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WHO Guidelines for Indoor Air Quality: Selected Pollutants. Geneva: World Health Organization; 2010.

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WHO Guidelines for Indoor Air Quality: Selected Pollutants.

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2Carbon monoxide

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General description

Carbon monoxide (CO) is a colourless, non-irritant, odourless and tasteless toxic gas. It is produced by the incomplete combustion of carbonaceous fuels such as wood, petrol, coal, natural gas and kerosene. Its molecular weight is 28.01 g/mol, melting point −205.1 °C, boiling point (at 760 mmHg) −191.5 °C (−312.7 °F), density 1.250 kg/m3 at 0 °C and 1 atm and 1.145 kg/m3 at 25 °C and 1 atm, and relative density (air = 1) 0.967 (1,2). Its solubility in water at 1 atm is 3.54 ml/100 ml at 0 °C, 2.14 ml/100 ml at 25 °C and 1.83 ml/100 ml at 37 °C.

The molecular weight of carbon monoxide is similar to that of air (28.01 vs approximately 29). It mixes freely with air in any proportion and moves with air via bulk transport. It is combustible, may serve as a fuel source and can form explosive mixtures with air. It reacts vigorously with oxygen, acetylene, chlorine, fluorine and nitrous oxide. Carbon monoxide is not detectible by humans either by sight, taste or smell. It is only slightly soluble in water, blood serum and plasma; in the human body, it reacts with haemoglobin to form carboxyhaemoglobin (COHb).

The relationship of carbon monoxide exposure and the COHb concentration in blood can be modelled using the differential Coburn-Forster-Kane equation (3), which provides a good approximation to the COHb level at a steady level of inhaled exogenous carbon monoxide.

Conversion factors

At 760 mmHg and 20 °C, 1ppm = 1.165 mg/m3 and 1 mg/m3 = 0.858 ppm; at 25 °C, 1 ppm = 1.145 mg/m3 and 1 mg/m3 = 0.873 ppm.

Indoor sources

Inhalation is the only exogenous exposure route for carbon monoxide. Anthropogenic emissions are responsible for about two thirds of the carbon monoxide in the atmosphere and natural emissions account for the remaining one third. Small amounts are also produced endogenously in the human body (4,5). Exposure to low levels of carbon monoxide can occur outdoors near roads, as it is also produced by the exhaust of petrol- and diesel-powered motor vehicles. Parking areas can also be a source of carbon monoxide (6).

Carbon monoxide is produced indoors by combustion sources (cooking and heating) and is also introduced through the infiltration of carbon monoxide from outdoor air into the indoor environment (7). In developed countries, the most important source of exposure to carbon monoxide in indoor air is emissions from faulty, incorrectly installed, poorly maintained or poorly ventilated cooking or heating appliances that burn fossil fuels. In homes in developing countries, the burning of biomass fuels and tobacco smoke are the most important sources of exposure to carbon monoxide. Clogged chimneys, wood-burning fireplaces, decorative fireplaces, gas burners and supplementary heaters without properly working safety features could vent carbon monoxide into indoor spaces. Incomplete oxidation during combustion may cause high concentrations of carbon monoxide in indoor air. Tobacco smoke can be a major source of indoor exposure, as can exhaust from motor vehicles operating in attached garages (6).

Combustion of low-grade solid fuel and biofuels in a small stove or fireplace can generate high carbon monoxide emissions, which may become lethal to occupants unless the flue gases are vented outdoors via a chimney throughout the entire combustion process. At the beginning of combustion, the pollutants released are dominated by particulate matter (elemental and organic carbon) but carbon monoxide dominates towards the end. Combustion of high-grade fuels such as natural gas, butane or propane usually produces much less carbon monoxide, provided that sufficient air is supplied to ensure complete combustion. Nevertheless, even devices using such fuels can cause lethal carbon monoxide intoxication if they are not properly maintained or vented or if air : fuel ratios are not properly adjusted.

Incense burning in homes and public buildings such as stores and shopping malls can be a source of exposure to carbon monoxide. Jetter et al. (8) reported emission rates of 23 different types of incense, such as rope, cones, sticks, rocks and powder, that are typically used indoors. The measured emission rates of carbon monoxide ranged from 144 to 531 mg/hour. The authors estimated a peak concentration of 9.6 mg/m3 caused by incense burning and therefore concluded that carbon monoxide concentrations could exceed the USEPA's National Ambient Air Quality Standard of 10 mg/m3 for an 8-hour average, depending on the room volume, ventilation rate and the amount of incense burned. Incense burning might be a significant contributor to carbon monoxide exposure in cultures where incense is burned frequently, for example in religious rituals.

Indoor levels and relationship with outdoor levels

Results of recent studies on carbon monoxide concentrations in indoor air are summarized in Table 2.1. The studies are listed by continent. Studies concerning accidental or peak exposures are presented separately in Table 2.2. Representativeness and data quality, as well as the form in which the data are presented, vary greatly between the studies and make detailed comparisons meaningless except when comparing data within the same study. The general levels of carbon monoxide, however, vary so much between the locations and studies that patterns are easily discernible.

Table 2.1. Indoor concentrations of carbon monoxide and indoor : outdoor (I : O) ratios.

Table 2.1

Indoor concentrations of carbon monoxide and indoor : outdoor (I : O) ratios.

