Carbon Monoxide

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

    Published under the joint sponsorship of
    the United Nations Environment Programme
    and the World Health Organization

    World Health Organization
    Geneva, 1979

    ISBN 92 4 154073 7

    (c) World Health Organization 1979

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         1.1. Summary
               1.1.1. Properties and analytical methods
               1.1.2. Sources of environmental pollution
               1.1.3. Environmental levels
               1.1.4. Effects on experimental animals
               1.1.5. Effects on man
               1.1.6. Evaluation of health risk
         1.2. Recommendations for further studies


         2.1. Physical and chemical properties
         2.2. Methods of measuring carbon monoxide in ambient air
         2.3. Biological monitoring


         3.1. Natural occurrence
         3.2. Man-made sources


         4.1. Atmospheric transport and diffusion
         4.2. Environmental absorption and transformation


         5.1. Ambient air concentrations and exposures
         5.2. Indoor concentrations and exposure
         5.3. Occupational exposure
         5.4. Carboxyhaemoglobin levels in the general population


         6.1. Endogenous carbon monoxide production
         6.2. Absorption
         6.3. Reactions with body tissues and fluids
         6.4. Excretion


         7.1. Species differences
         7.2. Cardiovascular system and blood
         7.3. Central nervous system

         7.4. Behavioural changes and work performance
         7.5. Adaptation
         7.6. Embryonal, fetal, neonatal, and teratogenic effects
         7.7. Carcinogenicity and mutagenicity
         7.8. Miscellaneous changes
         7.9. Interactions


         8.1. Healthy subjects
               8.1.1. Behavioural changes
               8.1.2. Work performance and exercise
               8.1.3. Adaptation
               8.1.4. Effects on the cardiovascular system and other
               8.1.5. Carboxyhaemoglobin levels resulting from exposure
                       to methane-derived halogenated hydrocarbons
               8.1.6. Levels and effects of carboxyhaemoglobin resulting
                       from smoking
               8.1.7. Interactions

         8.2. High-risk groups
               8.2.1. Individuals with cardiovascular and chronic
                       obstructive lung disease
               8.2.2. Anaemic individuals
               8.2.3. Embryo, fetus, neonate, and infants
               8.2.4. Individuals living at high altitudes
         8.3. Summary table


         9.1. Introduction
         9.2. Exposure
               9.2.1. Assessment of exposure
               9.2.2. Endogenous production
               9.2.3. Outdoor environmental exposure
               9.2.4. Indoor exposure
               9.2.5. Exposures related to traffic
               9.2.6. Occupational exposure
               9.2.7. Tobacco smoking
               9.2.8. Multiple exposures
         9.3. Effects
               9.3.1. Cardiovascular system
               Development of atherosclerotic
                                cardiovascular disease
               Acute effects on existing heart illness
               Acute effects on existing vascular disease
               9.3.2. Nervous system
               9.3.3. Work capacity

         9.4. Recommended exposure limits
               9.4.1. General population exposure
               9.4.2. Working population exposure
               9.4.3. Derived limits for carbon monoxide concentrations
                       in air


    ANNEX 1

    ANNEX 2


        While every effort has been made to present information in the
    criteria documents as accurately as possible without unduly delaying
    their publication, mistakes might have occurred and are likely to
    occur in the future. In the interest of all users of the environmental
    health criteria documents, readers are kindly requested to communicate
    any errors found to the Division of Environmental Health, World Health
    Organization, Geneva, Switzerland, in order that they may be included
    in corrigenda which will appear in subsequent volumes.

        In addition, experts in any particular field dealt with in the
    criteria documents are kindly requested to make available to the WHO
    Secretariat any important published information that may have
    inadvertently been omitted and which may change the evaluation of
    health risks from exposure to the environmental agent under
    examination, so that the information may be considered in the event of
    updating and re-evaluation of the conclusions contained in the
    criteria documents.



    Dr H. Buchwald, Assistant Deputy Minister, Alberta Department of
        Labour, Edmonton, Alberta, Canada  (Chairman)

    Dr V.A. Cizikov, Central Institute for Advanced Medical Training,
        Moscow, USSR

    Dr E. Haak, Physiology Branch, Clinical Studies Division, Health
        Effects Research Laboratory, US Environmental Protection Agency,
        Research Triangle Park, NC, USA

    Dr P. Iordanidis, National Technical University of Athens, Athens,

    Dr K. Ishikawa, Department of Public Health, School of Medicine, Chiba
        University, Chiba, Japan

    Dr V. Kodat, Hygiene Department, Ministry of Health of the Czech
        Socialist Republic, Prague, Czechoslovakia  (Vice-Chairman)

    Dr K. Kurppa, Department of Occupational Medicine, Institute of
        Occupational Health, Helsinki, Finland

    Professor P.J. Lawther, Clinical Section, Medical Research Council
        Toxicology Unit, St Bartholomew's Hospital Medical College,
        London, England

    Mr I.R.C. McDonald, Chemistry Division, Department of Scientific &
        Industrial Research, Petone, New Zealand  (Rapporteur)

    Dr G. Winneke, Institute for Air Hygiene & Silicosis Research,
        Düsseldorf, Federal Republic of Germany

     Representatives of other organizations

    Mr J. Janczak, Economic Commission for Europe, Geneva, Switzerland

    Dr D. Djordjevic, International Labour Office, Geneva, Switzerland

    Mr C. Satkunanthan, International Register of Potentially Toxic
        Chemicals of the United Nations Environment Programme, Geneva,


    Dr J.J. Vostal, Biomedical Science Department, General Motors Research
        Laboratories, Warren, MI, USA


    Mrs B. Goelzer, Scientist, Office of Occupational Health, Division of
        Noncommunicable Disease, WHO, Geneva, Switzerland

    Dr Y. Hasegawa, Medical Officer, Control of Environmental Pollution &
        Hazards, Division of Environmental Health, WHO, Geneva,

    Dr R. Horton, Senior Research Adviser, Health Effects Research
        Laboratory, US Environmental Protection Agency, Research Triangle
        Park, NC, USA  (Temporary Adviser)

    Dr J. Korneev, Scientist, Control of Environmental Pollution &
        Hazards, Division of Environmental Health, WHO, Geneva,
        Switzerland  (Secretary)

    Dr H. de Koning, Scientist, Control of Environmental Pollution &
        Hazards, Division of Environmental Health, WHO, Geneva,

    Dr M. Vandekar, Medical Officer, Pesticides Development & Safe Use,
        Division of Vector Biology & Control, WHO, Geneva, Switzerland

    Dr V.B. Vouk, Chief, Control of Environmental Pollution & Hazards,
        Division of Environmental Health, WHO, Geneva, Switzerland


        A WHO Task Group on Environmental Health Criteria for Carbon
    Monoxide met in Geneva from 11 to 17 October 1977. Dr V.B. Vouk,
    Chief, Control of Environmental Pollution and Hazards, opened the
    meeting on behalf of the Director-General. The Task Group reviewed and
    revised the second draft of the criteria document and made an
    evaluation of the health risks from exposure to carbon monoxide.

        The first and second drafts were prepared by Dr S.M. Horvath of
    the Institute of Environmental Studies, University of California,
    Santa Barbara, USA. The comments on which the second draft was based
    were received from the national focal points for the WHO Environmental
    Health Criteria Programme in Bulgaria, Canada, Czechoslovakia, France,
    Netherlands, Poland, USSR, and USA and from the International Labour
    Organisation (ILO), Geneva, the Food and Agriculture Organization of
    the United Nations (FAO), Rome, the United Nations Educational,
    Scientific and Cultural Organization (UNESCO), Paris, the United
    Nations Industrial Development Organization (UNIDO), Vienna, the
    Permanent Commission and International Association on Occupational
    Health, the Commission on Atmospheric Environment, International Union
    of Pure and Applied Chemistry (IUPAC), and from the Pan American
    Sanitary Engineering Center (CEPIS).

        The collaboration of these national institutions, international
    organizations and WHO collaborating centres is gratefully
    acknowledged. Without their assistance this document would not have
    been completed. The Secretariat wishes to thank, in particular,
    Professor P.J. Lawther and Mr R.E. Waller of the Medical Research
    Council Toxicology Unit, St Bartholomew's Hospital Medical College,
    London, and Dr G. Winneke of the Institute for Air Hygiene and
    Silicosis Research, Düsseldorf, for their help in the scientific
    editing of the document.

        This document is based primarily on original publications listed
    in the reference section. However, several recent publications broadly
    reviewing health aspects of carbon monoxide have also been used
    including those of the Commission of the European Communities (1974),
    NAS/NRC (1977), US Department of Health, Education and Welfare (1970,
    1972), and Committee on the Challenges of Modern Society (1972).

        Details of the WHO Environmental Health Criteria Programme,
    including some of the terms frequently used in the documents, may be
    found in the introduction to the publication "Environmental Health
    Criteria 1 -- Mercury" published by the World Health Organization,
    Geneva, 1976, and now available as a reprint.

    The following conversion factorsa have been used in this document:

       carbon monoxide      1 ppm = 1145 µg/m3   1 µg/m3 = 0.873 ppm

       methylene chloride   1 ppm = 3480 µg/m3   1 µg/m3 = 0.288 ppm

       nitrogen dioxide     1 ppm = 1880 µg/m3   1 µg/m3 = 0.532 ppm

       ozone                1 ppm = 2000 µg/m3   1 µg/m3 = 0.500 ppm

       peroxyacetyl nitrate  1 ppm = 5000 µg/m3  1 µg/m3 = 0.200 ppm

                    1 Torr = 1.333 × 102 pascals = 1 mmHg


    a  All conversion factors for atmospheric pollutants refer to 25°C
       and 101 kPa (1 atm) pressure.


    1.1  Summary

    1.1.1  Properties and analytical methods

        Carbon monoxide (CO) is a colourless, odourless, tasteless gas
    that is slightly less dense than air. It is a product of incomplete
    combustion of carbon-containing fuels and is also produced by some
    industrial and biological processes. Its health significance as a
    contaminant of air is largely due to the fact that it forms a strong
    coordination bond with the iron atom of the protohaem complex in
    haemoglobin forming carboxyhaemoglobin (HbCO) and thus impairs the
    oxygen-carrying capacity of the blood. The dissociation of
    oxyhaemoglobin is also altered by the presence in blood of
    carboxyhaemoglobin so that the supply of oxygen to tissues is further
    impaired. The affinity of haemoglobin for carbon monoxide is roughly
    240 times that of its affinity for oxygen; the proportions of
    carboxyhaemoglobin and oxyhaemoglobin in blood are largely dependent
    on the partial pressures of carbon monoxide and oxygen. Carbon
    monoxide is absorbed through the lungs and the concentrationa 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 time of exposure, pulmonary ventilation, and the
    carboxyhaemoglobin originally present before inhalation of the
    contaminated air. Formulae exist by which these estimates can be made.
    In addition to its reaction with haemoglobin, carbon monoxide combines
    with myoglobin, cytochromes, and some enzymes; the health significance
    of these reactions is not clearly understood but is likely to be of
    less importance than that of the reaction of the gas with haemoglobin.

        Methods available for the measurement of carbon monoxide in
    ambient airb range from fully automated methods using the non-
    dispersive infrared technique and gas chromatography to very simple
    semiquantitative manual methods using detector tubes. Since the
    formation of carboxyhaemoglobin in man is dependent on many factors


    a  Throughout the document, the word concentration refers to mass
       concentration, unless otherwise stated.

    b  Selected Methods of Measuring Air Pollutants, WHO Offset
       Publication No. 24 (1976) published under the joint sponsorship of
       the United Nations Environment Programme and the World Health
       Organization, Geneva.

    including the variability of ambient air concentrations of carbon
    monoxide, carboxyhaemoglobin concentrations should be measured rather
    than calculated. Several relatively simple methods are available for
    determining carbon monoxide either by analysis 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.

    1.1.2  Sources of environmental pollution

        At present, the significance of natural sources of carbon monoxide
    for man is uncertain. Estimates of man-made carbon monoxide emissions
    vary from 350 to 600 million tonnes per annum. By far the most
    important source of carbon monoxide at breathing level is the exhaust
    of petrol-powered motor vehicles. The emission rate depends on the
    type of vehicle, its speed, and its mode of operation. Other sources
    include heat and power generators, some industrial processes such as
    the carbonization of fuel, and the incineration of refuse. Faulty
    domestic cooking and heating appliances may be important sources that
    are often overlooked.

    1.1.3  Environmental levels

        Natural background levels of carbon monoxide are low
    (0.01-0.9 mg/m3 or 0.01-0.8 ppm). Carbon monoxide concentrations in
    urban areas are closely related to motor traffic density and to
    weather and vary greatly with time and distance from the sources. The
    configuration of buildings is important and concentrations fall
    sharply with increasing distance from the street.

        There are usually well-marked diurnal patterns with peaks
    corresponding to the morning and evening "rush hours". Data from Japan
    and the USA show that 8-h mean concentrations of carbon monoxide are
    generally less than 20 mg/m3 (17 ppm). However, maximum 8-h mean
    concentrations of up to 60 mg/m3 (53 ppm) have occasionally been
    recorded. Much higher relatively transient peaks may be observed in
    still weather where there is traffic congestion, and high
    concentrations can be found in confined spaces such as tunnels,
    garages, and loading bays in which vehicles operate and in vehicles
    with faulty exhaust systems. There may be relatively high pollution by
    carbon monoxide in workplaces and in some homes with cooking and
    heating appliances that are faulty or do not have flues.

        By far the commonest cause of high carboxyhaemoglobin
    concentrations in man is the smoking of tobacco and the inhalation of
    the products by the smoker.

    1.1.4  Effects on experimental animals

        Many experiments on animals have yielded valuable information
    about the effects of carbon monoxide. There is general agreement that
    most animals die when carboxyhaemoglobin levels exceed about 70% and

    that the rate of administration of the gas is important in determining
    the outcome. It is also agreed that carboxyhaemoglobin levels
    exceeding 50% are often associated with damage to organs including the
    brain and the heart. When animals are exposed to lower concentrations,
    the effects are more difficult to discern and may be manifested as
    changes in metabolism and biochemistry, alterations in the blood, or
    changes in behaviour. There is evidence that some animals adapt to
    exposure to comparatively low concentrations of carbon monoxide. As
    might be expected, the variability of reported results of experiments
    increases as the effects become less marked and the need for
    scrupulous experimental design and technique becomes more important.
    Of particular importance is the interpretation of the claims of some
    workers that continuous intermittent exposure of animals to
    concentrations resulting in carboxyhaemoglobin levels of 10-20% can
    produce demonstrable histological changes in the myocardium, blood
    vessels, and central nervous system. There are claims that such
    exposures affect cholesterol uptake in the aorta and the coronary
    arteries. The relevance of these findings, if accepted as real, are
    obvious for the aetiology of cardiovascular diseases in man and,
    therefore, must be assessed with great caution. It is also important
    to study carefully the reports of research workers who have failed to
    find evidence of damage.

    1.1.5  Effects on man

        The effects on man of exposure to high concentrations of carbon
    monoxide are well documented and the diagnosis, treatment, and
    sequelae of acute carbon monoxide poisoning are adequately dealt with
    in standard texts. Recently much attention has been paid to the
    possible effects on function and structure of exposure to carbon
    monoxide concentrations resulting in carboxyhaemoglobin levels of 10%
    or less. Carbon monoxide acts primarily by interfering with oxygen
    transport and as the central nervous system is more sensitive to
    hypoxia than the other systems of the body, much work has been done on
    the impairment of vigilance, perception, and the performance of fine
    tasks following exposure to concentrations of carbon monoxide too low
    to produce clinical signs or symptoms. Many common drugs, beverages,
    food, and fatigue can alter alertness, efficiency, and dexterity and
    reported observed effects of low concentrations of carbon monoxide are
    difficult, if not impossible, to interpret when no account is given of
    precautions taken in the experimental design to eliminate or assess
    the separate effects of other stresses. Again, great attention must be
    paid to reports of impeccable experiments that have failed to
    reproduce effects already reported. There would seem to be some
    justification for accepting the possibility that concentrations of
    carboxyhaemoglobin exceeding 2.5% might be associated with some
    impairment of vigilance and other modes of perception. However, it
    cannot be emphasized too strongly that when assessing the significance
    (health and social) of this, the effects that many other commonly
    acceptable factors might have on the tests should be taken into
    account. It is possible, even likely, that the damaged heart and

    respiratory system are more prone to impairment by carbon monoxide
    than the intact brain. Skeletal muscle is sensitive to hypoxia and
    obviously its sensitivity is enhanced by arterial disease. However, of
    much greater importance is the effect of carbon monoxide on the
    ischaemic myocardium which is especially vulnerable to additional
    hypoxia. Evidence has been reported of changes in cardiac function and
    the time of onset of angina pectoris on exercise when
    carboxyhaemoglobin levels exceed 2.5%. Changes in oxygen uptake and
    transfer are theoretically possible at or below these levels, and thus
    there will be some patients whose cardiac function is so impaired that
    any further hypoxic stress from carbon monoxide or from other factors,
    will be intolerable. Similarly, the gross hypoxia of all tissues seen
    in cases of severe respiratory disease renders the body even more
    susceptible to the effects of low concentrations of carbon monoxide.
    It follows that there is reason to regard carbon monoxide in this
    sense as a pollutant for which the "threshold" is that concentration
    which would be in equilibrium with the carboxyhaemoglobin produced
    endogenously by the breakdown of blood pigments. However, it must be
    realized that at these extremes of illness other usually trivial
    stresses, such as ambient and body temperatures, infection, noise, and
    anxiety, may be of much greater importance.

        In addition to patients with diseases of the heart and the lungs,
    it is likely that other groups, such as the anaemic, elderly,
    postoperative patients, or those with cerebrovascular arteriosclerosis
    may be at special risk. The effects on the fetus  in utero of carbon
    monoxide, especially that derived from maternal smoking, are of
    special interest. The effects of carbon monoxide on people living at
    high altitudes are greater than on those living at sea level and this
    added risk must be assessed. There is a distinct possibility that
    healthy man may adapt to the mild hypoxia caused by carboxyhaemo-
    globin levels of about 3-5% (or to even higher values) as he does to
    high altitude. Many workers in industry, and even more smokers,
    repeatedly have carboxyhaemoglobin values such as these and there have
    been few attempts to correlate symptoms or pathological findings
    specifically with these levels of carboxyhaemoglobin. There is little
    evidence that exposure to comparatively low concentrations of carbon
    monoxide causes disease though it is suspected of being an etiological
    factor in the association of heart disease with smoking.

    1.1.6  Evaluation of health risk

        There can be no doubt that the assessment of risk of exposure to
    the lower concentrations of carbon monoxide in inspired air in
    populations containing the sick and the fit, the smoker and nonsmoker,
    the very young and the very old, would be a complex, if not
    impossible, task, even if the ambient concentration of carbon monoxide
    remained constant in time and place. Rough guidance, therefore, is all
    that is possible in the light of available evidence derived from sound
    scientific work. Those responsible for the welfare of specially

    susceptible groups must refer critically to the evidence from
    published works and to that reviewed in this document and make their
    special decisions. There is general agreement that any individual
    should be protected from exposure to carbon monoxide that would result
    in carboxyhaemoglobin levels of 5% for any but transient periods, and
    that especially susceptible persons ought not to be subjected to
    concentrations giving carboxyhaemoglobin levels exceeding 2.5%. Advice
    concerning such subjects must depend on individual assessment of their
    clinical status and of other environmental factors including the
    demands of the tasks they have to perform (persons engaged in driving,
    monotonous tasks, keeping watch, etc., though healthy, might require
    special consideration). The real possibility that adaptation occurs
    makes consideration of the smoker and industrially exposed worker
    difficult; ethical as well as health factors might affect action but
    it would seem reasonable to have the same limit of 5% carboxy-
    haemoglobin for industrial workers as for the rest of the healthy
    population. The smoker inflicts high carboxyhaemoglobin values on
    himself, by choice; he ought to be told of the evidence that this
    habit might be harmful and then be subject to the levels of protection
    recommended above.

    1.2  Recommendations for Further Studies

        (a) Though some would maintain that there are enough data on
    levels of carbon monoxide in urban air, there is a need for further
    surveys of air and blood levels so that some more precise correlations
    may be established. Various populations in various places should be
    studied properly to assess the magnitude of the problem posed by
    carbon monoxide in the air of towns, houses, and workplaces.

        (b) Opinions concerning levels of carbon monoxide below which no
    adverse effects are seen and above which impairment of mental or
    bodily functions seems to occur are based on comparatively few data.
    These have been obtained from experiments concerning vigilance tests
    and other tests of perception and performance, or the effects of
    carbon monoxide on exercising cardiac and skeletal muscle and on
    symptoms in patients with cardiovascular disease. There is an obvious
    need to provide further data concerning larger numbers of subjects in
    soundly designed experiments, the results of which should be properly
    analysed. By such means it is hoped that dose-response and
    concentration-response relationships may be established. The continued
    refinement and application of epidemiological techniques must
    complement experimental work.

        (c) There are few data for assessing the possible consequences of
    exposure of man to long-term, low concentrations of carbon monoxide.
    There is a need to evaluate the possible effects of such exposures and
    to determine the role of adaptation.

        (d) Evidence that carbon monoxide plays a role in the observed
    deleterious effects of smoking has been produced by experiments on
    animals but more work is needed to confirm and extend these findings.
    The hazards to the fetus of maternal smoking need to be evaluated and
    the susceptibility of the fetus to carbon monoxide from whatever
    source needs to be studied.

        (e) The effects of comparatively low levels of carboxyhaemoglobin
    on such skills as driving, and on perception in other tasks, need
    further careful investigation. Not only must the possibility of the
    enhancement of effects of carbon monoxide by other commonly occurring
    factors be assessed, but there is a need to compare the effects of
    carbon monoxide on vigilance and performance with the effects of such
    common agents as therapeutic drugs, alcohol, fatigue, and food.
    Attention is drawn to the difficulties inherent in the design of such
    tests as well as to the problems involved in the assessment of the
    health and social significance of the results.

        (f) The possible effects of carbon monoxide on people living and
    working at high altitudes (including aircraft pilots) have received
    too little attention. There is a need for further work on this


    2.1  Physical and Chemical Properties

        Carbon monoxide (CO) is a colourless, odourless, and tasteless gas
    which is commonly formed during the incomplete combustion of
    carbonaceous material. It is slightly lighter than air and only
    slightly soluble in water. Carbon monoxide absorbs electromagnetic
    radiation in the infrared region with the main absorption band centred
    at 4.67 µm; this property is used for the measurement of carbon
    monoxide concentrations in air. Some other physical properties of
    carbon monoxide are listed in Table 1.

        Table 1.  Physical properties of carbon monoxide

    Relative molecular mass                      28.01
    Critical point                               -140.2°C at 34.5 atm (3.5 MPa)
    Melting point                                -205.1°C
    Boiling point                                -191.5°C
    Density, at 0°C, 1 atm                       1.250 g/litre
             at 25°C, 1 arm                      1.145 g/litre
    Specific gravity relative to air             0.967
    Solubility in water at 0°C, 1 atm            3.54 ml/100 ml
                        at 25°C, 1 atm           2.14 ml/100 ml
                        at 37°C, 1 atm           1.83 ml/100 mla
    Conversion factors:
         at 0°C, 1 atm                           1 mg/m3 = 0.800 ppmb
                                                 1 ppm = 1.250 mg/m3
         at 25°C, 1 atm                          1 mg/m3 = 0.873 ppm
                                                 1 ppm = 1.145 mg/m3

    a  Value obtained by graphic or calculated interpolation (Altman et al., 1971).
    b  Parts per million by volume.

        While carbon monoxide is chemically inert under normal conditions
    of temperature and pressure (25°C; 1 atm (101 kPa)), it becomes
    reactive at higher temperatures and can act as a strong reducing
    agent. At 90°C, it reacts with iodine pentoxide to produce iodine
    vapour. At 150°C, it also releases mercury vapour from mercury(II)
    oxide. Both reactions are used in the analytical chemistry of carbon
    monoxide. The oxidation of carbon monoxide to carbon dioxide (CO2)
    is accelerated by metallic catalysts such as palladium on silica gel,
    or by a mixture of manganese and copper oxides (Hopcalite).

        In forming carboxyhaemoglobin (HbCO), carbon monoxide reacts with
    the iron in protohaem -- a constituent of haemoglobin -- and forms
    strong coordination bonds. Thus carboxyhaemoglobin is toxic because it
    is about 200 times more stable than oxyhaemoglobin (HbO2). Carbon
    monoxide also combines reversibly with myoglobin and cytochromes,
    including P-450.

        The environmental chemistry of carbon monoxide is discussed in
    section 4.2.

    2.2  Methods of Measuring Carbon Monoxide in Ambient Air

        Three methods are most commonly used for the routine estimation of
    carbon monoxide in air. These are the continuous analysis method based
    upon nondispersive infrared absorption spectroscopy (NDIR); the semi-
    continuous analysis method using gas chromatographic techniques and a
    semiquantitative method employing detector-tubes. Other methods
    include catalytic oxidation, electrochemical analysis, mercury
    displacement, and the dual isotope technique (WHO, 1976).

        In the NDIR method, infrared radiation is divided into two beams
    that are directed through a reference and a sample cell, respectively.
    Any carbon monoxide introduced into the sample cell will absorb
    radiation at the characteristic band centred at 4.67 µg, causing the
    detector to produce an output signal proportional to the concentration
    of carbon monoxide in the sample cell. NDIR analysers are produced by
    several manufacturers in the form of continuous, automated
    instruments. Good commercial instruments have a detection limit of
    about 1 mg/m3 (0.87 ppm). Carbon dioxide and water vapour interfere
    but there are several techniques to minimize this interference.

        In chromatographic methods, carbon monoxide is first separated
    from water vapour, carbon dioxide, and hydrocarbons. It is then
    catalytically reduced to methane and passed through a flame ionization
    detector, the output signal of which is proportional to the carbon
    monoxide concentration in the air sample. The most common
    concentration range in commercial instruments is from about 1 to
    350 mg/m3 (1-300 ppm) but others are available with a range of about
    0.02 to 1.00 mg/m3 (0.017-0.87 ppm). Gas chromatography is
    particularly suitable, when low concentrations of carbon monoxide have
    to be measured with a high degree of specificity.

        The detector tube method is very simple and can be used for
    estimating concentrations above 5 mg/m3. Air is drawn through
    specially manufactured tubes containing a chemical agent that changes
    colour if carbon monoxide is present and can be used to estimate
    concentrations. The advantages and limitations of detector tubes are
    further discussed in a WHO manual (WHO, 1976).

        A well known method is based on the measurement of the temperature
    rise caused by the catalytic oxidation of carbon monoxide. The limit
    of detection is about 1 mg/m3. Most hydrocarbons will interfere
    unless removed (NAS/NRC, 1977). For measurements in ambient air, the
    sensitivity may not always be sufficient.

        Electrochemical analysers (Hersch, 1964, 1966) are based on the
    liberation by carbon monoxide of iodine from iodine pentoxide (at
    150°C), which is then reduced at the cathode of a galvanic cell. The
    current developed is a measure of the carbon monoxide concentration
    present in the air sample.

        A further highly sensitive method is based on the reduction of
    mercury(II) oxide by carbon monoxide at a temperature between 170 and
    210°C. Mercury vapour generated during this reaction is determined by
    absorption spectrophotometry at 253.7 nm. This method, as modified by
    Seller & Junge (1970), has a reported detection limit of about
    3 µg/m3.

        The slight difference in the fluorescence spectra of 16CO and
    18CO is used for carbon monoxide determination by the so-called dual
    isotope fluorescence method. Instruments using this principle are
    available with ranges of 0-20 mg/m3 (0-17.5 ppm) and 0-200 mg/m3
    (0-175 ppm) with a reported detection limit of about 0.2 mg/m3
    (0.17 ppm). Other pollutants present cause very little interference
    (McClatchie et al., 1972).

        An important part of any carbon-monoxide measurement procedure is
    the calibration technique. Many publications deal with this topic and
    the Deutsche Industrienormen Ausschuss (DIN) and the International
    Standard Organization (ISO) have special groups for establishing
    suitable calibration standards.

