue/response personnel are potentially exposed to carbon monoxide levels near or exceeding 

recommended occupational exposure limits. A study conducted from 1986 to 1989 in northern California 

was performed to estimate the level of carbon monoxide that wildland firefighters are exposed to during 

various job tasks associated with that profession (Materna et al. 1992). Following a series of prescribed 

burns, the instantaneous fireline carbon monoxide levels ranged from 3 to 80 ppmv; however, firefighters 

who tended gasoline powered pumping engines were exposed to levels as high as 300 ppmv. The mean 

time-weighted average (TWA) exposure level obtained from 46 personal measurements was 14.4 ppmv, 

but one employee had a TWA exposure of 38 ppmv and five firefighters had TWAs >25 ppmv. Industrial 

or in-home use of methylene chloride paint strippers in poorly ventilated areas can lead to high levels of 

carbon monoxide in blood, since carbon monoxide is a metabolic byproduct of methylene chloride. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 240 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

As with adults, children are exposed to carbon monoxide through the inhalation of indoor and outdoor air. 

The NHANES II survey (see Table 6-4) includes COHb levels of children. Several activities may 

influence the levels of carbon monoxide to which children or infants are exposed. Time spent indoors 

versus outdoors, riding in automobiles, and exposure to second-hand tobacco smoke influence the total 

carbon monoxide exposure that children receive. COHb levels in children were significantly greater 

when measured during the winter months of November–March, as opposed to levels obtained in May– 

September. The average COHb level for all children in the NHANES study aged 3–11 years was 0.87% 

for samples collected during the winter months and 0.58% during the summer months. The location 

where the children in the population resided also influenced the COHb levels observed in the study. 

Children residing in central cities with populations over 1 million tended to have the highest mean COHb 

levels (1.01% in winter months and 0.77% in summer months), while children living in rural areas had 

mean COHb levels of 0.79% in the winter months and 0.49% during the summer months (Radford and 

Drizd 1982). 

Pregnant females who smoke potentially expose their unborn fetus to carbon monoxide, and the health 

consequences of this activity have been discussed in Chapter 3. Carbon monoxide crosses the placenta 

and can accumulate in the fetus to a greater extent than in the mother. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 241 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Populations that are exposed to high levels of vehicular traffic are expected to have greater exposure to 

carbon monoxide, as compared to individuals in low traffic density areas. As discussed in Section 6.5, 

certain occupations such as toll workers, gas station attendants, firefighters, and other professions exposed 

to combustion sources may have high levels of exposure. 

Members of the general population who smoke or live with smokers are exposed to higher levels of 

carbon monoxide than nonsmoking members of the general population. COHb levels typically average 

about 5% in regular smokers, but may be as high as 10% in heavy smokers (Benowitz 2003). Data from 

the NHANES II study indicate that mean COHb levels in the blood of smokers are approximately 4 times 

greater than levels for members of the nonsmoking population (Radford and Drizd 1982). More recent 

data support these conclusions. In a study of 11,403 men aged 35–64 years, the mean COHb level for 

nonsmokers was 0.79%, but rose to 6.54% for those who smoked >40 cigarettes/day (Law et al. 1997). 

COHb levels were measured as part of pulmonary function testing in 100 subjects in one pulmonary 

laboratory located in a Virginia hospital outpatient setting (Mahoney et al. 2007). COHb levels for the 

entire group averaged 1.9%, with a range of 1–8%. The average COHb level for nonsmokers (n=85) was 

1.6%, while the level for smokers (n=15) was 3.5%. COHb levels were measured for smokers versus 

nonsmokers at four commercial establishments where cigarette smoking was not prohibited and COHb 

levels were also obtained in a control group of 50 college students and professors in a well-ventilated, 

nonsmoking environment (Light et al. 2007). The average COHb concentration of 33 smokers from the 

commercial establishments was 5.04%, while the average value for the 27 nonsmokers was 2.49%. 

COHb levels ranged from 1 to 6% in the nonsmokers and from 1 to 14% in the smoking group. The 

COHb levels in the control group were 1%. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5)(A) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with 

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of carbon monoxide is available. Where adequate information 

is not available, ATSDR, in conjunction with National Institute of Environmental Health Sciences 

(NIEHS), is required to assure the initiation of a program of research designed to determine the health 

effects (and techniques for developing methods to determine such health effects) of carbon monoxide. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 242 

6. POTENTIAL FOR HUMAN EXPOSURE 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. Information is available on the physical and chemical 

properties of carbon monoxide (George 2001; Lide 2008; O’Neil et al. 2006; Verschueren 2001). These 

data are captured in Chapter 4. No data needs are identified. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2007, became available in February of 2009. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. Adequate information on the production 

and use of carbon monoxide was located (George 2001); no information on the import/export of carbon 

monoxide was found, but these volumes are assumed to be low. Since carbon monoxide is not required to 

be reported under the TRI, the production and emissions from U.S. industrial facilities is not reported to 

the EPA. The EPA continuously updates the NEI database, which contains detailed information about 

sources that emit carbon monoxide. No data needs are identified. 