Table 2.2. Accidental or peak exposure studies.

Table 2.2

Accidental or peak exposure studies.

In the absence of indoor sources, current concentrations of carbon monoxide in indoor air in European and North American cities are well below the levels of existing air quality guidelines and standards. In the 1950s and 1960s, carbon monoxide levels in urban air often approached or even exceeded these reference values, but drastic reductions in emissions from space heating and traffic have substantially reduced anthropogenic emissions in spite of the growing size of cities and increasing traffic (9,29).

The highest reported non-accidental carbon monoxide levels are observed in public or residential garages and in primitive kitchens when cooking with open fires (Guatemala). Aside from open-fire cooking with solid fuels, the most common sources for elevated carbon monoxide concentrations in indoor air are unvented gas appliances, tobacco smoking and proximity to busy traffic. The lowest concentrations are found in homes, churches and schools at some distance (> 500 metres) from busy traffic and with no indoor sources. Carbon monoxide intoxication can be caused by single or repetitively generated high short-term peaks, and carbon monoxide poisoning is the leading cause of death from poisoning (accidental and intentional).

Carbon monoxide is a relatively unreactive gas under ambient air conditions and is not absorbed by building materials or ventilation system filters. Therefore, in the absence of indoor carbon monoxide sources, the indoor air concentration is the same as the concentration of ventilated or infiltrating outdoor air. Under these conditions, the indoor : outdoor (I : O) carbon monoxide concentration ratio should be 1.0; in practice, however, measured I : O ratios vary for two reasons.

  • The outdoor air carbon monoxide concentration at the point of measurement may be significantly higher or lower than the concentration at the point of ventilation air intake. Consequently, even in the absence of any indoor sources, the 15-minute I : O for carbon monoxide varies from 0.2 to 4.1 and the daily I : O from 0.4 to 1.2.
  • Normal indoor sources, gas appliances and tobacco smoking increase the I : O ratios.

Kinetics and metabolism

Carbon monoxide hypoxia

Since the time of Haldane (52), it has been assumed that the effect of carbon monoxide exposure is due to hypoxic effects (53). Carbon monoxide enters the body via inhalation and is diffused across the alveolar membrane with nearly the same ease as oxygen (O2). Carbon monoxide is first dissolved in blood, but is quickly bound to haemoglobin (Hb) to form COHb, which is measured as the percentage of haemoglobin so bound. The binding of carbon monoxide to haemoglobin occurs with nearly the same speed and ease as with which oxygen binds to haemoglobin, although the bond for carbon monoxide is about 245 times as strong as that for oxygen (54–56). Thus carbon monoxide competes equivocally with oxygen for haemoglobin binding sites but, unlike oxygen, which is quickly and easily dissociated from its haemoglobin bond, carbon monoxide remains bound for a much longer time. In this way, COHb continues to increase with continued exposure, leaving pro gressively less haemoglobin available for carrying oxygen. The result is arterial hypoxaemia. Another effect of COHb is to increase the binding strength of oxygen to haemoglobin, thus making release of oxygen into tissue more difficult (57). The latter effect is quantitatively described as a leftward shift in the oxyhaemoglobin dissociation curve, proportional to the COHb level (58).

The endogenous formation of COHb has been described by Coburn, Forster & Kane (3). The model has also been tested under a wide variety of carbon monoxide exposure conditions and found to predict COHb more accurate ly than empirical methods (54,59–66).

The most important variables in the formation of COHb are the concentration and duration of carbon monoxide in inhaled air and the rate of alveolar ventilation (67). Alveolar ventilation, largely determined by body energy expenditure (exercise), can vary over a wide range and is thus the major physiological determinant of the rate of COHb formation and elimination.

Carbon monoxide will also reduce the diffusion of oxygen into tissue via myoglobin by formation of carboxymyoglobin. The formation of carboxymyoglobin also acts as another sink for carbon monoxide. This process has been described by a multicompartmental physiological model (68,69). The models estimate the effects of carboxymyoglobin formation on carbon monoxide uptake, but the effect of carboxymyoglobin on tissue function is not clear. It is probable that such effects become important only for high levels of carbon monoxide exposure (70). Binding of carbon monoxide to other proteins (cytochrome P-450 and cytochrome oxidase) have also been demonstrated, but the dosimetry is unclear and the functional significance appears to be limited to high levels of carbon monoxide exposure (70).

Dosimetric compensations for COHb

Carbon monoxide, in addition to being an environmental contaminant, is produced endogenously. Thus, it is not surprising that physiological mechanisms have evolved to compensate for its presence in mammalian blood and tissues. These compensatory mechanisms must be considered when calculating the tissue dosimetry. For acute exposures, as COHb increases, arterial blood flow to the brain increases proportionally. Thus, even though the blood oxygen contents are decreased, in normal people the increased volume of blood tends to keep the amount of oxygen delivered to the brain constant, preventing hypoxia (71–74). These investigators have demonstrated that brain tissue metabolism remains constant as the COHb increases until it approaches 20%, implying that brain tissue hypoxia does not occur with lower COHb levels. Thus it is apparent that the increased compensatory flow is sufficient to account for the shift in the oxyhaemoglobin dissociation curve. This compensatory activity also occurs in neonates and fetuses (73,74). For chronic exposures to carbon monoxide, red cell volume increases or plasma volume decreases (70), thus increasing the amount of oxygen that can be delivered.