    2.3  Biological Monitoring

        Blood carboxyhaemoglobin can be satisfactorily determined in a
    venous blood sample, which should be collected in a closed container
    containing an anticoagulant (dry sodium heparin or di-sodium ethylene-
    diaminotetracetic acid, EDTA). Blood samples may be preserved for
    several days prior to analysis if kept cold (4°C) and in the dark.
    Complete mixing of blood must be attained if carbon monoxide and
    haemoglobin are to be measured separately. Total haemoglobin is
    conveniently determined by conversion to cyanmethaemoglobin (Van
    Kampen & Zijlstra, 1961), which is then determined spectrophoto-
    metrically (Drabkin & Austin, 1935).

        Various methods are available for the determination of carboxy-
    haemoglobin by spectrophotometry or by the liberation of carbon
    monoxide (WHO, 1976). One method consists of measuring the absorbance
    at 4 wavelengths in the Soret region (390-440 nm) of a blood sample

    diluted to about 1:70 with an aqueous solution of ammonia (Small et
    al., 1971). Carboxyhaemoglobin and methaemoglobin are estimated from
    absorbance values, and oxyhaemoglobin is obtained from the difference.
    The method is precise at low carboxyhaemoglobin concentrations (up to
    25% saturation). A very convenient method is the automated
    differential spectrophotometer (Malenfant et al., 1968), which is
    available commercially as CO-oximeter. Simultaneous absorbance
    measurements are made to determine the three component system (reduced
    haemoglobin, oxyhaemoglobin and carboxyhaemoglobin) contained in a
    haemolysed blood sample. The signals are processed and displayed in a
    digital form as haemoglobin (g/100 ml) and the percentage of
    oxyhaemoglobin and carboxyhaemoglobin. A method has recently been
    described (Rossi-Bernardi et al., 1977) for the simultaneous
    determination of four haemoglobin derivatives (deoxyhaemoglobin,
    oxyhaemoglobin, methaemoglobin, carboxyhaemoglobin) and total oxygen
    contents of 10 µl of whole blood. The spectrophotometric method of
    Commins & Lawther (1965), which has been validated by Lily et al.
    (1972), has the advantage of requiring only 0.01 ml blood obtained
    from a finger prick sample.

        Gas chromatography on molecular sieves with a suitable detection
    system is probably the most satisfactory procedure for the measurement
    of carbon monoxide liberated from carboxyhaemoglobin. Carbon monoxide
    liberation is achieved through acidification. The method described by
    Sotnikov (1971) requires only 0.1 ml of blood and has a limit of
    detection of 0.01 ml of carbon monoxide per 100 ml of blood. Dahms &
    Horvath (1974) have proposed a very accurate method for estimating low
    concentrations of carboxyhaemoglobin. Table 2 compares some techniques
    for the analysis of carboxyhaemoglobin in blood.

        Another approach to the estimation of exposure to carbon monoxide
    is by the analysis of expired air. The subject takes a deep breath and
    holds it for 20 sec. The first 350-500 ml of expired air (dead air
    space) is discarded and the remaining gas (alveolar air) is collected
    in an aluminized mylar bag for analysis, using an NDIR instrument. The
    value of the alveolar technique, pioneered by Sjöstrand (1948), is
    based on the assumption that, during breath-holding, the lung is a
    closed vessel in which blood carboxyhaemoglobin equilibrates with lung
    gas and that Haldane's relationship (see section 6) applies.
    Theoretically, the slope of the straight line relating %
    carboxyhaemoglobin to alveolar  pCO in ppm should be approximately
    0.155 at sea level for % carboxyhaemoglobin values equivalent to a
    carbon monoxide concentration between 0 and 50 ppm, and progressively
    lower for higher concentrations (Coburn et al., 1965). Values
    approximating to this theoretical ratio have been found experimentally
    (Forbes et al., 1945; Malenfant et al., 1968). Although the alveolar
    air method is less precise than the direct measurement of
    carboxyhaemoglobin in blood, it can be used in epidemiological studies
    and for general monitoring (McFarland, 1973) but cannot be used on
    persons with chronic pulmonary disease.

        Table 2.  Comparison of techniques for the analysis of carboxyhaemoglobin in blooda

    Detection method                Sample     Resolutionb    Sample      CVc       Reference
                                    volume     (ml/dl)        analysis    (%)
                                    (ml)                      time

         Van Slyke                  1.0        0.3            15          6         Horvath & Roughton (1942)
         syringe-capillary          0.5        0.02           30          2-4       Roughton & Root (1945)

         spectrophotometric         2.0        0.006          30          1.8       Coburn et al. (1964)
         spectrophotometric         0.1        0.08           10                    Small et al. ( 1971 )
         spectrophotometric         0.4        0.10            3                    Maas et al. (1970)
         spectrophotometric         0.01       0.10           20                    Commins & Lawther (1965)

         thermal conductivity       1.0        0.005          20d         1.8       McCredie & Jose (1967)
         flame ionization           0.1        0.002          20          1.8       Collison et al. (1968)
         thermal conductivity       1.0        0.001          30          2.0       Ayres et al. (1966)
         thermal conductivity       0.25       0.006           3          1.7       Dahms & Horvath (1974)

    a  Adapted from: Dahms & Horvath (1974).
    b  Smallest detectable difference between duplicate determinations.
    c  Coefficient of variation based on samples containing less than 2.0 ml of carbon monoxide
       per decilitre.
    d  Best estimate.


    3.1  Natural Occurrence

        The amount of carbon monoxide produced globally by natural sources
    is at present uncertain. Several investigators have estimated that
    natural sources (primarily oxidation of methane in the atmosphere and
    emissions from the oceans) produce about ten times as much carbon
    monoxide as man-made sources (Spedding, 1974). On the other hand, a
    recent study concluded that the natural production of carbon monoxide
    was much smaller and might be somewhat less than the emissions from
    man-made sources (Seiler, 1975). If this is the case, man-made
    emissions of carbon monoxide may play an important role in the global
    carbon monoxide cycle.

        Several estimates of the production of carbon monoxide by
    atmospheric reactions have been made. Stevens et al. (1972) estimated
    that in the northern hemisphere alone, more than 3 × 109 metric
    tonnes of carbon monoxide are produced annually by the oxidation of
    methane and other organic constituents. McConnell et al. (1971)
    considered that biologically produced methane could be the source of
    approximately 2.5 × 109 metric tonnes of carbon monoxide annually.
    Subsequently, it was calculated, by Weinstock & Nicki (1972), that the
    oxidation of methane alone could produce twenty-five times the
    quantity of carbon monoxide generated by man's activities. Estimates
    by Levy (1972) indicated that the oxidation of methane was a much
    larger source of carbon monoxide that man-made sources.

        The surface layers of the ocean are a second major natural source
    of carbon monoxide. Linnenbom et al. (1973) calculated an upper limit
    of 220 × 106 metric tonnes of carbon monoxide emitted from the oceans.
    Using a model of the flux of gases across the air-sea interface, Liss
    & Slater (1974) estimated a total ocean flux of carbon monoxide of
    43 × 106 metric tonnes per year.

        Among other natural sources of carbon monoxide are forest and
    grass fires, volcanoes, marsh gases, and electric storms. Some carbon
    monoxide is also formed in the upper atmosphere (above 75 km) by the
    photo-dissociation of carbon dioxide (Altshuller & Bufallini, 1965;
    Bates & Witherspoon, 1952). Another natural source of carbon monoxide
    is rainwater, where production of carbon monoxide in the clouds is
    tentatively attributed to the photochemical oxidation of organic
    matter or the slight dissociation of carbon dioxide induced by
    electrical discharges or both (Swinnerton et al., 1971). Some carbon
    monoxide is also formed during germination of seeds and seedling
    growth (Siegel et al., 1962; Wilks, 1959), by the action of
    microorganisms on plant flavonoids (Westlake et al., 1961), and in
    higher plants (Delwiche, 1970). Kelp may be a significant source of
    carbon monoxide. Chapman & Tocher (1966) reported that some float
    cells of kelp contained carbon monoxide concentrations as high as
    916 mg/m3 (800 ppm).

        Carbon monoxide is produced in measurable quantities in man and
    animals as a by-product of haem catabolism.

    3.2  Man-Made Sources

        According to Jaffe (1973), global emissions of man-made carbon
    monoxide in 1970 amounted to 360 million tonnes. Seller (1975)
    calculated the carbon monoxide emissions for 1973 as 600 million
    tonnes. A breakdown of Jaffe's estimate according to the type of
    source is shown in Table 3. The motor vehicle was by far the largest
    contributor accounting for 55% of total emissions. Other
    transportation sources, certain industrial processes, waste disposal
    and miscellaneous burning activities were responsible for the
    remaining carbon monoxide emissions.

    Table 3.  Estimated global man-made emissions of carbon monoxide,

    Source                                 Emissions (106 metric tonnes)

         Motor vehicles: gasoline                   197
                         diesel                       2
         Aircraft                                     5
         Watercraft                                  18
         Railroads                                    2
         Other (nonhighway) motor vehicles           26

         Coal combustion                              4
         Oil combustion                               1
         industrial processes                        41
         Refuse disposal                             23
         Miscellaneous                               41
           Total                                    360

    a  From: Jaffe (1973).

        The tremendous increase in the number and use of motor vehicles
    during the past 30 years has been accompanied by a rapid increase in
    carbon monoxide emissions. In the USA for example, the emission of
    carbon monoxide rose from approximately 73 million tonnes in 1940 to
    about 100 million tonnes in 1970 (US Environmental Protection Agency,
    1973a). In 1968, the upward trend was reversed because of the initial
    impact of motor vehicle emission controls. The rate at which carbon

    monoxide is emitted from motor vehicles varies not only with vehicle
    but also with the mode of operation of the vehicle. The emissions of
    carbon monoxide by other mobile sources are comparatively small;
    however, the emissions from locomotives, boats, and aircraft may
    create local problems.

        Among the stationary sources, the burning of waste material and
    certain industrial processes generate substantial amounts of carbon
    monoxide. Petroleum refineries, iron foundries, kraft-pulp mills,
    carbon-black plants, and sintering processes are the major sources.
    Emission rates for some of these processes are given in Table 4. The
    burning of refuse, either in incinerators or openly, is an important
    source of carbon monoxide. If uncontrolled, the emission rate of
    carbon monoxide from incinerators is about 17.5 kg per tonne of refuse
    burned. If burned openly, the emission rates can vary from about 25 to
    60 kg per tonne, depending upon the type of refuse (US Environmental
    Protection Agency, 1973b). The combustion of fossil fuels in electric
    generating plants, industries, and the home, while resulting in the
    emission of smaller quantities of carbon monoxide individually, may
    constitute a major source when combined.

        Any industrial process or operation, where incomplete combustion
    of carbonaceous material occurs, may easily be of importance as far as
    occupational exposure to carbon monoxide is concerned. Smelting of
    iron ore, gas production works, gasworks and coke ovens, distribution
    and use of both natural gas and coal gas, automobile manufacturing,
    garages, and service stations are among the most important sources for
    occupational exposure to carbon monoxide (Ministry of Labour, 1965).

        It should also be emphasized that tobacco smoke is a most
    significant source of man-made carbon monoxide in a closed environment
    and that the carboxyhaemoglobin levels found in smokers are
    consistently higher than those in nonsmokers.

    Table 4.  Emission rates for carbon monoxide in selected industrial

    Source                                    Emissions (uncontrolled)

     Petroleum refineries
         Fluid catalytic cracking units          39.2 kg/103 litre
         Moving bed catalytic cracking units     10.8 kg/103 litre

     Steel mills
         Blast furnaces--ore charge              875 kg/tonne
         Sintering                               22 kg/tonne
         Basic oxygen furnace                    69.5 kg/tonne

     Gray iron foundries
         Cupola                                  72.5 kg/tonne

     Carbon black
         Channel process                         16 750 kg/tonne
         Thermal process                         negligible
         Furnace process                         2650 kg/tonne

    a  From: US Environmental Protection Agency (1973b).


    4.1  Atmospheric Transport and Diffusion

        The ambient air concentrations of carbon monoxide at locations
    removed from man-made sources are low and variable. Junge et al.
    (1971) reported that background levels of carbon monoxide in the lower
    atmosphere may range from 0.01 to 0.23 mg/m3 (0.009-0.2 ppm).
    Concentrations have been reported of 0.025 to 0.9 mg/m3
    (0.022-0.8 ppm) in North Pacific marine air; 0.04 to 0.9 mg/m3
    (0.036-0.8 ppm) in rural areas of California; 0.07 to 0.30 mg/m3
    (0.06-0.26 ppm) at Point Barrow, Alaska; 0.06 to 0.8 mg/m3
    (0.05-0.7 ppm) in Greenland; and about 0.07 mg/m3 (0.06 ppm) in the
    South Pacific (Cavanagh et al., 1969; Goldman et al., 1973; Robbins et
    al., 1968; Robinson & Robbins, 1970). Seiler & Junge (1969) observed
    similar average concentrations over the North and South Atlantic Ocean
    (0.20 mg/m3 and 0.06 mg/m3 (0.18 and 0.05 ppm) respectively).
    Background levels of carbon monoxide are influenced by the origin of
    the air masses and vertical distributions of carbon monoxide have been
    reported by Seiler & Junge (1969, 1970). They found consistent carbon
    monoxide concentrations of 0.15 mg/m3 (0.13 ppm) at an altitude of
    10 km in both northern and southern hemispheres. In the troposphere,
    average concentrations of 0.11 mg/m3 (0.10 ppm) were observed,
    while, in the stratosphere, the concentrations ranged from 0.03 to
    0.06 mg/m3 (0.027-0.05 ppm). A recent study (Goldman et al., 1973)
    showed that a gradual decrease in carbon monoxide concentrations
    occurred with increasing altitude ranging from approximately
    0.09 mg/m3 (0.08 ppm) at 4 km to 0.05 mg/m3 (0.04 ppm) at 15 km.

    4.2  Environmental Absorption and Transformation

        The residence time of carbon monoxide in the atmosphere is
    believed to be approximately 0.2 years. Background levels do not
    appear to be increasing, indicating the presence of various scavenging
    and removal mechanisms (sinks). Oxidation in the atmosphere and take-
    up by the soil, vegetation, and inland fresh waters have been
    identified as the major removal mechanisms.

        The oceans act as reservoirs for carbon monoxide, since
    considerable quantities are dissolved in the water. Because of the
    equilibrium that exists, carbon monoxide is dissolved or released
    according to conditions depending on the partial pressure of carbon
    monoxide in the atmosphere and on the water temperature.

        The carbon monoxide produced at the earth's surface migrates by
    diffusion and eddy currents to the troposphere and stratosphere where
    it is oxidized to carbon dioxide (CO2 by the hydroxyl (OH) radical.
    This process, however, can account for only a portion of the carbon
    monoxide oxidation. Calvert (1973) suggested several possible
    reactions of carbon monoxide with other pollutants also involving the

    hydroxyl radical and Westberg et al. (1971) demonstrated that carbon
    monoxide can accelerate both the oxidation of nitric acid (NO) to
    nitrogen dioxide (NO2) and the rate of ozone formation.

        Microorganisms can metabolize carbon monoxide and large quantities
    of these organisms are present in the soil. Ingersoll et al. (1974)
    showed that desert soils took up carbon monoxide at the lowest rates
    and tropical soils at the highest. Cultivated soils had a lower carbon
    monoxide uptake rate than uncultivated soils, presumably because there
    is less organic matter in the surface layer.

        It has been reported that some plant species can remove carbon
    monoxide from the atmosphere by oxidation to carbon dioxide or by
    conversion to methane (Bidwell & Fraser, 1972). However, Ingersoll et
    al. (1974) could not measure carbon monoxide removal by any plants
    tested in an artificial atmosphere containing a carbon monoxide
    concentration of 115 mg/m3 (100 ppm). The process of plant
    respiration as a carbon monoxide sink still requires considerable
    further study.

        It is believed that inland fresh waters may remove some carbon
    monoxide from the atmosphere. Rainwater contains appreciable
    quantities of carbon monoxide and the runoff into the lakes and rivers
    may account for additional removal.


    5.1  Ambient Air Concentrations and Exposures

        Carbon monoxide concentrations in the ambient air have been
    measured in many large urban areas for a number of years. Although a
    substantial body of data is now available, it is still not possible to
    assess the overall human exposure to carbon monoxide adequately. Both
    the extreme temporal and spatial variability of carbon monoxide
    concentrations and the small number of monitoring stations in each
    urban area make the assessment of human exposure difficult. The
    available data, however, provide some indication of the patterns and
    trends of urban carbon monoxide concentrations.

        Concentrations in urban areas usually follow a very pronounced
    diurnal pattern, and, although influenced by factors such as location
    and meteorological conditions, their values are closely correlated
    with the amount of motor vehicle traffic. Thus, although the exact
    shape of the curve representing the temporal variation in carbon
    monoxide concentrations over a day, varies with the situation, it
    usually shows two peaks, corresponding to the morning and evening
    traffic rush hours. Such curves have been established by many authors
    (Colucci & Begeman, 1969; Göthe et al., 1969; Waller et al., 1965), by
    means of continuous carbon monoxide monitoring. In general, an initial
    peak is detected between 07h00 and 09h00 coinciding with heavy morning
    traffic, and another, in the late afternoon, as illustrated in Fig. 1.
    However, there may be exceptions to this typical pattern, as shown in
    Fig. 2, which presents data from a monitoring station in New York City
    (Martin & Stern, 1974). In this case, the traffic conditions were such
    that carbon monoxide concentrations remained high during most of the
    day. Because of changes in traffic patterns, the carbon monoxide
    concentrations are usually lower at weekends than on weekdays and
    follow a different diurnal pattern.

        At any location, the concentration of carbon monoxide due to motor
    vehicle traffic depends on the following specific variables:

        (a) number of vehicles operating;

        (b) engine characteristics of the operating vehicles (capacity,
            gasoline or diesel, use of emission control devices);

        (c) speed of traffic and gradient;

        (d) temperature (as it affects the operating efficiency of the

    More general variables include the meteorological conditions
    (including wind speed and direction, and temperature gradients) and
    the geometry of locality (shape and height of buildings, width of
    street, etc.).

    FIGURE 1

    FIGURE 2

        Carbon monoxide concentrations are normally reported in terms of
    8-h average concentrations. This averaging time has been used because
    it takes from 4 to 12 h for the carboxyhaemoglobin levels in the human
    body to reach equilibrium with the ambient carbon monoxide
    concentrations. Two types of approaches have been used for calculating
    the 8-h average (McMullen, 1975). One approach is to examine all
    possible 8-h intervals and calculate a moving 8-h average (24, 8-h
    averages each day). The other approach is to examine three
    consecutive, nonoverlapping, 8-h intervals per day. It would appear
    that the moving average approach offers some advantages in that it
    approximates the human body's integrating response to cumulative
    carbon monoxide exposure. In addition to the 8-h averages, carbon
    monoxide concentrations are also reported in terms of other averaging
    times and frequency distributions.

        Carbon monoxide concentrations in the ambient air vary
    considerably, not only among urban areas but within cities as well.
    The maximum 8-h mean concentrations measured at more than 200
    monitoring stations in the USA in 1973 ranged from less than
    10 mg/m3 to 58 mg/m3 (8.7-51 ppm) with most of the values being
    less than 30 mg/m3 (26 ppm) (Martin & Stern, 1974). The highest 8-h
    mean concentration of 59 mg/m3 was observed at a monitoring station
    in New York City. Data from a 38 station network in Japan showed that
    the 8-h standard of 23 mg/m3 (20 ppm) was not exceeded (Environment
    Agency, 1973). That carbon monoxide concentrations are extremely
    variable within an urban area is illustrated by the maximum 8-h means
    observed at monitoring stations in the metropolitan Los Angeles area
    in 1973. They ranged from 7 mg/m3 (6 ppm) in the outlying areas to
    49 mg/m3 (42.6 ppm) near the centre of the city. The maximum 1-h
    mean concentrations exhibit a similar variability ranging from less
    than 10 mg/m3 (8.7 ppm) in some areas to over 90 mg/m3 (78.3 ppm)
    in others. The highest 1-h mean concentration observed in 1973 was
    92 mg/m3 (80 ppm) at a monitoring station in Philadelphia; at more
    than 80% of the stations the maximum 1-h concentration was below
    50 mg/m3 43.5 ppm). In Japan the maximum 1-h concentrations ranged
    from 5 mg/m3 to 48 mg/m3 (4.3-41.8 ppm).

        Although the data presented above refer to measurements carried
    out in the USA and Japan, it is indicated that very similar conditions
    are prevalent in many parts of the world.

        Annual average concentrations of carbon monoxide are not of much
    value for assessing human exposure, although they do provide an
    indication of the long-term trends. Annual average concentrations of
    carbon monoxide in most locations fall well below 10 mg/m3 (8.7 ppm)
    (Stewart et al., 1976).

        Usually, the monitoring stations are located so that they can
    provide representative information of air pollution within the
    community. However, in certain areas, such as loading platforms and

    underpasses, the concentrations found are much higher than those in
    city streets. At Chicago post office loading platforms (Conlee et al.,
    1967), ambient carbon monoxide concentrations ranged from 10 to
    88 mg/m3 at various locations. Wright et al. (1975) determined the
    levels of carbon monoxide encountered by pedestrians and street
    workers in Toronto. They reported carbon monoxide levels ranging from
    11 to 57 mg/m3, with much higher concentrations in poorly ventilated
    underpasses and underground garages.

        Industry also contributes to the pollution of the ambient air. Gas
    generator plants (Nowara, 1975), smelters (Morel & Szemberg, 1971),
    steelworks (Butt et al., 1974; Maziarka et al., 1974); plastics works
    (Argirova, 1974, unpublished data)a, electric generating plants
    (Grigorov et al., 1968), and mines (Notov, 1959) have all been
    suggested, among other industrial activities, as sources of
    environmental carbon monoxide pollution. Rural work places, especially
    those involving intensive livestock production facilities, can provide
    high ambient levels of carbon monoxide. Concentrations up to
    136 mg/m3 (119 ppm) have been found in these conditions, with high
    levels of carboxyhaemoglobin in both animals and workers (Long &
    Donham, 1973).

    5.2  Indoor Concentrations and Exposure

        Carbon monoxide is widely generated indoors by heating, cooking,
    and tobacco smoking. According to Yocom et al. (1971), gas heating
    systems did not appear to affect indoor carbon monoxide
    concentrations, but gas stoves, water heaters, and automobile activity
    in attached garages could be major sources. These authors also
    reported that carbon monoxide concentrations were generally unrelated
    to outdoor levels. Obviously, peak concentrations in the kitchen were
    observed during meal times, Sofoluwe (1968) reported extremely high
    concentrations of carbon monoxide in Nigerian dwellings, where
    firewood was used for cooking. During the preparation of meals,
    average carbon monoxide concentrations were reported to be over
    1000 mg/m3 (870 ppm) with peak levels as high as 3400 mg/m3
    (2960 ppm). Sidorenko et al. (1970) found an indoor level of carbon
    monoxide of 32.3 mg/m3 (28 ppm) some two and a half hours after
    domestic gas combustion began, when there was no ventilation, but only
    13.4 mg/m3 (11.6 ppm) when ventilation was provided. The use of
    improved stoves resulted in better conditions (Sidorenko et al.,


    a  "Argirova, M. [Atmospheric air pollution by a plant processing
       plastics.] In:  Proceedings of the First National Conference on
       Sanitary Chemistry of the Air, Sofia, Bulgaria, 26-27 November,
       1974 (in Bulgarian).

        Rench & Savage (1976) have also investigated winter levels of
    carbon monoxide in the home. Outdoor concentrations were lower than
    those found indoors. Age of building, type of appliance, heating
    sources, and socio-economic status were statistically significantly
    related to indoor levels of carbon monoxide, higher levels occurring
    in the kitchens of old houses and in homes belonging to families in
    lower income groups. Levels were also higher in kitchens with space
    wall heaters compared with those with forced air, gravity feed, or hot
    water heating systems. Places of recreation may be problem areas.
    Excessive levels of carbon monoxide were found in ice-skating areas
    where ice-resurfacing machines were used. Levels as high as
    348 mg/m3 (304 ppm) were found in such an arena after complaints of
    illness among children skating there were reported to the local health
    department (Johnson et al., 1975). Improperly regulated space heaters
    in such premises could also produce high concentrations of carbon
    monoxide. This was recently reported to have occurred in an Alaskan
    ice-skating arena.

        That outdoor concentrations of carbon monoxide can sometimes
    strongly influence indoor levels was illustrated in a study conducted
    in New York City (Lee, 1972). As shown in Fig. 3, the concentrations
    inside and outside an apartment building followed the same general
    pattern and were closely related to nearby traffic flows.

        Relatively high concentrations of carbon monoxide have also been
    observed inside the passenger compartment of motor vehicles (Borst,
    1970). Carbon monoxide may enter the compartment from faulty or
    damaged exhaust systems or from the surrounding air, in road traffic.
    The carbon monoxide level in the compartment is often higher than that
    found outside the vehicle. Haagen-Smit (1966) found an average
    concentration in a vehicle passenger compartment of 42 mg/m3
    (36.5 ppm) on a Los Angeles freeway during the rush hour traffic
    (higher concentrations have been reported by Aronow et al. (1972).

        It should be emphasized that cigarette smoking is the most common
    source of carbon monoxide for the general population (Table 5).

        Exposure to smoking primarily affects the carboxyhaemoglobin level
    of the smoker himself (Kahn et al., 1974; Landaw, 1973). In some
    circumstances, such as poorly ventilated enclosed spaces, the tobacco
    smoke may affect all of the occupants (section 8.1.6).

    FIGURE 3

    Table 5.  Percentage carboxyhaemoglobin levels in smokers and

    Description                        Nonsmokers           Smokers

                                     mean    range       mean    range

    UK pregnant women                1.1                 3.6
    Meat porters                     1.6                 5.1
    Office workers                   1.3                 6.2
    London office workers            1.12    0.1-2.7     5.5     2.2-13.0
    29 000 USA blood donors          1.39    0.4-6.9     5.57    0.8-11.9
    3311 California longshoremen     1.3                 5.9
    Munich population                2.36                7.38
    Rural Bavarians                  1.03                6.06

    a  From: Wakeham (1976).

    5.3  Occupational Exposure

        Many occupational groups are subject to high carbon monoxide
    exposure. These include, traffic policemen, garage personnel, workers
    in the metallurgical, petroleum, gas, and chemical industries, and

        An average carbon monoxide level of 172 mg/m3 (149.6 ppm) was
    recorded in the air of a Paris police garage between 07h30 and 08h00
    and 205 mg/m3 (179 ppm) between 19h30 and 20h00 (Chovin, 1967).
    Similarly, Trompeo et al. (1964) found an average level of 112 mg/m3
    (97.4 ppm) in 12 underground garages in Rome; a maximum concentration
    of 570 mg/m3 (498.5 ppm) was recorded. In similar studies in
    enclosed garages with capacities of 300-500 vehicles, where the only
    ventilation was via the entrance, the average concentration of carbon
    monoxide for a period from 08h00 to 17h00 was 72 mg/m3 (62.6 ppm) in
    the summer and 61 mg/m3 (53 ppm) in the winter (Ramsey, 1967a).

