This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation or the World Health Organization.

Environmental Health Criteria 213

(SECOND EDITION)

First draft prepared by Mr J. Raub, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization       Geneva, 1999

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO) and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Carbon monoxide.

(Environmental health criteria ; 213)

1.Carbon monoxide - adverse effects 2.Carbon monoxide - pharmacology

3.Environmental monitoring - methods 4.Environmental exposure

5.Risk factors I.International Programme on Chemical Safety II.Series

ISBN 92 4 157213 2        (NLM classification: QV 662)

ISSN 0250-863X

The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 1999

Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

ENVIRONMENTAL HEALTH CRITERIA FOR CARBON MONOXIDE

Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda.

* * *

A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 22 - 9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

Environmental Health Criteria

Objectives

In 1973, the WHO Environmental Health Criteria Programme was initiated with the following objectives:

1. to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits;
2. to identify new or potential pollutants;
3. to identify gaps in knowledge concerning the health effects of pollutants;
4. to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results.

The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976, and since that time an ever-increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth.

Since its inauguration, the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals.

The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently, the work became an integral part of the International Programme on Chemical

Safety (IPCS), a cooperative programme of UNEP, ILO and WHO. In this manner, with the strong support of the new partners, the importance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely established, used and recognized throughout the world.

The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals.

Scope

The criteria monographs are intended to provide critical reviews on the effects on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents. As such, they include and review studies that are of direct relevance for the evaluation. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered, and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are used only when relevant published data are absent or when they are pivotal to the risk assessment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organization).

In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration.

The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. These latter are the exclusive purview of national and regional governments.

Content

The layout of EHC monographs for chemicals is outlined below.

• Summary — a review of the salient facts and the risk evaluation of the chemical
• Identity — physical and chemical properties, analytical methods
• Sources of exposure
• Environmental transport, distribution, and transformation
• Environmental levels and human exposure
• Kinetics and metabolism in laboratory animals and humans
• Effects on laboratory mammals and in vitro test systems
• Effects on humans
• Effects on other organisms in the laboratory and field
• Evaluation of human health risks and effects on the environment
• Conclusions and recommendations for protection of human health and the environment
• Further research
• Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR

Selection of chemicals

Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment; the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for the environment; international concern, i.e., the substance is of major interest to several countries; adequate data on the hazards are available.

If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the cooperating organizations and all the Participating Institutions before embarking on the preparation of the monograph.

Procedures

The order of procedures that result in the publication of an EHC monograph is shown in the flow chart. A designated staff member of IPCS, responsible for the scientific quality of the document, serves as Responsible Officer (RO). The IPCS Editor is responsible for layout and language. The first draft, prepared by consultants or, more usually, staff from an IPCS Participating Institution, is based initially on data provided from the International Register of Potentially Toxic Chemicals and from reference databases such as Medline and Toxline.

The draft document, when received by the RO, may require an initial review by a small panel of experts to determine its scientific quality and objectivity. Once the RO finds the document acceptable as a first draft, it is distributed, in its unedited form, to well over 150 EHC contact points throughout the world who are asked to comment on its completeness and accuracy and, where necessary, provide additional material. The contact points, usually designated by governments, may be Participating Institutions, IPCS Focal Points or individual scientists known for their particular expertise. Generally, some four months are allowed before the comments are considered by the RO and author(s). A second draft incorporating comments received and approved by the Director, IPCS, is then distributed to Task Group members, who carry out the peer review, at least six weeks before their meeting.

The Task Group members serve as individual scientists, not as representatives of any organization, government or industry. Their function is to evaluate the accuracy, significance and relevance of the information in the document and to assess the health and environmental risks from exposure to the chemical. A summary and recommendations for further research and improved safety aspects are also required. The composition of the Task Group is dictated by the range of expertise required for the subject of the meeting and by the need for a balanced geographical distribution.

The three cooperating organizations of the IPCS recognize the important role played by nongovernmental organizations. Representatives from relevant national and international associations may be invited to join the Task Group as observers. While observers may provide a valuable contribution to the process, they can speak only at the invitation of the Chairperson. Observers do not participate in the final evaluation of the chemical; this is the sole responsibility of the Task Group members. When the Task Group considers it to be appropriate, it may meet in camera.

All individuals who as authors, consultants or advisers participate in the preparation of the EHC monograph must, in addition to serving in their personal capacity as scientists, inform the RO if at any time a conflict of interest, whether actual or potential, could be perceived in their work. They are required to sign a conflict of interest statement. Such a procedure ensures the transparency and probity of the process.

When the Task Group has completed its review and the RO is satisfied as to the scientific correctness and completeness of the document, the document then goes for language editing, reference checking and preparation of camera-ready copy. After approval by the Director, IPCS, the monograph is submitted to the WHO Office of Publications for printing. At this time, a copy of the final draft is sent to the Chairperson and Rapporteur of the Task Group to check for any errors.

It is accepted that the following criteria should initiate the updating of an EHC monograph: new data are available that would substantially change the evaluation; there is public concern for health or environmental effects of the agent because of greater exposure; an appreciable time period has elapsed since the last evaluation.

All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed.

Members

Dr M.R. Carratu, Institute of Pharmacology, Medical School, University of Bari, Policlinico, Piazza G. Cesare, I-70124 Bari, Italy

Dr Qing Chen, Beijing Medical University, School of Public Health, Beijing, People’s Republic of China

Dr G. Cotti, Agenzia Regionale per la Prevenzione e l’Ambiente dell’Emilia-Romagna (ARPA), Sezione Provinciale di Bologna, via Triachini 17, I-40138 Bologna, Italy

Dr M.J. Hazucha, UNC Center for Environmental Medicine and Lung Biology, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-7310, USA

Dr M. Jantunen, KTL Environmental Health, EXPOLIS, Mannerheiminitie 166, FIN-00300 Helsinki, Finland

Professor E. Lahmann, Schützallee 136, D-14169 Berlin 37 (Dahlem), Germany

Dr P. Lauriola, Direzione Tecnica, ARPA Emilia Romagna, Via Po 5, I-40139 Bologna, Italy

Dr M. Mathieu-Nolf, Centre Anti-Poisons, 5 avenue Oscar Lambret, F-59037 Lille Cédex, France

Dr D. Pankow, Institute of Environmental Toxicology, Martin Luther University, Franzosenweg 1a, D-06097 Halle (Saale), Germany

Professor D.G. Penney, Department of Physiology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA

Dr J.A. Raub, National Center for Environmental Assessment, US Environmental Protection Agency (MD-52), Research Triangle Park, North Carolina 27711, USA (Rapporteur)

Professor J.A. Sokal, Institute of Occupational Medicine, Koscielna 13 str., PL-41-200 Sosnowiec, Poland

Dr F.M. Sullivan, Harrington House, 8 Harrington Road, Brighton, E. Sussex, BN1 6RE, United Kingdom (Chairman)

Observers

Dr J.H. Duffus, International Union of Pure and Applied Chemistry (IUPAC), The Edinburgh Centre for Toxicology, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, United Kingdom

Professor A. Mutti, International Commission on Occupational Health (ICOH), Laboratory of Industrial Toxicology, University of Parma Medical School, Via A. Gramsci 14, I-43100 Parma, Italy

Secretariat

Dr B.H. Chen, Medical Officer, Assessment of Risk and Methodologies, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary)

Dr M. Mercier, Director, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

The Environmental Health Criteria for Carbon Monoxide (First edition) was published in 1979. Since then, a lot of new health data on carbon monoxide have emerged, and the global exposure scenario has also changed. The information presented in this edition focuses primarily on the data that have become available since the publication of the first edition.

A WHO Task Group on Environmental Health Criteria for Carbon Monoxide met in Bologna, Italy, from 26 to 30 May 1997. The meeting was organized and supported financially by the Agenzia Regionale per la Prevenzione e l’Ambiente dell’Emilia-Romagna (ARPA), Sezione Provinciale di Bologna, Italy. Dr M. Mercier, Director of the International Programme on Chemical Safety (IPCS), opened the meeting and welcomed the participants on behalf of the three IPCS cooperating organizations (UNEP/ILO/WHO). From the Secretariat, Dr B.H. Chen, IPCS, served as Secretary of the meeting. The Task Group reviewed and revised the draft criteria monograph and made an evaluation of the risks for human health from exposure to carbon monoxide, and made a recommendation on the air quality guidelines for carbon monoxide.