Non-hypoxic mechanisms

An accumulating body of evidence indicates that direct carbon monoxide exposure (not COHb) can produce a number of brain cellular events that could potentially lead to serious functional consequences (see the section on health effects below). The direct effect of carbon monoxide on tissue has not been demonstrated in vivo, although such effects have been inferred by the observation of tissue effects in exposures in vivo that are very similar to such effects found with in vitro preparations. It would appear that the presence of carbon monoxide in tissues from in vivo exposure would depend on carbon monoxide dissolved in blood, because it had not yet bound with haemoglobin or because there could be some level of dissociation due to chemical equilibrium reactions. The amount of such dissolved carbon monoxide and the diffusion into various tissues has not been described or modelled. Thus, the dosimetry for putative non-hypoxic effects of carbon monoxide exposure is not known. The amount of dissolved carbon monoxide in blood would seem to be highest for high-level carbon monoxide exposure.

Comprehensive dosimetry

The final dose for carbon-monoxide-induced hypoxic effects is thus seen to be some measure of tissue oxygenation. This is an inverse measure in the sense that, as tissue oxygen increases towards the normal, function improves. As shown above, tissue oxygenation is determined by (a) the blood oxygen content (inversely proportional to COHb level), (b) the ease of dissociation from blood to tissue (the oxyhaemoglobin dissociation curve), (c) the volume of blood delivered to tissue and (d) the ability of tissue to utilize the oxygen (tissue respiration). To these we must add the rate of oxygen utilization by the tissue. The final criterion of tissue function is the energy metabolism rate in the tissue.

The issue of dosimetry is complex, but there exist physiologically based mathematical models to estimate many of the above variables and thus to predict tissue function. They are not mathematically trivial, but with modern computation tools the necessary calculations are readily performed (3,75). Many of these models have been combined into “whole-body” models, which hold much promise for estimating physiological function (http://physiology.umc.edu/themodelingworkshop/).

Exposure–response relationship

The information required for regulatory guidance setting is some measure of the biologically critical concentration and duration of carbon monoxide exposure in inhaled air. To estimate environmental guidelines that provide reasonable protection against adverse health effects, information is required about what tissue dose produces what health effects. Given this critical tissue dose, one can estimate the various environmental concentrations, subject characteristics and subject activities that will produce the critical tissue dose. Thus for a specific environmental case of interest, mathematical simulations can be done to estimate protective regulatory decisions. Therefore, for each health effect of interest, critical tissue oxygenation must be known.

It might be argued that the critical tissue dose is obtained from experimental evidence in which environmental exposure is given in the first place. Experiments, however, are not usually good simulations of actual scenarios of interest. The purpose of the simulations is to be able to simulate any environment of interest without having direct experimental evidence. Unfortunately, in the absence of adequate dosimetric information, and therefore dosimetric models, simulation by models is not possible. Thus for non-hypoxic effects, it is frequently necessary to use less general evidence from empirical environmental data to make estimates of critical exposures. To preserve exposure data from experiments and literature reviews, it would seem to be important to report both COHb and exposure concentration and duration. This would potentially permit calculation of tissue dose for non-hypoxic tissue effects when the dosimetry models are developed. It should be kept in mind that the tissue dose and the eventual health effect are not necessarily contemporaneous. Delayed sequelae may occur and cumulative exposure may be needed to become effective. These are really questions of physiological mechanisms.

Health effects

Identification of studies

For the acute health effects, the literature search was conducted in the PubMed and Web of Science databases, searching the keywords carbon monoxide and health. A special search for behavioural and neurological effects used PubMed with the following keyword statement: (“carbon monoxide” OR CO) AND (“human behaviour” OR “nervous system” OR CNS OR sensory OR “human performance” OR vision OR hearing OR auditory) NOT co- NOT smoking. Similar search statements were used for physiological and mechanistic articles. From these searches, 952 articles were found and, from these, 52 were deemed relevant and used in the review. The references in each of the relevant articles were searched to find any other articles that might have been missed by the automated searches.

A similar strategy was followed for a review of the health effects of chronic exposure. From these articles, 101 were deemed relevant and were used.

Chronic exposure

Definition of the health outcome

This review will discuss concisely and briefly human exposure to carbon monoxide in enclosed (i.e. closed) breathing spaces. Since outdoor air inevitably becomes indoor air, some consideration of carbon monoxide levels in outdoor air and their effects on humans are required. To that end, there will be some discussion of epidemiological studies involving ultra-low-level carbon monoxide found in outside air. Exposure to high, potentially lethal levels are not considered here at any length and “delayed effects” are not examined because neither would be seen in indoor carbon monoxide exposure situations under normal circumstances. Because animal studies cannot at present provide much useful data about many aspects of the carbon monoxide poisoning syndrome (76), they have been considered only in order to understand basic mechanisms by which carbon monoxide may impair human health.

This review extends the discussion of those issues involving carbon monoxide exposure in humans summarized in the 1999 WHO and 2005 European Union reports (77,78). There has been no major attempt to recapitulate the review of most studies before roughly 1999. Other recent reviews on carbon monoxide exposure are available in monographs by Penney (79–81) and Kleinman (6). Recourse to these works is strongly encouraged.