Environmental Fate. The environmental fate of carbon monoxide is well understood. When released 

to the atmosphere, carbon monoxide eventually reacts with photochemically produced hydroxyl radicals 

and is oxidized to CO2 (EPA 2000, 2010). Microorganisms have also been shown to oxidize carbon 

monoxide to CO2 (Tolli et al. 2006). Data on the half-life of carbon monoxide in indoor environments 

would be desirable. 

Bioavailability from Environmental Media. Carbon monoxide is a gas and is not considered 

bioavailable from environmental media other than air. No data needs are identified. 

Food Chain Bioaccumulation. Carbon monoxide is a gas and does not bioaccumulate in the food 

chain. No data needs are identified. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 243 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of carbon 

monoxide in contaminated media at hazardous waste sites are needed so that the information obtained on 

levels of carbon monoxide in the environment can be used in combination with the known body burden of 

carbon monoxide to assess the potential risk of adverse health effects in populations living in the vicinity 

of hazardous waste sites. 

The EPA continuously monitors carbon monoxide levels throughout the United States. The EPA's NEI 

database contains detailed information about sources that emit criteria air pollutants, including carbon 

monoxide for the 50 United States, Washington DC, Puerto Rico, and the U.S. Virgin Islands. The AQS 

database is EPA's repository of criteria air pollutant monitoring data since the 1970s. These databases are 

updated regularly. 

Exposure Levels in Humans. All humans are exposed to carbon monoxide through the inhalation 

of ambient air. Indoor air levels of carbon monoxide are highly variable and depend upon the type, 

condition, and venting procedures of appliances. The NHANES II survey, conducted from February 1976 

to February 1980, provided an analysis of COHb levels in blood of the population based on smoking 

status, age, race, and other factors (Radford and Drizd 1982). These data are not current; therefore, a data 

need exists to update these data with new monitoring results. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are exposed to carbon monoxide by the same pathway as adults 

(inhalation of air). While the levels of COHb in children’s blood from the NHANES II study is 

comprehensive, these surveys are over 2 decades old. Therefore, a data need exists to update this study 

with new monitoring results. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for carbon monoxide were located. This substance is 

not currently one of the compounds for which a sub-registry has been established in the National 

Exposure Registry. The substance will be considered in the future when chemical selection is made for 

sub-registries to be established. The information that is amassed in the National Exposure Registry 
 

 

 

 

 

 

 

 

CARBON MONOXIDE 244 

6. POTENTIAL FOR HUMAN EXPOSURE 

facilitates the epidemiological research needed to assess adverse health outcomes that may be related to 

exposure to this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2009) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. A study 

being conducted by Ohio State University (Ross Kauffman, principal investigator) seeks to study tobacco 

use in two Ohio prisons. One objective of this study is to examine the influence of an indoor tobacco ban 

on smoking behaviors among low-security prisoners. A second objective is to provide prison 

administrators with the information needed to develop successful policies by gathering information on 

prisoner attitudes toward tobacco control policies and cessation programs in correctional settings. The 

study is also intended to lay the groundwork for future studies of tobacco use in prison facilities. It is 

anticipated that this study will address COHb levels in the prison facilities. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 245 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring carbon monoxide, its metabolites, and other biomarkers of exposure and 

effect to carbon monoxide. The intent is not to provide an exhaustive list of analytical methods. Rather, 

the intention is to identify well-established methods that are used as the standard methods of analysis. 

Many of the analytical methods used for environmental samples are the methods approved by federal 

agencies and organizations such as EPA and the National Institute for Occupational Safety and Health 

(NIOSH). Other methods presented in this chapter are those that are approved by groups such as the 

Association of Official Analytical Chemists (AOAC) and the American Public Health Association 

(APHA). Additionally, analytical methods are included that modify previously used methods to obtain 

lower detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Carbon monoxide forms a strong coordination bond with the iron atom complex of Hb forming COHb, 

which is a unique biomarker for carbon monoxide exposure for humans. COHb absorbs radiation in the 

blue wavelength region of the visible spectrum known as the Soret region (390–440 nm) and COHb 

levels in blood can be analyzed spectrophotometrically (Rodkey et al. 1979). Carbon monoxideoximeters are specialized medical instruments that are employed in clinical and hospital settings to 

rapidly determine COHb, O2Hb, and methemoglobin (MetHb) levels in blood by taking the difference 

between the light absorption at each of these Hb derivatives and the total light absorption for all Hb 

derivatives that are present in the blood sample (Mahoney et al. 1993). This instrument is particularly 

useful for measuring high levels of COHb. Fetal Hb and bilirubin have the potential to interfere with 

spectrophotometric determination of COHb if present in sufficient quantities. Methylene blue cardiac dye 

and sulfhemoglobin can also adversely affect these measurements. In addition, some carbon monoxideoximeters have been shown to overestimate low concentrations of COHb as compared to gas 

chromatography (GC) methods (Mahoney et al. 1993). 