The first draft of this monograph was prepared by Mr J. Raub of the US Environmental Protection Agency (US EPA) in Research Triangle Park. The second draft was also prepared by Mr J. Raub, incorporating comments received following the circulation of the first draft to the IPCS Contact Points for Environmental Health Criteria monographs. Dr P. Pankow contributed to the final text of the metabolism chapter, Drs Carrat, Hazucha, and Penney contributed to the final text of the animal study chapter, and Mr Raub contributed significantly to the final text of the document.

Dr B.H. Chen, member of the IPCS Central Unit, and Ms M. Sheffer, Scientific Editor, Ottawa, Canada, were responsible for the overall scientific content and linguistic editing, respectively.

The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged.

Financial support for this Task Group meeting was provided by the Agenzia Regionale per la Prevenzione e l’Ambiente dell’Emilia Romagna (Regional Agency for Prevention and Environment of Emilia-Romagna Region, Italy).

Carbon monoxide (CO) is a colourless, odourless gas that can be poisonous to humans. It is a product of the incomplete combustion of carbon-containing fuels and is also produced by natural processes or by biotransformation of halomethanes within the human body. With external exposure to additional carbon monoxide, subtle effects can begin to occur, and exposure to higher levels can result in death. The health effects of carbon monoxide are largely the result of the formation of carboxyhaemoglobin (COHb), which impairs the oxygen carrying capacity of the blood.

Methods available for the measurement of carbon monoxide in ambient air range from fully automated methods using the non-dispersive infrared (NDIR) technique and gas chromatography to simple semiquantitative manual methods using detector tubes. Because the formation of carboxyhaemoglobin in humans is dependent on many factors, including the variability of ambient air concentrations of carbon monoxide, carboxyhaemoglobin concentration should be measured rather than calculated. Several relatively simple methods are available for determining carbon monoxide by analysis either of the blood or of alveolar air that is in equilibrium with the blood. Some of these methods have been validated by careful comparative studies.

Carbon monoxide is a trace constituent of the troposphere, produced by both natural processes and human activities. Because plants can both metabolize and produce carbon monoxide, trace levels are considered a normal constituent of the natural environment. Although ambient concentrations of carbon monoxide in the vicinity of urban and industrial areas can substantially exceed global background levels, there are no reports of these currently measured levels of carbon monoxide producing any adverse effects on plants or microorganisms. Ambient concentrations of carbon monoxide, however, can be detrimental to human health and welfare, depending on the levels that occur in areas where humans live and work and on the susceptibility of exposed individuals to potentially adverse effects.

Trends in air quality data from fixed-site monitoring stations show a general decline in carbon monoxide concentrations, which reflects the efficacy of emission control systems on newer vehicles. Highway vehicle emissions in the USA account for about 50% of total emissions; non-highway transportation sources contribute 13%. The other categories of carbon monoxide emissions are other fuel combustion sources, such as steam boilers (12%); industrial processes (8%); solid waste disposal (3%); and miscellaneous other sources (14%).

Indoor concentrations of carbon monoxide are a function of outdoor concentrations, indoor sources, infiltration, ventilation and air mixing between and within rooms. In residences without sources, average carbon monoxide concentrations are approximately equal to average outdoor levels. The highest indoor carbon monoxide concentrations are associated with combustion sources and are found in enclosed parking garages, service stations and restaurants, for example. The lowest indoor carbon monoxide concentrations are found in homes, churches and health care facilities. Exposure studies show that passive cigarette smoke is associated with increasing a non-smoker’s exposure by an average of about 1.7 mg/m³ (1.5 ppm) and that use of a gas cooking range at home is associated with an increase of about 2.9 mg/m³ (2.5 ppm). Other sources that may contribute to carbon monoxide in the home include combustion space and water heaters and coal- or wood-burning stoves.

Recent data on global trends in tropospheric carbon monoxide concentrations indicate a decrease over the last decade. Global background concentrations fall in the range of 60–140 µg/m³ (50–120 ppb). Levels are higher in the northern hemisphere than in the southern hemisphere. Average background concentrations also fluctuate seasonally. Higher levels occur in the winter months, and lower levels occur in the summer months. About 60% of the carbon monoxide found in the non-urban troposphere is attributed to human activities, both directly from combustion processes and indirectly through the oxidation of hydrocarbons and methane that, in turn, arise from agricultural activities, landfills and other similar sources. Atmospheric reactions involving carbon monoxide can produce ozone in the troposphere. Other reactions may deplete concentrations of the hydroxyl radical, a key participant in the global removal cycles of many other natural and anthropogenic trace gases, thus possibly contributing to changes in atmospheric chemistry and, ultimately, to global climate change.

During typical daily activities, people encounter carbon monoxide in a variety of microenvironments — while travelling in motor vehicles, working at their jobs, visiting urban locations associated with combustion sources, or cooking and heating with domestic gas, charcoal or wood fires — as well as in tobacco smoke. Overall, the most important carbon monoxide exposures for a majority of individuals occur in the vehicle and indoor microenvironments.

The development of small, portable electrochemical personal exposure monitors (PEMs) has made possible the measurement of carbon monoxide concentrations encountered by individuals as they move through numerous diverse indoor and outdoor microenvironments that cannot be monitored by fixed-site ambient stations. Results of both exposure monitoring in the field and modelling studies indicate that individual personal exposure determined by PEMs does not directly correlate with carbon monoxide concentrations determined by using fixed-site monitors alone. This observation is due to the mobility of people and to the spatial and temporal variability of carbon monoxide concentrations. Although they fail to show a correlation between individual personal monitor exposures and simultaneous nearest fixed-site monitor concentrations, large-scale carbon monoxide human exposure field studies do suggest that aggregate personal exposures are lower on days of lower ambient carbon monoxide levels as determined by the fixed-site monitors and higher on days of higher ambient levels. These studies point out the necessity of having personal carbon monoxide measurements to augment fixed-site ambient monitoring data when total human exposure is to be evaluated. Data from these field studies can be used to construct and test models of human exposure that account for time and activity patterns known to affect exposure to carbon monoxide.

Evaluation of human carbon monoxide exposure situations indicates that occupational exposures in some workplaces or exposures in homes with faulty or unvented combustion appliances can exceed 110 mg carbon monoxide/m³ (100 ppm), often leading to carboxyhaemoglobin levels of 10% or more with continued exposure. In contrast, such high exposure levels are encountered much less commonly by the general public exposed under ambient conditions. More frequently, exposures to less than 29–57 mg carbon monoxide/m³ (25–50 ppm) for any extended period of time occur among the general population; at the low exercise levels usually engaged in under such circumstances, the resulting carboxyhaemoglobin levels most typically remain 1–2% among non-smokers. These levels can be compared with the physiological norm for non-smokers, which is estimated to be in the range of 0.3–0.7% carboxyhaemoglobin. In smokers, however, baseline carboxyhaemoglobin concentrations average 4%, with a usual range of 3–8%, reflecting absorption of carbon monoxide from inhaled smoke.

Studies of human exposure have shown that motor vehicle exhaust is the most important source for regularly encountered elevated carbon monoxide levels. Studies indicate that the motor vehicle interior has the highest average carbon monoxide concentration (averaging 10–29 mg/m³ [9–25 ppm]) of all microenvironments. Furthermore, commuting exposures have been shown to be highly variable, with some commuters breathing carbon monoxide in excess of 40 mg/m³ (35 ppm).

The workplace is another important setting for carbon monoxide exposures. In general, apart from commuting to and from work, exposures at work exceed carbon monoxide exposures during non-work periods. Occupational and non-occupational exposures may overlay one another and result in a higher concentration of carbon monoxide in the blood. Most importantly, the nature of certain occupations carries an increased risk of high carbon monoxide exposure (e.g., those occupations involved directly with vehicle driving, maintenance and parking). Occupational groups exposed to carbon monoxide from vehicle exhaust include auto mechanics; parking garage and gas station attendants; bus, truck or taxi drivers; police; and warehouse workers. Certain industrial processes can expose workers to carbon monoxide produced directly or as a by-product; they include steel production, coke ovens, carbon black production and petroleum refining. Firefighters, cooks and construction workers may also be exposed at work to high carbon monoxide levels. Occupational exposures in industries or settings with carbon monoxide production represent some of the highest individual exposures observed in field monitoring studies.