Tikuisis (82) reviewed human carbon monoxide uptake and elimination in 1996. Chen & Wang (83) reviewed the health effects of carbon monoxide in air pollution in major Chinese cities in 2000. Flachsbart (84) reviewed ambient and very low concentrations of carbon monoxide on humans more recently. Penney (81) recently reviewed pitfalls in making diagnoses of carbon monoxide poisoning, especially chronic poisoning. “Chronic” is defined as any exposure lasting more than 24 hours; “acute” is an exposure of 24 hours or less (76).

Penney (85) reviewed the effects of carbon monoxide exposure on developing animals and humans in 1996. White (86) reviewed carbon monoxide poisoning in children in 2000. Public perceptions about carbon monoxide in the northern and southern regions of the United States, some relevant to indoor air, were investigated by Penney and published in 2008 (87).

Penney reviewed the general characteristics of chronic carbon monoxide poisoning in humans in 2000 (80) and 2008 (88), as did Hay et al. in 2000 (89) and Hay in 2008 (90). In 2000,Greiner & Schwab (91) reviewed engineering aspects of carbon monoxide as it occurs in the living space.

Helfaer & Traystman (71) reviewed the cerebrovascular effects of carbon monoxide in 1996. In 2000, Hazucha (92) reviewed the effects of carbon monoxide on work and exercise capacity in humans. McGrath (93) reviewed the interacting effects on humans of altitude and carbon monoxide.

In 1996, Hiramatsu et al. (94) reviewed the impairment of learning and memory and neuronal dysfunction resulting from carbon monoxide exposure. In 2008, Hopkins (95) and Armstrong & Cunningham (96) reviewed the neurocognitive and affective outcomes of carbon monoxide poisoning in adults and children. Helffenstein (97) recently reported on a study investigating the neurocognitive and neurobehavioural sequelae of chronic carbon monoxide poisoning.

Early studies of chronic carbon monoxide poisoning

The early studies of Beck (98,99), Lindgren (100), Barrowcliff (101), Wilson & Schaeffer (102), Davies & Smith (103), Trese et al. (104), Kowalska (105), Kirkpatrick (106), Jensen et al. (107), Ryan (108), Tvedt & Kjuus (109), Myers et al. (110) and Bayer et al. (111) on chronic carbon monoxide poisoning have been reviewed by Penney (76). Other older studies, many coming out of the Second World War, have not been included in published reviews by this author. For example, Helminen (112) describes changes in the visual field caused by chronic coal gas (i.e. carbon monoxide) poisoning in 180 patients. The investigation was part of an extensive, systematic examination carried out at the First Medical Clinic of the University in Helsinki, Finland.

Sumari (113) describes the method used in Finland in examining victims of coal gas poisoning and the observations made in connection with it. The subject material comprises the results of the examination of 135 patients of which 71 are certain, “pure” chronic carbon monoxide cases. Of the cohort of 71, objective neurological symptoms were found in 60 cases. Out of 69 cases ophthalmologically examined, 66 gave positive results. Out of 65 cases otoneurologically examined, the reaction of 52 was positive. In some cases the disease seemed to progress, although the patients being examined were then in surroundings free from coal gas.

Lumio, in an extensive 1948 study (114), found fatigue, headache, vertigo, irritation, memory impairment, tinnitus and nausea to be the most frequent symptoms resulting from chronic carbon monoxide poisoning. Hearing disturbances were noted in 78.3% of the patients suffering from chronic carbon monoxide poisoning. A smaller number of hearing disturbances (26.7%) were found in patients exposed to carbon monoxide at work but in whom chronic carbon monoxide poisoning could not be confirmed. Thus, hearing disturbances were present in approximately three times as many patients suffering chronic carbon monoxide poisoning as in patients not affected. The majority of patients had a similar pattern of hearing deficiencies. The threshold of hearing was about normal at frequencies up to 1000 Hz. Hearing loss occurred above that frequency. This pattern of hearing deficiency was noted in 67.7% of patients who had suffered chronic carbon monoxide poisoning, but in only 14% of patients not so affected. Often, patients themselves were not aware of the presence of a hearing deficiency. Of those suffering from chronic carbon monoxide poisoning, 47.9% complained of hearing impairment during the time they were exposed to the carbon monoxide. The audiogram, however, showed changes in 78.3% of the patients with carbon monoxide poisoning. Follow-up examinations revealed that typical hearing losses improved only slightly or not at all. An improvement in hearing was found in only 26.7% of the cases, and it was always slight. The data suggest that typical hearing deficiency may appear during the initial stage of chronic carbon monoxide poisoning, when vestibular symptoms are not yet present. For additional details see the Carbon Monoxide (CO) Headquarters web site (http://www.coheadquarters.com/ChronicCO/indexchronic2.htm).

Von Zenk (115) reported on rhino-cochlear-vestibular symptoms in 80 suspected cases of chronic carbon monoxide poisoning. The cochlear findings showed a perceptive disturbance with a high tone loss and largely retroganglionic damage. Subjective symptoms included vertigo that was accompanied by nystagmus more commonly in the confirmed group. There was also a diminution of the sense of smell.