GC with reduction gas detectors is a selective and sensitive method to measure the amount of carbon 

monoxide bound to Hb in the blood and is considered a highly reliable method for measuring exposure to 

carbon monoxide, especially at low levels. The addition of potassium ferricyanide to Hb-bound carbon 

monoxide oxidizes Hb to MetHb and releases carbon monoxide, which is injected in the gas 

chromatograph (Vreman et al. 1984). Carbon monoxide eluted from the GC column reacts with mercuric 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 246 

7. ANALYTICAL METHODS 

oxide (HgO) to form gaseous mercury vapor; the mercury released and measured spectrophotometrically 

at 254 nm is proportional to the amount of carbon monoxide gas released. The detection limits for this 

method were reported as 0.05 nL of carbon monoxide per μL of blood, corresponding to a saturation of 

approximately 0.005% COHb in blood (Vreman et al. 1984). 

Carbon monoxide levels in humans can be estimated by the analysis of exhaled breath using GC and 

electrochemical devices. In many measurement techniques, the subject performs an inhalation-breathhold 

maneuver and exhales through a mouthpiece into the instrument inlet. The alveolar air is retained for 

analysis, and the reading in ppm of carbon monoxide can be converted to COHb using a calibration curve 

(EPA 2000). A rapid and sensitive technique for the analysis of carbon monoxide in a single exhaled 

breath sample has been described (Fritsch et al. 2007). This analysis requires the subject to exhale into a 

mouthpiece that is attached to a Nafion® dryer and cooling trap to remove water, CO2, and other possible 

interfering species. Detection is by high resolution infrared cavity ring-down laser spectroscopy in a 

multipath absorption cell. Amperometric electrochemical sensors have also been used for the analysis of 

carbon monoxide in exhaled breath and ambient air (Vreman et al. 1994). These sensors typically consist 

of a series of electrodes (working, reference, and counter electrodes) immersed in an electrolyte solution. 

Carbon monoxide diffuses through a porous Teflon membrane and is oxidized at the working electrode. 

The transfer of electrons that accompanies the redox reaction yields the output signal of the sensor. A 

reference electrode measures the potential of the electrolyte. The current flowing through the working 

electrode is compensated by the third electrode, a counterelectrode through which an equal and opposite 

current flows (Vreman et al. 1994). 

The analytical methods used for the detection of carbon monoxide in biological samples are summarized 

in Table 7-1. 

7.2 ENVIRONMENTAL SAMPLES 

Analytical methods for the detection of carbon monoxide in environmental samples have been thoroughly 

discussed in several review articles (EPA 1991, 2000; Novelli 1999). Table 7-2 provides a summary of 

many of these analytical methods that are commonly employed in environmental monitoring studies of 

carbon monoxide. Analytical methods used to measure carbon monoxide in environmental samples 

require the use of high purity standard reference gas in order to frequently calibrate the instrument and 

ensure consistent measurements between different laboratories. 
 

 

 

 

 

CARBON MONOXIDE 247 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Carbon Monoxide in Biological
	

Samples
	

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Blood Collect sample and 

transfer to a 5 mL 

heparinized syringe and 

shake for 1 minute before 

analysis. 

Spectrophotometric 

determination 

using COoximeters 

<5% COHb Mahoney et al. 

1993 

Blood Blood placed into 2 mL 

CO-free GC vial 

containing 100 g/L 

K3Fe(CN)6 in 0.1 mol/L 

potassium phosphate 

buffer, pH 6.0, containing 

10 g of saponin/L. 

GC with mercury 

reduction gas 

detector 

0.005% COHb Mahoney et al. 

1993 

Blood Obtain blood by heel stick 

(infant) or fingerstick 

(adult) and venipuncture. 

Mix with K3Fe(CN)6 

containing solution to 

liberate carbon monoxide 

GC with mercury 

reduction gas 

detector 

0.005% COHb Vreman et al. 

1984 

to a headspace. 

Breath Breath samples collected 

with a reverse syringe 

pump and analyzed within 

30 minutes or kept on ice 

until analysis within 

3 hours. 

EC sensor or GC 

with mercury 

reduction gas 

detector 

EC: 0.1 μL

carbon 

monoxide/L air 

GC: 50% of the 

noise level of 

0.01 μL carbon 

Vreman et al. 

1994 

monoxide/L air 

COHb = carboxyhemoglobin; EC = electrochemical; GC = gas chromatography; K3Fe(CN)6 = potassium ferricyanide 
 

 

 

 

CARBON MONOXIDE 248 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Carbon Monoxide in 

Environmental Samples
	

Sample 

Sample 

matrix Preparation methoda 

Analytical 

method 

detection 

limitb 

Percent 

recovery Reference 

Air Atmospheric constituents GC-FID 25–50 ppbv NR Novelli 1999 

separated using twocolumn isothermic 

chromatography in a 

GC-HgO/UV 

GC-ECD 

GC-FID 

10 ppb GCECD 

temperature-controlled 

oven, followed by analysis 

using FID, HgO/UV 

1–2 ppb GCHgO/UV 

absorbance, or ECD. 