        The same author (Ramsey, 1967b) reported that the carboxyhaemo-
    globin levels of 14 nonsmoking parking garage employees, exposed to an
    average concentration of carbon monoxide of 68 mg/m3 (59 ppm),
    increased from 1.5 to 7.3%. He also noted that, in smokers exposed to
    the same environment, initial carboxyhaemoglobin levels of 2.9% rose
    to 9.3% at the end of the day. Smokers not exposed to this environment
    had final levels of only 3.9%. Ramsey stated that occupational
    exposure played a greater role than smoking in increasing
    carboxyhaemoglobin levels. However, in a study of some 350 Canadian

    garage and service station personnel, Buchwald (1969) found that
    cigarette smoking was the more significant contributor to the high
    levels of carboxyhaemoglobin measured. Of the smokers, 70% had levels
    in excess of 5%, while a similar level was found in only 30% of the
    nonsmokers. Breysse & Bovee (1969) used expired air samples to
    determine exposure to carbon monoxide in stevedores, gasoline-powered
    lift truck drivers, and winch operators. They made some 700 estimates
    of carboxyhaemoglobin, almost 6% of which exceeded 10%. Seven percent
    of the stevedores and 18% of the lift truck operators had
    carboxyhaemoglobin levels over 10%. Smoking contributed substantially
    to the attainment of these high levels. Carboxyhaemoglobin levels as
    high as 10% were also found in dock workers in studies by Petrov
    (1968). Inspectors at USA-Mexico border crossing stations were found
    to be exposed to ambient levels of carbon monoxide that fluctuated
    between 6 and 195 mg/m3 (5 and 170.5 ppm). During one hour of an
    evening shift, ambient carbon monoxide averaged 131 mg/m3 (114 ppm).
    Carboxyhaemoglobin levels of smokers and nonsmokers which were 4.0 and
    1.4% respectively, prior to duty rose to 7.6 and 3.8% (Cohen et al.,

        Data obtained by Balabaeva & Kalpazanov (1974) in studies on
    traffic policemen in 4 large towns in Bulgaria were similar to those
    Chovin (1967) obtained in his study on the exposure of Paris policemen
    to carbon monoxide. However, Göthe et al. (1969) found relatively low
    levels of carboxyhaemoglobin in Swedish traffic policemen. When blood
    lead levels were studied in 50 London taxi drivers using their
    carboxyhaemoglobin levels as an index of exposure to exhaust products,
    carboxyhaemoglobin levels were higher in day drivers than in night
    drivers and in smokers than in nonsmokers. Concentrations in all
    groups ranged from 0.4 to 9.7%, and those in nonsmokers (day and
    night) from 0.4 to 3.0%.

        Direct measurement of carboxyhaemoglobin levels in firefighters
    engaged in prolonged firefighting indicated that 10% had values
    exceeding 10% (Gordon & Rogers, 1969). However, the high levels of
    carboxyhaemoglobin found in the control (non-firefighting) groups make
    these conclusions somewhat uncertain. Goldsmith's study (1970) of
    longshoremen suggested that the expired alveolar concentrations of
    carbon monoxide in smokers were age-related. For example, subjects
    smoking one packet of 20 cigarettes per day in the 45-54 year age
    group had an average alveolar value of 31 mg/m3 (27 ppm), while the
    75-84 year age group had an average of only 16 mg/m3 (14.4 ppm).
    Nonsmokers did not exhibit this age-related pattern, since even up to
    84 years of age, alveolar concentrations remained at the same level
    4 mg/m3 (3.6 ppm).

        Exposure to low levels of carbon monoxide may have a significant
    influence on the health and efficiency of these workers but this
    awaits further study. Many other instances of occupational exposure
    are available but most studies are complicated by the unknown or
    unreported smoking habits of the workers under study (Grut, 1949).

    5.4  Carboxyhaemoglobin Levels in the General Population

        The most extensive study of blood carboxyhaemoglobin levels in the
    general population was carried out by Stewart and his associates
    (1973c and 1974), who took blood samples in 18 urban areas and in some
    small towns in the States of New Hampshire and Vermont, USA. Similar
    blood samples were evaluated for carboxyhaemoglobin levels by Kahn et
    al. (1974), Davis & Gantner (1974), and Wallace et al. (1974) in
    metropolitan St Louis. A total of 45 649 blood donors provided blood
    for analysis. Stewart's subjects (29 000 including 1016 from St Louis)
    were studied in March 1971 and Kahn's (16 649 subjects all from St
    Louis) from October 1971 to October 1972. Stewart et al. concluded
    that 45% of all the non-smoking donors exposed to ambient carbon
    monoxide had a carboxyhaemoglobin saturation greater than 1.5%, while
    Kahn's group reported a level of less than 1%.


        The primary factors that determine the final level of
    carboxyhaemoglobin are: the amount of inspired carbon monoxide; minute
    alveolar ventilation at rest and during exercise; endogenous carbon
    monoxide production; blood volume; barometric pressure; and the
    relative diffusion capability of the lungs. The rate of diffusion from
    the alveoli and the binding of carbon monoxide with the blood
    haemoglobin are the steps limiting the rate of uptake into the blood.

    6.1  Endogenous Carbon Monoxide Production

        Carbon monoxide can be produced endogenously from the catabolism
    of pyrrole rings, originating from haemoglobin, myoglobin,
    cytochromes, and other haem-containing pigments. Haem catabolism is
    the main source of endogenous carbon monoxide production, but recent
     in vitro investigations suggest additional endogenous sources, e.g.,
    lipid peroxidation (Wolff & Bidlack, 1976).

        The endogenous carboxyhaemoglobin level in man is estimated to be
    about 0.1-1.0%. Increased production of endogenous carbon monoxide has
    been found in haemolytic anaemias (Coburn et al., 1966), and could be
    expected in haematomas and after exposure to certain toxic chemicals
    capable of causing haemolysis. The liver is probably the major source
    of endogenous carbon monoxide as a consequence of an increase in liver
    cytochromes induced by certain drugs (Coburn, 1970a), or in porphyria
    cutanea tarda (acquired or symptomatic porphyria) (White, 1970).
    Similarly, bone marrow can become a major source of carbon monoxide in
    haematological diseases, such as sideroblastic anaemia, being
    characterized by ineffective erythropoiesis (White, 1970). In neonates
    endogenous carbon monoxide can be markedly elevated, as well as in
    females during the progesterone phase of the menstrual cycle
    (Delivoria-Papadopoulos et al., 1970; Longo, 1970), and even more so
    during pregnancy (see section 8.2.3). Another important cause of
    carboxyhaemoglobin elevation is exposure to several methane-derived
    halogenated hydrocarbons (see section 8.1.5).

    6.2  Absorption

        The classical absorption curves of Forbes et al. (1945) have been
    re-evaluated for man at rest by Peterson & Stewart (1970) who exposed
    volunteers to a variety of different concentrations of carbon monoxide
    for periods ranging from 0.5 to 24 h. Using a regression approach,
    they derived the following empirical relationship for blood carboxy-
    haemoglobin as a function of ambient carbon monoxide concentration
    and exposure time:

       log10 y = 0.85753 log10 x + 0.62995 log10 t - 2.29519

    where    y = % carboxyhaemoglobin
             x = carbon monoxide concentration in ppm
             t = time in minutes

    Although these new data come closer to presenting potential uptake in
    individuals exposed to present-day ambient concentrations of carbon
    monoxide, they do not apply to the uptake that would occur in active
    man. Furthermore, they fit only the linear, non-steady-state portion
    of the absorption curve. Ott & Mage (1974) have objected to the
    Peterson & Stewart equation as being basically a static model. They
    indicate that the use of averaging periods as long as 1 h compared
    with 10-15 min introduces an error into recorded urban concentrations.
    This error may be serious if many sharp, ambient peaks are present.

        The data presented by Forbes et al. (1945) are still the only
    experimental information available that takes ventilation into account
    and, even so, this information is inadequate since the full range of
    inspired, ventilatory volumes possible in exercising man was not
    considered. Coburn et al. (1965) have developed an equation from which
    it is possible to calculate blood carboxyhaemoglobin (Peterson &
    Stewart, 1970) as a function of time, considering appropriate
    physiological and physical factors. Their basic differential equation
    is as follows:

     d(CO)         [HbCO]     pCo2            1              pIco
          =  Vco -        ×        ×                +                 
      dt           [HbO2]      M       1     pB - 47      1     pB - 47
                                         +                +          
                                      DL       VA        DL       VA

    where       is the rate of change of CO in the body (ml/min)

    [HbCO] is the concentration of CO in the blood (ml CO/ml blood)
    [HbO2] is the concentration of O2 in the blood (ml O2/ml blood)
     DL is the diffusion capacity of the lung (ml/min/mmHg)
     VA is the alveolar ventilation rate (ml/min)
     pB is barometric pressure (mmHg)
     pIco is inspired carbon monoxide pressure (mmHg)
     pCo2 is the mean pulmonary capillary oxygen pressure (mmHg)
     M is the Haldane constant (220-240 at pH 7.4)
     Vco is the rate of endogenous CO production (ml/min)

        One solution of the equation depends on the assumption that
     pCo2, and HbO2 are constant and independent of HbCO. However,
    HbO2 concentration depends upon HbCO in a complex way and, in
    general, solution of the equation requires some special computer
    techniques using a second approximation; these have been attempted and
    general solutions are available (Coburn et al., 1965). Further

    development of Coburn's concepts will undoubtedly improve the basis on
    which theoretical uptakes can be calculated. For immediate, practical
    purposes, calculations based on the Haldane formula (see section 6.3)
    can be used.

        Table 6 indicates the equilibrium percentage saturation of the
    haemoglobin with carbon monoxide at various alveolar pressures of
    carbon monoxide, calculated from the Haldane formula:a

                 % HbCO      230 pAco
                 % HbO2       pAo2

    where  pAco and  pAo2, are the alveolar pressures of carbon
    monoxide and oxygen respectively.

        Table 6.  Percent carboxyhaemoglobin versus carbon monoxide alveolar pressure

       % HbCO       mg/m3         ppm         % in air        Pa            Torr

        0.87          5.7           5          0.0005        0.506         0.0038
        1.73         11.5          10          0.001         1.013         0.0076
        3.45         23.0          20          0.002         2.026         0.0152
        5.05         34.5          30          0.003         3.305         0.0248
        6.63         46.0          40          0.004         4.052         0.0304
        8.16         57.5          50          0.005         5.065         0.0380
        9.63         69.0          60          0.006         6.078         0.0456
       11.08         80            70          0.007         7.091         0.0532
       12.46         92.0          80          0.008         8.104         0.0608
       13.80        103.0          90          0.009         9.117         0.0684
       15.11        114.5         100          0.010        10.130         0.0760
       16.37        126.0         110          0.011        11.143         0.0836
       17.60        130.0         120          0.012        12.156         0.0912
       18.78        149.0         130          0.013        13.170         0.0988
       19.95        160.0         140          0.014        14.183         0.1064
       21.05        172.0         150          0.015        15.196         0.1140
       22.15        183.0         160          0.016        16.209         0.1216
       23.23        195.0         170          0.017        17.209         0.1291
       24.26        206.0         180          0.018        18.235         0.1368
       25.25        218.0         190          0.019        19.221         0.1442
       26.22        229.0         200          0.020        20.261         0.1520

    a  The alveolar oxygen pressure is assumed to be 13 kPa (98 Torr)

    6.3  Reactions with Body Tissues and Fluids

        An adequate oxygen supply to maintain tissue metabolism is
    provided by the integrated functioning of the respiratory and
    cardiovascular systems to transport oxygen from the ambient air to the
    various tissues of the body. Nearly all of the oxygen, except that
    dissolved in plasma, is bound reversibly to the haemoglobin contained
    within the erythrocytes. The most significant chemical characteristic
    of carbon monoxide is that it also is reversibly bound by haemoglobin.
    Therefore, it is a competitor with oxygen for the four binding sites
    on the haemoglobin molecule.

        The equilibrium constant M expresses the relative affinity of
    haemoglobin for carbon monoxide and oxygen when the concentration of
    reduced haemoglobin is minimal. This Haldane constant (Douglas et al.,
    1912) is defined by the following equation:

                     HbCO         pCO
                          =  M x      
                     HbO2         pO2

    where  pCO and  pO2 represent the equilibrium partial gas
    pressures: each pressure being the same in the erythrocytes or
    haemoglobin solution as in the equilibrated gas phase. [HbCO] and
    [HbO2] are the concentrations of carboxyhaemoglobin and
    oxyhaemoglobin, respectively. The value of  M is about 200 in most
    species, in spite of the fact that carbon monoxide combines with
    haemoglobin more slowly than oxygen. Carboxyhaemoglobin dissociates
    very slowly due to the tight binding of carbon monoxide to
    haemoglobin. Technically, it is not possible to measure the rate of
    dissociation of carbon monoxide from partly saturated haemoglobin. The
    dissociation velocity constant has been measured by only a few
    investigators on sheep and human haemoglobin fully saturated with
    carbon monoxide. Roughton (1970), however, has presented the most
    comprehensive analysis of the interaction of carbon monoxide with
    erythrocyte haemoglobin, showing clearly that, for man, M is higher
    than commonly thought, i.e., it is more likely to be between 240 and
    250; however, the value for  M depends on the point of reference on
    the dissociation curve.

        Solution of Haldane's equation would give an approximate level of
    carboxyhaemoglobin, e.g., exposure to ambient air containing carbon
    monoxide levels of 28.7, 57.5, or 115 mg/m3 (25, 50, or 100 ppm)
    would lead to carboxyhaemoglobin saturations of approximately 4.8, 9.2
    and 16.3%, if the arterial oxygen pressure were 10.7 kPa (80 Torr).
    The carbon monoxide enters the lungs with each breath and diffuses
    across the alveolar-capillary membrane in a manner similar to oxygen.
    If air with a constant concentration of carbon monoxide is breathed
    for several hours, the rate of uptake of carbon monoxide decreases

    approximately exponentially until an equilibrium state is attained in
    which the partial pressure of carbon monoxide in the pulmonary
    capillary blood is the same as that in the alveolar.

        Oxygen transport in the blood is best described by the
    oxyhaemoglobin dissociation curve (Fig. 4). In the presence of
    carboxyhaemoglobin, this curve is no longer typically sigmoid but is
    shifted to the left so that a lower oxygen pressure is present for the
    same oxyhaemoglobin saturation compared with blood without
    carboxyhaemoglobin (Roughton & Darling, 1944). Fig. 5 illustrates the
    extent of the Haldane shift to the left more clearly than the typical
    curves of Fig. 4. Mulhausen et al. (1968) illustrated this shift by
    showing that the half saturation oxygen tension shifted from 3.6 to
    3.1 kPa (26.7 to 23.2 Torr) in subjects who were intermittently
    exposed to a high concentration of ambient carbon monoxide. Carbon
    monoxide not only diminishes the total amount of oxygen available by
    direct replacement of oxygen (Fig. 4) but also alters the dissociation
    of the remaining oxygen so that it is held more tenaciously by
    haemoglobin and released at lower oxygen tensions. The oxyhaemoglobin
    curve in the presence of carboxyhaemoglobin progressively resembles
    the simple oxygen dissociation curve of myoglobin. Myoglobin is a haem
    compound with only one haem unit per molecule and does not exhibit
    haem-haem interactions. It is possible that the combination of one or
    more of the four haem groups in haemoglobin with carbon monoxide
    decreases the haem-haem interactions of the remaining haem units and
    results in a molecule approaching the behaviour of myoglobin.

        Any consideration of the toxicity of carbon monoxide must include
    not only the decrease in the oxygen carrying capacity of haemoglobin
    but also the interference with oxygen release at the tissue level.

        The venous  pO2 values expected to result from various
    carboxyhaemoglobin levels can be calculated (Forster, 1970; Permutt &
    Fahri, 1969). If blood flow and metabolic rate remain constant,
    equilibration with an ambient carbon monoxide concentration of
    230 mg/m3 or 200 ppm (25% carboxyhaemoglobin) will lower venous
     pO2 from 5.3 to less than 4 kPa (40 to less than 30 Torr). A
    similar degree of venous hypoxaemia results from an ascent to an
    altitude of 3658 metres or a 35% reduction in oxygen capacity in an
    anaemic patient. It can also be calculated that, at 5%
    carboxyhaemoglobin, there will be only a slight drop in the mixed
    venous  pO2. Even more valuable relationships can be obtained by
    plotting oxygen content against the partial pressure of oxygen
    (Roughton & Darling, 1944). The difference in oxygen content at
    various percentages of carboxyhaemoglobin from 0 to 20 reveal the
    minimal magnitude of the relative unavailability of oxygen due to the
    Haldane effect (Fig. 4). It was this evaluation that led Roughton &
    Darling to conclude that carboxyhaemoglobin concentrations of less
    than 40% produce relatively easily compensated restrictions in the
    amount of oxygen available for tissue delivery. This can only be
    applied to subjects with normal respiratory and circulatory systems.

    FIGURE 4

    FIGURE 5

    The small reductions in oxygen content at 5-10% carboxyhaemoglobin may
    be quite critical for patients suffering from cardiovascular diseases
    or chronic obstructive lung disease. Coburn et al. (1965) published a
    detailed theoretical analysis of the physiology and variables that
    determine blood carboxyhaemoglobin levels in man. The details of the
    formulae used in these calculations are presented in section 6.2.

        With regard to the intracellular effects of carbon monoxide,
    consideration must be given to the interactions of all substances
    within the tissue cells that are involved with oxygen delivery. Since
    haemoglobin and myoglobin are structurally related, they react with
    carbon monoxide in a similar manner. The function of myoglobin,  in
     vivo, may be to act as a reservoir for oxygen within the muscle
    fibre. The carbon monoxide and oxygen equilibria of human myoglobin
    has been studied  in vitro and a hyperbolic oxygen dissociation curve
    established (Rossi-Fanelli & Antonini, 1958). This curve, unlike that
    for haemoglobin, is not affected by the hydrogen ion concentration,
    the ionic strength, or the concentration of myoglobin. The relative
    affinity constant,  M, is approximately 40 but is still sufficient to
    induce appreciable formation of carboxymyoglobin. Both Coburn et al.
    (1970b, 1973) and Luomanmaki (1966) have studied the interrelation-
    ships between carboxyhaemoglobin and carboxymyoglobin. Coburn, using
    14CO, showed that identical carbon monoxide exposures can produce
    different degrees of saturation of haemoglobin, depending upon the
    partial pressures of oxygen in blood and tissue. Coburn (1970b)
    determined the ratio of the carbon monoxide content in muscle to the
    content in blood as a function of arterial  pO2. This ratio, for
    skeletal muscle, is approximately 1, but in myocardial tissue it was
    found to be 3. When arterial  pO2 fell below 5.3-4 kPa (40-30
    Torr), carbon monoxide disappeared from the blood, presumably entering
    the muscle. Considerable amounts of extravascular carbon monoxide are
    stored in muscle. The higher ratio for cardiac tissue may be of
    considerable significance. In an individual with a blood
    carboxyhaemoglobin level of 10%, some 30% of cardiac myoglobin may be
    saturated with carbon monoxide. Coburn and associates (1973) estimated
    the mean  pO2 of skeletal muscle and myocardium and found that they
    were 0.8-1.1 and 0.5-0.8 kPa (6-8 and 4-6 Torr), respectively.

        Although no final judgement can be made regarding the next lower
    step involved in oxygen transport, i.e., the role of cytochromes  a3
    and P-450, the fact that, experimentally, they react with carbon
    monoxide in the same way as other haem-containing substances suggests
    that they may play a role in carbon monoxide poisoning. Available
    evidence suggests that interactions between carbon monoxide and
    cytochrome oxidases are of minor significance at the concentrations of
    carbon monoxide found in community air pollution. All of the data on
    the cytochromes have been obtained from  in vitro experiments.
    Whether similar events occur  in vivo remains uncertain. The most
    likely oxidase for  in vivo inhibition is P-450. Cooper et al. (1965)
    reported that the ratio of carbon monoxide to oxygen required for 50%

    inhibition is close to 1, in contrast to a similar ratio of between
    2.2 and 28 for cytochrome  a3. Root (1965) believes that at a  pCO
    compatible with life, only nonsignificant blocking of the oxygen
    consumption system occurs. In terms of the total distribution
    throughout the body of an inhaled dose of carbon monoxide, the amounts
    bound to these haemoproteins are small compared with haemoglobin and
    myoglobin. A diagrammatic representation of the factors influencing
    body carbon monoxide stores has been presented by Coburn (1970b). The
    possible significance of the role of these haemoproteins lies in the
    concept that, under conditions where tissue  pO2 is decreased, the
    affinity of intracellular haemoproteins for carbon monoxide may

    6.4  Excretion

        Adequate data are available on the rate of absorption of carbon
    monoxide but there is considerably less information concerning the
    rates of carbon monoxide egress from the lungs. The same factors that
    determine how much carbon monoxide is taken up by the blood should
    apply in reverse when clearance of carbon monoxide from blood is
    considered. The primary factors involved are the amounts of carbon
    monoxide and oxygen present, the magnitude of ventilation, and the
    quality of the diffusion barrier. Age influences the quality of the
    barrier and it appears that with advancing age the barrier becomes
    "thicker" and there are fewer gas exchange membranes. Sedov et al.
    (1971) presented data on the elimination of carbon monoxide at various
    atmospheric pressures and ambient temperatures. Neither lower
    barometric pressures nor high temperatures appreciably altered the
    rates of elimination. It has been implied by Pace et al. (1950) that a
    sex difference in elimination may also exist, a faster rate occurring
    in females than in males, at least under the experimental conditions
    of their study. Some sex differences in excretion have been reported
    by Goldsmith et al. (1963).

        Available evidence suggests that there is a biphasic decline in
    the percentage of carboxyhaemoglobin in the arterial blood (Godin &
    Shephard, 1972; Wagner et al., 1975). There is a rapid, initial,
    exponential decline (distribution phase), probably related to the
    distribution of carbon monoxide from the circulating blood to splenic
    blood, myoglobin, and cytochrome enzymes. Elimination of carbon
    monoxide through the lungs also occurs during this phase. The
    distribution phase, which persists for the first 20-30 min, is
    followed by a slower linear decline (elimination phase). This phase
    probably reflects the rates of release of carbon monoxide from
    haemoglobin and myoglobin, pulmonary diffusion, and ventilation, as
    well as the fact that  pCO decreases with time. Myhre (1974) found
    that a similar biphasic excretion pattern occurred at an altitude of
    1630 metres. However, he noted that the half-time of carboxyhaemo-
    globin was much longer (5.5 h). After continuous exposure to carbon
    monoxide for 49 h, 50% was eliminated in 30-180 min and 90% within

    180-420 min (Tiunov & Kustov, 1964). Other investigators (Godin &
    Shephard, 1972; Peterson & Stewart, 1970) reported exponential
    carboxyhaemoglobin elimintation curves over many hours. However,
    because of inadequate sampling in the early phase of elimination, they
    were unable to observe the more rapid initial decline. The absolute
    level of carboxyhaemoglobin, when the elimination studies began,
    apparently modified the rate of disappearance of carbon monoxide from
    the blood. Considerable individual variability has been observed and
    the duration of exposure may also be an important factor. It has been
    shown that prolonged exposure (more than 3 years) to concentrations of
    carbon monoxide of 11.5-115 mg/m3 (10-100 ppm) results in a markedly
    retarded elimination of carbon monoxide (Kodat, 1971).

        In summary, discharge of carbon monoxide occurs rapidly at first
    becoming slower with time and the lower the initial level of
    carboxyhaemoglobin, the slower the rate of elimination. Apparently, no
    studies have been made to determine elimination rates at the low
    levels of carboxyhaemoglobin (2-4%) that might be present following
    exposure to ambient concentrations of carbon monoxide.

        Several procedures have been tested that could accelerate the
    excretion of carbon monoxide from the blood of individuals with high
    levels of carboxyhaemoglobin (40-70%). Pace et al. (1950) reported
    that treatment of such individuals in a recompression chamber with an
    oxygen level equivalent to 2.5 atmospheres (partial pressure of oxygen
    equal to 253 kPa (1900 Torr) or an alveolar oxygen pressure of 239 kPa
    (1801 Tort)) would facilitate removal of carbon monoxide. They
    indicated that 1 h in such a chamber would result in the reduction of
    the carboxyhaemoglobin level to 10 to 15% of the initial level. In a
    revival of the old Henderson & Haggard treatment concept, Malorny et
    al. (1962) evaluated the influence of breathing different gas mixtures
    on the excretion of carbon monoxide in animals having high
    carboxyhaemoglobin levels (60-74%). It was determined that 50% of
    carbon monoxide could be excreted in 19 min if 5% carbon dioxide and
    95% oxygen were breathed, compared with a time of 28 min for 100%
    oxygen, and 41 min for ambient air. Another approach was suggested by
    Agostini et al. (1974), who employed a total body asanguineous, hypo-
    thermic procedure. These approaches to the removal of the body burden
    of excessive amounts of carbon monoxide remain to be evaluated fully
    in clinical trials.


        Great caution must be used in applying the resultsa obtained
    from animal experiments to man. Nonetheless, animal studies have
    provided valuable insight into both the potentially adverse effects of
    carbon monoxide and the basic mechanisms by which this substance
    influences physiological processes. However, many studies have used
    extraordinarily high levels of carbon monoxide, rarely found in air.
    These studies are not referred to in this document, since the toxic
    effects of very high levels of carbon monoxide have been well
    documented for both animals and man.

    7.1  Species Differences

        The oxygen dissociation curves for different animal species used
    in carbon monoxide studies are not the same. There are also questions
    concerning the relative affinities for carbon monoxide of the
    haemoglobin in various animal species. Fodor & Winneke (1971.)
    reported  in vitro studies that showed different affinities for
    different species, the highest being in man followed by rat, mouse,
    and rabbit, in descending order. Klimisch et al. (1975) found the
    following sequence of affinities: hamster, rat, pig, rabbit. Apart
    from different affinities there may well be species differences with
    respect to susceptibility to carbon monoxide. According to Alexandrov
    (1973) certain mammals can be classified in order of decreasing carbon
    monoxide susceptibility as follows: mouse, rat, cat, dog, guineapig,
    and rabbit. This difference might, in part, be related to different
    ventilation/body weight-ratios.

        Species differences in reaction are ideally illustrated in the
    studies by De Bias et al. (1972a,b, 1973) on dogs and cynomolgus
    monkeys  (Macaca fascicularis = M. irus). Chronic exposure (23 h per
    day) over several months to 115 mg/m3 (100 ppm) resulted in
    carboxyhaemoglobin levels of 14 and 12.4% in dogs, and monkeys,
    respectively. The dogs (De Bias et al, 1972a) remained clinically in
    good health with no untoward signs that could be interpreted as
    induced by carbon monoxide. Serum enzymes, haematological variables,
    and electrocardiograms did not change significantly. Carbon monoxide
    exposure of normal monkeys resulted in myocardial effects.
    Experimentally infarcted monkeys had greater P-wave amplitudes and
    increased incidence of T-wave inversions than normal monkeys similarly
    exposed. One important fact that may partly explain this difference
    between dogs and monkeys is, that monkeys, like man, have end-
    arteries, whereas dogs have a well developed collateral circulation.


    a  Animal studies have been reported in other sections of this
       document wherever necessary. Consequently, some data on animals
       (such as sheep) are not repeated in this section.

    7.2  Cardiovascular System and Blood

        Increase of coronary blood flow is the normal response of the
    myocardium to carbon monoxide exposure. Permutt & Farhi (1969)
    calculated theoretically, that, when carboxyhaemoglobin levels are
    approximately 5%, an increase in coronary blood flow of about 20% more
    than the resting level would be necessary to prevent coronary sinus
     pO2 from falling below minimum levels. This calculation has been
    confirmed experimentally by Adams et al. (1973) and Horvath (1973),
    both of whom demonstrated approximately similar increases in coronary
    blood flow in spite of using very different methods to increase
    carboxyhaemoglobin levels.

        There is considerable controversy concerning the cardiovascular
    effects of carbon monoxide in dogs. Long-term exposures of animals to
    carbon monoxide concentrations sufficiently high to produce
    carboxyhaemoglobin levels in excess of 20% can induce pathological
    changes in the heart and brain. As in acute high level intoxication in
    man, serious sequelae develop. Lindenberg et al. (1961) exposed 8 dogs
    to carbon monoxide concentrations of 115 mg/m3 (100 ppm). Four were
    exposed continuously for 24 h a day, 7 days per week, for 6 weeks and
    another 4 were exposed intermittently. All dogs had abnormal
    electrocardiograms and some of the hearts showed histological
    degeneration of muscle. In another study, Preziosi et al. (1970)
    exposed dogs continuously to 115 mg/m3 for 6 weeks and reported
    abnormal electrocardiograms, right and left heart dilatation, and
    myocardial thinning. Histological examination showed older scarring in
    some cases and fatty degeneration of heart muscle in others.
    Carboxyhaemoglobin levels of 7.7 to 12% were lower than would be
    predicted from the exposure. When 4 dogs were exposed intermittently
    to a carbon monoxide concentration of 115 mg/m3 for 11 weeks,
    central nervous system and cardiac effects were found (Lewey &
    Drabkin, 1944).