Komatsu et al. (116) examined 733 workers at a steel-making facility. Mean ages of four groups broken out of the cohort was approximately 32 years (no significant difference). Group A1 was exposed to 58–291 mg/m3, Group A2 to 70–1595 mg/m3, Group B to < 23 mg/m3 and Group C to < 12 mg/m3 carbon monoxide in the course of their normal work. Median COHb saturation was 10–15% in Group A1, 20–25% in Group A2, 1–5% in Group B and 1–5% in Group C. The average frequency of health complaints was much higher for members of Groups A1 and A2 than for those of Groups B and C. A large variety of subjective health complaints were made by Group A1 and especially Group A2 members. For example, the highest frequency of complaints in reports included headache, poor hearing, chest pain, lassitude, fatigue and forgetfulness. A variety of objective health complaints were made by Group A1 and especially Group A2 members. The highest incidences, for example, included pallor, cardiac enlargement (cardiomegaly), coldness of the extremities and hyperactive patellar reflex. Average vital capacity was significantly less for members of Group A at any age than for members of Groups B or C. Average back strength was significantly less for members of Group A at age 30–40 years than for same-age members of Group C. The difference from members of Group B was very large and significant over the entire age range of the two groups.

Smith & Landaw (117) reported that smokers develop polycythaemia. Furthermore, smoking at increased elevation dramatically increases the extent of the polycythaemia. This, along with cardiomegaly, has been demonstrated numerous times following chronic carbon monoxide exposure in animals (118,119).

Stern et al. (120) studied the effects of carbon monoxide exposure on deaths of New York City bridge and tunnel employees over the period 1952–1981. It was found that the tunnel workers experienced a 35% excess risk compared with the New York City general population; among the less exposed bridge workers the risk was not elevated. The elevated risk among the tunnel workers declined significantly within five years after ending occupational exposure, and there was also a significant decline after 1970, when a new ventilation system lowered carbon monoxide levels inside the tunnels and tunnel booths. The 24-hour average tunnel carbon monoxide concentrations were approximately 58 mg/m3 in 1961 and 47 mg/m3 in 1968. During periods of rush hour traffic in 1968, carbon monoxide concentrations in tunnel toll booths were as high as 76–192 mg/m3.

Retrospective and case studies

Two questionnaire studies (A and B) of chronic carbon monoxide poisoning in North America have been reported by Penney (76). A third questionnaire study (C) of 61 individuals sustaining chronic carbon monoxide poisoning was recently reported by Penney (121). The large questionnaire study conducted in the United Kingdom in 1997 under the title “Carbon monoxide support” has been reviewed by Hay et al. (89).

Two cases of chronic carbon monoxide poisoning in children (122,123) have been discussed by White (86) and another (124) by Hay (90). Armstrong & Cunningham (96) report on three cases of chronic carbon monoxide poisoning in young children and the functional and developmental effects that resulted. A review of the effect of chronic or intermittent hypoxia on cognition in childhood (125) included carbon monoxide poisoning; it concluded that adverse effects have been noted at even mild levels of oxygen desaturation and that “studies of high-altitude and carbon monoxide poisoning provide evidence for causality”.

Other studies looking at neuropsychological aspects of chronic carbon monoxide exposure such as those of Ryan (108), Myers et al. (110), Pinkston et al. (126), Hartman (127) and Devine et al. (128) have recently been thoroughly reviewed by Helffenstein (97). Helffenstein's findings from his own study of 21 people chronically exposed to carbon monoxide are detailed in that same 2008 source.

Ely et al. (129) describe 30 people who developed “warehouse workers' headache”. COHb levels in the workers most exposed to exhaust gases were 21.1%. It is understood that this condition in the warehouse had continued for some time, making the exposure “chronic” rather than “acute”. A majority of the people experienced acute difficulty with headache, dizziness, weakness, nausea and chest pain. Some complained of shortness of breath, vomiting, muscle cramps, difficulty in concentrating, visual changes and confusion. Follow-up symptoms present two years after the carbon monoxide exposure included numbness in the extremities, restlessness, persistent headaches, irritability, confusion, difficulty in walking or moving the extremities, and memory loss.

Walker (130) states that the incidence of chronic carbon monoxide exposure in Great Britain is officially 200 per year, while at the same time “250 000 gas appliances are condemned annually”. He speculates that if only 10% of these appliances give off significant amounts of carbon monoxide that reach the breathing space of residents, as many as 25 000 people every year may be exposed to carbon monoxide in their homes. The carbon monoxide support study (89) found that “only one case out of 77 was correctly identified (i.e. diagnosed) on the basis of symptoms alone” and that medical professionals were the least likely group to “discover” the fact of the carbon monoxide poisoning.

Thyagarajan et al. (131) report on a 37-year-old woman chronically exposed to carbon monoxide for seven years. Her symptoms included seizure, persistent tiredness, problems with balance, headache associated with cognitive symptoms, personality changes and depression. Magnetic resonance imaging of her brain five years after the end of carbon monoxide exposure showed a well-defined lesion in the globus pallidus, on the left. Hippocampal atrophy was also suggested. This case indicates that unilateral lesioning resulting from carbon monoxide poisoning can occur.

Prochop (132) reports on the case of four people chronically exposed to carbon monoxide in an apartment building in Florida as the result of a faulty gas heater. All four suffered transient loss of consciousness immediately prior to discovery of the problem. All four incurred cognitive impairments, while two also experienced residual coordinative deficits. Magnetic resonance imaging of the four people was said to be normal. One victim had an abnormal magnetic resonance spectroscopy scan.