Air Air samples passed NDIR-GFC 22–70 ppbv NR Novelli 1999 

through reference and 

measurement optical 

cells. An optical filter is 

used to transmit only a 

small band width of 

infrared radiation. 

Air Air samples introduced FTIR 1 ppbv NR Novelli 1999 

into commercial 

instruments over a wide 

spectral bandwidth or the 

use of optical filters can 

be employed to narrow 

the spectral wavelength. 

Air Tune laser to 4.7 μm and TDLS <1 ppbv NR Novelli 1999 

measure absorption by 

carbon monoxide gas. 

Air Measure in fluorescence RF 5 ppbv NR Novelli 1999 

chambers operated at low 

pressure to avoid O2 

absorption. 

Workplace Each sample collected by GC-DID 0.12 ppmv; OSHA 1991 (Method 

air drawing a known volume (0.400 ppmv 210) 

of air into a five-layer quantitative) 

aluminized gas sampling 

bag. A portion of the gas 

sample is introduced into 

a gas sampling loop, 

injected into a gas 

chromatograph, and 

analyzed using a 

discharge ionization 

detector. 
 

 

 

 

 

 

CARBON MONOXIDE 249 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Carbon Monoxide in 

Environmental Samples
	

Sample 

matrix Preparation methoda 

Analytical 

method 

Sample 

detection 

limitb 

Percent 

recovery Reference 

Sea water Water samples siphoned 

into a glass stopcock and 

a portion of the water 

replaced with carbon 

monoxide free synthetic 

air to create a headspace. 

The flask was shaken 

GC-FID 6 nL of carbon 

monoxide/L of 

water 

Ohta 1997 

vigorously by hand for 

1 minute and kept 

standing at room 

temperature for 5 minutes 

in the dark. 

Soil gas Samples collected using a 

1-cm3 syringe fitted with a 

50-mm-long 26-gauge 

side port needle. A 1-cm3 

sample was obtained 

(sampling time, about 

60 seconds); the syringe 

was then raised, and its 

GC-HgO/UV <5 ppbv NR King 1999b 

contents were rapidly 

analyzed in the field by 

using GC. 

a

Hydrogen-rich carrier gas is used to reduce carbon monoxide to methane prior to analysis by FID and N2O is added 

to a nitrogen rich carrier gas for analysis by ECD. Helium gas is used as the carrier gas for analysis by DID. b

Measurements of atmospheric carbon monoxide levels are relative to high purity reference gas used to calibrate the 

instruments. 

DID = discharge ionization detector; ECD = electron capture detector; FID = flame ionization detector; GC = gas 

chromatography; FTIR = Fourier transform spectroscopy; GFC = gas filter correlation; HgO = mercuric oxide; 

NDIR = non-dispersive infrared; NR = not reported; RF = resonance fluorescence; TDLS = tunable diode laser 

spectroscopy; UV = ultraviolet 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 250 

7. ANALYTICAL METHODS 

Most techniques used for the measurement of carbon monoxide in the environment employ spectroscopic 

methods or GC. Non-dispersive infrared (NDIR) spectroscopy and GC using flame ionization detection 

(FID) are the two most common methods used to analyze carbon monoxide in environmental samples. 

Commercial instruments are capable of detection limits in the ppb range. For analysis by NDIR 

spectroscopy, air is pumped into samples cells and the absorption is measured at a carbon monoxide 

vibrational band at 2,174 cm-1 (4.7 μm). An optical filter is employed before the sample to remove light 

of other frequencies. Most NDIR spectrometers use gas filter correlation (GFC) methodology to improve 

sensitivity and reduce interferences by other gasses. In this method, the sample is simultaneously passed 

through both a reference cell containing a high concentration of carbon monoxide and a sample cell 

containing nitrogen gas. Gas species other than carbon monoxide will attenuate radiation equally in both 

cells; however, when carbon monoxide is present, the amount of light passing through the reference cell is 

unchanged, but that passing through the sample cell is absorbed at the characteristic carbon monoxide 

frequency. This difference in absorption between the light passing through the cells is linearly related to 

carbon monoxide concentrations in the air sample (EPA 2000). 

In GC analysis of carbon monoxide, air samples are pumped through a silica gel or alumina pre-column 

followed by an analytical column composed of a molecular sieve. The pre-column captures CO2, nonmethane hydrocarbons, and water, and the molecular sieve effectively separates carbon monoxide from 

hydrogen gas and methane. Since the sensitivity for carbon monoxide by FID is low, a hydrogen-rich 

carrier gas is used to reduce carbon monoxide to methane using heated nickel as a catalyst prior to FID 

analysis. Minimum detection limits of 0.05 ppmv or better have been achieved (Novelli 1999). With the 

development of the discharge ionization detector (DID) for use with GC analysis, it is possible to measure 

carbon monoxide concentrations directly at low levels in occupational settings (OSHA 1991). Helium is 

generally used as the sample carrier gas and as the ionized species. Helium passes through a chamber 

where a glow discharge is generated and high-energy photons are produced. The high-energy photons 

pass through an aperture to a second chamber and ionize the carbon monoxide in the sample stream. The 

resulting ions produce an electrical current, which is measured with a standard electrometer (OSHA 

1991). The greater the concentration of carbon monoxide in the sample, the more ions will be produced, 

resulting in a greater current. OSHA method 210 discusses the GC-DID analysis for carbon monoxide 

and reports a detection limit of 0.12 ppmv and quantification limit of 0.40 ppmv. 