        Ehrich et al. (1944) also exposed 4 dogs to 115 mg/m3 on an
    intermittent schedule. They observed that electrocardiographic changes
    occurred at variable times during the 11 weeks of exposure. The gross
    appearance of the hearts after exposure were normal but microscopic
    examination revealed marked degenerative changes in individual fibres.
    Lindenberg et al. (1961) exposed dogs to a carbon monoxide
    concentration of 57 mg/m3 (50 ppm) on the same schedule as for his
    115 mg/m3 exposure studies. Carboxyhaemoglobin levels of 2.6-5.5%
    were observed. No changes in haemoglobin levels or haematocrit were
    noted. Electrocardiographic changes were observed in the third week of
    exposure similar to, but less severe than, those observed in animals
    exposed to the higher ambient level of carbon monoxide. Dogs were
    exposed by Musselman et al. (1959) to a carbon monoxide concentration
    of 57 mg/m3 for 24 h per day, 7 days per week, for 3 months. No
    changes in the electrocardiogram or heart rates were observed.

    Pathological examination of organs and tissues did not reveal any
    changes after exposure. Experimental data have been presented by
    Orellano et al. (1976) who claim that carbon monoxide injected
    intraperitoneally into dogs is nontoxic. This study, as well as other
    reports from these investigators, raise some intriguing questions as
    to the mechanisms involved in carbon monoxide toxicity.

        Continuous exposure of cynomolgus monkeys to a carbon monoxide
    concentration of 115 mg/m3 resulted in demonstrable electro-
    cardiographic effects in the myocardium of both normal monkeys
    and monkeys with myocardial infarction (De Bias et al., 1972b, 1973).
    The same investigators (De Bias et al., 1976) also studied the
    susceptibility of the ventricles to induced fibrillation. Normal and
    infarcted monkeys were exposed to a carbon monoxide concentration of
    115 mg/m3 for 6 h. Application of high voltages were required to
    produce fibrillation in normal monkeys in air but when infarcted
    animals were exposed to carbon monoxide, the voltage level required
    was very low. Animals with either infarction alone or carbon monoxide
    exposure alone also required significantly less voltage to produce
    fibrillation; when the two were combined, the effects were additive.
    Intermittent exposure to carbon monoxide (30 min per h, 12 h per day,
    over a period of 14 months) of cynomolgus monkeys fed either a normal
    or a semipurified cholesterol diet did not result in myocardial
    infarctions or electrocardiographic abnormalities (Malinow et al.,
    1976). In these animals, the blood carboxyhaemoglobin concentration
    reached 21.6% at the end of the daily period of breathing carbon
    monoxide at 529 mg/m3 (460 ppm).

        Carbon monoxide exposure did not increase the aortic and coronary
    atherosclerosis induced in cynomolgus monkeys by cholesterol feeding.
    Eckardt et al. (1972) exposed cynomolgus monkeys (22 h per day, 7 days
    per week, for 2 years) to carbon monoxide concentrations of 23 or
    75 mg/m3 (20 or 65 ppm). Carboxyhaemoglobin levels, which showed
    considerable variation during the experimental period, ranged from 2.0
    to 5.5% and 4.8 to 10.2% for low and high carbon monoxide ambient
    concentrations, respectively. These levels of carboxyhaemoglobin did
    not lead to compensatory increases in haematocrit, haemoglobin, or
    erythrocyte counts nor to cardiac fibrosis or pathological effects in
    the brain. Cholesterol-fed squirrel monkeys were exposed to carbon
    monoxide at 229-344 mg/m3 (200-300 ppm) for several hours per day
    for 7 months (Webster et al., (1968). No differences were found in
    plasma cholesterol or in aortic and carotid atherosclerosis which
    could be ascribed to carbon monoxide. However, the authors did observe
    an increase in coronary atherosclerosis. Somewhat similar results were
    later reported in studies on cynomolgus monkeys (Malinow et al.,
    1976). Jones et al. (1971) exposed rats, guineapigs, dogs, and monkeys
    to 58, 110, or 229 mg/m3 (51, 96 or 200 ppm) continuously for 90
    days. Haematocrit and haemoglobin levels remained constant at the
    lowest level of carbon monoxide exposure but were significantly
    elevated at the two higher levels in all species except the dog.

    Cynomolgus monkeys  (Macaca irus) were exposed to a concentration of
    286 mg/m3 (250 ppm) for 2 weeks by Thomsen (1974). In all the
    exposed animals, the coronary arteries showed widening of the
    subendothelial spaces in which cells with or without lipid droplets
    were accumulating. He suggested that monkeys were more sensitive to
    carbon monoxide than the rabbits studied by Astrup et al. (1967).
    Experimental studies on rabbits exposed to relatively high
    concentrations of carbon monoxide at 195-206 mg/m3 (170-180 ppm) for
    extended periods indicated the presence of high levels of cholesterol
    in the arteries or enhanced vascular disease (Astrup et al., 1970).
    The lesions observed, which included subendothelial oedema, a gap
    between endothelial cells, and increased infiltration of cells with
    lipid droplets, might be early precursors of atherosclerotic disease.
    However, such lesions occurred only in animals concurrently on a high
    cholesterol or fat diet or on both. Exposure to carbon monoxide alone
    induced some changes such as endothelial hypertrophy and

        One experimental study on the effects of carbon monoxide on the
    natural history of heart disease in the cynomolgus monkey has been
    reported. De Bias et al. (1973) exposed animals to a carbon monoxide
    concentration of 137 mg/m3 (120 ppm) for 24 weeks. The average
    carboxyhaemoglobin level of 12.4% resulted in a polycythaemia with an
    increase in haematocrit from 35 to 50%. All animals developed
    increased P-wave amplitude and T-inversion which suggested nonspecific
    myocardial stress rather than ischaemia. Animals in which an
    experimental myocardial infarction was produced prior to exposure to
    carbon monoxide had more marked electro-cardiographic changes than
    animals breathing room air. In 1976, Ramsey & Casper reported that
    erythrocytic 2,3-diphosphoglycerate (2,3-DPG) played neither a
    compensatory nor an aggravating role in the hypoxia induced by the
    presence of 20 or 30% carboxyhaemoglobin. Stupfel & Bouley (1970)
    exposed mice and rats for 95 h per week to a carbon monoxide
    concentration of 57 mg/m3 (50 ppm) for either 1 to 3 months or for
    their natural life expectancy of up to 2 years. A large number of
    measurements were made during exposure followed by pathological
    examination after death. The authors did not observe any important
    effects of carbon monoxide exposure on the animals. In a study by
    Penney et al. (1974a,b), the influence of hypoxic hypoxia on the
    development of cardiac hypertrophy in the rat was compared with that
    of carbon monoxide hypoxia. Exposure to various levels of carbon
    monoxide resulted in hypertrophy of both the fight and left ventricles
    in contrast with the right ventricle hypertrophy observed in response
    to the hypoxic hypoxia stress.

        Cardiac hypertrophy and a reduction in cytochrome oxidase levels
    were demonstrated in chick embryos exposed to carbon monoxide for 144
    and 168 h (Tumasonis & Baker, 1972). The resistance of young chickens
    to carbon monoxide decreased with age. Body temperatures decreased
    during exposure to carbon monoxide with the greatest fall in

    temperature and the longest survival time occurring in the youngest
    chickens. Total body asanguineous hypothermic perfusion (total body
    exsanguination exchange transfusion) has been suggested as a
    therapeutic measure for carbon monoxide poisoning (Agostini et al.,
    1974). In an attempt to explain this beneficial effect, Ramirez et al.
    (1974) compared the survival of normal dogs exposed to high levels of
    carbon monoxide with that of acutely anaemic dogs transfused with
    carboxyhaemoglobin blood to normal blood volumes. All normal dogs with
    carboxyhaemoglobin levels of 54-100% died within 0.25-10 h but the
    transfused animals, having a final mean carboxyhaemoglobin level of
    80% after transfusion, survived. The authors suggested that hypoxic
    anaemia was not the principal mechanism of carbon monoxide toxicity
    but rather a blocking out of the energy supply on the cellular level,
    governed by the cytochrome system.

        Most of the investigations using rabbits for carbon monoxide
    related research originated in Astrup's laboratories, where they first
    demonstrated that low carboxyhaemoglobin levels enhanced the
    development of atheromatosis (Astrup et al., 1967). Additional studies
    (Hellung-Larsen et al., 1968; Thomsen & Kjeldsen, 1975) have shown
    that lactate dehydrogenase isoenzymes (M subunits) increase and that a
    higher incidence of focal intimal changes occur in rabbits exposed to
    carbon monoxide. The myocardial ultrastructure of rabbits exposed to a
    concentration of 206 mg/m3 (180 ppm) for at least 4 h showed
    degenerative changes such as contraction bands, myofibrillar
    disintegration, myelin body formation, and dehiscence of the
    intercalated discs (Thomsen & Kjeldsen, 1974). Exposure of rabbits to
    a similar concentration of carbon monoxide for 2 weeks resulted in
    more extensive myocardial damage (Kjeldsen et al., 1974).

        Astrup et al. (1970) furnished evidence that carbon monoxide
    increases endothelial membrane permeability. They found that rabbits
    exposed to carbon monoxide developed arterial lesions resulting in a
    considerable accumulation of lipids. It has also been shown that human
    coronary arteries exposed to carbon monoxide  in vitro have a higher
    uptake of cholesterol, although no significant changes in lipid
    synthesis were observed (Sarma et al., 1975). Myocardial damage and
    impaired myocardial performance have also been reported in animals and
    man exposed to carbon monoxide (Ayres et al., 1970). Although there is
    some evidence which suggests that exposure to carbon monoxide can
    induce changes in blood vessels and the myocardium, there is also
    evidence to the contrary (section 8.1).

    7.3  Central Nervous System

        Because of the brain's high oxygen demand, cerebral function
    should be influenced at low carboxyhaemoglobin levels. However, data
    concerning this are contradictory. Sensitivity to carbon monoxide may
    follow a circadian rhythm (Stupfel, 1975; Stupfel et al., 1973).
    Maximum sensitivity in rats occurred during the dark period of a

    12-12 h light-dark cycle. Dyer & Annau (1976) could find no effect on
    superior colliculus evoked potentials of rats until the level of
    ambient carbon monoxide had reached 573 mg/m3 (500 ppm) in marked
    contrast to Xintaras et al. (1966), who observed a 20% increase in the
    amplitude of superior colliculus evoked potentials after only 1 h
    exposure to 57 mg/m3 (50 ppm), and a 50% increase after a 2-h period
    of exposure at this level. This study has, however, been criticized
    for not taking into account the effects of dark adaptation on the
    amplitude of visual evoked potentials in rats (Dyer & Annau, 1976).

        In view of the conflicting reports it is of some interest to
    examine the available data on cerebral  pO2 tensions, cerebral
    blood flow (CBF) and cerebral metabolism. Zorn (1972) studied the
    effects of carbon monoxide inhalation on brain and liver  pO2 using
    platinum electrodes. Tissue  pO2 fell in both organs, even at a
    carboxyhaemoglobin concentration of 2%, and the fall was approximately
    linear to increases in carboxyhaemoglobin. There was a decrease in
     pO2 of 0.027-0.24 kPa (0.2-1.8 Torr) for each 1% fall in
    oxyhaemoglobin percentage saturation. These data suggest that the
    carbon monoxide influenced levels other than the intracellular level,
    since if its effects were limited to this area then tissue  pO2
    would have been expected to increase. Similar studies were performed
    by Weiss & Cohen (1974) on rat brain and muscle. They found a decrease
    in cerebral cortical  pO2 following inhalation of low levels of
    carbon monoxide. Unfortunately, they did not measure
    carboxyhaemoglobin levels in these rats but, in a group of sham-
    operated animals exposed to similar levels of inhaled carbon monoxide,
    carboxyhaemoglobin had increased to 3.3%. During progressive
    administration of carbon monoxide to dogs, CBF did not increase until
    carboxyhaemoglobin levels reached 20%. Thereafter, CBF increased
    progressively and was double that in the controls when the
    carboxyhaemoglobin level reached 50% (Häggendal et al., 1966). On the
    other hand, Traystman (1976) did observe a progressive increase in CBF
    in dogs even at very low carboxyhaemoglobin values. The lowest level
    studied was 2.5%, which produced a slight but significant CBF
    increase. Thus, Traystman did not believe in a threshold effect. The
    effects were produced with both hypoxic hypoxia and carbon monoxide
    hypoxia. It remains to be seen, how these data relate to cerebral
    circulation in man.

        The respiratory centre or arterial chemoreceptors were not
    stimulated to increase respiratory minute volume even when
    carboxyhaemoglobin levels were as high as 40% (Chiodi et al., 1941).
    Mills & Edwards (1968) measured the frequency of electrical impulses
    in the afferent nerves from the aortic and carotid chemoreceptors and
    showed that administration of carbon monoxide did result in
    chemoreceptor stimulation. The response appeared to have an
    approximately linear relationship with the carboxyhaemoglobin
    concentration (at least above 8%). These findings suggest that carbon
    monoxide might stimulate breathing. Failure to observe an increased
    minute volume may be explained by the fact that, in the presence of

    carbon monoxide, the chemoreceptor stimulation was offset by hypoxic
    depression  of brain structures involved in breathing. There is some
    evidence that this balancing between chemoreceptors and central
    nervous depression is operative in anaemia (Santiago & Edelman, 1972).
    Additional investigations are needed to clarify this effect of carbon
    monoxide inhalation.

    7.4  Behavioural Changes and Work Performance

        In extensive studies on rabbits, guineapigs, rats, and mice
    (Gadaskina, 1960; Ljublina, 1960; Rylova, 1960) exposure to a carbon
    monoxide level of 30 mg/m3 (26 ppm), although not inducing any
    morphological blood changes, did result in a number of unfavourable
    physiological changes. Among these were decreased work capacity, poor
    adjustment to postural shifts (orthostatic tests), and increased
    thyroid activity. These changes were more evident during the initial
    period of the exposure but reverted towards normal later, suggesting
    some adaptation to carbon monoxide exposure.

    7.5  Adaptation

        Adaptation apparently can occur in animals exposed to moderate
    concentrations of carbon monoxide (Gorbatov & Noro, 1948; Tiunov &
    Kustov, 1969) as shown by their ability to tolerate, with apparent
    ease, acute exposure to higher concentrations. Both Clark & Otis
    (1952) and Tiunov & Kustov (1969) have demonstrated that, after long-
    term exposure to carbon monoxide, animals developed tolerance to
    short-term, high altitude exposure, and vice versa, an indication of
    the development of a common adaptive mechanism. Acclimatization
    continued despite a subsequent decrease in the initial elevation of
    the haemoglobin concentration (Gorbatov & Noro, 1948). These
    investigators noted an acclimatization effect in rats exposed daily to
    0.4-0.5% carbon monoxide until loss of consciousness occurred. A
    progressive improvement in tolerance time to unconsciousness was noted
    so that by the eighth day of exposure a 3-fold improvement over the
    time required on the first day had developed. In spite of apparent
    acclimatization, the general condition of test animals became worse.
    Unexpectedly, daily exposure to a carbon monoxide concentration of
    1.0%, which on the first day necessitated a 5-min exposure prior to
    unconsciousness, failed to induce any improvement in tolerance. A
    possible correction of leftward shift of the oxygen dissociation by
    alterations in the concentration of 2,3-diphosphoglycerate (inducing a
    shift to the right) has been suggested. However, conflicting results
    and the necessity to produce high levels of carboxyhaemoglobin negate
    the possibilities of this beneficial effect (Astrup, 1970; Dinman et
    al., 1970).

        Evidence for adaptation to carbon monoxide is inconclusive.
    Further studies appear to be warranted with special attention devoted
    to studies using more realistic current ambient levels of carbon
    monoxide, and also studies on the possible physiological cost of
    adaptation, if it occurs.

    7.6  Embryonal, Fetal, Neonatal, and Teratogenic Effects

        Few studies have been made on the effects of carbon monoxide on
    mammalian fetal growth and survival. Wells (1933) exposed pregnant
    rats for 5-8 min to a carbon monoxide concentration of 1718 mg/m3
    (1500 ppm) every other day during pregnancy. Maternal unconsciousness
    and abortion or absorption of most of the fetuses resulted. Data
    concerning carboxyhaemoglobin levels and numbers of animals studied
    were not given. Rats were exposed to 0.34% carbon monoxide for 1 h
    (carboxyhaemoglobin 60-70%) daily for a period of 3 months (Williams &
    Smith, 1935). Among 7 pregnant females, the number of young per litter
    was only half that of the controls and only 2 of the 13 newborns
    survived to weaning age. Astrup et al. (1972) exposed rabbits during
    their 30 days of pregnancy to carbon monoxide resulting in
    carboxyhaemoglobin levels of either 9-19 or 16-18%. Neonatal mortality
    in the 2 groups increased by 10 and 35%, respectively, compared with a
    control value of 4.5%. Birth weights decreased by 12 and 17%,

        In their studies on the ewe and fetal lamb, Longo & Hill (1977)
    indicated that fetal uptake and elimination of carbon monoxide was
    relatively slow compared with that of the mother. They also reported
    that, during steady-state conditions, fetal levels of
    carboxyhaemoglobin were about 25% higher than maternal levels. These
    results may be related to species differences, since Longo & Hill
    (1970) found that the  M valuesa for sheep maternal and fetal blood
    were 218 and 216 respectively, while Engel et al. (1969) reported that
    fetal haemoglobin had 20% less preferential binding of carbon monoxide
    over oxygen than haemoglobin A.

        There are very few studies on the teratogenicity of carbon
    monoxide exposure. When fertilized chicken eggs were continuously
    exposed to a carbon monoxide concentration of 747 mg/m3 (650 ppm)
    for up to 18 days of incubation, the percentage of eggs hatching
    decreased to 46% and developmental anomalies of the tibia and
    metatarsal bones were noted (Baker & Tumasonis, 1972).


    a   M = Relative affinity of haemoglobin for carbon monoxide
       compared with oxygen.

    7.7  Carcinogenicity, and Mutagenicity

        No evidence is available on carcinogenicity and mutagenicity in
    relation to exposure to carbon monoxide.

    7.8  Miscellaneous Changes

        Kustov et al. (1972) exposed rats to carbon monoxide at 53 mg/m3
    (46 ppm) and noted slower weight gains and an increase in haemoglobin.
    Some enzyme systems were also found to have increased activity, when
    rats were exposed to carbon monoxide (Pankow & Ponsold, 1972; Pankow
    et al., 1974b). A slowing of  in vivo metabolism of the drugs
    hexobarbital and zoxazolamine, with prolongation of their
    pharmacological effects has been reported in rats exposed to carbon
    monoxide concentrations of 286-3435 mg/m3 (250-3000 ppm) (Montgomery
    & Rubin, 1971). With prolonged exposure, these metabolic effects
    became less pronounced and reverted to normal more quickly following
    removal from the carbon monoxide environment. Sokal (1975) compared
    the effect on blood pH and certain carbohydrate metabolic products
    resulting from either a bolus administration or a fixed level of
    inspired carbon monoxide, both resulting in equivalent final levels of
    carboxyhaemoglobin. His data suggest that more intense biochemical
    effects resulted following a gradual increase in carboxyhaemoglobin
    levels compared with effects seen following rapid elevation of
    carboxyhaemoglobin from the bolus. Data presented by Marks & Swiecicki
    (1971) indicated that exposure to high levels of carbon monoxide
    induced a stresslike response in the form of an elevation in
    catecholamines. Swiecicki (1973) reported that increased
    carboxyhaemoglobin levels stimulated the adrenergic system and
    increased carbohydrate metabolism. He also noted that physical
    training of the rat neither prevented nor reduced changes in
    carbohydrate metabolism following carbon monoxide exposure and
    vibration. Exposure of rats to 57 mg/m3 (50 ppm) for 5 h per day, 5
    days per week, for 12 weeks produced an effect on trace metals at the
    subcellular level, with a possible reduction in cellular respiration
    and nucleoprotein synthesis.

        Guineapigs exposed to carbon monoxide concentrations of
    1.7-30 mg/m3 (1.5-26 ppm) for 21 days, 8 h per day, did not show any
    allergenic effects related to carbon monoxide exposure (Vinogradov et
    al., 1974). Plasma leucine aminopeptidase (EC and
    glutamic pyruvic transaminase (EC activity, normally


    a  The numbers within parentheses following the names of enzymes are
       those assigned by the Enzyme Commission of the Joint IUPAC-IUB
       Commission on Biochemical Nomenclature.

    increased by exposure to carbon tetrachloride, were further
    potentiated when blood carboxyhaemoglobin levels were elevated. Pankow
    et al. (1974a) also observed an additive effect on some enzymes with a
    combination of alcohol and carbon monoxide giving a carboxyhaemoglobin
    concentration of 50%.

        Rondia (1970) observed a significant reduction of benzopyrene-
    hydroxylase (EC activity in the liver homogenates of rats
    exposed to a carbon monoxide concentration of 70-150 mg/m3
    (60-130 ppm) for only a few days. This finding might be interpreted as
    meaning that carbon monoxide contributes to the induction of lung
    cancer by lengthening the time of retention of carcinogens in the
    lung. Additional work is necessary to clarify this important question.

    7.9  Interactions

        Much of the data reviewed by Pankow & Ponsfold (1974) concerning
    the combined effects of carbon monoxide and other biologically active
    agents are based on animal experiments. Because of the extreme
    exposure conditions used in most of these studies, only a few of them
    are directly relevant to the environmental exposure of man to carbon

        The experimental evidence on the aggravation of carbon monoxide-
    induced atherosclerosis in rabbits by dietary cholesterol has already
    been mentioned (see section 7.2). No significant additive effects were
    noted from ethanol when dogs exposed to a carbon monoxide
    concentration of 115 mg/m3 (100 ppm) for 21 weeks, 5 days a week,
    and 6 h per day were given a daily oral dose of 120 ml of a 15%
    ethanol solution (Pecora, 1959). However, the excretion of total
    lipoproteins was higher when carbon monoxide and ethanol treatments
    were combined than with exposure to carbon monoxide alone. An
    indication of interaction of sulfur dioxide and carbon monoxide was
    given by Prohorov & Rogov (1959) in their experiments on rabbits. The
    depressed activity of succinate dehydrogenase (EC on heart,
    liver, and kidney due to exposure to sulfur dioxide at 200 mg/m3
    (76 ppm) was exacerbated by exposure to carbon monoxide at a level of
    200-400 mg/m3 (174-348 ppm), for 3 h per day, over a 3-week period.
    As for the combined effects of carbon monoxide and temperature, Tiunov
    & Kustov (1969) showed clearly that carbon monoxide toxicity in mice
    increased at temperatures above or below normal ambient levels.


    8.1  Healthy Subjects

    8.1.1  Behavioural changes

        Demonstrable changes in the central nervous system (CNS) function
    of subjects inadvertently exposed to high levels of ambient carbon
    monoxide in illuminating gas and in automobile exhaust resulted in a
    series of studies to determine psychomotor and psychological
    aberrations in subjects having more modest blood levels of
    carboxyhaemoglobin than those observed in the potentially moribund
    patients. Deficiencies in earlier studies have been related to
    inadequate understanding of the significance of behavioural changes,
    the inability to distinguish between simple perceptual motor
    performance and the more complex performance involving sustained
    and/or selective attention, short-term memory, and decision making
    among possible alternatives. Furthermore, the physiological mechanisms
    involved in carbon monoxide intoxication were not appreciated and the
    available physiological and psychological tools were not adequately
    exploited. Even today, some physiological and behavioural studies
    suffer from similar or other inadequacies, e.g., the failure to
    measure blood carboxyhaemoglobin levels, the inability to distinguish
    between the physiological effects of a carbon monoxide bolus of high
    concentration or the slow, insidious increment in carboxyhaemoglobin
    levels over time with lower inhaled concentrations, the amount of
    carbon monoxide brought to or removed from the lungs by changes in
    alveolar ventilatory volumes, and the small number of volunteers
    examined. Other factors involve failure to provide control measures
    for bias and effects of the experimental worker (by means of double-
    blind administration), control periods so that task-learning effects
    do not mask negative results, homogeneity of the groups labelled
    "smokers" and "nonsmokers", and control of possible boredom and
    fatigue effects, all essentially amounting to a failure to adopt a
    proper experimental design that would produce statistically
    significant information.

        A reduction of logical memory and recognition was demonstrated by
    Chalupa (1960) in individuals subjected to acute carbon monoxide
    intoxication. However, these functions returned to normal. Sayers et
    al. (1929) did not find any significant changes in 6 exposed men
    despite carboxyhaemoglobin levels of approximately 20-30%;
    observations included hand-eye coordination and steadiness, tapping
    speed, arithmetic (continuous addition), location memory, and simple
    reaction time. Simple sensory-motor times decreased by 10% in subjects
    with carboxyhaemoglobin concentrations of approximately 6.2% (5.5-7%)
    (Tiunov & Kustov, 1969). Simulated driving performance did not
    deteriorate despite carboxyhaemoglobin levels of 25%, although a small
    deterioration was observed when the carboxyhaemoglobin levels were
    above 35% (Forbes et al., 1937). The first demonstrable influences of

    carbon monoxide on higher CNS functions were noted by McFarland et al.
    (1944) in conjunction with their altitude studies, when they observed
    reduction of visual acuity at carboxyhaemoglobin levels as low as 5%.
    These observations were extended by Halperin et al. (1959) when they
    reported that visual function was impaired at carboxyhaemoglobin
    levels as low as 4% and that impairment increased at higher levels.
    More recently, McFarland et al. (1973) showed that, for glare
    recovery, the dark adaptation final threshold values increased as
    carboxyhaemoglobin levels rose from control to 6-17%. Peripheral
    recognition tasks were not affected until levels reached 17%. They
    also stated that central and peripheral complex tasks were not
    influenced by low levels of carboxyhaemoglobin. Schulte (1963)
    demonstrated that there was a decrease in performance in higher
    intellectual processes that was observable when the carboxyhaemoglobin
    level exceeded 5%; further deterioration was noted as the level
    increased. These results were in direct contradiction to the negative
    results obtained by Dorcus & Weigand (1929) who used a similar series
    of tests but with subjects exposed for a shorter period. In studies by
    Beard & Wertheim (1967), the ability to judge correctly slight
    differences in successive short time intervals showed significant
    impairment when carboxyhaemoglobin levels were approximately 2 to 3%
    above basal levels. These findings, suggesting an altered mental
    function, represent the lowest levels of carboxyhaemoglobin that
    produce a significant alteration in behavioural performance. However,
    attempts to replicate them have been less than satisfactory (O'Donnell
    et al., 1971a,b; Stewart et al., 1973a) even though the subjects in
    all these other studies attained higher levels of carboxyhaemoglobin.
    Some of the discrepancies may be explained on the basis of differences
    in protocol and in the environmental conditions under which the tests
    were conducted. Some of the investigators designed their experiments
    to minimize the factors of boredom and fatigue while others attempted
    to minimize external influences and conducted their experiments for a
    relatively long time.