Sari et al. (133) investigated an association between chronic carbon monoxide exposure and P-wave and QT interval characteristics of the electrocardiogram in 48 healthy male indoor barbecue workers and 51 age-matched healthy male controls. COHb in the two groups was 6.48% and 2.19%, respectively. Using Pearson analysis, there were significant correlations between COHb level and P-wave duration, maximum QT height, QT duration and corrected QT duration.

In a clinical review, Weaver (134) states that “lower level CO exposures can cause headache, malaise, and fatigue and can result in cognitive difficulties and personality changes”. This assertion is borne out by Chambers et al. (135) (see Hopkins (95)), who prospectively followed 256 patients, 55 with “less severe” and 201 with “more severe” carbon monoxide poisoning. Less severe poisoning was defined as no loss of consciousness and a COHb level of ≤ 15%, while more severe poisoning was defined as loss of consciousness or a COHb of >15%. Of the less severely poisoned patients, 39% had cognitive deficits at six weeks. Of those more severely poisoned, 35% had cognitive deficits. In the less vs more severe groups, the incidence of depression was 21% and 16%, respectively, and that of anxiety was 30% and 11%, respectively. There was no difference in cognitive outcomes between the two groups. Interestingly, the prevalence of depression was higher in patients with the less compared with the more severe poisoning at six months. Likewise, the prevalence of anxiety was higher in patients with the less compared with the more severe poisoning at six weeks. These results suggest that loss of consciousness is not a requirement for carbon-monoxide-induced brain damage, and that carbon-monoxide-related cognitive (and other) outcomes may be independent of poisoning severity when that severity is based on COHb saturation.

In a recent clinical study, Keles et al. (136) characterized their patients as having acute carbon monoxide poisoning, when in actual fact most had chronic poisoning since the authors cite coal stoves and water heaters as carbon monoxide sources. These devices do not deteriorate overnight. Many studies do not characterize the exposure condition at all, or will characterize it as acute when in fact it is chronic. The study found that COHb could not be used to rule out carbon monoxide poisoning. This has been known for some time, i.e. the poor relationship between COHb, symptoms and outcome. The most common symptoms they recorded were headache, nausea, dizziness and syncope.

Table 2.3 provides summary data from five studies on chronic carbon monoxide poisoning: Bayer et al. (111), Penney (76,121) and Helffenstein (97). N1 is the number of cases for which air carbon monoxide concentration data are available. N2 is the number of cases for which COHb data are available. It should be noted that, for all five studies, average COHb levels fall within the “less severe” carbon monoxide poisoning group as defined by Chambers et al. (135).

Table 2.3. Summary data from five studies on chronic carbon monoxide poisoning.

Table 2.3

Summary data from five studies on chronic carbon monoxide poisoning.

Epidemiological studies

Epidemiological studies reported prior to 2000 dealing with carbon monoxide effects relative to mortality, birth weight, asthma, congestive heart failure, coronary artery disease, psychiatric admissions, etc. in humans have been reviewed by Penney (76). The topic of congestive heart failure and environmental carbon monoxide levels was also reviewed by Morris (137).

Mar et al. (138) evaluated the association between mortality in the elderly and air pollutants over a three-year period in Phoenix, Arizona. Total mortality was found to be significantly correlated with changes in ambient carbon monoxide and nitrogen dioxide, whereas cardiovascular mortality was significantly associated with carbon monoxide, nitrogen dioxide, sulfur dioxide, etc.

Moolgavkar (139) investigated non-accidental cardiovascular, cerebrovascular and chronic obstructive pulmonary disease deaths over eight years in three American metropolitan areas: two in California and one in Illinois. Carbon monoxide level was particularly found to have a stronger association with mortality than level of particulate matter. This association was noted to be stronger in Los Angeles County. This study is similar to an earlier epidemiological investigation by Hexter & Goldsmith (140), reviewed by Penney (76).

Hajat et al. (141) found a relationship between ambient carbon monoxide and asthma consultations for children in London. Sheppard et al. (142) examined the relationship between asthma and air carbon monoxide levels in Seattle for data during the period 1987–1994. They found a 6% increase in the rate of hospital admissions for asthma related to carbon monoxide, with a three-day lag.

Yu et al. (143), in another study in Seattle, found a 30% increase in asthma in children for a 1.2-mg/m3 increment in carbon monoxide that lagged one day. They estimated 25% increases in the odds of increases in carbon monoxide, conditional on the previous day's asthma symptoms. It was concluded that there is an association between change in short-term air pollution levels and the occurrence of asthma symptoms among children in Seattle.

Karr et al. (144) analysed nearly 12 000 diagnoses of infant bronchiolitis between 1999 and 2002 in south-west British Columbia. They looked at infants' exposure within 10 km of home, and were able to account for confounding variables including sex, gestational age, maternal smoking and breastfeeding. An interquartile increase in exposure to nitric oxide, nitrogen dioxide, sulfur dioxide and carbon monoxide increased bronchiolitis risk by 8%, 12%, 4% and 13%, respectively. Infants living within 50 metres of a highway had an increased risk of 6%; those living in an area with higher exposure to wood smoke had an increase of 8% in their risk of bronchiolitis. Carbon monoxide posed the largest risk for bronchiolitis among the pollutants examined.