As discussed in Novelli (1999), electron capture detection (ECD) can also be used in conjunction with 

GC to measure atmospheric levels of carbon monoxide. Carbon monoxide does not elicit a strong 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 251 

7. ANALYTICAL METHODS 

response from the ECD because it does not easily capture electrons; however, the addition of N2O to a 

N2 carrier gas improves sensitivity. In addition, GC/mass spectrometry, GC with mercury reduction gas 

detection, Fourier transform infrared (FTIR) spectroscopy, tunable diode laser spectroscopy (TDLS), and 

resonance fluorescence spectroscopy have also been used to measure carbon monoxide levels in air 

(Novelli 1999). 

Commercially available electrochemical carbon monoxide detectors for home use can be purchased at 

most hardware or home improvement stores. These detectors use electrodes that reside in an electrolyte 

solution such as dilute sulfuric acid. Carbon monoxide is oxidized at one electrode to CO2 and O2 is 

consumed at the other electrode (Vreman et al. 1994). Measurement of the current in the cell provides a 

measure of the concentration of carbon monoxide in the atmosphere. Metal oxide semiconductor 

detectors such as tin oxide sensors operate on the principle that the resistance of a tin oxide layer 

decreases as carbon monoxide adsorbs to the surface of the sensor and is oxidized to CO2 (Dobos and 

Zimmer 1985). When the conductance exceeds a preset threshold level, an 85 dB alarm is sounded (the 

same loudness as a smoke alarm). Biomimetic detectors use a gel-coated disc containing synthetic Hb 

that turns black when carbon monoxide is present at high levels. Reduction in the amount of transmitted 

light through the disc alerts the sensor to possible carbon monoxide contamination and sets off the alarm. 

Early carbon monoxide detectors were designed to provide an audible warning at relatively low levels of 

exposure and were often difficult to reset (Leikin 1996). Furthermore, the general public’s knowledge 

regarding the use and placement of these alarms in the residence was limited. Recent changes to the 

design and standards of these alarms have made them more user friendly to the general population and 

helped to eliminate low-level activations, which can be caused by a variety of common occurrences. The 

use and effectiveness of these home-based alarms, including guideline standards from Underwriters 

Laboratory, have been reviewed by Rhee and Leikin (2007). 

Ohta (1997) discussed a GC-FID method for the detection of carbon monoxide in seawater. Water 

samples were collected in a glass stopcock and a portion of the water was replaced with carbon monoxide 

free synthetic air to create a headspace. The flask was shaken vigorously by hand for 1 minute and kept 

standing at room temperature for 5 minutes in the absence of sunlight in order to complete the 

equilibration between aqueous and gaseous phases. A small portion of air (1–2 mL) was injected into the 

GC for analysis. Carbon monoxide concentrations were corrected based on equilibrium constants of 

carbon monoxide between the aqueous and gaseous phases in the flask for headspace preparation. The 

concentrations were further corrected for water vapor contained in the headspace gas at concentrations of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 252 

7. ANALYTICAL METHODS 

3.8–4.1% in volume at 26–27 °C. The detection limit was reported as 6 nanoliters of carbon monoxide 

per liter of water. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of carbon monoxide is available. Where adequate information 

is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of 

research designed to determine the health effects (and techniques for developing methods to determine 

such health effects) of carbon monoxide. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. COHb is a unique biomarker of exposure for humans to carbon monoxide and accurate, 

sensitive methods exist for its measurement (Mahoney et al. 1993). GC methods are also available for 

measuring Hb-bound carbon monoxide (Vreman et al. 1984). 

Effect. No specific biomarkers of effect for carbon monoxide were identified. Effects and symptoms of 

carbon monoxide poisoning are generally related to tissue hypoxia and are not specific for carbon 

monoxide exposure. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Sensitive analytical methods are available for determining the levels of carbon monoxide in air 

samples. Thorough reviews on this subject are available from the EPA (1991, 2000) and Novelli (1999). 

Analytical methods are also available for the determination of carbon monoxide in water samples (Ohta 

1997). 
 

 

 

 

 

 

CARBON MONOXIDE 253 

7. ANALYTICAL METHODS 

7.3.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2009) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified. Platypus Technologies LLC 

located in Madison, Wisconsin is developing a liquid crystal-based sensor for real-time detection of 

ozone, carbon monoxide, and CO2. Kestrel Labs Inc. located in Boulder, Colorado is developing a new 

carbon monoxide-oximeter that can use laser light sources for accurate photoplethysmographic 

measurements of COHb. 
 

CARBON MONOXIDE 254 

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CARBON MONOXIDE 255 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
	

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

MRLs were not derived for carbon monoxide, as discussed in Section 2.3. 