Carbon monoxide is absorbed through the lungs, and the concentration of carboxyhaemoglobin in the blood at any time will depend on several factors. When in equilibrium with ambient air, the carboxyhaemoglobin content of the blood will depend mainly on the concentrations of inspired carbon monoxide and oxygen. However, if equilibrium has not been achieved, the carboxyhaemoglobin concentration will also depend on the duration of exposure, pulmonary ventilation and the carboxyhaemoglobin originally present before inhalation of the contaminated air. In addition to its reaction with haemoglobin, carbon monoxide combines with myoglobin, cytochromes and metalloenzymes such as cytochrome c oxidase and cytochrome P-450. The health significance of these reactions is not clearly understood but is likely to be of less importance at ambient exposure levels than that of the reaction of the gas with haemoglobin.

The exchange of carbon monoxide between the air we breathe and the human body is controlled by both physical (e.g., mass transport and diffusion) and physiological (e.g., alveolar ventilation and cardiac output) processes. Carbon monoxide is readily absorbed from the lungs into the bloodstream. The final step in this process involves competitive binding between carbon monoxide and oxygen to haemoglobin in the red blood cell, forming carboxyhaemoglobin and oxyhaemoglobin (O₂Hb), respectively. The binding of carbon monoxide to haemoglobin, producing carboxyhaemoglobin and decreasing the oxygen carrying capacity of blood, appears to be the principal mechanism of action underlying the induction of toxic effects of low-level carbon monoxide exposures. The precise mechanisms by which toxic effects are induced via carboxyhaemoglobin formation are not understood fully but likely include the induction of a hypoxic state in many tissues of diverse organ systems. Alternative or secondary mechanisms of carbon monoxide-induced toxicity (besides carboxyhaemoglobin) have been hypothesized, but none has been demonstrated to operate at relatively low (near-ambient) carbon monoxide exposure levels. Blood carboxyhaemoglobin levels, then, are currently accepted as representing a useful physiological marker by which to estimate internal carbon monoxide burdens due to the combined contribution of (1) endogenously derived carbon monoxide and (2) exogenously derived carbon monoxide resulting from exposure to external sources of carbon monoxide. Carboxyhaemoglobin levels likely to result from particular patterns (concentrations, durations, etc.) of external carbon monoxide exposure can be estimated reasonably well from the Coburn-Forster-Kane (CFK) equation.

A unique feature of carbon monoxide exposure, therefore, is that the blood carboxyhaemoglobin level represents a useful biological marker of the dose that the individual has received. The amount of carboxyhaemoglobin formed is dependent on the concentration and duration of carbon monoxide exposure, exercise (which increases the amount of air inhaled per unit time), ambient temperature, health status and the characteristic metabolism of the individual exposed. The formation of carboxyhaemoglobin is a reversible process; however, because of the tight binding of carbon monoxide to haemoglobin, the elimination half-time is quite long, ranging from 2 to 6.5 h, depending on the initial levels of carboxyhaemoglobin and the ventilation rate of the individuals. This might lead to accumulation of carboxyhaemoglobin, and even relatively low concentrations of carbon monoxide might produce substantial blood levels of carboxyhaemoglobin.

The level of carboxyhaemoglobin in the blood may be determined directly by blood analysis or indirectly by measuring carbon monoxide in exhaled breath. The measurement of exhaled breath has the advantages of ease, speed, precision and greater subject acceptance than measurement of blood carboxyhaemoglobin. However, the accuracy of the breath measurement procedure and the validity of the Haldane relationship between breath and blood remain in question for exposures at low environmental carbon monoxide concentrations.

Because carboxyhaemoglobin measurements are not readily available in the exposed population, mathematical models have been developed to predict carboxyhaemoglobin levels from known carbon monoxide exposures under a variety of circumstances. The best all-around model for carboxyhaemoglobin prediction is still the equation developed by Coburn, Forster and Kane. The linear solution is useful for examining air pollution data leading to relatively low carboxyhaemoglobin levels, whereas the non-linear solution shows good predictive power even for high carbon monoxide exposures. The two regression models might be useful only when the conditions of application closely approximate those under which the parameters were estimated.

Although the principal cause of carbon monoxide toxicity at low exposure levels is thought to be tissue hypoxia due to carbon monoxide binding to haemoglobin, certain physiological aspects of carbon monoxide exposure are not explained well by decreases in the intracellular oxygen partial pressure related to the presence of carboxyhaemoglobin. Consequently, secondary mechanisms of carbon monoxide toxicity related to intracellular uptake of carbon monoxide have been the focus of a great deal of research interest. Carbon monoxide binding to many intracellular compounds has been well documented both in vitro and in vivo; however, it is still uncertain whether or not intracellular uptake of carbon monoxide in the presence of haemoglobin is sufficient to cause either acute organ system dysfunction or long-term health effects. The virtual absence of sensitive techniques capable of assessing intracellular carbon monoxide binding under physiological conditions has resulted in a variety of indirect approaches to the problem, as well as many negative studies.

Current knowledge pertaining to intracellular carbon monoxide binding suggests that the proteins most likely to be inhibited functionally at relevant levels of carboxyhaemoglobin are myoglobin, found predominantly in heart and skeletal muscle, and cytochrome oxidase. The physiological significance of carbon monoxide uptake by myoglobin is uncertain at this time, but sufficient concentrations of carboxymyoglobin could potentially limit the maximal oxygen uptake of exercising muscle. Although there is suggestive evidence for significant binding of carbon monoxide to cytochrome oxidase in heart and brain tissue, it is unlikely that significant carbon monoxide binding would occur at low carboxyhaemoglobin levels.

The health significance of carbon monoxide in ambient air is largely due to the fact that it forms a strong bond with the haemoglobin molecule, forming carboxyhaemoglobin, which impairs the oxygen carrying capacity of the blood. The dissociation of oxyhaemoglobin in the tissues is also altered by the presence of carboxyhaemoglobin, so that delivery of oxygen to tissues is reduced further. The affinity of human haemoglobin for carbon monoxide is roughly 240 times that for oxygen, and the proportions of carboxyhaemoglobin and oxyhaemoglobin formed in blood are dependent largely on the partial pressures of carbon monoxide and oxygen.

Concerns about the potential health effects of exposure to carbon monoxide have been addressed in extensive studies with both humans and various animal species. Under varied experimental protocols, considerable information has been obtained on the toxicity of carbon monoxide, its direct effects on the blood and other tissues, and the manifestations of these effects in the form of changes in organ function. Many of the animal studies, however, have been conducted at extremely high levels of carbon monoxide (i.e., levels not found in ambient air). Although severe effects from exposure to these high levels of carbon monoxide are not directly germane to the problems resulting from exposure to current ambient levels of carbon monoxide, they can provide valuable information about potential effects of accidental exposure to carbon monoxide, particularly those exposures occurring indoors.

1.6.1 Cardiovascular effects

Decreased oxygen uptake and the resultant decreased work capacity under maximal exercise conditions have clearly been shown to occur in healthy young adults starting at 5.0% carboxyhaemoglobin, and several studies have observed small decreases in work capacity at carboxyhaemoglobin levels as low as 2.3–4.3%. These effects may have health implications for the general population in terms of potential curtailment of certain physically demanding occupational or recreational activities under circumstances of sufficiently high carbon monoxide exposure.

However, of greater concern at more typical ambient carbon monoxide exposure levels are certain cardiovascular effects (i.e., aggravation of angina symptoms during exercise) likely to occur in a smaller, but sizeable, segment of the general population. This group, chronic angina patients, is currently viewed as the most sensitive risk group for carbon monoxide exposure effects, based on evidence for aggravation of angina occurring in patients at carboxyhaemoglobin levels of 2.9–4.5%. Dose–response relationships for cardiovascular effects in coronary artery disease patients remain to be defined more conclusively, and the possibility cannot be ruled out at this time that such effects may occur at levels below 2.9% carboxyhaemoglobin. Therefore, new published studies are evaluated in this document to determine the effects of carbon monoxide on aggravation of angina at levels in the range of 2–6% carboxyhaemoglobin.