        However, the Beard & Wertheim study may actually be more relevant
    to questions of vigilance and ideally should be discussed in this
    context. Assessment of vigilance is the determination of an
    individual's ability to detect small changes in his environment,
    changes that take place at unpredictable times and so demand
    continuous attention. In such monotonous tasks, subjects miss signals
    that they would not have missed when starting the task. Such signals
    are presented visually or aurally. Fodor & Winneke (1972) and Groll-
    Knapp et al. (1972) used auditory signals for their vigilance task.
    The former investigators used a white noise (frequency range from 20
    to 20 000 Hz lasting 0.36 sec and repeated at 2-sec intervals. About 3
    out of every 100 of these noises were slightly less intense and were
    used as the signal to which the subjects responded by pressing a
    button. Twelve nonsmokers (male and female) were tested at carbon
    monoxide concentrations of 0 and 57 mg/m3 (0-50 ppm). They breathed
    this concentration for 80 min prior to the first of three vigilance

    tests. Carboxyhaemoglobin levels were estimated to be 2.3 and 3.1% at
    the beginning and the end of the first vigilance test, respectively.
    Subjects were likely to miss signals during this initial test. This
    was not observed during the next two vigilance tests (total exposure
    to carbon monoxide being 210 min with the carboxyhaemoglobin level
    estimated to have finally reached 4.3%). These data suggest an initial
    decrement in performance followed by a compensatory response. Groll-
    Knapp et al. (1972) exposed 20 subjects for a 2-h period to carbon
    monoxide concentrations of 0, 57, 115, or 172 mg/m3 (0, 50, 100,
    150 ppm). There is some doubt as to which subjects, if any, were
    smokers. Carboxyhaemoglobin levels were also estimated by these
    investigators at the end of the test period to be 0, 3.0, 5.4, and
    7.6%. Over the 90 min of the auditory test, some 200 paired tones were
    given in which a weaker second tone was the signal. The mean number of
    signals missed during the control test was 26. The number missed
    increased in the presence of elevated carboxyhaemoglobin levels so
    that 35, 40, and 44 misses occurred in environments containing carbon
    monoxide levels of 57, 114, and 172 mg/m3, respectively. This
    suggests a significant impairment when a concentration of 57 mg/m3
    is inhaled. Winneke (1974) used a similar test in studies at carbon
    monoxide concentrations of 0, 57, and 115 mg/m3. Results with all
    levels of carbon monoxide exposure were negative, in marked contrast
    to the previous data despite an estimated carboxyhaemoglobin level of
    approximately 9% at the end of the 115 mg/m3 exposure.

        Beard & Grandstaff (1975) examined the effect of carbon monoxide
    exposure on a visual vigilance task. The signal was a shorter flash of
    light than the non-signals. Following a 30-min control period, 9
    subjects were exposed to carbon monoxide concentrations of 0, 57, 200,
    or 286 mg/m3 (0, 50, 175, 250 ppm). Subjects exposed to room air
    detected 73% of the signals presented to them in three vigils. In
    environments containing carbon monoxide concentrations of 57 and
    200 mg/m3, respectively, 64% of the signals were detected. These
    differences were statistically significant at the 5% level. However,
    exposure to a concentration of 286 mg/m3 yielded a correct
    identification rate of about 70% that was not statistically
    significant. They estimated blood carboxyhaemoglobin levels from
    alveolar breath samples to be 1.8, 5.2, and 7.5%, respectively. The
    alveolar samples were obtained 30 min after the exposures were
    completed. Krotova & Muzyka (1974) studied subjects working for about
    2 years in an environment containing carbon monoxide. Mean
    carboxyhaemoglobin levels were approximately 3.2% before, and 4% after
    work. Eleven of 56 workers reported a loss of vigilance. It has been
    reported by Rummo & Sarlanis (1974) that, during a 2-h vigilance
    driving simulator task, subjects with carboxyhaemoglobin levels of
    6-8% were significantly slower in responding to lead car speed
    changes. Horvath et al. (1971) also used a visual vigilance test and
    were the only group of investigators that actually measured blood
    levels of carboxyhaemoglobin. The vigilance task in these studies was
    the detection of a light pulse that was slightly brighter than the

    base level light pulse. A 1-h vigil was preceded by a short alerting
    pre-test during which a randomly interspersed 10 of 60 light pulses
    were the brighter signals. After a 1-min rest, the 60-min vigilance
    task was begun. Only 40 of 1200 light pulses were signals. Ten of
    these signals appeared randomly out of the 300 presented each 15 min.
    Three levels of ambient carbon monoxide were used, 0, 30, and
    127 mg/m3 (0, 26, and 111 ppm) with each subject serving as his own
    control. Exposures were randomized, with 1 week elapsing between each
    exposure. Fig. 6 illustrates the changes in blood levels of
    carboxyhaemoglobin with time under all conditions and compares the
    concentrations with the levels determined from the data obtained by
    Forbes et al. (1945). The control group breathing filtered air (no
    carbon monoxide present) had carboxyhaemoglobin levels of 0.9% before
    and at the completion of the task. Exposure to a carbon monoxide
    concentration of 30 mg/m3 led to a level of 1.6% after the first
    hour (before the vigilance task) and 2.3% at the end. Carbon monoxide
    exposure at 127 mg/m3 resulted in carboxyhaemoglobin levels of 4.2%
    after the first hour and 6.6% at completion of the vigilance test.
    Performance during the pre-test period gave approximately 88 correct
    responses in all three conditions, carbon monoxide exposure having no
    discernible effect. During the vigilance test itself, subjects
    breathing a concentration of 127 mg/m3 made significantly fewer
    correct responses (4.2-6.6% carboxyhaemoglobin) than the same subjects
    breathing 0 or 27 mg/m3 (Fig. 7). It appeared that when the
    carboxyhaemoglobin level was approximately 5%, a significant decrement
    in performance occurred. It should be noted that the slight
    improvement at the end of the test period probably represented the
    usual alerting response observed whenever subjects estimate that the
    task is completed. Recently, Winneke et al. (1976) attempted to
    replicate this study without success. Although Horvath's experiments
    were started with 15 alleged nonsmokers, pre-exposure blood samples
    from 5 of the subjects showed carboxyhaemoglobin levels of almost 3%.
    At the completion of all the exposures, these subjects admitted
    smoking, thus confirming the blood levels. Data on these subjects were
    not included in this analysis. When these smokers' data were analysed,
    performance on the vigilance task showed no deterioration even though,
    with exposure to a carbon monoxide concentration of 127 mg/m3,
    carboxyhaemoglobin levels increased from an initial 2.8% to 5.1% after
    the first hour and to 6.9% at the completion of the vigilance task
    (O'Hanlon, 1975). There were too few subjects to permit more than a
    suggestion that prior, continuous exposure to nonambient carbon
    monoxide may result in some degree of questionable adaptation. Beard &
    Wertheim's (1967) earlier indications that some deleterious
    psychological effects would appear at carboxyhaemoglobin levels of
    about 2% have not been confirmed or even replicated.

        The design and experimental control in the major studies concerned
    with this subject have been poor with errors of omission, and failure
    to present finalized data. In the early studies of Forbes et al.
    (1937), 5 subjects were exposed to a carbon monoxide concentration

    FIGURE 6

    FIGURE 7

    sufficient to raise carboxyhaemoglobin to a level as high as 30% and
    their reaction times, coordination, and perceptual skill determined
    within the context of a test of driving skill. They failed to present
    adequate control data and did not consider the adaptation that occurs
    following repetitive tests. McFarland (1973) also studied subjects
    with relatively high carboxyhaemoglobin levels (17%) in actual driving
    conditions. The exact effects on driving skills could not be
    determined from the data presented. Studies by Ray & Rockwell (1970)
    and Weir & Rockwell (1973) although first reported in 1970, are still
    in a preliminary form and despite some interesting indications of
    effects, the data cannot be really considered of value in determining
    effects. A "standard driving simulator" was used by Wright et al.
    (1973) with both smokers and nonsmokers as subjects (final
    carboxyhaemoglobin levels were 5.6 and 7.0% respectively). They
    suggested that a 3.4% increase in carboxyhaemoglobin was sufficient to
    cause unsafe driving. While questions regarding the data raise doubts
    as to the value of this interpretation, these conclusions should be
    noted in view of the data reported in the vigilance studies. However,
    a certain amount of caution must be applied to any extrapolation of
    specific, behavioural changes and driving performance, since the
    latter requires integration of many signals in a complex interaction
    not measured in any of the simpler tasks used in most behavioural

        The available information on reaction times and time
    discrimination is presented in considerable detail in a report from
    the National Research Council (NAS/NRC, 1977). Despite apparently
    well-controlled studies on both of these variables, the negative and
    positive effects reported make it impossible to form any valid
    conclusionsa. It would appear that considerable additional effort,
    using a larger number of subjects, more adequate control of
    experimental conditions (especially control of boredom and fatigue),
    direct determinations of carboxyhaemoglobin, and attention to the
    potential effects of low levels of carboxyhaemoglobin are required
    before any valid conclusions can be drawn.

        Apparently, coordination, dexterity, steadiness, and tracking
    ability were not influenced by a carbon monoxide concentration which
    raised carboxyhaemoglobin to levels exceeding 20%. McFarland et al.
    (1944) and Halperin et al. (1959) reported that carboxyhaemoglobin 


    a  The studies by Beard & Wertheim (1967) suggesting a critical
       carboxyhaemoglobin level of approximately 2% were evaluated under
       vigilance and are not repeated here. Attempts by other
       investigators (O'Donnell et al., 197 lb; Stewart et al., 1975) to
       reproduce their results have not been successful.

    levels of 4-5% resulted in impaired brightness discrimination. Their
    findings have been confirmed by Beard & Wertheim (1967). However,
    Ramsey (1973) was unable to reproduce these deleterious effects on
    brightness discrimination. The effects of carbon monoxide exposure on
    complex learned behaviour have been studied by a number of
    investigator's. Exposure of firemen to a concentration of 115 mg/m3
    (100 ppm) for various periods of time (Schulte, 1963) resulted in
    considerable changes in the performance of a series of complex tasks.
    In a test where subjects were required to underline all plural nouns
    in prose passages, decreased performance was noted when the carboxy-
    haemoglobin level was approximately 8%. The mean time to complete an
    arithmetic test significantly increased at similar or slightly lower
    carboxyhaemoglobin levels. This investigator may have underestimated
    the carboxyhaemoglobin levels since the subjects, although mostly
    smokers, had initial values close to zero. O'Donnell et al. (1971a)
    studied the ability of 4 subjects to perform arithmetic problems
    without pencil and paper. While the subjects required a longer time to
    complete the answers (89.8 versus 98.6 sec) when carboxyhaemoglobin
    levels were 5.9% and 12.7%, respectively, some questions as to the
    experimental design of these studies and the limited number of
    subjects used preclude full acceptance of the results. A deterioration
    in the ability to learn meaningless syllables was found by Bender et
    al. (1972), when the carboxyhaemoglobin levels were about 7%. Other
    tests failed to show deterioration at these levels of

        O'Donnell et al. (1971a) sought to determine how overnight
    exposure to carbon monoxide concentrations of 86.0 mg/m3 and
    172 mg/m3 (75 and 150 ppm) (carboxyhaemoglobin levels up to 12.7%)
    affected sleep and found small but unreliable changes that they
    interpreted as a possible reduction in central nervous activation. A
    significant reduction in REM (rapid eye movement) sleep in subjects of
    both sexes exposed for 7 h to a carbon monoxide concentration of
    115 mg/m3 (100 ppm) was reported by Groll-Knapp et al. (1976).

        Earlier, Helmchen & Künkel (1964) reported changes in the rhythmic
    after-potential fluctuations following photic excitation of the brain
    during and following carbon monoxide exposure. However, in contrast,
    Dinman (1969) analysed the photic responses in subjects with
    carboxyhaemoglobin levels of 22% and 37% and did not find any changes
    in latency or voltage following photic stimulation. Sul'ga (1962) did
    not find any disturbances of the alpha rhythm in 2 subjects exposed to
    a carbon monoxide concentration of 20 mg/m3 (17.4 ppm) for 15 min.
    Carbon monoxide-induced visual invoked responses were reported by
    Hosko (1970) and Stewart et al. (1973a) but only at carboxyhaemoglobin
    levels of 20-28%. Stewart et al. (1973b) later reported that neither
    the spontaneous nor the evoked electrical activity of the brain
    exhibited significant changes attributable to carbon monoxide exposure
    (carboxyhaemoglobin levels from 3.2% to 15.2%). Slow-wave brain

    potentials (correlated to anticipatory responses) were measured by
    Groll-Knapp et al. (1972) who noted a diminution in the height reached
    by the anticipation wave and the extent of the drop seen after
    response stimulus following exposure to a carbon monoxide
    concentration of 172 mg/m3 (150 ppm). It appears that another
    conical function test, critical flicker fusion frequency (CFFF) is not
    influenced even by carboxyhaemoglobin levels of between 10% and 12.7%
    (Guest et al., 1970; O'Donnell et al., 1971a; Ramsey, 1973; Winneke,
    1974). Guest et al. (1970) also used an auditory analogue of CFFF, the
    auditory flutter fusion threshold. This threshold was not affected by
    a carboxyhaemoglobin level of 10%. The literature has been reviewed by
    Grandstaff et al. (1975).

    8.1.2  Work performance and exercise

        Maximum exercise can increase the oxygen uptake of the whole body
    by 20 or more times the resting uptake; at this level the oxygen
    transport system will be maximally stressed. Indeed, Mitchell et al.
    (1958) have suggested that the maximum sustained energy output is
    determined by the capability of the cardiovascular system to transport
    oxygen to the exercising muscle. Assuming this concept to be true, any
    impairment of oxygen transport, such as can occur when
    carboxyhaemoglobin is present could limit maximum aerobic capacity
    ( Vo2 max). In fact, it has been appreciated for some time that
    individuals, having a large burden of carbon monoxide experience
    difficulty in performing physical work. Subjects studied by Chiodi et
    al. (1941) were unable to perform tasks requiring only low levels of
    physical exertion when their blood levels of carboxyhaemoglobin
    reached 40-50%. Several collapsed while attempting to perform routine
    laboratory exercise tests. Roughton & Darling (1944) also suggested,
    on theoretical grounds, that work capacity would be reduced to zero
    when carboxyhaemoglobin levels approached 50%. An impaired performance
    by competitive swimmers was associated with exposure to a carbon
    monoxide level of 34 mg/m3 (30 ppm) originating from traffic
    (MacMillan, 1969)a. Douze (1971) presented information on the
    incidence of carbon monoxide poisoning due to the use of natural gas
    heaters in Utrecht.


    a  Quoted by the US National Research Council, Division of Medical
       Sciences, Committee on Effects of Atmospheric Contaminants on Human
       Health and Welfare, 1969, p.  55.

        There appears to be complete agreement that performance of light
    to moderate work (up to 70%  Vo2 max)b for a short period of time
    is not significantly influenced by carboxyhaemoglobin levels as high
    as 33%. All the submaximal exercise tests were of short duration
    (5-60 min). Oxygen uptake during work was unchanged despite the
    presence of carboxyhaemoglobin (Chevalier et al., 1966; Ekblom & Huot,
    1972; Gliner et al., 1975; Mitchell et al., 1958; Nielsen, 1971;
    Pirnay et al., 1971; Vogel & Gleser, 1972; Vogel et al., 1972). The
    only clear indication of physiological load appeared to be a slight
    increase in heart rate. Chevalier and associates (1963, 1966) studying
    men carrying out light work for a period of 5 min, reported that while
    the oxygen uptake was unaffected when the carboxyhaemoglobin level was
    approximately 4% (estimated value), there was a significant increase
    in oxygen debt when this was related to the total increased oxygen
    uptake. Five subjects studied by Pirnay et al. (1971) performing work
    for 15 min had an oxygen uptake of 1.5 litre per min. No changes in
    oxygen uptake were found even though the carboxyhaemoglobin level
    reached 15%. In a rather involved study, where carboxyhaemoglobin
    levels fluctuated between 5% and 17%, Klausen et al. (1968) did not
    find any differences in energy expenditure in relation to exposure
    when subjects exercised for 15 min at 50% of their  Vo2 max. It is
    rather interesting that, despite the considerable variations in such
    experimental conditions as the duration and magnitude of exercise, the
    level of carboxyhaemoglobin and the method of administration of carbon
    monoxide, and also the small numbers and limited age ranges of the
    exposed subjects -- the results from all these studies were
    essentially similar. Pirnay et al. (1971), Vogel & Gleser (1972), and
    Vogel et al. (1972) reported consistently higher heart rates for given
    selected submaximal work loads and increased ventilatory volume
    exchange per unit of oxygen uptake.

        Since populations may be exposed to polluted environments for long
    periods, Gliner et al. (1975) studied the responses of 2 groups of 10
    and 9 men, respectively (mean age 23.0 and 48~4 years) each of which
    included 5 subjects who smoked. A work load of 35%  Vo2 max was
    selected (untrained men can work at this level for approximately 8 h
    with minimum physiological changes), and the men walked for 4 h in an
    environment containing a carbon monoxide concentration of 57 mg/m3


    b  This figure may be in error for all levels of carboxyhaemoglobin
       above 5% since  Vo2 max decreases with increasing level of
       carboxyhaemoglobin and the initial percentages of  Vo2 max were
       apparently determined on the basis of a  Vo2 max measured at
       0.5% carboxyhaemoglobin for the fixed work loads used in the
       studies. Thus, the highest percentage of  Vo2 max reported (70%)
       may have been as high as 91% and would represent hard work.  Vo2
       max is identical to the maximum aerobic capacity representing the
       capability of the organism to take up oxygen.

    (50 ppm). Final carboxyhaemoglobin levels were 5.3 and 6.1% for
    nonsmokers and smokers, respectively. An additional study was
    conducted on 4 men exposed to a carbon monoxide concentration of
    115 mg/m3 (100 ppm). Final carboxyhaemoglobin levels for nonsmokers
    and smokers were 10.3 and 13.2%, respectively. Ambient temperatures
    were 25°C and 35°C, with a relative humidity of 30%. Cardiovascular
    and respiratory variables were measured. The only significant change
    was a higher heart rate in the carbon monoxide environment,
    irrespective of age of subject (Fig. 8), confirming observations,
    previously reported. Cardiac index remained constant at approximately
    6 litres/min × m2 in both filtered air and in carbon monoxide
    concentrations of 57-115 mg/m3 (50-100 ppm). The full significance
    of this change in long-term performance in carbon monoxide polluted
    environments is not apparent, at present.

        The oxygen transport capacity of blood is reduced in the presence
    of carboxyhaemoglobin. In short-term maximum exercise of several
    minutes duration, where capacity for effort depends mainly on aerobic
    metabolism, maximum aerobic capacity would be expected to diminish
    approximately in proportion to the level of carboxyhaemoglobin present
    in the blood. Such a diminution in  Vo2 max, when the carboxyhaemo-
    globin level is between 7% and 33% has been observed by a number of
    investigators (Chiodi et al., 1941; Ekblom & Huot, 1972; Horvath et
    al., 1975; Nielsen, 1971; Pirnay et al. 1971). In most of these
    studies, bouts of exercise ranged from 2-6 min and the mode of
    administration of carbon monoxide involved either breathing relatively
    high concentrations of the gas or the administration of a bolus with
    additional carbon monoxide to maintain the desired levels of
    carboxyhaemoglobin. In some of these studies, the smoking habits of
    the subjects were not identified.

        In all of these studies, the levels of carboxyhaemoglobin were
    considerably in excess of those anticipated to occur in men exposed to
    the concentrations of carbon monoxide designated as limiting levels by
    various governing bodies or even reported to occur in the outdoor air
    of certain metropolitan areas. The initial studies by Horvath's group
    (Drinkwater et al., 1974; Raven et al., 1974a, b) were made on
    subjects breathing a carbon monoxide concentration of 57 mg/m3
    (50 ppm) at one of 2 thermal environments, i.e., 25°C or 35°C with a
    relative humidity of 20%. A walking test requiring some 15-24 min to
    complete was carried out on a treadmill with progressively increasing
    grade, in order to measure  Vo2 max. The 2 populations consisted of
    20 young (24+ years) and 16 middle-aged (48+ years) subjects with
    equal numbers of smokers and nonsmokers in the young group and 7
    smokers and 9 nonsmokers in the older group. The middle-aged subjects
    demonstrated the anticipated decrease in  Vo2 max associated with
    advancing age. However, the middle-aged nonsmokers had a  Vo2 max
    that was about 27% greater than that of smokers of the same age. As
    the test progressed, the carboxyhaemoglobin levels of nonsmokers

    FIGURE 8

    increased from 0.7% to approximately 2.8%, while those of smokers rose
    from 2.6-3.2% to 4.1-4.5%. During control studies conducted on these
    subjects while breathing filtered air, carboxyhaemoglobin levels
    decreased in both smokers and nonsmokers. The results of these studies
    (Drinkwater et al., 1974; Gliner et al., 1975; Raven et al., 1974a, b)
    failed to demonstrate any reduction in  Vo2, max. The decrement in
     Vo2 max that occurred as a consequence of working in a hot
    environment was greater than the changes observed while breathing
    carbon monoxide. Other cardiovascular, respiratory, metabolic, and
    temperature measurements made concurrently with the oxygen uptake
    studies also failed to show any decrements associated with carbon
    monoxide exposure. However, a decrease in absolute exercise time
    consistently observed in nonsmoking subjects but not in smokers was
    significantly related to carbon monoxide exposure. These observations
    confirmed those found earlier by Ekblom & Huot (1972), although they
    reported a surprisingly large (38%) decrease in work time at a
    carboxyhaemoglobin level of 7%. Aronow & Cassidy (1975) have recently
    reported a slight decrease in work time during a maximum exercise test
    on 10 middle-aged (50.7 years) subjects. The only ischaemic S-T
    segment depression occurred in one female subject. No electro-
    cardiographic changes were observed in the subjects studied by
    Horvath's group. Nielsen (1971) found that exercising subjects
    developed higher internal body temperatures in the presence of carbon
    monoxide than in its absence. Reductions in skin conductance suggested
    a redistribution of the circulation to the working muscle and away
    from the skin.

        Horvath and co-workers had some doubts about the changes in
    carboxyhaemoglobin levels in smokers and nonsmokers as well as the
    lack of change in  Vo2 max under the ambient and exercise
    conditions employed. For their next series of studies (Dahms et al.,
    1975), they developed a more precise method to regulate relatively low
    levels of carboxyhaemoglobin (Fig. 9). It should be noted that a low
    ambient level of carbon monoxide will reduce the rate of pulmonary
    excretion of carbon monoxide particularly if the carboxyhaemoglobin
    level is low. In these experiments, a double-blind study was again
    used in which subjects breathed either filtered air or air containing
    carbon monoxide which resulted in stable levels of carboxyhaemoglobin.
    The data suggest that a critical level of carboxyhaemoglobin must be
    present before significant physiological alterations can be
    demonstrated. Statistically significant decreases in  Vo2 max were
    noted when carboxyhaemoglobin levels exceeded 4.3%. Although this was
    a double-blind, randomized study in which neither the investigators
    nor the subjects knew the composition of the air breathed, it was
    subsequently determined that all subjects correctly identified the
    experiment in which they had been exposed to the highest level of
    ambient carbon monoxide. In all instances, they noted a heaviness in
    the lower extremities and greater difficulty in performing the task.

    FIGURE 9

        Data obtained by Horvath's group and others are summarized in
    Fig. 10. There is a linear decline in  Vo2 max when
    carboxyhaemoglobin levels range from 4 to 33%. This can be expressed
    as: % decrease in  Vo2 max = 0.91 (% HbCO) + 2.2. It should be
    noted that this does not apply to smokers in Horvath's series, who
    frequently had carboxyhaemoglobin levels considerably in excess of
    4-5% with no decrement in their respective  Vo2 max values.

        According to data available at present, carbon monoxide can modify
    physiological responses. The level of blood carboxyhaemoglobin
    required to induce these effects appears to be approximately 5%. The
    carboxyhaemoglobin concentration is probably a more accurate
    assessment of exposure than a statement of the exposure conditions,
    ambient carbon monoxide concentrations, time, etc. Therefore,
    physiological effects should be related to a carboxyhaemoglobin level
    even though in some circumstances the method of exposure, i.e. rapid
    loading versus slow loading may produce effects not evident from the
    carboxyhaemoglobin concentration.

    8.1.3  Adaptation

        The implication that, in the presence of a clinical state of
    chronic carbon monoxide poisoning, adaptation to carbon monoxide
    occurs has not been verified. It would appear that such a state could
    have been identified by studies on long-term heavy smokers. or
    individuals exposed to environmental sources of carbon monoxide. Early
    concern with carbon monoxide intoxication in England and Scandinavia
    resulted in studies suggesting the possibility of such a condition
    (Grut, 1949; Killick, 1940). However, doubts regarding the use of high
    levels of inspired carbon monoxide (several hundred parts per million)
    and inadequate experimental methods give rise to some scepticism about
    the conclusions presented. Killick (1940), using herself as a subject,
    reported that she developed acclimatization in the form of diminished
    symptoms, slower heart rate, and the attainment of a lower
    carboxyhaemoglobin equilibrium level following exposure to a given
    inspired concentration of carbon monoxide. A similar finding
    concerning the attainment of a different carboxyhaemoglobin
    equilibrium following exposure to a fixed level of carbon monoxide in
    the ambient air had been reported earlier by Haldane & Priestley
    (1935). Additional information on other possible adaptation effects in
    the pre-1940 literature can be found in Killick's review.

        The changes indicated above, which have been reported as evidence
    of adaptation, are probably related to compensatory haematological
    changes. Some polycythaemia occurs as a response to chronic or
    repeated exposure corresponding roughly to the ambient levels of
    carbon monoxide. Brieger (1944) reported an increase in red cell mass
    following exposure to 115 mg/m3 (100 ppm) and industrial workers

    FIGURE 10

    exposed to rather ill-defined levels of carbon monoxide have been
    reported to be polycythaemic (Jenkins, 1932). Wilks et al. (1959)
    believed that acclimatization was purely a function of increased red
    cell mass.

        The possibility that adaptation to carbon monoxide following
    extensive exposure (as occurs in the case of adaptation to high
    altitudes) could alter the position of the oxygen dissociation curve
    appears to have been answered. Mulhausen et al. (1968) did not find
    any change in the degree of left shift in the blood of individuals
    exposed to carbon monoxide for a period of 8 days. Unfortunately, the
    average carboxyhaemoglobin level of 13% was based on considerable
    individual variations in carboxyhaemoglobin levels and periodic
    exposure to relatively high concentrations of inhaled carbon monoxide.
    Several investigators have sought evidence of a potential shift of the
    curve back to the right. Red cell levels of 2,3-diphosphoglycerate
    compounds are higher in individuals with anaemia and also during
    residence at high altitudes (2,3-diphosphoglycerate is a
    phosphorylated by-product of glycolysis). In the erythrocytes of man
    and most other mammals, the molar concentration of this compound is
    roughly equal to that of haemoglobin. Both it and some other organic
    phosphates are bound rather strongly to deoxyhaemoglobin but have
    little affinity for oxyhaemoglobin. Increases in 2,3-diphospho-
    glycerate shift the effective oxygen affinity, i.e., there is a shift
    of the oxyhaemoglobin dissociation to the right. Astrup (1970) found a
    small decrease in erythrocyte 2,3-diphospho-glycerate in human
    subjects with carboxyhaemoglobin levels maintained at 20% for 24 h.
    Conversely, Dinman et al. (1970) found a small increase in 2,3-
    diphosphoglycerate in human subjects after 3 h at an approximate
    carboxyhaemoglobin level of 20% and in rats exposed to higher but
    variable concentrations of carbon monoxide. A shift in the
    dissociation curve does not appear to be an important adaptation
    mechanism when carbon monoxide exposure lasts less than a few days.

    8.1.4  Effects on the cardiovascular system and other effects

        Functional heart disturbances (lability of blood pressure and
    heart acceleration, extrasystoles, exacerbations of angina pectoris),
    as well as temporary heart dilatation and cardiac asthma have been
    reported in cases of acute carbon monoxide poisoning (Lazarev, 1965).
    According to the same author, various changes were also seen in the
    peripheral vascular system (vasodilation, stasis, vasopermeability
    etc.). Lazarev (1965) also noted severe cardiovascular disturbances
    such as heart acceleration, extra-systoles, pulse and blood pressure
    lability (more often hypotension than hypertension) in groups of
    workers exposed to carbon monoxide for long periods. Disturbances of
    atrioventricular and interventricular conductance were observed after
    1 to 1.5 years of exposure and even after cessation of contact with
    carbon monoxide.

        The first evidence of left ventricular abnormality was presented
    by Corya et al. (1976) in 5 cases of nonfatal poisoning (carboxyhaemo-
    globin level of 20%). Abnormal left ventricular wall motion was shown
    by echocardiograph in 3 of the 5 cases. A similar number showed mitral
    valve prolapse. A ballistocardiogram was used by Gorski (1962) to
    demonstrate hypoxaemia of the myocardium in similar cases. Byczkowska
    & Milan (1971) described functional kidney disturbances in a patient
    poisoned with carbon monoxide. Clinical and physiological haemodynamic
    studies on 2 groups (individuals in constant contact with carbon
    monoxide and individuals having no evidence of chronic carbon monoxide
    intoxication) were conducted by Zenkevic (1973). He noted considerable
    cardiovascular abnormalities in the carbon monoxide-exposed group. A
    study on cast-iron workers by Ejam-Berdjev (1973) also suggested a
    larger frequency of cardiovascular, as well as central nervous system
    disturbances in these workers, related to their increased blood levels
    of carboxyhaemoglobin.