EPA (IRIS 2009) has not established an oral reference dose (RfD) or an inhalation reference 

concentration (RfC) for carbon monoxide. 

The International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and 

EPA have not classified carbon monoxide for human carcinogenicity (IARC 2009; IRIS 2009; NTP 

2005). 

OSHA has required employers of workers who are occupationally exposed to carbon monoxide to 

institute engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2009). The employer must use engineering and work practice 

controls to reduce exposures to not exceed 55 mg/m3

 (50 ppmv) for carbon monoxide at any time (OSHA 

2009). 

EPA has designated carbon monoxide as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) 

(EPA 2009c). Additionally, under the National Ambient Air Quality Standards (NAAQS), EPA is 

required to set limits to protect public health, including the health of "sensitive" populations, such as 

asthmatics, children, and the elderly. Carbon monoxide is required to not to exceed levels of 10 and 

40 mg/m3

 (9 and 35 ppmv) for 8- and 1-hour averaging times, respectively, and not to be exceeded more 

than once per year (EPA 2009d). 

The international and national regulations, advisories, and guidelines regarding carbon monoxide in air, 

water, and other media are summarized in Table 8-1. 
 

 

 

 

 

 

 

CARBON MONOXIDE 256 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Carbon 

Monoxide 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2009 

WHO Air quality guidelines WHO 2000 

TWA based on effects other than 

cancer or odor/annoyance using 

an averaging time of: 

15 minutes 100 mg/m3

 (87 ppm) 

30 minutes 60 mg/m3

 (52 ppm) 

1 hour 30 mg/m3

 (26 ppm) 

8 hours 10 mg/m3

 (9 ppm) 

Drinking water quality guidelines No data WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 29 mg/m3

 (25 ppm) ACGIH 2008 

TLV-basis (critical effect) Carboxyhemoglobinemia

 AIHA ERPG-1a

 229 mg/m3 (200 ppm) AIHA 2008

 ERPG-2a

 401 mg/m3 (350 ppm) 

ERPG-3a

 573 mg/m3 (500 ppm) 

EPA AEGL-1b Not recommended due to EPA 2009b 

insufficient data 

AEGL-2b 

10 minutes 481 mg/m3

 (420 ppm) 

30 minutes 172 mg/m3

 (150 ppm) 

60 minutes 95 mg/m3

 (83 ppm) 

4 hours 38 mg/m3

 (33 ppm) 

8 hours 31 mg/m3

 (27 ppm)

 AEGL-3b 

10 minutes 1,948 mg/m3

 (1,700 ppm) 

30 minutes 687 mg/m3

 (600 ppm) 

60 minutes 378 mg/m3

 (330 ppm) 

4 hours 172 mg/m3

 (150 ppm) 

8 hours 149 mg/m3

 (130 ppm) 

Hazardous air pollutant No EPA 2009c 

42 USC 7412 
 

 

 

 

 

CARBON MONOXIDE 257 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Carbon 

Monoxide 

Agency Description Information Reference 

NATIONAL (cont.)

National Ambient Air Quality 

Standards 

 EPA 2009d 

NIOSH 

8-hour averaging timec

1-hour averaging timec

REL (10-hour TWA) 

Ceiling 

IDLH 

 10 mg/m3 (9 ppm) 

 40 mg/m3

 (35 ppm) 

40 mg/m3

 (35 ppm) 

229 mg/m3

 (200 ppm) 

1,375 mg/m3

 (1,200 ppm) 

NIOSH 2005

 OSHA 

 Target organs 

PEL (8-hour TWA) for general 

industry 

Cardiovascular system, 

lungs, blood, and central 

nervous system 

55 mg/m3

 (50 ppm) OSHA 2009 

29 CFR 1910.1000, 

Table Z-1 

b. Water 

EPA Drinking water standards and health 

advisories 

No EPA 2006a 

National primary drinking water 

standards 

No EPA 2003 

National recommended water quality 

criteria 

No EPA 2006b 

c. Food

 FDA EAFUSd

 No FDA 2008 

d. Other 

ACGIH Carcinogenicity classification No ACGIH 2008 

Biological exposure indices (end of 

shift) 

Carboxyhemoglobin in blood 

Carbon monoxide in end-exhaled 

air 

3.5% hemoglobin 

23 mg/m3

 (20 ppm) 

EPA Carcinogenicity classification No IRIS 2009 

RfC No

 RfD No 

Superfund, emergency planning, 

and community right-to-know 
 

 

 

 

CARBON MONOXIDE 258 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Carbon 

Monoxide 

Agency Description Information Reference 

NATIONAL (cont.)