Five key studies have investigated the potential for carbon monoxide exposure to enhance the development of myocardial ischaemia during exercise in patients with coronary artery disease. An early study found that exercise duration was significantly decreased by the onset of chest pain (angina) in patients with angina pectoris at post-exposure carboxyhaemoglobin levels as low as 2.9%, representing an increase of 1.6% carboxyhaemoglobin over the baseline. Results of a large multicentre study demonstrated effects in patients with reproducible exercise-induced angina at post-exposure carboxyhaemoglobin levels of 3.2%, corresponding to an increase of 2.0% carboxyhaemoglobin from the baseline. Others also found similar effects in patients with obstructive coronary artery disease and evidence of exercise-induced ischaemia at post-exposure carboxyhaemoglobin levels of 4.1% and 5.9%, respectively, representing increases of 2.2% and 4.2% carboxyhaemoglobin over the baseline. One study of subjects with angina found an effect at 3% carboxyhaemoglobin, representing an increase of 1.5% carboxyhaemoglobin from the baseline. Thus, the lowest-observed-adverse-effect level in patients with exercise-induced ischaemia is somewhere between 3% and 4% carboxyhaemoglobin, representing an increase of 1.5–2.2% carboxyhaemoglobin from the baseline. Effects on silent ischaemia episodes, which represent the majority of episodes in these patients, have not been studied.

The adverse health consequences of low-level carbon monoxide exposure in patients with ischaemic heart disease are very difficult to predict in the at-risk population of individuals with heart disease. Exposure to carbon monoxide that is sufficient to achieve 6% carboxyhaemoglobin, but not lower levels of carboxyhaemoglobin, has been shown to significantly increase the number and complexity of exercise-induced arrhythmias in patients with coronary artery disease and baseline ectopy. This finding, combined with the time-series studies of carbon monoxide-related morbidity and mortality and the epidemiological work of tunnel workers who are routinely exposed to automobile exhaust, is suggestive but not conclusive evidence that carbon monoxide exposure may provide an increased risk of sudden death from arrhythmia in patients with coronary artery disease.

Previous assessments of the cardiovascular effects of carbon monoxide have identified what appears to be a linear relationship between the level of carboxyhaemoglobin in the blood and decrements in human maximal exercise performance, measured as maximal oxygen uptake. Exercise performance consistently decreases at a blood level of about 5% carboxyhaemoglobin in young, healthy, non-smoking individuals. Some studies have even observed a decrease in short-term maximal exercise duration at levels as low as 2.3–4.3% carboxyhaemoglobin; however, this decrease is so small as to be of concern mainly for competing athletes rather than for ordinary people conducting the activities of daily life.

There is also evidence from both theoretical considerations and experimental studies in laboratory animals that carbon monoxide can adversely affect the cardiovascular system, depending on the exposure conditions utilized in these studies. Although disturbances in cardiac rhythm and conduction have been noted in healthy and cardiac-impaired animals, results from these studies are not conclusive. The lowest level at which effects have been observed varies, depending upon the exposure regime used and species tested. Results from animal studies also indicate that inhaled carbon monoxide can increase haemoglobin concentration and haematocrit ratio, which probably represents a compensation for the reduction in oxygen transport caused by carbon monoxide. At high carbon monoxide concentrations, excessive increases in haemoglobin and haematocrit may impose an additional workload on the heart and compromise blood flow to the tissues.

There is conflicting evidence that carbon monoxide exposure will enhance development of atherosclerosis in laboratory animals, and most studies show no measurable effect. Similarly, the possibility that carbon monoxide will promote significant changes in lipid metabolism that might accelerate atherosclerosis is suggested in only a few studies. Any such effect must be subtle, at most. Finally, carbon monoxide probably inhibits rather than promotes platelet aggregation. In general, there are few data to indicate that an atherogenic effect of exposure would be likely to occur in human populations at commonly encountered levels of ambient carbon monoxide.

1.6.2 Acute pulmonary effects

It is unlikely that carbon monoxide has any direct effects on lung tissue except for extremely high concentrations associated with carbon monoxide poisoning. Human studies on the effects of carbon monoxide on pulmonary function are complicated by the lack of adequate exposure information, the small number of subjects studied and the short exposures explored. Occupational or accidental exposure to the products of combustion and pyrolysis, particularly indoors, may lead to acute decrements in lung function if the carboxyhaemoglobin levels are high. It is difficult, however, to separate the potential effects of carbon monoxide from those due to other respiratory irritants in the smoke and exhaust. Community population studies on carbon monoxide in ambient air have not found any significant relationship with pulmonary function, symptomatology and disease.

1.6.3 Cerebrovascular and behavioural effects

No reliable evidence demonstrating decrements in neurobehavioural function in healthy, young adults has been reported at carboxyhaemoglobin levels below 5%. Results of studies conducted at or above 5% carboxyhaemoglobin are equivocal. Much of the research at 5% carboxyhaemoglobin did not show any effect even when behaviours similar to those affected in other studies at higher carboxyhaemoglobin levels were involved. However, investigators failing to find carbon monoxide-related neurobehavioural decrements at 5% or higher carboxyhaemoglobin levels may have utilized tests not sufficiently sensitive to reliably detect small effects of carbon monoxide. From the empirical evidence, then, it can be said that carboxyhaemoglobin levels greater than or equal to 5% may produce decrements in neurobehavioural function. It cannot be said confidently, however, that carboxyhaemoglobin levels lower than 5% would be without effect. However, only young, healthy adults have been studied using demonstrably sensitive tests and carboxyhaemoglobin levels of 5% or greater. The question of groups at special risk for neurobehavioural effects of carbon monoxide, therefore, has not been explored.

Of special note are those individuals who are taking drugs with primary or secondary depressant effects that would be expected to exacerbate carbon monoxide-related neurobehavioural decrements. Other groups at possibly increased risk for carbon monoxide-induced neurobehavioural effects are the aged and ill, but these groups have not been evaluated for such risk.

Under normal circumstances, the brain can increase blood flow or tissue oxygen extraction to compensate for the hypoxia caused by exposure to carbon monoxide. The overall responses of the cerebrovasculature are similar in the fetus, newborn and adult animal; however, the mechanism of the increase in cerebral blood flow is still unclear. In fact, several mechanisms working simultaneously to increase blood flow appear likely, and these may involve metabolic and neural aspects as well as the oxyhaemoglobin dissociation curve, tissue oxygen levels and even a histotoxic effect of carbon monoxide. Whether these compensatory mechanisms will continue to operate successfully in a variety of conditions where the brain or its vasculature are compromised (i.e., stroke, head injury, atherosclerosis, hypertension) is also unknown. Aging increases the probability of such injury and disease. It is also possible that there exist individual differences with regard to carboxyhaemoglobin sensitivity and compensatory mechanisms.

Behaviours that require sustained attention or sustained performance are most sensitive to disruption by carboxyhaemoglobin. The group of human studies on hand–eye coordination (compensatory tracking), detection of infrequent events (vigilance) and continuous performance offers the most consistent and defensible evidence of carboxyhaemoglobin effects on behaviour at levels as low as 5%. These effects at low carbon monoxide exposure concentrations, however, have been very small and somewhat controversial. Nevertheless, the potential consequences of a lapse of coordination and vigilance on the continuous performance of critical tasks by operators of machinery such as public transportation vehicles could be serious.

1.6.4 Developmental toxicity

Studies in several laboratory animal species provide strong evidence that maternal carbon monoxide exposures of 170–230 mg/m³ (150–200 ppm), leading to approximately 15–25% carboxyhaemoglobin, produce reductions in birth weight, cardiomegaly, delays in behavioural development and disruption in cognitive function. Isolated experiments suggest that some of these effects may be present at concentrations as low as 69–74 mg/m³ (60–65 ppm; approximately 6–11% carboxyhaemoglobin) maintained throughout gestation. Studies relating human carbon monoxide exposure from ambient sources or cigarette smoking to reduced birth weight are of concern because of the risk for developmental disorders; however, many of these studies have not considered all sources of carbon monoxide. The current data from children suggesting a link between environmental carbon monoxide exposures and sudden infant death syndrome are weak.