        Evidence of a myocardosis was found in 18% of Japanese farmers
    chronically exposed to a mean carbon monoxide concentration of
    80 mg/m3 (70 ppm), (Komatsu, 1959). The exposure occurred as a
    result of spending the winter months preparing hemp in enclosed
    dwellings heated by charcoal fires. Following exposure, the farmers
    exhibited symptoms of dizziness, palpitation, and congestive heart
    failure. The diagnosis of a myocardosis was supported by clinical
    evidence of congestive heart failure and ECG changes such as prolonged
    QT interval, ST segment depression, and T-wave flattening.

        Aleksieva & Dimitrova (1971) studied a large group of workers
    exposed to a carbon monoxide concentration of 60 mg/m3 (52 ppm) and
    reported changes in peripheral vessels suggesting impaired vascular

        An additional hazard to patients, especially those undergoing
    cardiovascular surgery, may develop during anaesthesia. Markedly
    elevated carboxyhaemoglobin levels have been reported in patients
    under cardiac bypass surgery (Middleton et al., 1965). This increase
    could be related in part to the carbon monoxide present in transfused
    blood and to the closed-circuit method of anaesthesia that precludes
    the loss of endogenously produced carbon monoxide. This is also
    important for infants undergoing transfusions (see sections 5.4 and

    8.1.5  Carboxyhaemoglobin levels resulting from exposure to
           methane-derived halogenated hydrocarbons

        The belated discovery that at least one chemical substance used in
    industry and commerce is "degraded" within the body to carbon monoxide
    has potentially significant epidemiological and clinical implications.
    Methane-derived halogenated hydrocarbons have been widely used as
    organic solvents, replacing carbon tetrachloride. A chance observation

    (Stewart et al., 1972b) indicated that the inhalation of
    dichloromethane (methylene chloride, CH2CI2) was followed by a
    sustained elevation in carboxyhaemoglobin concentrations. Inhalation
    of methylene chloride at a concentration of 1740-3480 mg/m3
    (500-1000 ppm) (industrial TLVs for USA and USSR = 1740 mg/m3
    (500 ppm) and 50 mg/m3 (14 ppm), respectively) for 1-2 h resulted in
    carboxyhaemoglobin levels of more than 14% (Stewart et al., 1972a).
    This elevation in carboxyhaemoglobin levels continued beyond the time
    of exposure and gradually returned to normal during the next 24 h.
    Nunes & Schoenborn (1973) demonstrated that the binding affinity of
    carbon monoxide for haemoglobin increased in the presence of methylene
    chloride. A number of studies have confirmed that methylene chloride
    was metabolized to carbon monoxide (Divicenzo & Hamilton, 1975; Kubic
    et al., 1974; Ratney et al., 1974; Roth et al., 1975). Roth et al.
    (1975) noted that rabbits rarely succumbed to methylene chloride at a
    concentration of 40 g/m3 (11 520 ppm) possibly because of saturation
    of the pathways of methylene chloride metabolism and the rate of
    carbon monoxide excretion. The mechanism by which methylene chloride
    is metabolized to carbon monoxide has still to be elucidated.  In
     vitro studies (Ahmed et al., 1977; Hogan et al., 1976) suggest that
    the mixed function oxygenase system of microsomes is responsible for
    the metabolic conversion of methylene chloride to carbon monoxide.

        Several investigators have studied the influence of methylene
    chloride on physiological functions. Astrand et al. (1975) examined
    the effects on work performance of exposure to concentrations of 870
    and 1740 mg/m3 for four, 30-min periods but did not find any
    impairment, apparently because carboxyhaemoglobin levels were low
    (4%). Central nervous system depression was observed in some subjects
    exposed to concentrations of 1740-3480 mg/m3 (500-1000 ppm) (Stewart
    et al., 1972a).

        In studies by Winneke (1974), the effects of exposure to ambient
    levels of carbon monoxide of up to 115 mg/m3 (100 ppm) on vigilance
    and CFFF were less marked than those resulting from exposure to
    methylene chloride at 1044-2784 mg/m3 (300-800 ppm).

        According to Stewart & Hake (1976) a potentially more dangerous
    complication of exposure to methylene chloride is the sustained
    carboxyhaemoglobin level that results from the metabolic production of
    carbon monoxide from lipid stores of methylene chloride and continues
    for many hours following exposure. The potential hazard of chemical
    compounds that may be metabolized to carbon monoxide deserves further

    8.1.6  Levels and effects of carboxyhaemoglobin resulting from smoking

        It would be extremely presumptive in a review of the effects of
    ambient carbon monoxide to discuss all the possibilities arising from
    the incomplete combustion of tobacco and paper. Many of the products

    inhaled may produce subtle physiological and biochemical effects on
    the smoker. Individuals breathing either pre-inhaled materials or the
    smokers' exhaled products are affected to a much lesser degree than
    the smoker (Russell et al., 1973; Srch, 1967). It is suggested that
    those interested in the problems related to smoking tobacco,
    carcinogenesis, and cardiovascular and pulmonary disease, refer to the
    documents specifically concerned with these matters (Fletcher & Horn,
    1970; Hammond, 1962; US Department of Health, Education and Welfare,
    1973; WHO, 1975). Prospective and retrospective epidemiological
    studies have, identified cigarette smoking as one of the major factors
    in the development of coronary heart disease. The risk of developing
    coronary heart disease for pipe and cigar smokers is apparently much
    less than it is for cigarette smokers but more than for nonsmokers.
    Furthermore, experimental studies suggest that tobacco smoking may
    contribute to the development and aggravation of coronary heart
    disease through the action of several independent or complementary
    mechanisms, one of these being the formation of significant levels of
    carboxyhaemoglobin. The role of carboxyhaemoglobin in cancer
    development appears to be negligible and unproven. The possible
    interaction of carbon monoxide and other constituents of smoke that
    may occur in the lungs and other tissues and so induce pathological
    changes remains to be elucidated since the basic chemistry has not
    been adequately defined.

        Kuller et al. (1975) in their epidemiological study in Baltimore,
    USA, stated that, if there is an association between carbon monoxide
    exposure and heart attacks, the significant exposures are probably
    related to micro-environmental factors and cigarette smoking rather
    than to community air pollution. They noted that relatively few heart
    attacks occurred while an individual was smoking a cigarette. In Los
    Angeles, USA (Cohen et al., 1969; Goldsmith & Landaw, 1968; Hexter &
    Goldsmith, 1971), the case fatality rate for hospitalized myocardial
    infarction (M.I.) patients was higher in areas with high ambient
    levels of carbon monoxide (9-16 mg/m3 or 8-14 ppm) and was
    positively correlated with ambient carbon monoxide levels. However,
    there was no association between ambient carbon monoxide levels and
    the admission rates per day. Wallace et al. (1974) concluded that
    "from the human health hazard point of view, restriction or
    elimination of cigarette smoke makes the most sense in terms of
    protecting the atherosclerotic population and preventing a possible
    future incidence of coronary heart disease due to chronic carbon
    monoxide exposure". It has also been suggested by Astrup (1972) that
    the risk of developing arterial diseases from intermittent exposure:
    to carbon monoxide may be much higher for smokers than for nonsmokers.
    Wald et al. (1973) and Ball & Turner (1974) came to similar
    conclusions. In a study by Rissanen et al. (1972), cigarette smokers
    had more advanced atherosclerosis than nonsmokers. An extensive review
    and some experimental evidence for this viewpoint has been presented
    by Kjeldsen (1969).

        Smoking cigarettes resulted in higher carboxyhaemoglobin levels
    than exposure to carbon monoxide levels present in street air
    (Castleden & Cole, 1975; Göthe et al., 1969). Manual workers had lower
    carboxyhaemoglobin levels than sedentary workers (both groups being
    tobacco smokers), probably because of the increased ventilation
    required by the occupations of the manual workers (Castleden & Cole,
    1975; Summons & Coleman, 1974). Unless extreme experimental conditions
    are considered (Russell et al., 1973; Srch, 1967), carbon monoxide
    produced by passive smoking does not seem to present a health risk
    (Hinds & First, 1975; Antweiler, 1975; Harke, 1975). Rylander (1974)
    also concluded that carbon monoxide exposure through passive smoking
    was negligible and that adverse effects upon health would not be
    expected. The quantity of carbon monoxide actually entering the lung
    depends upon the form in which the tobacco is smoked, the pattern of
    smoking, and depth of inhalation. Very little carbon monoxide is
    absorbed in the mouth and larynx (approximately 5%) so that most of
    the carbon monoxide available for transfer to haemoglobin must reach
    the alveoli in order to raise the level of carboxyhaemoglobin present
    in the blood stream. Cigarette smokers inhale to a greater extent than
    cigar smokers who, in turn, inhale more than pipe smokers, but there
    are quite marked individual differences in this pattern. Heavy
    cigarette smokers may have carboxyhaemoglobin levels as high as
    15-17%. The carbon monoxide concentration in the mainstream smoke of
    cigarettes (Table 7) is approximately 4% (V/V) (Fletcher & Horn, 1970;
    Hoffman & Wynder, 1972; Wald & Howard, 1975). It has been estimated
    that the cigarette smoker may be exposed to a carbon monoxide
    concentration of 460-575 mg/m3 (400-500 ppm) for the approximately
    6 min needed to smoke a cigarette. Landaw (1973) noted that the half-
    time of carbon monoxide elimination in smokers was approximately
    291 min. Fig. 11 illustrates the pattern of change in carboxyhaemo-
    globin in a typical heavy cigarette smoker (Horvath, personal
    communication). An indwelling venous catheter permitted the frequent
    sampling of this smoker's blood. The subject smoked only during his
    working hours. It should be noted that, by the time he began to smoke
    the next day, he still had a body burden of 1.7%. Cigarette smokers
    generally excrete carbon monoxide into the air rather than inhale it
    from the ambient environment.

    Table 7.  Carbon monoxide (volume percent) in main stream smokea

    Cigarette                  Cigar

    (nonfilter)  (filter)      A (85 mm)      B (85 mm)    C (95 mm)

    4.6          4.5           5.3            11.1         7.1

    a  From: Hoffman & Wynder (1972).

    FIGURE 11

        Dalhamn et al. (1968) determined the retention of cigarette smoke
    components in the human lung. They found a 54% retention of carbon
    monoxide and an 86-97% retention of all other compounds. Carbon
    monoxide yields from cigarettes increased with puff volume and tobacco
    moisture decreased with increased paper porosity, but remained
    constant with puff duration (Robinson & Forbes, 1975). In studies by
    Haebisch (1970), the carbon monoxide content of smoke increased as a
    greater portion of the cigarette was consumed. Although Cohen et al.
    (1971b) reported that different cigarette preparations did not result
    in significant variations in the smoker's levels of
    carboxyhaemoglobin, more recent studies (Gori, 1976; Turner et al.,
    1974) suggested that so-called "low toxicity" cigarettes produced
    significantly smaller amounts of carbon monoxide. However, the smoking
    pattern of the individual smoker markedly altered the absolute amount
    of carbon monoxide inhaled. Frankenhaeuser et al. (1971) reported
    another response to cigarette smoking that may have important
    consequences for the smoker. They observed a progressive increase in
    adrenaline excretion with the number of cigarettes smoked. They also
    found that, in moderate smokers, certain psychophysical performance
    measures did not deteriorate when the subjects smoked, in contrast to
    the decrement observed in nonsmoking conditions (Myrsten et al.,
    1972). Aronow et al. (1971a) carried out cardiovascular measurements
    on 8 volunteer anginal patients who, after abstaining for 12 h, smoked
    3 cigarettes. One week later the same subjects were given carbon
    monoxide to breathe so that the final carboxyhaemoglobin levels were
    almost equivalent (3.90 and 3.86, respectively). As the patients were
    smokers, their initial carboxyhaemoglobin levels were above 2%.
    Catheterization of both the left and right ventricles permitted an
    evaluation of the functions of the myocardium. The major differences
    observed under the two conditions were as follows: cardiac output
    decreased with carbon monoxide inhalation but did not change with
    smoking; heart rate did not change with carbon monoxide inhalation but
    increased with smoking; systolic and diastolic arterial pressures did
    not change with carbon monoxide inhalation but increased with smoking;
    left ventricular stroke work  (dp/dt) decreased with inhalation but
    did not change with smoking; left ventricle end-diastolic pressure
    increased in both situations; and, finally, the partial pressure of
    oxygen in arterial, mixed venous, and coronary sinus blood decreased
    in patients inhaling carbon monoxide. These divergent effects need to
    be further evaluated. The authors believed that the increased systemic
    pressure and heart rates following cigarette smoking were related to
    the nicotine in the cigarette.

        A critical problem arises in attempts to separate the effects of
    carbon monoxide in cigarette smoking from those of other substances
    present in the inhaled cigarette smoke. In further studies by Aronow
    et al. (1971b), 10 male angina patients smoked lettuce leaf, non-
    nicotine cigarettes, resulting in blood carboxyhaemoglobin levels of
    7.8%. Heart rate and blood pressure were unaffected by smoking this

    type of cigarette but again angina occurred earlier on effort. The
    investigators suggested that the presence of carboxyhaemoglobin
    following the smoking of cigarettes is the major factor in decreasing
    exercise tolerance in subjects with angina pectoris.

        It has been suggested by Ball & Turner (1974) that carbon monoxide
    and nicotine from cigarette smoke may, by different mechanisms,
    accelerate thrombus formation and the development of atherosclerosis.
    Carbon monoxide reduces the amount of oxygen available to the
    myocardium at the time when the work of the heart has been increased
    by the absorption of nicotine. Kjeldsen (1969) reported that in a
    group of 1000 Danish individuals a clear relationship between high
    carboxyhaemoglobin concentrations after smoking and the occurrence of
    atherosclerotic disease was observed. On the other hand, selective
    evidence would suggest that carbon monoxide exposure might not be
    related to the underlying atherosclerosis. Heavy cigarette smokers in
    Japan, where diets are low in fat and cholesterol, do not appear to be
    at high risk as regards heart attacks.

        As Wald & Howard (1975) stated in their overall review on smoking,
    carbon monoxide exposure, and arterial disease: "There is at present
    only indirect evidence that carbon monoxide may be a cause of atheroma
    in man" and "For the present, however, it is necessary to reserve
    judgement on whether carbon monoxide is a cause of arterial disease,
    while at the same time suspecting that it may be the principal agent
    in tobacco smoke". Aronow and co-workers, as well as Anderson et al.
    (1973) have shown that, in patients with ischaemic heart disease,
    exercise-induced angina occurs earlier when the patients are exposed
    to low levels of carbon monoxide (section 8.2.1). Carbon monoxide
    exposure also exacerbates the pain of intermittent claudication and
    the duration of effects in patients with this disease. The potential
    deleterious influences of cigarette smoking and/or carbon monoxide
    exposure on the pregnant woman, fetus, and neonate will be considered
    in section 8.2.3. The only direct evidence that carbon monoxide
    adversely influences fetal development was derived from studies
    conducted on rabbits (Astrup et al., 1972).

        A number of studies have suggested that cigarette smoking reduces
    working capacity (Goldbarg et al., 1971; Krone et al., 1972; US
    Department of Health, Education & Welfare, 1973) and, as presented in
    section 8.1.2, this reduction has been directly related to the level
    of carboxyhaemoglobin present in the exercising subject. In young
    smokers, 21-30 years of age, no differences in maximal aerobic
    capacity were observed in spite of reductions in vital capacity and
    maximum breathing capacities (Raven et al, 1974a). Older smokers
    (40-57 years of age) had significantly lower (27%), aerobic capacity
    than nonsmokers of a similar age (Raven et al., 1974b). Younger
    smokers had only a 6% lower aerobic capacity than nonsmokers of the
    same age. There still remain some questions as to the possible role
    played by materials other than carbon monoxide in cigarette smoke in
    the reduction of aerobic capacity.

    8.1.7  Interactions

        There is only a small amount of data available on the combined
    effects in man of carbon monoxide and other chemical or physical
    agents. Experimental work, carried out by Horvath and his
    collaborators (Drinkwater et al., 1974; Gliner et al., 1975; Raven et
    al., 1974b), dealt with the combined effects of a concentration of
    carbon monoxide of 57 mg/m3 (50 ppm) and peroxyacetylnitrate
    1.4 mg/m3 (0.27 ppm) on the work capacity of healthy men. Combined
    exposure to both pollutants did not produce greater effects than
    exposure to carbon monoxide alone. Hackney et al. (1975) did not find
    any consistent changes (synergistic or additive) in pulmonary
    functions in a 2-h exposure of young male subjects to a combination of
    pollutants namely ozone at 0.5 mg/m3 (0.25 ppm), nitrogen dioxide at
    0.56 mg/m3 (0.30 ppm) and carbon monoxide at 34.5 mg/m3 (30 ppm).
    As for the combined effects of carbon monoxide and physical agents,
    there are occupational data suggesting additive effects of carbon
    monoxide and heat (Vyskocil, 1957), and of carbon monoxide
    (carboxyhaemoglobin levels up to 35%) and noise in workers exposed to
    this stress combination for more than 10 years (Wagemann, 1960; Zorn,

        There is a complete lack of information on the combined effects of
    carbon monoxide and drugs or alcohol in man. Furthermore, it is quite
    apparent that the question of interactions on the organism of carbon
    monoxide and other air contaminants needs clarification.

    8.2  High-Risk Groups

        The limited clinical research on populations other than healthy,
    normal subjects makes it difficult to identify with certainty the
    groups that are at increased risk from exposure to carbon monoxide.
    However, as will be discussed later in this section, one of these
    groups includes individuals with known coronary heart disease. In view
    of the susceptibility of this group to the hypoxic stress of carbon
    monoxide exposure, it is implicit that other groups are also
    potentially subject to increased risk including individuals with
    cerebrovascular and peripheral vascular diseases, anaemias, and lung
    diseases. In addition, hospitalized individuals suffering from tissue
    hypoxia (e.g. shock) or those undergoing operations may be at
    increased risk. Individuals with undetected or undiagnosed coronary
    artery disease as well as the fetus  in utero, the newborn, or, even
    pregnant women may be assumed to be at increased risk because of the
    anticipated reduced capacity to accommodate hypoxic stress or some
    inherent sensitivity to hypoxia. Furthermore, other populations such
    as those living at high altitudes, young children, or older adults may
    also be at increased risk.

    8.2.1  Individuals with cardiovascular and chronic obstructive lung

        This section will not be concerned with the potential pathological
    effects of cigarette smoking on the development of cardiovascular
    disease, chronic pulmonary obstructive disease, and cancer (section
    8.1.6). No adequate evidence has been presented, as yet, that carbon
    monoxide  per se is directly involved in the pathogenesis of these
    disorders. Only the potential influence of ambient carbon monoxide on
    individuals at risk will be considered.

        Epidemiological studies in Los Angeles County (Cohen et al., 1969;
    Goldsmith & Landaw, 1968; Hexter & Goldsmith, 1971), have suggested
    the possibility of increased mortality from myocardial infarction,
    associated with high (9-16 mg/m3 or 8-14 ppm) atmospheric levels of
    carbon monoxide. There have been some differences of opinion
    concerning the interpretation of these data. A somewhat similar study,
    at least in design, was completed in Baltimore by Kuller et al.
    (1975). The Baltimore data did not indicate any apparent relationship
    between either the incidence of myocardial infarction or sudden death
    due to atherosclerotic heart disease and average 24-h ambient carbon
    monoxide concentrations. Neither group of investigators was able to
    detect a relationship between post mortem carboxyhaemoglobin levels
    and causes of sudden death. In the latter study the diagnoses of
    disease state were more precise and the population involved more
    clearly defined. The ambient levels of carbon monoxide in Baltimore
    appeared to be considerably lower than those reported for Los Angeles.
    Thus, the possibility of an association between ambient carbon
    monoxide and the incidence of myocardial infarction or sudden deaths
    remains questionable. It is apparent that more comprehensive and
    extensive epidemiological studies need to be conducted in order to
    clarify this issue.

        There are no adequate studies in man describing the relationship
    between exposure to carbon monoxide and the rate of development of
    atherosclerotic heart disease. Goldsmith & Aronow (1975) have reviewed
    the available evidence.

        The heart has a specialized circulatory system in which the
    primary response to increased metabolic demands can only be secured by
    an increased coronary blood flow. Even under no-stress conditions
    (rest) there is an almost complete extraction, roughly 75-80%, of the
    available oxygen supply. Adams et al. (1973) monitored conscious dogs
    breathing a carbon monoxide concentration of 1718 mg/m3 (1500 ppm)
    for a period of 30 min and were able to show a linear relationship
    between carboxyhaemoglobin concentration and coronary blood flow. A
    13% increase in coronary blood flow occurred at a carboxyhaemoglobin
    level of 4% and, at a concentration of 20%, flow rate increased by
    54%. Since measurements were not reported for the lower
    carboxyhaemoglobin levels, the existence of a threshold could not be
    determined. The observations of Mehmel et al. (1973) suggest that

    increases in coronary blood flow are stimulated by shifts in the
    oxyhaemoglobin dissociation curve. They demonstrated that increasing
    pH from 7.4 to 7.6 decreased the P50 ( pO2 at half saturation of
    haemoglobin) from 4 to 3.2 kPa (30 to 24 Torr) and increased coronary
    blood flow by more than 20%. Earlier studies by Ayres et al. (1969,
    1970) also indicated increased blood flow in response to the presence
    of increased levels of carboxyhaemoglobin.

        Ayres' studies of the haemodynamic and respiratory responses of
    man during diagnostic coronary catheterization suggested that carbon
    monoxide would have a significant effect on arterial  pO2 in
    patients with lung disease as well as in patients with certain
    cardiovascular disorders.

        Studies by Anderson et al. (1973) Aronow et al. (1972) and Aronow
    & Isbell (1973) on patients with angina pectoris are listed in
    Table 8. Aronow et al. (1972) studied the influence of riding in an
    open car on a major Los Angeles freeway. Two trips were made, in one
    of which the patients breathed compressed carbon monoxide-free air.
    Carboxyhaemoglobin levels after this ride averaged 0.65%, in contrast
    to the 5.08% observed in the trip in the open car. The trips were of
    90 min duration and ambient carbon monoxide levels in the car averaged
    61 mg/m3 (53 ppm). Exercise time, on a bicycle ergometer, to the
    onset of angina, was determined prior to, and after the completion of
    the exposure. Although no changes in the length of time of work to
    onset of anginal pain were noted in the ride while breathing
    compressed air, a significant reduction from a mean time of 247 to
    174 sec was found when the carboxyhaemoglobin concentration was
    elevated. Anginal pain also appeared to persist for a longer time
    under these conditions. In a study by Anderson et al. (1973), patients
    with stable angina walked on a treadmill. They then breathed air
    containing 57 or 115 mg/m3 (50 or 100 ppm) intermittently while
    resting for a period of 4 h, raising their carboxyhaemoglobin levels
    to 2.9% and 4.5% respectively. The repeat exercise tests clearly
    demonstrated a reduction in walking time to onset of angina. No
    differences in time were observed at the 2 carboxyhaemoglobin levels
    although the duration of the pain was longer at the higher level.
    There appeared to be some additional depression of the ST segment but
    the degree was not of a significant order. Other measures of cardiac
    function-systolic time intervals, left ventricular ejection time, pre-
    ejection period index, and pre-ejection peak to ejection time ratio
    remained within normal limits.

        Table 8.  Exercise-induced angina and carbon monoxide (10 subjects per study)

    Carboxyhaemoglobin      Ambient CO    Time to        Reference
    (%)                     mg/m3(ppm)    angina
    Initial     Final

    1.12        5.08        61a (53)      Shortened      Aronow et al (1972)
    1.07        2.68        57b (50)      Shortened      Aronow & Isbell (1973)
    1.40        2.90        57c (50)      Shortened      Anderson et al. (1973)

    a  Freeway trip.
    b  Continuous exposure for 2 h in laboratory,
    c  Intermittent exposure for 4 h in laboratory.

        Another study by Aronow & Isbell (1973) was somewhat similar to
    that of Anderson et al. (1973). Aronow and his co-workers exposed
    patients (nonsmokers at the time of the test to a carbon monoxide
    concentration of 57 mg/m3, resulting in a carboxyhaemoglobin
    concentration of 2.68%. This study was also conducted as a double-
    blind random trial with one day of breathing carbon monoxide and
    another day breathing compressed carbon monoxide-free air. The angina
    pectoris of all patients was documented by history and coronary
    angiography. A 23% reduction in exercise time (bicycle) resulted
    following the carbon monoxide exposure. No electro-cardiographic
    changes were seen in these patients during any exercise period.
    Plotting of Aronow's data suggests that there was a linear
    relationship between carboxyhaemoglobin levels and the decrease in
    time to angina.

        This evidence suggests that a deleterious effect could occur at
    carboxyhaemoglobin levels as low as 2.5% in certain subjects with
    coronary heart diseases. The USA National Health Survey Examination
    (US Environmental Protection Agency, 1975) reported that in the USA
    there were 3 215 000 adults, aged 18-79 years, with definite coronary
    heart disease and another 2 410 000 with suspected disease. Many of
    these individuals, as well as others in the general population, have
    carboxyhaemoglobin levels equal to, or above 2.5%. It would be rash to
    even suggest that the above-mentioned studies implicate carbon
    monoxide as a factor in determining the natural history of heart
    disease in a community. It is even more dangerous to imply that
    exposure to carbon monoxide increases the frequency or severity of
    chest pain, or shortens life expectancy among patients with angina

    pectoris or other clinical manifestations of heart disease. The
    necessary epidemiological evidence for an association between the
    frequency of episodes of angina pectoris and community ambient levels
    of carbon monoxide is inadequate and additional information from more
    and varied sources is required.

        Patients with chronic obstructive pulmonary disease are probably
    at high risk, although few studies on them have been reported. Any
    increase in hypoxia could result in respiratory failure. However,
    these individuals may absorb less carbon monoxide because of their
    disease as the hypoxia may be compensated for by increased
    erythropoiesis and a shift of the oxygen dissociation curve to the
    right. An interesting approach to the evaluation of individuals at
    risk from carbon monoxide and other pollutants can be found in a
    publication of the US Environmental Protection Agency (US
    Environmental Protection Agency, 1975). Ogawa et al. (1974) have
    presented evidence on the development of pulmonary oedema and
    discussed possible mechanisms of the role of carbon monoxide in the

    8.2.2  Anaemic individuals

        The information available on the effects of carbon monoxide on
    anaemic patients is still inadequate.

        The oxygen dissociation curve of blood obtained from patients with
    anaemia is shaped like the normal curve but is vertically compressed.
    However, when curves from individuals with a 50% reduction in
    haemoglobin content are compared with dissociation curves determined
    in the presence of 50% carboxyhaemoglobin, there are striking
    differences. Consequently, the tendency to make such comparisons is
    likely to lead to erroneous deductions concerning effects occurring at
    the tissue level. Brody & Coburn (1970) discussed these differences in
    relation to arterial and venous  pCO and  pO2. Because the capacity
    of the oxygen transport system is reduced in anaemic persons,
    it can be assumed  a priori that they could be more at risk from
    carbon monoxide exposure than normal persons. Brody & Coburn (1970)
    indicated that, if the oxygen content of the mixed venous blood is
    abnormally low, as in anaemia or carbon monoxide poisoning, the effect
    of the shunted blood in lowering arterial  pO2 will be greater than
    normal, and a small increase in the alveolar-arterial pressure
    difference (AaDO2) will result. The change in the shape of the
    oxyhaemoglobin curve due to the presence of carbon monoxide will also
    increase the AaDO2. Furthermore, Brody & Coburn (1970) showed that
    mild increases in carboxyhaemoglobin concentrations would have little
    or no influence on the AaDO2 in normal subjects. However, in
    patients with large intra-cardiac right-to-left shunts or with chronic
    lung disease and regional variation in the ventilation perfusion ratio
    ( VA/ QA), the presence of carbon monoxide in the blood will increase
    the AaDO2.