In studies by Hong et al. (145,146), the occurrence of acute stroke mortality in Seoul is reported to be related to air pollution. Data covering 4- and 7-year periods were analysed. In the first study, stroke mortality increased 4.1% with a two-day lag. In the second study, a significantly increased risk of 1.06 (95% CI 1.02–1.09) was found for carbon monoxide, with a one-day lag. Nitrogen dioxide and ozone also appeared to play a role. This suggests, according to the authors, “an acute pathogenetic process in the cerebrovascular system induced by air pollution”.

Yang et al. (147), in a “case cross-over study” carried out on data for Kaohsiung (Taiwan, China), found that carbon monoxide and other air pollutants were significantly associated with increased numbers of admissions for cardiovascular diseases (CVD) on both warm and cool days. This study provides evidence that exposure to “higher levels of ambient contaminants, particularly carbon monoxide, increase the risk of hospital admissions for CVD”.

Barnett et al. (148), looking at data from Australia and New Zealand, found an association between outdoor air quality and cardiovascular hospital admissions. They found that for a 1-mg/m3 increase in carbon monoxide, there were significant increases in hospital admissions of elderly people for total cardiovascular disease (2.2%), all cardiac disease (2.8%), cardiac failure (6.0%), ischemic heart disease (2.3%) and myocardial infarction (2.9%). In matched analyses, carbon monoxide had the most consistent association.

Bell et al. (149) studied hospital admissions for cardiovascular disease in 126 urban counties in the United States during 1999–2005. They found a positive and statistically significant association between same-day carbon monoxide exposure and increased risk of hospitalization for multiple cardiovascular outcomes (ischemic heart disease, heart rhythm disturbances, heart failure, cerebrovascular disease and total cardiovascular disease). A 1.2-mg/m3 increase in same-day daily 1-hour maximum carbon monoxide was associated with a 0.96% (95% CI 0.79–1.12) increase in risk of cardiovascular admissions.

In 1995, Morris et al. (150) reported an association between ambient carbon monoxide levels in seven United States cities and hospital admissions for congestive heart failure among elderly people, which showed a consistent association with daily variations in ambient carbon monoxide. This association was independent of season, temperature and other major gaseous pollutants. In 1997, Burnett et al. (151) found a similar association in ten Canadian cities. The logarithm of the daily high-hour ambient carbon monoxide concentration recorded on the day of admission displayed the strongest and most consistent association with hospital admission rates among the pollutants, after stratifying the time series by month of the year and simultaneously adjusting for temperature, dew point and the other ambient air pollutants. The relative risk for a change from 1.2 mg/m3 to 3.5 mg/m3, the 25th and 75th percentiles of the exposure distribution, was 1.065.

Yang (152) re-examined the reported association between air pollutant levels and hospital admissions for congestive heart failure in Taipei in 2008. The data examined covered the period 1996–2004. The number of admissions for congestive heart failure was significantly associated with the environmental presence of carbon monoxide and several other pollutants. Statistically significant positive effects on increased congestive heart failure admissions on cool days were observed only for the carbon monoxide levels.

Stieb et al. (153) conducted a study of nearly 400 000 emergency department visits to 14 hospitals in Canada between the early 1990s and the early 2000s. Twenty-four-hour averages of carbon monoxide and nitrogen dioxide exhibited the most consistent associations with cardiac conditions: 2.1% (95% CI 0.0–4.2) and 2.6% (95% CI 0.2–5.0) increase in visits, respectively, for myocardial infarction and angina per 0.8 mg/m3 carbon monoxide. Thus, daily average concentrations of carbon monoxide and nitrogen dioxide exhibited the most consistent associations with emergency department visits for cardiac conditions.

Dales et al. (154) examined an association between air pollution and daily numbers of hospital admissions for headache in seven Chilean urban centres during the period 2001–2005. Relative risks for migraine associated with interquartile-range increases for carbon monoxide was 1.11 (95% CI 1.06–1.17) for a 1.3-mg/m3 increase in carbon monoxide concentration. The authors concluded that air pollution increases the risk of headache in Santiago Province. There was no significant effect of modification by age, sex or season.

In a massive epidemiological study, Ritz & Yu (155) studied a cohort of 125 573 singleton children born in Los Angeles. Excluded were infants born before 37 or after 44 weeks of gestation, those weighing below 1000 or above 5500 grams at birth, those for whom fewer than 10 days of carbon monoxide measurements were available during the last trimester, and those whose mothers suffered from hypertension, diabetes or uterine bleeding during pregnancy. Within the cohort, 2813 (2.2%) were low in birth weight (between 1000 and 2499 grams). Exposure to higher levels of ambient carbon monoxide (> 6.4 mg/m3, 3-month average) during the last trimester was associated with a significantly increased risk for low birth weight (odds ratio (OR) 1.22; 95% CI 1.03–1.44) after adjustment for potential confounders, including commuting habits in the monitoring area, sex of the child, level of prenatal care, and the age, ethnicity and level of education of the mother. Levels of environmental carbon monoxide previously thought to be extremely low were shown to reduce birth weight in women exposed to carbon monoxide during the last trimester of pregnancy.

Maisonet et al. (156) followed the Los Angeles study with an investigation on birth weight in Boston, MA, Hartford, CT, Philadelphia, PA, Pittsburgh, PA, Springfield, IL and Washington, DC. Their results suggest that exposure to ambient carbon monoxide (and sulfur dioxide) increases the risk of low birth weight at term. This risk is increased by a unit rise in the average concentration of carbon monoxide in the third trimester.