1.6.5 Other systemic effects

Laboratory animal studies suggest that enzyme metabolism of xenobiotic compounds may be affected by carbon monoxide exposure. Most of the authors of these studies have concluded, however, that effects on metabolism at low carboxyhaemoglobin levels (15%) are attributable entirely to tissue hypoxia produced by increased levels of carboxyhaemoglobin, because they are no greater than the effects produced by comparable levels of hypoxic hypoxia. At higher levels of exposure, where carboxyhaemoglobin concentrations exceed 15–20%, carbon monoxide may directly inhibit the activity of mixed-function oxidases. The decreases in xenobiotic metabolism shown with carbon monoxide exposure might be important to individuals receiving treatment with drugs.

Inhalation of high levels of carbon monoxide, leading to carboxyhaemoglobin concentrations greater than 10–15%, has been reported to cause a number of other systemic effects in laboratory animals, as well as effects in humans suffering from acute carbon monoxide poisoning. Tissues of highly active oxygen metabolism, such as heart, brain, liver, kidney and muscle, may be particularly sensitive to carbon monoxide poisoning. The effects of high levels of carbon monoxide on other tissues are not as well known and are, therefore, less certain. There are reports in the literature of effects on liver, kidney, bone and the immune capacity of the lung and spleen. It is generally agreed that the severe tissue damage occurring during acute carbon monoxide poisoning is due to one or more of the following: (1) ischaemia resulting from the formation of carboxyhaemoglobin, (2) inhibition of oxygen release from oxyhaemoglobin, (3) inhibition of cellular cytochrome function (e.g., cytochrome oxidases) and (4) metabolic acidosis.

Only relatively weak evidence points towards possible carbon monoxide effects on fibrinolytic activity, and then only at rather high carbon monoxide exposure levels. Similarly, whereas certain data also suggest that perinatal effects (e.g., reduced birth weight, slowed postnatal development, sudden infant death syndrome) are associated with carbon monoxide exposure, insufficient evidence exists by which to either qualitatively confirm such an association in humans or establish any pertinent exposure–effect relationships.

1.6.6 Adaptation

The only evidence for short- or long-term compensation for or adaptation to increased carboxyhaemoglobin levels in the blood is indirect. Experimental animal data indicate that increased carboxyhaemoglobin levels produce physiological responses that tend to offset other deleterious effects of carbon monoxide exposure. Such responses are (1) increased coronary blood flow, (2) increased cerebral blood flow, (3) increased haemoglobin through increased haematopoiesis and (4) increased oxygen consumption in muscle.

Short-term compensatory responses in blood flow or oxygen consumption may not be complete or might even be lacking in certain persons. For example, it is known from laboratory animal studies that coronary blood flow increases with increasing carboxyhaemoglobin, and it is known from human clinical studies that subjects with ischaemic heart disease respond to the lowest levels of carboxyhaemoglobin (6% or less). The implication is that in some cases of cardiac impairment, the short-term compensatory mechanism is impaired.

From neurobehavioural studies, it is apparent that decrements due to carbon monoxide have not occurred consistently in all subjects, or even in the same studies, and have not demonstrated a dose–response relationship with increasing carboxyhaemoglobin levels. The implication from these data is that there might be some threshold or time lag in a compensatory mechanism such as increased blood flow. Without direct physiological evidence in either laboratory animals or, preferably, humans, this concept can only be hypothesized.

The mechanism by which long-term adaptation would occur, if it could be demonstrated in humans, is assumed to be an increased haemoglobin concentration via an increase in haematopoiesis. This alteration in haemoglobin production has been demonstrated repeatedly in laboratory animal studies, but no recent studies have been conducted indicating or suggesting that some adaptational benefit has occurred or would occur. Furthermore, even if the haemoglobin increase is a signature of adaptation, it has not been demonstrated to occur at low ambient concentrations of carbon monoxide.

1.7.1 High-altitude effects

Although there are many studies comparing and contrasting the effects of inhaling carbon monoxide with those produced by exposure to altitude, there are relatively few reports on the combined effects of inhaling carbon monoxide at altitude. There are data to support the possibility that the effects of these two hypoxia episodes are at least additive. These data were obtained at carbon monoxide concentrations that are too high to have much significance for regulatory concerns.

There are even fewer studies of the long-term effects of carbon monoxide at high altitude. These studies indicate few changes at carbon monoxide concentrations below 110 mg/m³ (100 ppm) and altitudes below 4570 m. The fetus, however, may be particularly sensitive to the effects of carbon monoxide at altitude; this is especially true with the high levels of carbon monoxide associated with maternal smoking.

1.7.2 Carbon monoxide interaction with drugs

There remains little direct information on the possible enhancement of carbon monoxide toxicity by concomitant drug use or abuse; however, there are some data suggesting cause for concern. There is some evidence that interactions between drug effects and carbon monoxide exposure can occur in both directions; that is, carbon monoxide toxicity may be enhanced by drug use, and the toxic or other effects of drugs may be altered by carbon monoxide exposure. Nearly all the published data that are available on carbon monoxide combinations with drugs concern the use of alcohol.

The use and abuse of psychoactive drugs and alcohol are ubiquitous in society. Because of the effect of carbon monoxide on brain function, interactions between carbon monoxide and psychoactive drugs could be anticipated. Unfortunately, little systematic research has addressed this question. In addition, little of the research that has been done has utilized models for expected effects from treatment combinations. Thus, it is often not possible to assess whether the combined effects of drugs and carbon monoxide exposure are additive or differ from additivity. It is important to recognize that even additive effects of combinations can be of clinical significance, especially when the individual is unaware of the combined hazard. The greatest evidence for a potentially important interaction of carbon monoxide comes from studies with alcohol in both laboratory animals and humans, where at least additive effects have been obtained. The significance of this is augmented by the high probable incidence of combined alcohol use and carbon monoxide exposure.

1.7.3 Combined exposure of carbon monoxide with other air pollutants and environmental factors

Many of the data concerning the combined effects of carbon monoxide and other pollutants found in the ambient air are based on laboratory animal experiments. Only a few human studies are available. Early studies in healthy human subjects on common air pollutants such as carbon monoxide, nitrogen dioxide, ozone or peroxyacetyl nitrate failed to show any interaction from combined exposure. In laboratory studies, no interaction was observed following combined exposure to carbon monoxide and common ambient air pollutants such as nitrogen dioxide or sulfur dioxide. However, an additive effect was observed following combined exposure to high levels of carbon monoxide and nitric oxide, and a synergistic effect was observed after combined exposure to carbon monoxide and ozone.

Toxicological interactions of combustion products, primarily carbon monoxide, carbon dioxide and hydrogen cyanide, at levels typically produced by indoor and outdoor fires have shown a synergistic effect following carbon monoxide plus carbon dioxide exposure and an additive effect with hydrogen cyanide. Additive effects were also observed when carbon monoxide, hydrogen cyanide and low oxygen were combined; adding carbon dioxide to this combination was synergistic.

Finally, studies suggest that environmental factors such as heat stress and noise may be important determinants of health effects when combined with exposure to carbon monoxide. Of the effects described, the one potentially most relevant to typical human exposures is a greater decrement in the exercise performance seen when heat stress is combined with 57 mg carbon monoxide/m³ (50 ppm).

1.7.4 Tobacco smoke

Besides being a source of carbon monoxide for smokers as well as non-smokers, tobacco smoke is also a source of other chemicals with which environmental carbon monoxide could interact. Available data strongly suggest that acute and chronic carbon monoxide exposure attributed to tobacco smoke can affect the cardiopulmonary system, but the potential interaction of carbon monoxide with other products of tobacco smoke confounds the results. In addition, it is not clear if incremental increases in carboxyhaemoglobin caused by environmental exposure would actually be additive to chronically elevated carboxyhaemoglobin levels due to tobacco smoke, because some physiological adaptation may take place.