        Tissue oxygenation may be involved initially because of the
    anaemic state, since mixed venous  pO2 is decreased (Cropp, 1970)
    and the reduction in venous  pO2 from a particular carboxyhaemo-
    globin value is somewhat greater in anaemic than in normal subjects.
    In patients with haemolytic anaemia and sickle cell disease (Engel et
    al., 1971), the rate of endogenous carbon monoxide production from
    haemoglobin catabolism is increased. Normal subjects produce
    approximately 18 µmoles of carbon monoxide per hour, resulting in
    carboxyhaemoglobin levels of 0.5 to 0.8%. Carbon monoxide production
    in anaemic patients (Coburn et al., 1966; Logue et al., 1971) has been
    reported to vary from 31 to 158 µmoles per hour, producing
    carboxyhaemoglobin levels of 1.3-5.2%.

        Anaemic subjects approach equilibrium levels of carboxyhaemoglobin
    more rapidly than those with normal haemoglobin levels at any given
    exposure to carbon monoxide. Exposure to a concentration of
    22.9 mg/m3 (20 ppm) for approximately 4 h in an individual with a
    haemoglobin level of 7 g/100 ml could result in a carboxyhaemoglobin
    concentration of 4-5% compared with an anticipated level of 2.5% for
    normal individuals. Exogenous carbon monoxide exposure of anaemic
    individuals could result, in conjunction with higher endogenous
    production, in their attaining critical levels of carboxyhaemoglobin
    more rapidly than normal individuals.

    8.2.3  Embryo, fetus, neonate, and infants

        Pregnant mothers and their fetuses may be exposed acutely or
    chronically to carbon monoxide either by maternal smoking or by
    environmental pollution. The biological effects of carbon monoxide
    exposure on fetal tissues during intrauterine development or during
    the newborn period are far from clear.

        Several studies (Astrup et al., 1972; MacMahon et al., 1966) have
    demonstrated that babies delivered by mothers who smoke cigarettes
    weigh less than those delivered by nonsmoking mothers. Relative
    maternal, fetal, or placental hypoxia may be responsible, as suggested
    by the observation that infants born at high altitudes also weigh less
    than those born at sea level (Grahn & Kratchman, 1963). The New Mexico
    State Department of Public Health (1975) provided additional
    confirmation of the relationship between altitude and birth weights.

        Mothers who smoked were reported to have carboxyhaemoglobin
    concentrations ranging from 2 to 14%,. while concentrations in the
    fetuses ranged from 2.4 to 9.8%. These values may not represent
    conditions present during pregnancy, since these data were obtained
    just prior to birth. Another factor that may produce differential
    effects on the fetus is related to the endogenous production of carbon
    monoxide by pregnant women. Delivoria-Papadopoulos et al., (1969)
    indicated that nonsmoking pregnant women produced 0.9 ml of carbon
    monoxide per hour in contrast to the nonpregnant female's production

    of 0.4 ml reported by Longo (1970). Fetal production of endogenous
    carbon monoxide accounted for 3% of the total carboxyhaemoglobin
    present in the blood of a nonsmoking normal pregnant woman. The source
    of the remainder is not well known but may be related to progesterone
    levels (Delivoria-Papadopoulos et al., 1969). Even though
    hyperventilation of pregnancy may partially compensate for the
    increased carbon monoxide production in the absence of exogenous
    exposure, the maternal carboxyhaemoglobin still remains about 13%
    above that in nonpregnant women (Longo, 1970). It should be noted that
    the post partum (24 h) female may be producing 3 times as much carbon
    monoxide as a near term nonsmoking pregnant woman.

        Behrman et al. (1971) measured carboxyhaemoglobin concentrations
    in 25 relatively normal newborn infants in a downtown Chicago nursery
    and found the mean value to be 6.98%. These investigators indicated
    that absolute carboxyhaemoglobin levels were related to ambient levels
    of carbon monoxide. Some doubts about this conclusion exist, since the
    monitoring reference site was 2.4 km from the nursery; the
    investigators did not report any untoward clinical effects from
    exposure to these levels, and no consideration was given to the
    possibility of increased endogenous carbon monoxide production in
    these infants.

        Of the several mechanisms that may account for the influence of
    carbon monoxide on developing tissue, the most important is the
    interference with tissue oxygenation. Carbon monoxide decreases the
    capacity of haemoglobin to transport oxygen and shifts the oxygen
    saturation curve to the left. The normal arterial  pO2 supplying
    fetal tissue is approximately 3.7 kPa (28 Torr). The shift to the left
    will tend to further decrease the oxygen gradient from maternal to
    fetal blood across the tissue. The decreased  pO2 and the
    diminished oxygen transport due to the presence of carboxyhaemoglobin
    may also produce undesired influences on the fetus. One of the
    possible mechanisms by which carbon monoxide or other components of
    tobacco smoke may adversely influence fetal development is through
    interference with the metabolic function of placental cells. These
    cells have a role in metabolizing hormones as well as in the transport
    of vitamins, carbohydrates, amino acids, and other substances through
    their energy dependent processes. Tanaka (1965) reported that the
    oxygen uptake of placental slices from mothers who smoked varied
    inversely with maternal levels of carboxyhaemoglobin, being markedly
    reduced when this level was higher than 7.0%. The preponderance of
    evidence concerning maternal carboxyhaemoglobin levels, along with
    fetal and perinatal exposure, tends to warrant the reduction of
    exposure to exogenous carbon monoxide sources that might cause this
    group to be at risk, to a minimum.

        The potential toxicity of carbon monoxide present in transfused
    blood has received little attention. Kandall et al. (1973) measured
    carboxyhaemoglobin concentrations in donor blood and in relatively
    healthy infants receiving exchange blood transfusions. The mean pre-
    transfusion carboxyhaemoglobin concentration in 6 cases was 1.34%.
    Donor blood contained a carboxyhaemoglobin concentration of 5.17%,
    resulting in a mean value of 4.92% in the transfused infant. In one
    infant transfused with blood containing a carboxyhaemoglobin
    concentration of 8.87%, the resultant carboxyhaemoglobin value in the
    infant was 7.43%. Although it was stated that the infants did not
    appear to be adversely affected by the levels of carboxyhaemoglobin
    reached during exchange transfusion, it should be noted that adverse
    effects have been observed in adults at these levels. Furthermore, in
    individuals whose oxygen transport system or cardiovascular reserve is
    already compromised, the presence of additional carboxyhaemoglobin,
    from transfused blood, may result in a further and more potentially
    dangerous decrement in arterial, mixed venous, and coronary sinus
    oxygen tensions. It should be recalled that some blood samples
    collected from blood donors had carboxyhaemoglobin values that
    exceeded 18%.

    8.2.4  Individuals living at high altitudes

        The effects of carbon monoxide and of hypoxia induced by high
    altitude are similar. Carbon monoxide produces effects that aggravate
    the oxygen deficiency present at high altitudes. When high altitude
    and carbon monoxide exposures are combined (Table 9) the effects are
    apparently additive. It should be noted, however, that decreased
     pO2 in the air and increased carboxyhaemoglobin, produce different
    physiological responses. They have different effects on blood  pO2,
    on the affinity of oxygen for haemoglobin, on the extent of
    oxyhaemoglobin saturation (carbon monoxide hypoxaemia shifts the
    oxyhaemoglobin dissociation curve to the left, and a decrease in
     PAo2 shifts it to the right), and on ventilatory drive. These
    effects have been discussed earlier.

        The actual influence of a combination of increased carboxy-
    haemoglobin and decreased oxyhaemoglobin has not been adequately
    documented by experimental data. The few available studies refer
    only to acute exposures to lower  pO2 and raised  pCO. The
    most supportive information on the additive nature of this combination
    originates from psychophysiological studies and even this information
    is not very convincing. When Blackmore (1974) analysed the cause of
    aircraft accidents in Britain, he found that carboxyhaemoglobin levels
    provided valuable information in relation to altitude and sources of
    carbon monoxide. The high levels of carbon monoxide found (up to 74%)
    could be attributed to equipment failure, smoking, and fires. No data
    are available on the effects of carbon monoxide on the native
    inhabitants at high altitudes or on the reactions of these natives
    when they are suddenly removed to sea level and possible high ambient
    carbon monoxide concentrations.

    Table 9.  Approximate physiologically equivalent altitudes at
              equilibrium with ambient carbon monoxide levelsa

    Ambient CO concentration      Actual altitude (metres)

    mg/m3           ppm           0 (sea level)    1524       3048

                                  Physiologically equivalent altitudes
                                  with carboxyhaemoglobin

        0             0           0 (sea level)    1524       3048
       28.6          25           1829             2530       3962
       67.3          50           3048             3658       4672
      114.5         100           3749             4663       5486

    a  From: NAS/NRC (1977).

        In their studies on altitude exposures of young males, McFarland
    et al. (1944) showed that changes in visual threshold occurred at
    carboxyhaemoglobin levels as low as 5% or at a simulated altitude of
    2425 m. These observations were confirmed by Halperin et al. (1959),
    who also noted that recovery from the detrimental effects on visual
    function lagged behind the elimination of carbon monoxide. However,
    the data given were sparse and the variability among the four subjects
    was not given. Vollmer et al. (1946) studied the effects of carbon
    monoxide at simulated altitudes of 3070 and 4555 m and reported that
    there were no additive effects of carbon monoxide and altitude. They
    suggested that the effects of carbon monoxide were masked by some
    compensatory mechanisms. The data presented were not convincing.
    However, Lilienthal & Fugitt (1946) indicated that a combination of
    altitude (1540 m) and a carboxyhaemoglobin level of 5-9% induced a
    decrease in flicker fusion frequency, although either one alone did
    not have any effect. They also reported that the presence of 8-10%
    carboxyhaemoglobin was effective in reducing altitude tolerance by
    1215 m. During light activity at an altitude of 4875 m, carbon
    monoxide uptake increased, probably owing to the hyperventilation at
    altitude caused by the respiratory stimulus of decreased  pO2
    (Forbes et al., 1945). Evidence that carbon monoxide elimination was
    similar at sea level and at altitudes up to 10 000 m was obtained by
    several investigators (Gorodinsky et al., 1970; Sedov et al., 1971).
    However, increased ambient temperatures up to 35°C and hard physical
    work increased the rate of elimination (Vollmer et al., 1946). Pitts &
    Pace (1947) stated that every 1% increase in carboxyhaemoglobin (up to
    13%) was equivalent to a 109 m rise in altitude if the subjects were

    at altitudes of 2100-3070 m. These observations were based on changes
    in the heart rate response to work. A number of unanswered questions
    arise from all these studies, which in general were obscured by such
    factors as poor control and no identification of subjects who may have
    been smokers.

        Two groups of investigators have presented data comparing the
    physiological responses of subjects to altitude and carbon monoxide
    exposure where the hypoxaemia due to altitude and the presence of
    carboxyhaemoglobin were approximately equal. In one study (Astrup &
    Pauli, 1968), the carboxyhaemoglobin concentration was about 12%
    (although the mode of exposure to carbon monoxide was such that
    carboxyhaemoglobin ranged from 5% to 20% and the altitude study was
    conducted at 3977 m). The second study (Sedov et al., 1971) compared
    responses at an altitude of 4000 m and a carboxyhaemoglobin content of
    20%. In both studies, carboxyhaemoglobin content was much in excess of
    that anticipated for typical ambient pollution. However, they both
    suggested that the effects attributable to carbon monoxide and to
    altitude were equal.

    8.3  Summary Table

        Table 10 is a summary of controlled human studies that provide
    useful information for evaluating the relationship between exposure to
    carbon monoxide and its health effects.

        Table 10.  Summary of exposure-effect relationships

    Exposure       Reported effects                                       Reference
    (HbCO %)

     (a) Behavioural changes

       20          Essentially no impairment in time discrimination       Stewart et al. (1973b)
                   (using Beard-Wertheim task)
       11.3        No vigilance decrement (using Horvath task)            Winneke et al. (1976)
        9a         No vigilance decrement (using Fodor-Winneke            Winneke (1974)
                   task); no change in reaction time
        8.4        No vigilance decrement (using their own                Groll-Knapp et al. (1976)
                   vigilance task (1972))
        7.6        Longer reaction times                                  Ramsey (1973)
        7.3        Disturbance in certain perceptual and cognitive        Bender et al. (1972)
        5          Vigilance decrement                                    Horvath et al. (1971)
        4.5        Longer reaction times                                  Ramsey (1972)
        3.1b       Initial vigilance decrement with subsequent            Fodor & Winneke (1972)
                   normalization; no change in response latency
        3b         Vigilance decrement                                    Groll-Knapp et al. (1972)
        2b         Impaired performance in time-discrimination            Beard & Wertheim (1967)

     (b) Changes in work performance

        6.3        Decrease in maximal work time                          Ekblom & Huot (1972)
        4.3        Decrease in a maximal oxygen uptake (VO2)              Horvath et al. (1975)
        4.0        Decrease in mean exercise time until exhaustion        Aronow & Cassidy (1975)
        2.5        Decrease in absolute exercise time in non-             Drinkwater et al. (1974)

    Table 10 (Cont'd)

    Exposure       Reported effects                                       Reference
    (HbCO %)

     (c) Aggravation of symptoms in patients with cardiovascular disease

        5.1        Shortened time to angina response immediately          Aronow et al. (1972)
                   after exposure
        2.9        Shortened time to angina response 2 h after            Aronow et al. (1972)
       (1.1c)      exposure
        2.9        Shortened time to angina response                      Anderson et al. (1973)
        2.8        Decrease in mean exercise time until onset of          Aronow et al. (1974)
                   intermittent claudications
        2.7        Shortened time to angina response                      Aronow & Isbell (1973)

    a  Estimated values using the formula by Coburn et al. (1965).
    b  Estimated values using the formula by Peterson & Stewart (1970).
    c  HbCO % before exposure to CO.


    9.1  Introduction

        The acute toxicity of carbon monoxide has long been recognized and
    is well documented. Much has been learned of the main sources of the
    gas, its absorption, the kinetics of its reactions with blood, and the
    biochemical and pathological consequences of poisoning by excessive
    absorption. More recently, a great deal of attention has been paid to
    the effects, demonstrable or suspected, of exposure to concentrations
    much lower than those that cause definite poisoning. Such
    concentrations are those commonly found in urban air (caused almost
    wholly by traffic pollution) and indoors (caused by faulty ventilation
    of heating or cooking appliances), but there has been much concern
    with the effects of the gas on smokers, who inhale considerable
    quantities of carbon monoxide with tobacco smoke. Since the main
    source of carbon monoxide as an urban pollutant is the petrol engine,
    the problems posed by the inhalation of relatively low concentrations
    of the gas are likely to grow rather than diminish, as traffic becomes
    denser and more widespread. The recognition of the importance of
    pollution of the domestic environment is relatively recent and
    deserves more study; the problems posed by smoking tobacco are common
    and are, unfortunately, increasing. There is much published evidence,
    some of which is of debatable value, that suggests that the
    comparatively low concentrations of carboxyhaemoglobin produced by
    exposure to pollution of the ambient air and the higher concentrations
    usually associated with smoking, might cause demonstrable impairment
    of vigilance, discrimination, and of the performance of fine tasks and
    physical work in healthy subjects, and the exacerbation of symptoms
    such as angina pectoris on effort in patients with cardiovascular
    diseases. Likewise there is evidence, derived from experimentation on
    animals, that chronic exposure to carbon monoxide leading to the
    levels of carboxyhaemoglobin commonly found in smokers may, in
    association with high cholesterol intakes, play a part in the genesis
    of atherosclerosis. Moreover, there are reasons to suspect that
    exposure to carbon monoxide may enhance the effects of other
    pollutants, commonly administered therapeutic agents, socially
    acceptable amounts of beverages such as alcohol, and other
    environmental stresses. This section is intended as a brief assessment
    of these topics in the hope that sound advice may be given on the need
    to control levels of carbon monoxide in the ambient air.

    9.2  Exposure

    9.2.1  Assessment of exposure

        Concentrations of carbon monoxide in air may be measured with
    comparative ease by such methods as non-dispersive spectroscopy, gas
    chromatography etc. But human body burdens of carboxyhaemoglobin
    depend on many factors other than the partial pressure of carbon

    monoxide in the inhaled air; among these factors are time of exposure,
    pulmonary ventilation (which mainly depends on work done), and blood
    volume. Since these quantities, especially ambient concentrations of
    carbon monoxide, may vary widely, it is obviously difficult, if not
    impossible at times, to calculate the likely body burden of
    carboxyhaemoglobin in an exposed individual. There is, therefore, much
    to be gained by sampling blood to obtain an integrated estimate of
    carboxyhaemoglobin derived from all sources under various conditions
    of exposure. It must be emphasized that the measurements of carbon
    monoxide in air and in blood give complementary results and are not
    merely alternative forms of monitoring. Methods of analysis are
    discussed in sections 2.2 and 2.3.

        There is a tendency to forget that the reaction between
    haemoglobin and carbon monoxide is reversible and that, in a given
    environment, a subject may acquire carbon monoxide, excrete it, or
    remain in equilibrium with the ambient air depending on the carbon
    monoxide concentration and the initial level of carboxyhaemoglobin in
    the individual. The time taken to achieve equilibrium between blood
    and ambient air depends on the initial carboxyhaemoglobin
    concentrations as well as on the factors mentioned above. The rate of
    excretion of carbon monoxide will depend not only on ambient air
    levels, the initial carboxyhaemoglobin and on factors such as
    pulmonary ventilation, but also on the partial pressure of oxygen in
    inspired air, which might be introduced therapeutically to increase
    elimination. Fig. 12 shows estimates of equilibrium times for various
    ambient concentrations and levels of activity. The half-life for
    excretion, at rest, is approximately 4“ h.

    9.2.2  Endogenous production

        The normal breakdown in the body of blood pigments produces carbon
    monoxide to give endogenous carboxyhaemoglobin values of 0.1-1.0% and
    normal blood is in equilibrium with carbon monoxide levels in air of
    roughly 5 mg/m3 (4.3 ppm). These data could be used as a basis for
    establishing air quality criteria for carbon monoxide. Various causes
    of increased endogenous production of carbon monoxide are discussed in
    section 6.1.

    9.2.3  Outdoor environmental exposure

        Natural sources of carbon monoxide (section 3.1) are of
    considerable magnitude but are diffuse, and ambient air concentrations
    at locations removed from man-made sources range from 0.01 to
    0.9 mg/m3 (0.01 and 0.8 ppm) which is negligible in the context of this
    report. By far the most important sources of carbon monoxide at
    breathing level are petrol engine vehicle exhausts (section 3.2). The
    diesel engine (compression ignition), when properly adjusted, emits
    little carbon monoxide. The density, distribution, and mode of
    operation of vehicles vary greatly and these and other factors, the

    FIGURE 12

    most important of which is the weather, produce great variations in
    the concentrations of pollutants produced by traffic. Concentrations
    fall steeply with distance from the street. However, distinct patterns
    are often discernible (section 5.1). Concentrations for 8-h averaging
    times are frequently used and quoted and usually vary from
    <10 mg/m3 (8.7 ppm) to over 60 mg/m3 (52.2 ppm) but are mostly
    <20 mg/m3 (17.6 ppm) in city streets. Away from heavy traffic, even
    in towns, annual average concentrations are usually well under
    10 mg/m3 (8.7 ppm). Obviously, in especially stagnant weather, very
    heavy traffic may produce much higher levels. There is little
    information about concentrations of carbon monoxide near large
    stationary sources.

    9.2.4  Indoor exposure

        Carbon monoxide diffuses readily and, being relatively chemically
    inert and not absorbed on surfaces, concentrations indoors are usually
    similar to those found immediately outside. Not infrequently, however,
    high concentrations may be found in kitchens and living rooms in which
    there are coal, gas, or oil-fired cooking or heating appliances that
    are maladjusted and inadequately vented to outside air; in some
    countries, cases of acute and even fatal poisoning due to these causes
    are not uncommon. The possible contribution of the domestic
    environment must be noted in surveys. The smoking of tobacco indoors
    can obviously increase the carbon monoxide concentration of the air
    but recent work has shown that, before carbon monoxide reaches
    significant levels, the irritation from the other constituents of
    tobacco smoke becomes unacceptable if not actually intolerable.

    9.2.5  Exposures related to traffic

        In garages and tunnels, being in effect closed streets, pollution
    by carbon monoxide can reach high levels. However, since transit time
    in tunnels is relatively short, higher concentrations than those found
    in streets are tolerable. Usually, there are monitoring instruments
    that control ventilation and sound alarms if concentrations exceed
    agreed values, which may vary from 115 to 570 mg/m3 (100-500 ppm)
    depending on the use and length of the tunnel. High (sometimes lethal)
    concentrations of carbon monoxide may accumulate inside motor vehicles
    because of fractures in exhaust systems or other mechanical defects.

    9.2.6  Occupational exposure

        Traffic policemen, garage attendants, and drivers of taxis and
    trucks are exposed to pollution from traffic and many studies have
    shown a consequent increase in carboxyhaemoglobin levels (up to about
    3% in nonsmokers), but there is much evidence that this increase may
    be relatively undramatic, when compared with the manifest effects of
    cigarette smoking. Exposure in certain industries, especially in iron
    and steel works and in the manufacture of various gases, may be

    relatively massive (in excess of 115 mg/m3 or 100 ppm), and high
    carboxyhaemoglobin levels (>15% in nonsmokers) have been reported in
    workers. Firemen may be exposed to very high concentrations of carbon
    monoxide in fighting certain fires, but this exposure is obviously
    episodic. These matters are discussed in section 5.3.

    9.2.7  Tobacco smoking

        The smoking of tobacco, especially in the form of cigarettes, has
    been shown in many studies to be the major cause of raised
    carboxyhaemoglobin levels in adult populations. Table 7 displays some
    of this evidence and the topic is discussed in detail in section
    8.1.6. Whereas carboxyhaemoglobin concentrations of 3% are rarely
    found in nonsmokers exposed to town air, concentrations of 5-15% are
    often found in smokers. It is important to remember that the effects
    of smoking and exposure to town air are not simply additive and that
    the resulting carboxyhaemoglobin levels will depend on other factors
    already discussed.

    9.2.8  Multiple exposures

        Enough has been said to leave no doubt that carbon monoxide,
    produced exogenously or endogenously, is a widespread pollutant
    emanating from many sources to which people may be exposed in various
    ways. This variety of exposure must be taken into account in the
    interpretation of epidemiological surveys, the design of experiments,
    and, above all, in giving advice about the fixing of air quality

    9.3  Effects

        The main areas of concern that have arisen from acute or chronic
    exposure to low levels of carbon monoxide in experimental and
    epidemiological research in animals and man are: (a) its role in the
    genesis of arteriosclerotic vascular diseases; (b) its role in the
    aggravation of symptoms of cardiovascular diseases; (c) its
    contribution to performance deficits in certain psychomotor tasks; and
    (d) its role in limiting the working capacity of exercising man.

    9.3.1  Cardiovascular system  Development of atherosclerotic cardiovascular disease

        Extensive experimental work has been carried out over many years
    on animals, mainly rabbits, showing that prolonged exposure to
    moderate levels of carbon monoxide can produce atherosclerotic
    changes, especially in the presence of high cholesterol levels (1-2%)
    in the diet. The relevance of this work for man has not been
    established. However, other animal work, and some epidemiological
    studies of prolonged human exposures to elevated carbon monoxide

    levels through smoking, occupation, or both, such as those carried out
    in Denmark, Finland, and Japan, indicate the need for further
    investigation of the possible role of carbon monoxide in the genesis
    of atherosclerotic vascular changes in animals and man. The degree of
    intermittency of exposure at various levels should be taken into
    account as well as the possible contribution of other agents such as
    nicotine and high-fat diets. There is some evidence of adaptation, but
    such changes may not be entirely beneficial. None of the information,
    currently available, is useful for the purpose of setting standards.  Acute effects on existing heart illness

        The few existing epidemiological studies on the possible effects
    of carbon monoxide on the severity or fatality of coronary occlusion
    are insufficient to allow any conclusions. It is hoped that additional
    work of this type will clarify matters.

        Two carefully conducted human studies of the effects of low carbon
    monoxide exposure and exercise on pain in volunteer patients with
    angina pectoris offer valuable quantitative information. Although
    limited in the number of patients studied, the findings are consistent
    in the 2 investigations showing effects at carboxyhaemoglobin
    concentrations of 2.5-3.0%. A third single-blind study revealed the
    same detrimental effects in patients with angina pectoris when
    exposure to traffic exhausts caused carboxyhaemoglobin levels to rise
    to 5.1%. A no-adverse-effect level has not been established in these
    observations, nor is it possible to determine whether there is a
    graded response in this type of experiment. More work of a similar
    nature would be useful to explore these questions.  Acute effects on existing vascular disease

        One study, similar to those done on patients with angina, has been
    carried out on patients with intermittent claudication from peripheral
    vascular disease. Effects on pain with exercise were observed in the
    same exposure range as with angina i.e., at carboxyhaemoglobin
    concentrations of 2.5-3.1%, with a mean of 2.8%. Here, too, more data
    of a similar kind are needed, preferably designed to provide dose-
    response relationships.

    9.3.2  Nervous system

        As for the role of carbon monoxide in affecting psychomotor
    functions, no definite conclusions can be drawn from the existing
    data. The behavioural functions tested in such studies include
    vigilance and psychomotor performance, visual acuity and sensitivity,
    the ability to estimate time intervals, complex motor coordination as
    tested by driving simulators, and different perceptual and mental

    operationsa. Some workers observed detrimental effects at
    carboxyhaemoglobin levels as low as 2%, whereas others were unable to
    detect significant impairment even at levels from above 5% to about

    20%. In evaluating these discrepancies, it should be mentioned, that
    these behavioural functions are easily influenced by a number of other
    factors besides carbon monoxide-induced hypoxia, e.g., degree of
    sensory deprivation, compensatory abilities, drugs, temperature, time
    of day, competition, etc.

    9.3.3  Work capacity

        That elevated carboxyhaemoglobin levels affect work capacity has
    long been known. Levels of 40-50% will usually prevent working
    entirely. Recent studies in the laboratory, on man, using maximum work
    capacity or maximum aerobic capacity as indicators of performance,
    have been carried out in relation to carboxyhaemoglobin levels. Here,
    dose-response data are available for maximum effort. The limitation
    appears at a carboxyhaemoglobin concentration of about 4% and
    increases at higher levels. Lower exposure levels have been studied
    and do not produce this effect. It should be noted that while levels
    of carboxyhaemoglobin of 2.5-4%, did not reduce maximum work capacity,
    they did reduce the length of time for which such effort could be
    carried out. It is not known what specific levels of carboxy-
    haemoglobin will reduce the capacity of individuals to perform at
    ordinary work levels, such as 30-50% of their maximum capacity, for
    prolonged periods of time.

    9.4  Recommended Exposure Limits

        It has already been stated that the major contributor to
    carboxyhaemoglobin concentrations in the body is the smoking of
    tobacco; however, in many of the experiments currently quoted to
    justify the formulation of exposure limits, the smoking habits of the
    subjects were not taken into account. Results of recent work suggest
    that smokers and ex-smokers might be less sensitive to carbon monoxide
    exposure than nonsmokers. In view of this suggestion, and because of
    the deficiencies in the experiments mentioned, recommendations for
    exposure limits should be confined to the protection of nonsmokers.
    There is an urgent need for more work on possible adaptation following


    a  The possible importance of performance deficiencies resulting
       from carbon monoxide is considerable, particularly in relation to
       accidents at work, and while driving or flying. Further studies,
       particularly of the vigilance type are urgently needed for a better
       understanding of this problem.

    exposure to carbon monoxide from smoking or from other sources. It is
    also important to note that carboxyhaemo-globin levels have been the
    measurement of exposure in most experimental work. Thus, it is
    desirable to recommend the primary exposure limits in terms of
    carboxyhaemoglobin, and follow this by comments on the derivation of
    an appropriate air concentration equivalent.