Designated CERCLA hazardous 

substance 

No EPA 2009e 

40 CFR 302.4 

Effective date of toxic chemical 

release reporting 

No EPA 2009f 

40 CFR 372.65 

NTP Carcinogenicity classification No NTP 2005 

a

ERPG-1 is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour 

without experiencing other than mild, transient health effects. ERPG-2 is the maximum airborne concentration below
 

which nearly all individuals could be exposed for up to 1 hour without experiencing irreversible or other serious 

adverse effects. ERPG-3 is the maximum airborne concentration below which nearly all individuals could be exposed 

for up to 1 hour without life-threatening health effects (AIHA 2008). b

AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population, 

including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory
 

effects; however, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 

is the airborne concentration of a substance above which it is predicted that the general population, including 

susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an 

impaired ability to escape. AEGL-3 is the airborne concentration of a substance above which it is predicted that the 

general population, including susceptible individuals, could experience life-threatening health effects or death (EPA 

2009b).
 c

Not to be exceeded more than once per year. 

d

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, 

Compensation, and Liability Act; CFR = Code of Federal Regulations; EAFUS = Everything Added to Food in the 

United States; EPA = Environmental Protection Agency; ERPG = emergency response planning guidelines; 

FDA = Food and Drug Administration; GRAS = Generally Recognized As Safe; IARC = International Agency for 

Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; 

NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values; 

TWA = time-weighted average; USC = United States Code; WHO = World Health Organization
 
 

 

 

 

 

 

_______________________ 

 

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CARBON MONOXIDE 303 

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Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 304 

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Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 305 

10. GLOSSARY 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 306 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 307 

10. GLOSSARY 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE 308 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 
 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Human Health Sciences (proposed), expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the 

public. They are subject to change as new information becomes available concomitant with updating the 

toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously 

published levels. For additional information regarding MRLs, please contact the Division of Toxicology 

and Human Health Sciences (proposed), Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop F-62, Atlanta, Georgia 30333. 

MRLs were not derived for carbon monoxide, as discussed in Section 2.3. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1. What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE B-4 

APPENDIX B 

(9)		 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)		 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)		 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)		 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)		 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)		 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)		 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)		 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)		 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
 

 

 

 

 

CARBON MONOXIDE B-5 

APPENDIX B 

(18)		 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)		 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
1 2 3 4 12 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalatio

→→

Exposure frequency/ 

Species duration 

Key to figurea INTERMEDIATE EXPOSURE 

↓6 

↓

5 

Systemic 

System ↓7 

NOAEL (ppm) ↓8 

LOAEL (effect) Less serious (ppm) 

↓

9 

Serious (ppm) 

Re

↓

10 

→→

Nit

CHRONIC EXPOSURE 

WoNTNT

(CEL, multiple organs) (CEL, lung tumors, nasal tumors) (CEL, lung tumors, hemangiosarcomas) 

10 (hyperplasia) 

11 ↓20 10 10 

3b 13 wk Resp 

5 d/wk 6 hr/d 18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

Rat Rat Rat Mouse 

18 Cancer 38 39 40 a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent exby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

CARBON MONOXIDE B-8 

APPENDIX B 

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CARBON MONOXIDE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 
 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CARBON MONOXIDE C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
 

 

CARBON MONOXIDE C-5 

APPENDIX C 

> greater than 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
CARBON MONOXIDE C-6 

APPENDIX C 

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CARBON MONOXIDE D-1 

APPENDIX D. INDEX 

absorbed dose............................................................................................................................................ 188 

active transport............................................................................................................................................ 96 

adipose tissue ...................................................................................................................................... 12, 145
	

adrenal gland............................................................................................................................................. 184 

adsorption.................................................................................................................................................. 211 

aerobic........................................................................................................................................... 64, 96, 220
	

ambient air ..................................... 12, 15, 16, 18, 19, 25, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 49, 50, 54, 

71, 80, 88, 92, 93, 95, 98, 104, 105, 106, 117, 118, 120, 121, 122, 

123, 124, 139, 150, 154, 179, 186, 192, 196, 199, 232, 243, 246
	

anaerobic................................................................................................................................................... 220 

anemia....................................................................................................................................... 149, 190, 193
	

biomarker ............................ 13, 15, 19, 20, 92, 93, 94, 95, 97, 187, 188, 196, 199, 200, 201, 202, 245, 252
	

breast milk................................................................................................................................................. 240 

cancer.................................................................................................................. 36, 139, 185, 199, 201, 256
	

carboxyhemoglobin (see COHb) ........................................ 10, 102, 103, 160, 163, 164, 168, 171, 237, 247
	

carcinogenic .............................................................................................................................................. 199 

carcinogenicity.................................................................................................................. 139, 196, 199, 255
	

cardiac arrhythmia ........................................ 14, 15, 16, 22, 31, 34, 54, 64, 70, 71, 72, 79, 90, 91, 189, 192
	

cardiovascular ...................................... 10, 14, 15, 16, 20, 23, 31, 34, 36, 37, 53, 54, 55, 64, 70, 71, 72, 89, 

90, 99, 101, 177, 182, 188, 189, 191, 192, 196, 198, 199, 201
	

cardiovascular effects.................................................. 15, 16, 23, 53, 54, 70, 71, 90, 91, 192, 198, 199, 201
	