Most information on the health effects of carbon monoxide involves two carefully defined population groups — young, healthy adults and patients with diagnosed coronary artery disease. On the basis of the known effects described, patients with reproducible exercise-induced ischaemia appear to be best established as a sensitive group within the general population that is at increased risk for experiencing health effects of concern (i.e., decreased exercise duration due to exacerbation of cardiovascular symptoms) at ambient or near-ambient carbon monoxide exposure concentrations that result in carboxyhaemoglobin levels down to 3%. A smaller sensitive group of healthy individuals experiences decreased exercise duration at similar levels of carbon monoxide exposure, but only during short-term maximal exercise. Decrements in exercise duration in the healthy population would therefore be of concern mainly to competing athletes, rather than to ordinary people carrying out the common activities of daily life.

It can be hypothesized, however, from both clinical and theoretical work and from experimental research on laboratory animals, that certain other groups in the population may be at probable risk from exposure to carbon monoxide. Identifiable probable risk groups can be categorized by gender differences; by age (e.g., fetuses, young infants and the elderly); by genetic variations (i.e., haemoglobin abnormalities); by pre-existing diseases, either known or unknown, that already decrease the availability of oxygen to critical tissues; or by the use of medications, recreational drugs or alterations in environment (e.g., exposure to other air pollutants or to high altitude). Unfortunately, little empirical evidence is currently available by which to specify health effects associated with ambient or near-ambient carbon monoxide exposures for most of these probable risk groups.

Most of this document is concerned with the relatively low concentrations of carbon monoxide that induce effects in humans at, or near, the lower margin of carboxyhaemoglobin detection by current medical technology. Yet health effects associated with exposure to this pollutant range from the more subtle cardiovascular and neurobehavioural effects at low ambient concentrations to unconsciousness and death after acute exposure to high concentrations of carbon monoxide. The morbidity and mortality resulting from the latter exposures can be a significant public health concern.

Carbon monoxide is responsible for a large percentage of the accidental poisonings and deaths reported throughout the world each year. Certain conditions exist in both the indoor and outdoor environments that cause a small percentage of the population to become exposed to dangerous levels of carbon monoxide. Outdoors, concentrations of carbon monoxide are highest near street intersections, in congested traffic, near exhaust gases from internal combustion engines and from industrial sources, and in poorly ventilated areas such as parking garages and tunnels. Indoors, carbon monoxide concentrations are highest in workplaces or in homes that have faulty or poorly vented combustion appliances or downdrafts or backdrafts.

The symptoms and signs of acute carbon monoxide poisoning correlate poorly with the level of carboxyhaemoglobin measured at the time of arrival at the hospital. Carboxyhaemoglobin levels below 10% are usually not associated with symptoms. At higher carboxyhaemoglobin saturations of 10–30%, neurological symptoms of carbon monoxide poisoning can occur, such as headache, dizziness, weakness, nausea, confusion, disorientation and visual disturbances. Exertional dyspnoea, increases in pulse and respiratory rates and syncope are observed with continuous exposure, producing carboxyhaemoglobin levels from 30% to 50%. When carboxyhaemoglobin levels are higher than 50%, coma, convulsions and cardiopulmonary arrest may occur.

Complications occur frequently in carbon monoxide poisoning (immediate death, myocardial impairment, hypotension, arrhythmias, pulmonary oedema). Perhaps the most insidious effect of carbon monoxide poisoning is the delayed development of neuropsychiatric impairment within 1–3 weeks and the neurobehavioural consequences, especially in children. Carbon monoxide poisoning during pregnancy results in high risk for the mother, by increasing the short-term complications rate, and for the fetus, by causing fetal death, developmental disorders and cerebral anoxic lesions. Furthermore, the severity of fatal intoxication cannot be assessed by the maternal rate.

Carbon monoxide poisoning occurs frequently, has severe consequences, including immediate death, involves complications and late sequelae and is often overlooked. Efforts in prevention and in public and medical education should be encouraged.

The following guideline values (ppm values rounded) and periods of time-weighted average exposures have been determined in such a way that the carboxyhaemoglobin level of 2.5% is not exceeded, even when a normal subject engages in light or moderate exercise:

100 mg/m³ (87 ppm) for 15 min

60 mg/m³ (52 ppm) for 30 min

30 mg/m³ (26 ppm) for 1 h

10 mg/m³ (9 ppm) for 8 h

Carbon monoxide (CO) is a tasteless, odourless, colourless, non-corrosive and quite stable diatomic molecule that exists as a gas in the Earth’s atmosphere. Radiation in the visible and near-ultraviolet (UV) regions of the electromagnetic spectrum is not absorbed by carbon monoxide, although the molecule does have weak absorption bands between 125 and 155 nm. Carbon monoxide absorbs radiation in the infrared region corresponding to the vibrational excitation of its electronic ground state. It has a low electric dipole moment (0.10 debye), short interatomic distance (0.123 nm) and high heat of formation from atoms or bond strength (2072 kJ/mol). These observations suggest that the molecule is a resonance hybrid of three structures (Perry et al., 1977), all of which contribute nearly equally to the normal ground state. General physical properties of carbon monoxide are given in Table 1.

Table 1. Physical properties of carbon monoxide^a

2.2.1 Introduction

Because of the low levels of carbon monoxide in ambient air, methods for its measurement require skilled personnel and sophisticated analytical equipment. The principles of the methodology have been described by Smith & Nelson (1973). A sample introduction system is used, consisting of a sampling probe, an intake manifold, tubing and air movers. This system is needed to collect the air sample from the atmosphere and to transport it to the analyser without altering the original concentration. It may also be used to introduce known gas concentrations to periodically check the reliability of the analyser output. Construction materials for the sampling probe, intake manifold and tubing should be tested to demonstrate that the test atmosphere composition or concentration is not altered significantly. The sample introduction system should be constructed so that it presents no pressure drop to the analyser. At low flow and low concentrations, such operation may require validation.

The analyser system consists of the analyser itself and any sample preconditioning components that may be necessary. Sample preconditioning might require a moisture control system to help minimize the false-positive response of the analyser (e.g., the non-dispersive infrared [NDIR] analyser) to water vapour and a particulate filter to help protect the analyser from clogging and possible chemical interference due to particulate buildup in the sample lines or analyser inlet. The sample preconditioning system may also include a flow metering and flow control device to control the sampling rate to the analyser.

A data recording system is needed to record the output of the analyser.

2.2.2 Methods

A reference method or equivalent method for air quality measurements is required for acceptance of measurement data. An equivalent method for monitoring carbon monoxide can be so designated when the method is shown to produce results equivalent to those from the approved reference monitoring method based on absorption of infrared radiation from a non-dispersed beam.

The designated reference methods are automated, continuous methods utilizing the NDIR technique, which is generally accepted as being the most reliable method for the measurement of carbon monoxide in ambient air. As of January 1988, no equivalent methods that use a principle other than NDIR have been designated for measuring carbon monoxide in ambient air.

There have been several excellent reviews on the measurement of carbon monoxide in the atmosphere (National Air Pollution Control Administration, 1970; Driscoll & Berger, 1971; Leithe, 1971; American Industrial Hygiene Association, 1972; NIOSH, 1972; Verdin, 1973; Stevens & Herget, 1974; Harrison, 1975; Schnakenberg, 1976; NRC, 1977; Repp, 1977; Lodge, 1989; OSHA, 1991a; ASTM, 1995; ISO, 1996).

2.2.2.1 Non-dispersive infrared photometry method

Currently, the most commonly used measurement technique is the type of NDIR method referred to as gas filter correlation (Acton et al., 1973; Burch & Gryvnak, 1974; Ward & Zwick, 1975; Burch et al., 1976; Goldstein et al., 1976; Gryvnak & Burch, 1976a,b; Herget et al., 1976; Bartle & Hall, 1977; Chaney & McClenny, 1977).

Carbon monoxide has a characteristic infrared absorption near 4.6 µm. The absorption of infrared radiation by the carbon monoxide molecule can therefore be used to measure the concentration of carbon monoxide in the presence of other gases. The NDIR method is based on this principle (Feldstein, 1967).

Most commercially available NDIR analysers incorporate a gas filter to minimize interferences from other gases. They operate at atmospheric pressure, and the most sensitive analysers are able to detect minimum carbon monoxide concentrations of about 0.05 mg/m³ (0.044 ppm). Interferences from carbon dioxide and water vapour can be dealt with so as not to affect the data quality. NDIR analysers with detectors as designed by Luft (1962) are relatively insensitive to flow rate, require no wet chemicals, are sensitive over wide concentration ranges and have short response times. NDIR analysers of the newer gas filter correlation type have overcome zero and span problems and minor problems due to vibrations.