    9.4.1  General population exposure

        Data used in arriving at a recommendation for an exposure limit
    for the general population were mainly those obtained from the
    exposure of subjects with cardiovascular illness to carbon monoxide in
    conjunction with exercise. Agreement was not reached on a single
    level. Thus, a range of carboxyhaemoglobin concentrations of 2.5-3.0%
    is recommended for the protection of the general population including
    those who have impaired health. The recommendation must be regarded as
    tentative, since ideal dose-response or concentration-response
    information is not yet available. However, it must also be recognized
    that complete protection of all persons, at all times, cannot
    reasonably be sought by environmental control alone. Persons who are
    in should be educated by their physicians concerning their own
    responsibility to avoid stressful exposures.

    9.4.2  Working population exposure

        Better quality data are available for recommending an exposure
    limit for the working population. In this case, the Task Group
    unanimously agreed on maintaining carboxyhaemoglobin levels below 5%,
    on the basis of present knowledge, since working populations comprise
    individuals who are assumed to be healthy, physiologically resilient,
    and under regular supervision.

    9.4.3  Derived limits for carbon monoxide concentrations in air

        It is important, wherever possible, to have both biological and
    environmental assessments of human exposure to pollutants. While the
    biological measurements may be more relevant in relation to effects,
    they may be more difficult to use in practice. For carbon monoxide,
    the relationship between concentrations in air and carboxyhaemoglobin
    levels is affected by several variables, including exposure time and
    it is not easy to estimate. However, such estimates may be
    sufficiently accurate for many practical purposes (for reviews see
    Committee on the Challenges of Modern Society, 1972; Commission of the
    European Communities, 1974; NAS/NRC, 1977; Winneke, 1977; Ott & Mage,
    1978). It should be emphasized yet again that analyses of carbon
    monoxide in air and of carboxyhaemoglobin in blood are complementary,
    and should in no way be regarded as alternative methods of monitoring.
    Obviously, air monitoring has its uses in the planning and
    implementation of control measures, and for warning purposes, but such
    measurements have limited value in estimating the actual human
    exposure defined by carboxyhaemoglobin levels.


    ADAMS, J. D., ERICKSON, H. H., & STONE, H. L. (1973) Myocardial
        metabolism during exposure to carbon monoxide in the conscious
        dog.  J. appl. Physiol., 34: 238-242.

        ABSOLON, K. B. (1974) Successful reversal of lethal carbon
        monoxide intoxication by total body asanguineous hypothermic
        perfusion.  Surgery, 75: 213-219.

    AHMED, A. E., KUBIC, V. L., & ANDERS, M. W. (1977) Metabolism of the
        haloforms to carbon monoxide. I.  In vitro studies.  Drug
         Metabol. Disposition, 5: 198-204.

    ALEXANDROV, N. P. (1973) [Choice of experimental animals for
        elaboration of standards for CO.]  Gig. i Sanit., 11: 92-95 (in

    ALEKSIEVA, T. & DIMITROVA, M. (1971) [Some oscillographic changes in
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    Annex 1


    (1) Several empirical equations have been proposed for estimating
    carboxyhaemoglobin levels from environmental exposure conditions.
    These equations were based on controlled exposures of human
    volunteers. Most of them referred to subjects at rest, or performing
    sedentary activities or light work. The simplest empirical equations
    described carboxyhaemoglobin levels as a linear function of carbon
    monoxide concentration in the inspired air [CO], and of exposure time
    (t) (Forbes et al., 1945; Pace et al., 1946). They were applicable
    only within a limited range of exposure conditions. Hanks & Farquhar
    (1969) and Peterson & Stewart (1970) compiled empirical equations
    involving more complex functional relationships that had a wider

    (2) In addition, models have been proposed that relate carboxyhaemo-
    globin levels to both environmental exposure conditions and a number
    of physiological variables such as blood volume, VB, endogenous
    carbon monoxide production,  Vco, diffusion capacity of the lung,
     DL, and alveolar ventilation rate,  VA. The best known model,
    developed by Coburn et al. (1965), has been briefly discussed in
    section 6.2. A more recent model, that took into account the dynamic
    condition of urban carbon monoxide concentrations, was suggested by
    Ott & Mage (1978) (p. 118).

    (3) A simple linear relationship, proposed by Forbes et al. (1945),
    linked the increase in the carboxyhaemoglobin level with the carbon
    monoxide concentration in air, [CO](ppm) and exposure time,  t(min):


    a  "This annex has been prepared by the Secretariat and has not been
       reviewed by the Task Group, with the exception of Table 3.
       Equations are presented in the form given in the original studies
       and no attempt has been made to change to SI units. The Secretariat
       wishes to express its appreciation to Dr H. Buchwald (Canada),
       Chairman of the Task Group, for providing information contained in
       Tables 3 and 4 and to Dr R. Horton, Dr D. J. McKee, USEPA, and
       Dr V. Armstrong, Health and Welfare, Canada for reviewing the

                            [HbCO](%) = k × [CO] ×  t                 (1)

    where k was a constant equal to 0.0003 for "an individual at rest"
    ( VA = 6 litre/min, pulse rate 70), 0.0005 for "light activity"
    ( VA = 9.5 litre/min, pulse rate 80), 0.0008 for "light work"
    (50 watts,  VA = 18 litre/min, pulse rate 110), and 0.0011 for
    "heavy work"a (about 100 watts,  VA = 30 litre/min, pulse rate 135).

        This equation was based on sets of controlled exposure
    observations on human volunteers. Exposure concentrations ranged from
    100 to 20 000 ppm (0.01 to 2.0%), and exposure times up to 6 h. At a
    [CO] of 100 ppm, the equation holds only up to delta[HbCO] of about
    7%. At 1000 ppm, the equation is applicable up to 30% [HbCO].

        The equation of Forbes et al. was used by the California State
    Department of Health for estimating [HbCO] after shorter periods of
    exposure to carbon monoxide concentrations higher than 100 ppm in
    individuals at rest or engaged in light work (Goldsmith & Landow,

    (4) The empirical equation suggested by Pace et al. (1945) was derived
    from controlled carbon monoxide exposures of 32 volunteers, aged 18-40
    years. The concentrations of carbon monoxide in the inspired air
    varied from 90 to 21 800 ppm, and the subjects were either sitting
    quietly or walking on a level treadmill (about 4.3 km/h,  VA about
    19.2 litre/min). The exposure times ranged from 20 to 300 min. The
    equation was also linear, but it took into account the alveolar
    ventilation rate,  VA, and the blood volume,  VB:

                     [CO](ppm) ×  VA (litre/min) ×  t(min)
    DELTA[HbCO](%) =                                                 (2)
                               4650 × VB(litre)

        If it is assumed that the blood volume equals 5.51 and
     VA = 6 litre/min (rest or light sedentary activity) or 18 litre/min
    (light physical work), the equation takes the same form as that of
    Forbes et al, but k values are somewhat lower (0.00023 and 0.00070,

    (5) Hanks & Farquhar (1969) also conducted carefully controlled
    exposure studies on sedentary volunteers, and expressed their results
    by the equation:

                        [HbCO](%) = 0.147[CO](1 - e-0.00289 t)        (3)

    where [CO] is in ppm and t in min. The equation was valid for subjects
    having a ventilation rate of about 6 litre/min.


    a  VA for heavy physical work may be as high as 60 litre/min.

        According to Chovin (1974), the "coefficient of (pulmonary)
    ventilation" K could be introduced into equation (3), which then
    became applicable to subjects performing various degrees of activity.
    Chovin's modified equation read:

                                              -       t
                  [HbCO](%) = 0.147[CO](1 - e         )              (4)

    where  t was in hours. For subjects at rest, K = 0.025, and for those
    performing heavy physical work, K = 0.065. For intermediate degrees of
    activity, Chovin proposed K values of 0.035, 0.045, and 0.055.

    (6) Another empirical equation, referred to on p. 36, was suggested by
    Peterson & Stewart (1970). It could also be written in the following

                    [HbCO](%) = 0.0051[CO]0.858 ×  t0.63              (5)

    where [CO] is in ppm, and  t in min. The equation was based on
    controlled human exposure data. The volunteers (18 healthy graduate
    students) were exposed to carbon monoxide concentrations of <1, 25,
    50, 100, 200, 500, and 1000 ppm for periods ranging from 30 min to
    24 h, while performing strictly sedentary activities. Like linear
    equations, this equation needed to be used with caution, since it did
    not yield a finite [HbCO] value for an infinite exposure time. It was
    used in developing US national ambient air quality standards, and is
    strictly valid for constant [CO] and for shorter periods of exposure
    (Ott & Mage, 1978).

    (7) A model proposed by Coburn et al. (1965) has been discussed on
    pp. 36 and 37. It is valid for male subjects only.a A solution of
    their differential equation has been provided in the original paper; it
    assumes that the mean pulmonary capillary oxygen pressure ( pCo2)
    and the concentration of oxyhaemoglobin [HbO2] are constant and
    independent of carboxyhaemoglobin levels [HbCO]. However, the
    oxyhaemoglobin level depends on carboxyhaemoglobin concentrations in a
    complex way. Solutions of the differential equation taking this into
    account are available, and their application is illustrated in the
    NAS/NRC (1977) document. Nevertheless, for most practical purposes,
    the solution given in the original paper appears to be adequate. It
    has been used, for example, by Peterson & Stewart (1970) and in the
    criteria document of the National Institute of Occupational Safety and
    Health (US Department of Health, Education and Welfare, 1972). A
    useful form of this solution is given in the document of the Committee
    on the Challenges of Modern Society (1972):


    a  Endogenous CO production may be different for females due to
       menstruation, pregnancy, and other metabolic factors.

        [HbCO] t =   {e- kt(A[HbCO]o - VcoB - [CO]) + VcoB + [CO]}       (6)

    where [HbCO] t and [HbCO]o are the carboxyhaemoglobin levels at

                                    pCo2         1    ( pB - 47)
     t and  t = 0, [CO] =  pIco, A =        , B = (   +           ) and
                                  M[HbO2]        DL       VA

                                         k =     

    the symbols used to define [CO], A, and B are explained on p. 36. The
    relationships between [CO] in ppm and  pIco, and between [HbCO]% and
    [HbCO] in ml CO/ml blood are:

                                         pIco × 106
                           [CO](ppm) =             ,


                   [HbCO](%) = 497.5 [HbCO](ml CO/ml blood)

    (8) Ott & Mage (1978) designed a model that took into consideration
    the dynamic characteristics of urban carbon monoxide concentrations.
    The differential equation describing it reads:

                     tau   dt    + [HbCO] - ß = alpha[CO]           (7)

                           O < [CO] < 100 ppm

    where ß was the endogenous level of blood carboxyhaemoglobin and was
    assumed to be 0.5%, alpha was assumed to be 0.15, and tau = 2.49h.

        The main conclusion of the authors was that [CO] in ambient air
    should be reported for averaging periods of 10-15 min, if the
    monitoring stations were located near heavy traffic or on congested
    streets. In such cases, sharp carbon monoxide peaks of short duration
    might occur fairly often, and concentrations reported with longer
    averaging periods, e.g., 1 h or more, might introduce an error of up
    to 21% in the estimated [HbCO].

    (9) Several empirical equations are compared with Coburn's model in
    Table 1, for persons at rest ( VA - 6 litre/min) or performing light
    physical work ( VA = 18 litre/min), at a carbon monoxide exposure
    concentration of 100 ppm. For subjects performing light work, Hanks &
    Farquhar's equation has been used in Chovin's modification with

    K = 0.060. The following assumptions have been made in calculating
    [HbCO]t values from Coburn's equation (6): [HbCO] = 0.5% or
    0.001 ml CO/ml blood,  Vco = 0.007 ml/min, VB = 5500 ml,
     pCo2 = 100 mmHg, [HbO2] = 0.2 ml O2/ml blood, M = 218,
     pB - 47 = 713 mmHg; sedentary subjects:  DL = 40 ml/min/mmHg,
     VA = 6000 ml/min; light work:  DL = 40 ml/min/mmHg,
     VA = 18 000 ml/min. For all empirical equations, [HbCO]o = 0.5%
    has been added to the calculated values of [HbCO].

        Table 1 shows clearly that Hanks & Farquhar's equation agrees best
    with Coburn's model. Peterson & Stewart's equation gives values that
    are higher than the other equations up to 6 h of exposure; then it
    gives lower results than Forbes' equation. At a carbon monoxide
    concentration of 100 ppm, Pace's equation gives lower [HbCO] values
    for subjects at rest than the other equations, up to 7 h of exposure;
    for subjects performing light work, it is applicable up to 2 h of
    exposure. For subjects at rest, Forbe's equation is applicable up to
    6 h, and for persons performing light work, up to 2 h.

    (10) Table 2 shows [HbCO] values predicted by Coburn's model.a The
    assumptions are the same as those specified in paragraph 9. For heavy
    work, it has been assumed that  DL = 60 ml/min/mmHg and that
     VA=30 000 ml/min.

    (11) Guidelines on exposure conditions that would prevent
    carboxyhaemoglobin levels exceeding 2.5-3% in general nonsmoking
    populations are given in Table 3.

        These guidelines were reviewed by the Task Group. Comparison with
    Tables 1 and 2 indicates the degree of protection provided, if these
    guidelines are applied, both for sedentary individuals and for persons
    performing light work. The exposure guidelines for 8-24 h have been
    added by the Secretariat, after the Task Group meeting, to facilitate
    comparison with national air quality standards.

    (12) Guidelines on exposure conditions, which would prevent carboxy-
    haemoglobin levels exceeding 5% in nonsmoking occupational groups, are
    shown in Table 4. They were prepared, after the meeting, by Dr
    Buchwald, at the request of the Secretariat, and have not been
    reviewed by the Task Group. Guidelines for heavy work have been
    suggested by the Secretariat, also after the meeting. Heavy work has
    been defined by  DL = 60 ml/min/mmHg and  VA = 30 000 ml/min. The
    degree of protection provided by these guidelines is indicated in
    columns 3 and 4 of Table 4. Column 3 shows carbon monoxide
    concentrations that would produce 5% HbCO within exposure times given 

    a  The Secretariat wishes to thank Dr M. A. Vouk, University
       Computing Centre, Zagreb, Yugoslavia, for programming Coburn's
       equations and providing computer printouts.

    in column 2, for light and heavy work, respectively. Column 4 provides
    "safety factors" obtained by dividing the concentrations in column 3
    by concentrations in column 1. Unless otherwise indicated, the
    guidelines given in Table 4 should be considered as desirable
    conditions rather than maximum acceptable limits.

        Table 1.  [HbCO](%) predicted by different empirical equations and by the model of Coburn et al. (1965). 
              Exposure to a carbon monoxide concentration of 115 mg/m3 (100 ppm)

    Time      Subjects at rest                                    Subjects performing light work
                F         P         H         PS        C         F         P         H         C
       15       1.0       0.8       1.1       2.0       1.2       1.7       1.6       1.9      2.0
       30       1.4       1.0       1.7       2.8       1.8       2.9       2.6       3.2      3.3
       45       1.9       1.5       2.3       3.4       2.4       4.1       3.6       4.4      4.6
       60       2.3       1.9       2.8       4.0       3.0       5.3       4.7       5.4      5.7
      120       4.1       3.3       4.7       5.9       5.0      10.1       8.9       8.7      9.2
      180       5.9       4.5       6.4       7.5       6.8      14.9      13.1      10.9     11.6
      240       7.7       6.0       7.8       8.9       8.3      19.7      17.3      12.3     13.2
      300       9.0       7.4       9.0      10.1       9.6      24.5      21.5      13.3     14.1
      360      10.8       8.8      10.0      11.3      10.7      29.3      25.7      13.9     15.1
      420      12.6      10.2      10.8      12.4      11.6      34.1      29.9      14.3     15.6
      480      14.4      11.5      11.5      13.5      12.4      38.9      34.1      14.6     15.9

    F = Forbes et al. (1945),  P = Pace et al. (1946),  H = Hanks & Farquhar (1969),
    PS = Peterson & Stewart (1970),  C = Coburn et al. (1965).

    Table 2.  [HbCO] values predicted from Coburn et al. (1965) model
    Time        200 ppm                        100 ppm                       75 ppm                         50 ppm
                 S         L         H         S         L         H          S        L         H          S         L         H
    15 min        1.8       3.5       5.2       1.2       2.0       2.8       1.0       1.6       2.2       0.82      1.2      1.6
    30 min        3.1       6.2       9.2       1.8       3.3       4.8       1.5       2.6       3.7       1.1       1.9      2.6
    45 min        4.3       8.7      12.6       2.4       4.6       6.5       1.9       3.5       4.9       1.4       2.5      3.4
    60 min        5.5      11.0      15.5       3.0       5.7       7.9       2.3       4.3       6.0       1.7       3.0      4.1
    90 min        7.7      14.9      20.2       4.0       7.6      10.2       3.1       5.8       7.7       2.2       4.0      5.2
    2h            9.7      18.1      23.7       5.0       9.2      11.9       3.9       7.0       9.0       2.7       4.7      6.1
    4h           16.3      26.2      30.4       8.3      13.2      16.3       6.3      10.0      11.5       4.4       6.9      7.7
    6h           21.1      30.0      32.4      10.7      15.1      16.2       8.1      11.3      12.2       5.5       7.6      8.2
    8h           24.5      31.7      32.9      12.4      15.9      16.5       9.4      12.0      12.4       6.4       8.0      8.3
    24h          32.7      33.2      33.2      16.5      16.7      16.6      12.4      12.5      12.5       8.4       8.4      8.3
    infinity     33.4      33.2      33.2      16.8      16.7      16.6      12.7      12.5      12.5       8.5       8.4      8.3

    Time        35 ppm                         25 ppm                        10 ppm                          5 ppm
                 S         L         H         S         L         H          S        L         H          S         L         H
    15 min        0.72      1.0       1.3       0.66      0.84      1.0       0.55      0.61      0.67      0.52      0.54     0.56
    30 min        0.93      1.4       1.9       0.80      1.2       1.5       0.61      0.72      0.82      0.54      0.57     0.60
    45 min        1.1       1.9       2.5       0.95      1.4       1.9       0.66      0.81      0.95      0.56      0.61     0.64
    60 min        1.3       2.2       3.0       1.1       1.7       2.2       0.71      0.90      1.1       0.58      0.63     0.68
    90 min        1.7       2.9       3.7       1.3       2.1       2.7       0.80      1.1       1.2       0.62      0.69     0.74
    2 h           2.0       3.4       4.3       1.6       2.5       3.1       0.89      1.2       1.4       0.66      0.73     0.78
    4 h           3.2       4.7       5.4       2.4       3.4       3.9       1.2       1.5       1.6       0.77      0.84     0.86
    6 h           4.0       5.4       5.7       2.9       3.9       4.1       1.4       1.6       1.7       0.85      0.88     0.88
    8 h           4.5       5.7       5.8       3.3       4.1       4.2       1.5       1.7       1.7       0.91      0.91     0.89
    24 h          5.9       5.9       5.9       4.3       4.2       4.2       1.9       1.8       1.7       1.05      0.93     0.89
    infinity      6.0       5.9       5.9       4.4       4.2       4.2       1.9       1.8       1.7       1.06      0.93     0.89

    S = sedentary subjects,  L = light physical work,  H = heavy physical work, all as defined in sections 9 and 10.

        Table 3.  Guidelines for exposure conditions to prevent carboxyhaemoglobin levels exceeding
              2.5-3% in nonsmoking populations

    (a)  A ceiling or maximum permitted exposure of 115 mg/m3 (100 ppm) for periods of exposure
         not exceeding 15 min (No exposure over 115 mg/m3 (100 ppm) permitted, even for very
         short time periods).
    (b)  A time-weighted average exposure of 55 mg/m3 (50 ppm) for periods of exposure not
         exceeding 30 min.
    (c)  A time-weighted average exposure of 29 mg/m3 (25 ppm) for periods of exposure not
         exceeding one h.
    (d)  A time-weighted average exposure of 15 mg/m3 (13 ppm) for periods of exposure of more
         than one h.
    (e)  A time-weighted average exposure of 11.5 mg/m3 (10 ppm) for periods of exposure of
         8-24 h.a

    a  Suggested by the Secretariat.
        Table 4.  Guidelines for exposure conditions that would prevent carboxyhaemoglobin levels
              exceeding 5% in nonsmoking occupational groups performing light and heavy
              physical work.

    Concentration       Exposure time not to     Concentrations that      Safety factor
                        be exceeded              would produce 5% HbCOc
    ppm      mg/m3                                                                       
                        Light        Heavy        Light       Heavy       Light     Heavy
                        worka        workb         work        work       work      work

    200d       230      15 min       -              298           -       1.5       -
    100e,f     115      30 min       15 min         157         193       1.6       1.9
     75f        86      60 min       30 min          87         105       1.2       1.4
     50f        55      90 min       60 min          64          62       1.3       1.2
     35f        40       4 h          2 h            37          41       1.1       1.2
     25f        29       8 h          8 h            31          30       1.2       1.2

    a  Limits suggested by Dr Buchwald.
    b  Limits suggested by the Secretariat.
    c  Calculated from Coburn's equation (6).
    d  Short-term limit or maximum permissible concentration for light work.
    e  Short-term limit or maximum permissible concentration for heavy work.
    f  Time weighted average.

    HANKS, T. G. & FARQUHAR, R. D. (1969)  Analysis of human performance
         capabilities as a function of exposure to carbon monoxide.
        (SystMed Corporation Report R 9001, Contract PH-22-68-31).

    PACE, N., CONSOLAZIO, W. V., WHITE, W. A. JR. & BEHNKE, A. R. (1945)
        Formulation of principal factors affecting the rate of uptake of
        carbon monoxide by man.  Am. J. Physiol., 147: 352-359.

        All other references are included in the list of references for
    the main body of the document (pp. 98-114).

    Annex 2



    1.1  Canada (1974)

    National air quality objectives

        Desirable concentrations:

        (a)  0-6 mg/m3 (0-5 ppm)b average concentration over an 8-h
        (b)  0-15 mg/m3 (0-13 ppm) average concentration over a one-h

        Acceptable concentrations:

        (a)  6-15 mg/m3 (5-13 ppm) average concentration over an 8-h
        (b)  15-35 mg/m3 (13-31 ppm) average concentration over a one-h

        Method of measurement:

        Nondispersive infrared spectrometry, Report No. EPS 1-AP-73-1.

        Source: Velma Ouellet (1978)  The Clean Air Act--Compilation of 
     Regulations and Guidelines, Ottawa, Environment Canada (Report EPS

        In addition to the desirable and acceptable concentrations listed,
    a tolerable range of 15-20 mg/m3 average concentration over a
    continuous 8-h period was prescribed in 1978.

    Source: Canada Gazette (1978) Part 2, Volume 112, No. 3 (February 8).


    a  Prepared by the Secretariat.
    b  Concentrations in alternative units have been added by the
       Secretariat to facilitate comparison of national quality standards.

    1.2  Federal Republic of Germany (1974)

        In the Federal Republic of Germany, immissionsc (Immissionen)
    are legally defined as "air pollutants, noise, vibrations, light,
    heat, radiations, and analogous environmental factors affecting human
    beings, animals, plants, or other objects". "As a rule, air pollutants
    occurring at a height of 1.5 metres above ground or at the upper limit
    of vegetation or at a distance of 1.5 metres from the surface of a
    building shall be considered active air pollutants."

        "Immission standards are the values for long-term exposure (IW 1)
    and short-term exposure (IW 2)."

        The following immission standards have been established for carbon

        Long-term exposure (IW 1): 10.0 mg/m3 (9 ppm).

        Short-term exposure (IW 2): 30.0 mg/m3 (26 ppm).

        Method of measurement: VDI 2455, Sheet 1 (August 1970) and 2455,
    Sheet 2 guidelines (October 1970).

        "Characteristic value I 1 for comparison with IW 1 shall be the
    arithmetic mean of all individual data for a measurement area.
    Characteristic value I 2 for comparison with IW 2 shall be the 95%
    value for the cumulative frequency distribution of all individual
    values for a measurement area; this may be also calculated with the
    formula I 2 = x +  ts where x is the arithmetic mean of individual
    data for a measurement area,

                                      2SUM(x - xi)2
                          s = + SQRT                    ,
                                          2z - 1

    xi = individual data which are greater than x, z = number of
    individual data, which are greater than x, and  t = 1.64 for the 95%
    confidence level."

        Source: Federal Minister of the Interior (1974)  Technical
     Instructions for Maintaining Air Purity, 28 August 1974, Bonn.


    c  Immission A German term for which there is no simple English
       equivalent. Immissions are to be distinguished from emissions
       (Emissionen), which are defined as air pollutants, noise,
       vibrations, light, heat, radiations, and analogous phenomena
       originating from an installation (Federal Republic of Germany, Law
       on Protection against Emissions, 15 March 1974).

    1.3  Japan (1973)

        Ambient air quality standards are defined as follows:

        (a) Average of hourly values in 8 consecutive hours shall not
    exceed 20 ppm (23 mg/m3).

        (b) Daily average of hourly values shall not exceed 10 ppm
    (11 mg/m3).

        These standards do not apply to industrial zones, roadways, and
    other areas or places where people do not usually live.

        Source: Environment Agency (1978)  Environmental Laws and
     Regulations in Japan (II) Air. Tokyo.

    1.4  Union of Soviet Socialist Republics (1971)

        Maximum permissible (single exposure) concentration for carbon
    monoxide is 3 mg/m3 (2.6 ppm). This concentration should not provoke
    reflex (i.e., subsensory) reactions in human organisms.

        Maximum permissible (24-hour average) concentration for carbon
    monoxide is 1.0 mg/m3 (0.9 ppm). This concentration should not have
    either a direct or indirect harmful effect on man, for unlimited in
    time, continuous exposure, 24 hours a day.

        Method not specified.

        Source: Krotov, Ju. A. (1975)  Maximum permissible concentrations
     of harmful substances in air and water, Himija, Moscow.

    1.5  United States of America (1971)

        "The national primary and secondary ambient air quality standards
    for carbon monoxide, measured by the reference method described in
    Appendix C to this part, or by an equivalent method, are:

        (a) 10 milligrams per cubic meter (9 ppm) -- maximum 8-hour
            concentration not to be exceeded more than once per year.

        (b) 40 milligrams per cubic meter (35 ppm) -- maximum 1-hour
            concentration not to be exceeded more than once per year."

        Reference method for the continuous measurement of carbon monoxide
    in the atmosphere is nondispersive infrared spectrometry.

        Source:  Federal Register, 36 (228), Thursday, November 25, 1971,
    Washington DC, pp. 22385 and 22391-22392.

    1.6  Other Member States

        For further information on national ambient air quality standards
    for carbon monoxide, the reader is referred to W. Martin & A. C. Stern
    (1974)  The world's air quality management standards, Washington, DC,
    US Environmental Protection Agency (EPA-650/a-75-001-a).


        An occupational exposure limit for carbon monoxide of 50 ppm or
    55 mg/m3 has been set in the following Member States: Australia,
    Belgium, Finland, Federal Republic of Germany, Italy, Japan,
    Netherlands, Switzerland, the USA, and Yugoslavia.

        Bulgaria and the USSR have established a limit of 20 mg/m3
    (17 ppm), Hungary and Poland, 30 mg/m3 (26 ppm) and Sweden,
    40 mg/m3 (35 ppm). Czechoslovakia's standard includes average and
    maximum values of 30 mg/m3 (26 ppm) and 150 mg/m3 (130 ppm),
    respectively. Other standards that include both average and maximum
    values are those of the German Democratic Republic, (35 and
    110 mg/m3) (30 and 96 ppm) and Romania, (30 and 50 mg/m3) (26 and
    44 ppm).

        These values should be interpreted in terms of definitions of
    occupational exposure limits, which may be different in different
    countries. The reader is referred to the International Labour Office
    publication:  Occupational Exposure Limits for Airborne Toxic
     Substances, Occupational Safety and Health Series 37, ILO, Geneva,
    1977. The values given in paragraphs 1 and 2 have been extracted from
    this publication.

        The US National Institute of Occupational Safety and Health
    (NIOSH, 1972) has recommended environmental exposure limits of 35 ppm
    (40 mg/m3) (time weighted average) and 200 ppm (229 mg/m3)
    (ceiling) (Summary of NIOSH Recommendations for Occupational Health
    Standards, July, 1978).

    See Also:
       Toxicological Abbreviations
       Carbon monoxide (EHC 213, 1999, 2nd edition)
       Carbon monoxide (ICSC)