CFK model............................................ 13, 16, 17, 18, 20, 23, 30, 34, 35, 71, 141, 156, 158, 159, 162, 173
	

clearance ................................................................................................................................................... 194 

cognitive function ..................................................................................................................................... 201 

COHb (see carboxyhemoglobin) ............... 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 29, 30, 

31, 34, 35, 39, 52, 53, 54, 55, 64, 70, 71, 72, 80, 90, 91, 92, 

95, 96, 97, 99, 100, 101, 102, 103, 104, 124, 136, 138, 141, 

143, 145, 147, 148, 149, 150, 152, 154, 155, 156, 158, 159, 

160, 161, 162, 163, 164, 165, 168, 169, 171, 173, 174, 176, 

182, 185, 188, 189, 192, 194, 195, 196, 198, 201, 202, 203, 

237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 252, 253 

COMb ......................................................................................................... 12, 145, 149, 152, 169, 173, 202
	

death............................................................................ 14, 16, 22, 34, 36, 104, 105, 123, 124, 186, 199, 258
	

deoxyribonucleic acid (see DNA)..................................................................................................... 139, 140
	

dermal effects.............................................................................................................................................. 97 

developmental effects ......................................... 16, 17, 23, 91, 98, 105, 124, 136, 186, 199, 200, 201, 203 

DNA (see deoxyribonucleic acid)..................................................................................... 139, 140, 187, 199
	

dopamine................................................................................................................................................... 137 

elimination half-time........................................................................................... 13, 154, 169, 173, 188, 201
	

elimination rate ......................................................................................................................... 155, 188, 195
	

endocrine..................................................................................................................................... 97, 183, 184
	

endocrine effects ......................................................................................................................................... 97 

endogenous production ....................................................... 11, 12, 23, 31, 32, 145, 148, 154, 165, 179, 202
	

fetal tissue ................................................................................................................... 12, 147, 165, 168, 185
	

fetus............................................................... 15, 31, 147, 148, 165, 169, 184, 185, 188, 193, 195, 201, 240
	

gastrointestinal effects ................................................................................................................................ 92 

general population............................................................................................... 10, 215, 235, 241, 251, 258
	

genotoxic................................................................................................................................................... 139 

genotoxicity....................................................................................................................................... 196, 199
	
 

CARBON MONOXIDE D-2 

APPENDIX D 

growth retardation..................................................................................................................................... 120 

Haldane coefficient ........................................................... 147, 159, 160, 161, 162, 163, 164, 166, 170, 203
	

Haldane constant............................................................................................... 143, 145, 150, 151, 152, 158 

half-life.............................................................................................................................. 154, 187, 219, 242
	

hematological effects .............................................................................. 17, 19, 92, 105, 136, 138, 186, 200
	

hepatic effects ............................................................................................................................................. 96 

hydroxyl radical ........................................................................................................................ 214, 219, 242
	

hypoxic mechanisms ....................................................... 11, 13, 20, 23, 25, 31, 32, 176, 177, 179, 202, 203
	

immune system ......................................................................................................... 17, 19, 97, 98, 138, 200
	

immunological ................................................................................................ 17, 97, 99, 105, 136, 186, 200 

immunological effects........................................................................................... 17, 97, 105, 136, 186, 200
	

Kow ............................................................................................................................................................ 209 

menstrual..................................................................................................................................... 11, 117, 148
	

micronuclei ............................................................................................................................... 139, 196, 199
	

musculoskeletal effects...............................................................................................................................95 

neonatal............................................................................... 16, 105, 106, 123, 186, 196, 199, 200, 201, 204
	

neurobehavioral................................................................................................................... 98, 184, 196, 201
	

neurodevelopmental............................................................................................................................ 17, 200
	

neurological effects............................................................................................................................. 98, 182
	

norepinephrine .......................................................................................................................................... 137 

nuclear................................................................................................................................................. 96, 181
	

ocular effects............................................................................................................................................... 97 

odds ratio............................... 25, 40, 49, 50, 51, 79, 80, 88, 89, 94, 117, 118, 119, 120, 121, 122, 123, 124
	

pharmacodynamic ..................................................................................................................................... 155 

pharmacokinetic................................................................................ 155, 156, 157, 174, 185, 188, 201, 202
	

placenta ..................................................................................................................................................... 240 

poisoning.............................................. 10, 13, 14, 18, 25, 30, 31, 35, 36, 38, 96, 97, 98, 99, 100, 104, 149, 

155, 188, 189, 190, 194, 196, 199, 202, 203, 204, 235, 237, 252
	

rate constant ...................................................................................................................................... 151, 219
	

renal effects................................................................................................................................................. 96 

reproductive effects........................................................................................................................... 104, 199
	

respiratory effects................................................................................ 18, 38, 39, 52, 53, 186, 198, 199, 201
	

retention ............................................................................................................................................ 150, 152
	

solubility ................................................................................................................................................... 209 

systemic effects........................................................................................................................................... 38 

T3.................................................................................................................. 26, 41, 56, 65, 73, 81, 107, 125 

toxicokinetic.......................................................................................................................... 13, 25, 141, 202
	

weanling.................................................................................................................................................... 136