2.2.2.2 Gas chromatography method

A more sensitive method for measuring low background levels of carbon monoxide is gas chromatography (Porter & Volman, 1962; Feldstein, 1967; Swinnerton et al., 1968; Bruner et al., 1973; Dagnall et al., 1973; Tesarik & Krejci, 1974; Bergman et al., 1975; Smith et al., 1975; ISO, 1989). This technique is an automated, semicontinuous method in which carbon monoxide is separated from water, carbon dioxide and hydrocarbons other than methane by a stripper column. Carbon monoxide and methane are then separated on an analytical column, and the carbon monoxide is passed through a catalytic reduction tube, where it is converted to methane. The carbon monoxide (converted to methane) passes through a flame ionization detector, and the resulting signal is proportional to the concentration of carbon monoxide in the air. This method has been used throughout the world. It has no known interferences and can be used to measure levels from 0.03 to 50 mg/m³ (0.026 to 43.7 ppm). These analysers are expensive and require continuous attendance by a highly trained operator to produce valid results. For high levels, a useful technique is catalytic oxidation of the carbon monoxide by Hopcalite or other catalysts (Stetter & Blurton, 1976), either with temperature-rise sensors (Naumann, 1975; Schnakenberg, 1976; Benzie et al., 1977) or with electrochemical sensors (Bay et al., 1972, 1974; Bergman et al., 1975; Dempsey et al., 1975; Schnakenberg, 1975; Repp, 1977). Numerous other analytical schemes have been used to measure carbon monoxide in air.

2.2.2.3 Other analysers

Other systems to measure carbon monoxide in ambient air include gas chromatography/flame ionization, in which carbon monoxide is separated from other trace gases by gas chromatography and catalytically converted to methane prior to detection; controlled-potential electrochemical analysis, in which carbon monoxide is measured by means of the current produced in aqueous solution by its electro-oxidation by an electro-catalytically active noble metal (the concentration of carbon monoxide reaching the electrode is controlled by its rate of diffusion through a membrane, which depends on its concentration in the sampled atmosphere; Bay et al., 1972, 1974); galvanic cells that can be used to measure atmospheric carbon monoxide continuously, in the manner described by Hersch (1964, 1966); coulometric analysis, which employs a modified Hersch-type cell; mercury replacement, in which mercury vapour formed by the reduction of mercuric oxide by carbon monoxide is detected photometrically by its absorption of UV light at 253.7 nm; dual-isotope fluorescence, which utilizes the slight difference in the infrared spectra of isotopes of carbon monoxide; catalytic combustion/thermal detection, which is based on measuring the temperature rise resulting from catalytic oxidation of the carbon monoxide in the sample air; second-derivative spectrometry, which utilizes a second-derivative spectrometer to process the transmission versus wavelength function of an ordinary spectrometer to produce an output signal proportional to the second derivative of this function; and Fourier-transform spectroscopy, which is an extremely powerful infrared spectroscopic technique.

Intermittent samples may be collected in the field and later analysed in the laboratory by the continuous analysing techniques described above. Sample containers may be rigid (glass cylinders or stainless steel tanks) or non-rigid (plastic bags). Because of location and cost, intermittent sampling may at times be the only practical method for air monitoring. Samples can be taken over a few minutes or accumulated intermittently to obtain, after analysis, either "spot" or "integrated" results.

Additional techniques for analysing intermittent samples include colorimetric analysis, in which carbon monoxide reacts in an alkaline solution with the silver salt of p-sulfamoyl-benzoate to form a coloured silver sol; a National Institute of Standards and Technology colorimetric indicating gel (incorporating palladium and molybdenum salts), which involves colorimetric comparison with freshly prepared indicating gels exposed to known concentrations of carbon monoxide; a length-of-stain indicator method, which uses an indicator tube containing potassium palladosulfite; and frontal analysis, in which air is passed over an adsorbent until equilibrium is established between the concentration of carbon monoxide in the air and the concentration of carbon monoxide on the adsorbent.

A simple and inexpensive measurement technique uses detector tubes (indicator tubes) (Leichnitz, 1993). This method is widely applied in industrial hygiene and is suitable for analysis of highly polluted atmospheric air. The measurement with Dräger tubes (Drägerwerk, 1994) is based on the reaction: 5CO + I₂O₅ --> I₂ + 5CO₂. The iodine-coloured layer in the tube corresponds in length to the carbon monoxide concentration in the sample.

2.2.3 Measurement using personal monitors

Until the 1960s, most of the data available on ambient carbon monoxide concentrations came from fixed monitoring stations operated routinely in urban areas. The accepted measurement technique was NDIR spectrometry, but the instruments were large and cumbersome, often requiring vibration-free, air-conditioned enclosures. Without a portable, convenient monitor for carbon monoxide, it was extremely difficult to measure carbon monoxide concentrations accurately in the microenvironments that people usually visited.

Ultimately, small personal exposure monitors (PEMs) were developed that could measure carbon monoxide concentrations continuously over time and store the readings automatically on internal digital memories (Ott et al., 1986). These small PEMs made possible the large-scale field studies on human exposure to carbon monoxide in Denver, Colorado, and Washington, DC, USA, in the winter of 1982–83 (Akland et al., 1985).

2.2.4 Carbon monoxide detectors/alarms

Carbon monoxide detectors have been designed like residential smoke detectors — to be low cost, yet provide protection from a catastrophic event by sounding an audible alarm. The carbon monoxide detector industry is young, however, and is in a stage of rapid growth. In the USA, an estimated 7–8 million detectors have been purchased since the early 1990s, but the numbers used in homes will continue to rise as local municipalities change building codes to require the installation of carbon monoxide detectors in new residential structures containing combustion-source appliances, stoves or fireplaces.

Currently available carbon monoxide detectors are based on an interactive-type sensor (e.g., tin oxide, Figaro-type gel cell, fuel cell, artificial haemoglobin) that relies on direct interaction between carbon monoxide and the sensitive element in order to generate a response. They are battery-powered, alternating current-powered or both. The most popular alternating current-powered detectors have a heated metallic sensor that reacts with carbon monoxide; the battery-powered detectors have a chemically treated gel disk that darkens with exposure to carbon monoxide or a fuel cell. Small, inexpensive carbon monoxide detection cards or tablets that require frequent visual inspection of colour changes do not sound an alarm and are not recommended as a primary detector.

Carbon monoxide detectors are sensitive to location and environmental conditions, including temperature, relative humidity and the presence of other interfering gases. They may also become less stable with time. For example, they should not be installed in dead-space air (i.e., near ceilings), near windows or near doors where there is a lot of air movement, and they should not be exposed to temperature or humidity extremes. Excessive heat or cold will affect performance, and humidity extremes will affect the activation time. Utilization of non-interactive infrared technology (e.g., NDIR) in indoor carbon monoxide detection would overcome all of the shortcomings of the currently available carbon monoxide detectors.

In the USA, a new voluntary standard for carbon monoxide detectors was published in 1992 by the Underwriters Laboratories (UL Standard 2034) and revised in 1995. This standard provides alarm requirements for detectors that are based on both the carbon monoxide concentration and the exposure time. It is designed so that an alarm is activated within 90 min of exposure to 110 mg/m³ (100 ppm), within 35 min of exposure to 230 mg/m³ (200 ppm) or within 15 min of exposure to 460 mg/m³ (400 ppm) (i.e., when exposures are equivalent to 10% carboxyhaemoglobin [COHb]; see section 2.3). Approximately 15 manufacturers produce detectors listed under UL Standard 2034.

Because UL Standard 2034 covers a wide range of exposure conditions, there has been some ambiguity about its interpretation. For example, it is not clear if a detector meets the standard if the alarm is activated anytime between 5 and 90 min in the presence of 110 mg carbon monoxide/mg³ (100 ppm). In fact, alarm sensitivities are still a problem for the industry, and further discussion and direction are needed. Moreover, the 10% carboxyhaemoglobin level is protective of healthy individuals only (see chapter 8). It would be necessary to avoid exposures to 10 mg carbon monoxide/m³ (9 ppm) for 8 h or 29 mg/m³ (25 ppm) for 1 h in order to protect sensitive individuals with coronary heart disease at the 3% carboxyhaemoglobin level. Thus, current detectors provide warning against carbon monoxide levels that are protective of the healthy population only. Despite these limitations, carbon monoxide detectors are reliable and effective, continue to improve and should be recommended for use in homes in addition to smoke detectors and fire alarms.

A unique feature of carbon monoxide exposure is that there is a biological marker of the dose that the individual has received: the level of carbon monoxide in the blood. This level may be calculated by measuring carboxyhaemoglobin in blood or carbon monoxide in exhaled breath.

2.3.1 Blood carboxyhaemoglobin measurement

The level of dissolved carbon monoxide in blood is normally below the level of detection but may be of importance in the transportation of carbon monoxide between cells and tissues (see chapter 6). Thus, the blood level of carbon monoxide is conventionally represented as a percentage of the total haemoglobin available (i.e., the percentage of haemoglobin that is in the form of carboxyhaemoglobin, or simply percent carboxyhaemoglobin).

Any technique for the measurement of carboxyhaemoglobin in blood must be specific and must have sufficient sensitivity and accuracy for the purpose of the values obtained. The majority of technical methods that have been published on measurement of carbon monoxide in blood have been for forensic purposes. These methods are less accurate than generally required for the measurement of low levels of carboxyhaemoglobin (<5%). Blood levels of carbon monoxide resulting from exposure to existing ambient levels of carbon monoxide would not be expected to exceed 5% carboxyhaemoglobin in non-smoking subjects. The focus of the forensic methods has been the reliability of measurements over the entire range of possible values: from less than 1% to 100% carboxyhaemoglobin. These forensically oriented methods are adequate for the intended use of the values and the non-ideal storage conditions of the samples being analysed.

In the areas of exposure assessment and low-level health effects of carbon monoxide, it is more important to know the accuracy of any method in the low-level range of <5% carboxyhaemoglobin. There is little agreement upon acceptable reference methods in this range, nor are there accurate reference standards available in this range. The use of techniques that have unsubstantiated accuracy in the low range of carboxyhaemoglobin levels can lead to considerable differences in estimations of exposure conditions. Measurement of low levels of carboxyhaemoglobin demands careful evaluation because of the implications, based upon these data, for the setting of air quality standards. Therefore, this section will focus on the methods that have been evaluated at levels below 10% carboxyhaemoglobin and the methods that have been extensively used in assessing exposure to carbon monoxide.

The measurement of carbon monoxide in blood can be accomplished by a variety of techniques, both destructive and non-destructive. Carboxyhaemoglobin can be determined non-destructively by observing the change in the absorption spectrum in either the Soret or visible region brought about by the combination of carbon monoxide with haemoglobin. With present optical sensing techniques, however, all optical methods are limited in sensitivity to approximately 1% of the range of expected values. If attempts are made to expand the lower range of absorbances, sensitivity is lost on the upper end where, in the case of carboxyhaemoglobin, total haemoglobin is measured. For example, in the spectrophotometric method described by Small et al. (1971), a change in absorbance equal to the limit of resolution of 0.01 units can result in a difference in 0.6% carboxyhaemoglobin. Therefore, optical techniques cannot be expected to obtain the resolution that is possible with other means of detection of carbon monoxide (Table 2).

Table 2. Representative methods for the analysis of carbon monoxide in blood^a

The more sensitive (higher-resolution) techniques require the release of the carbon monoxide from the haemoglobin into a gas phase; the carbon monoxide can then be detected directly by (1) infrared absorption (Maas et  al., 1970) following separation using gas chromatography, (2) the difference in thermal conductivity between carbon monoxide and the carrier gas (Ayres et al., 1966; McCredie & Jose, 1967; Dahms & Horvath, 1974; Goldbaum et al., 1986; Horvath et al., 1988b; Allred et al., 1989b), (3) the amount of ionization following quantitative conversion of carbon monoxide to methane and ionization of the methane (Collison et al., 1968; Dennis & Valeri, 1980; Guillot et al., 1981; Clerbaux et al., 1984; Kane, 1985; Katsumata et al., 1985; Costantino et al., 1986) or (4) the release of mercury vapour resulting from the combination of carbon monoxide with mercuric oxide (Vreman et al., 1984).

2.3.1.1 Sample handling

Carbon monoxide bound to haemoglobin is a relatively stable compound that can be dissociated by exposure to oxygen or UV radiation (Horvath & Roughton, 1942; Chace et al., 1986). If the blood sample is maintained in the dark under cool, sterile conditions, the carbon monoxide content will remain stable for a long period of time. Various investigators have reported no decrease in percent carboxyhaemoglobin over 10 days (Collison et al., 1968), 3 weeks (Dahms & Horvath, 1974), 4 months (Ocak et al., 1985) and 6 months (Vreman et al., 1984). The blood collection system used can influence the carbon monoxide level, because some ethylenediaminetetraacetic acid vacutainer tube stoppers contain carbon monoxide (Vreman et al., 1984). The stability of the carbon monoxide content in properly stored samples does not indicate that constant values will be obtained by all techniques of analysis. The spectrophotometric methods are particularly susceptible to changes in optical qualities of the sample, resulting in small changes in carboxyhaemoglobin with storage (Allred et al., 1989b).

Therefore, the care needed to make a carboxyhaemoglobin determination depends upon the technique that is being utilized. It appears as though measurement of low levels of carboxyhaemoglobin with optical techniques should be conducted as soon as possible following collection of the samples.

2.3.1.2 Potential reference methods

Exposure to carbon monoxide at equilibrium conditions results in carboxyhaemoglobin levels of between 0.1 and 0.2% for each milligram of carbon monoxide per cubic metre air (part per million). A reference technique for the measurement of carboxyhaemoglobin should be able to discriminate between two blood samples with a difference of 0.1% carboxyhaemoglobin (approximately 0.02 ml/dl). To accomplish this task, the coefficient of variation (standard deviation of repeated measures on any given sample divided by the mean of the values times 100) of the method should be less than 5%, so that the two values that are different by 0.1 percentage points can be statistically proven to be distinct. In practical terms, a reference method should have the sensitivity to detect approximately 0.025% carboxyhaemoglobin to provide this level of confidence in the values obtained.

The accurate measurement of carboxyhaemoglobin requires the quantitation of the content of carbon monoxide released from haemoglobin in the blood. Optically based techniques have limitations of resolution and specificity due to the potential interference from many sources. The techniques that can be used as reference methods involve the quantitative release of carbon monoxide from the haemoglobin followed by the measurement of the amount of carbon monoxide released. Classically, this quantitation was measured manometrically with a Van Slyke apparatus (Horvath & Roughton, 1942) or a Roughton-Scholander syringe (Roughton & Root, 1945). These techniques have served as the "Gold Standard" in this field for almost 50 years. However, there are limitations of resolution with these techniques at the lower ranges of carboxyhaemoglobin. The gasometric standard methodology has been replaced with headspace extraction followed by the use of solid-phase gas chromatographic separation with several different types of detection: thermal conductivity, flame ionization and mercury vapour reduction. The carbon monoxide in the headspace can also be quantitated by infrared detection, which can be calibrated with gas standards. However, there is no general agreement that any of the more sensitive methods of carbon monoxide analysis are acceptable reference methods.

The following techniques all conform to all the requirements of a reference method:

1. Flame ionization detection: This technique requires the separation of carbon monoxide from the other headspace gases and the reduction of the carbon monoxide to methane by catalytic reduction.
2. Thermal conductivity detection: This technique uses vacuum extraction of carbon monoxide from blood in a Van Slyke apparatus and gas chromatographic separation with thermal conductivity analysis of the carbon monoxide.
3. Infrared detection: This technique uses a method for extracting carbon monoxide from blood under normal atmospheric conditions and then injecting the headspace gas into an infrared analyser.

The conventional means of representing the quantity of carbon monoxide in a blood sample is the percent carboxyhaemoglobin: the percentage of the total carbon monoxide combining capacity that is in the form of carboxyhaemoglobin. This is conventionally determined by the use of the following formula:

where CO content is the carbon monoxide concentration, measured in millilitres per decilitre blood at standard temperature and pressure, dry; Hb is the haemoglobin concentration, measured in grams per decilitre blood; a