Chen et al. (157) assessed the association between ambient air pollution and daily elementary school absenteeism in Washoe County, Nevada in the period 1996–1998. A total of 27 793 students were enrolled. The daily average absence rate was 5.09% (SD = 1.54%). The daily average carbon monoxide concentration was 3.2 mg/m3. After adjustment for the effects of weather, day of the week, month, holidays and time trend, they found that carbon monoxide and oxygen were statistically significant predictors of daily absenteeism. For every 1.2-mg/m3 increase in carbon monoxide concentration, absence increased by 3.79% (95% CI 1.04–6.55).

Two studies examining cardiovascular events and long-term exposure to carbon monoxide at ultra-low levels (i.e. 1.2–1.8 mg/m3) found no significant association with changes in the carbon monoxide concentration in ambient air (158,159).

Experimental studies

Past reviews of air quality mainly discuss acute studies of carbon monoxide exposure at lower concentrations. Even though hypoxic stress may have been the only underlying mechanism at work, some nonetheless reported positive effects. It can be argued that when considering exposure to air pollution in human residential and work environments, these studies have limited significance and model rather poorly human responses to long-term carbon monoxide exposure.

Symptomatology

Recognizing the onset of carbon monoxide poisoning is crucial, as it can be fatal in just a few minutes. The symptoms are usually non-specific and appear to involve many of the body systems. Common symptoms include headache, lethargy/fatigue, nausea, dizziness and confusion. A victim may also suffer from shortness of breath, cardiac palpitations, convulsion, paralysis, loss of consciousness, coma and eventually death. Many reviews list the step-wise onset of various symptoms in acute carbon monoxide poisoning as they relate to blood COHb levels. However, the relationship in reality between blood carbon monoxide levels and symptomatology is extremely poor. There is no hyperventilation induced by carbon monoxide poisoning or increased salivation, taste/odour changes, eye watering or coughing, as are produced by carbon monoxide's toxic twin, hydrogen cyanide. Age, anaemia, increased elevation, cardiopulmonary disease and prior exposure to carbon monoxide can increase susceptibility to carbon monoxide toxicity. The median level of COHb in people dying of uncomplicated carbon monoxide poisoning is 53–55%.

An important key to identifying carbon monoxide poisoning is the victim's environment and immediate past living or work situation. Was the victim exposed to sources of carbon monoxide such as uncontrolled fires, motor vehicles, fuel-burning heaters or other internal combustion engines in a poorly ventilated enclosed space? Are others in that environment (e.g. family members or pets living in the same house) displaying similar symptoms? These facts are critical in accurately identifying carbon monoxide poisoning.

First and foremost, the victim must be moved out of the contaminated area into fresh air. Eventually, the carbon monoxide will be eliminated from the blood through normal ventilation, although often serious health damage may be done before this can occur, so emergency measures should be started immediately.

In 1895, John Scott Haldane demonstrated that rats survive carbon monoxide poisoning when placed in oxygen at two atmospheres pressure. In 1942, End & Long treated carbon monoxide poisoning in experimental animals with hyperbaric oxygen. The first human clinical use of hyperbaric oxygen therapy in carbon monoxide poisoning was by Smith & Sharp in 1960 (80). This type of therapy is now recommended for most seriously, acutely poisoned victims, but there have been some studies that fail to show its efficacy (81). If hyperbaric oxygen therapy is to be used, it must be initiated immediately (within 12 hours) on reaching a health care facility.

Pathophysiological mechanisms

Since the time of Haldane (52), it has been presumed that the attachment of carbon monoxide to haemoglobin, thus preventing the carriage of adequate oxygen and the impaired release of oxygen from the remaining oxyhaemoglobin (i.e. hypoxic stress) was the major mechanism by which carbon monoxide exerts its health-damaging effects. At low COHb levels and in the presence of normal vasomotion and hyperaemia, it has been difficult to understand how carbon monoxide can cause immediate or long-term cellular, tissue and organ damage. Evidence for various cellular mechanisms not requiring hypoxic stress has recently appeared. See also http://www.coheadquarters.com/coacute.mech1.htm.

Ischiropoulos et al. (160) found in rat studies that the potent oxidant species, peroxynitrite, was generated in the brain from nitric oxide and that a cascade of events could lead to “oxidative stress” in carbon monoxide poisoning. Thom & Ischiropoulos (161) reported that platelets released nitric oxide when incubated with carbon monoxide and that carbon monoxide concentrations as low as 12 mg/m3 were capable of doing this in vitro. They concluded that carbon monoxide levels produced in vivo when humans are exposed to carbon monoxide “can cause endothelial cells to liberate nitric oxide and derived oxidants, and that these products can adversely affect cell physiology”. Using microelectrodes in rats, it was seen that carbon monoxide exposure caused nitric oxide concentration to nearly double to 280 nM through the modulation of nitric oxide synthase (162).

It was found that platelet activating factor was involved in the adherence of neutrophils to brain endothelium after carbon monoxide poisoning and that the process required nitric-oxide-derived oxidants (163). Thom et al. (164) postulated that carbon monoxide poisoning causes “adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade”. It was found that carbon-monoxide-poisoned rats displayed impaired maze-learning that did not occur in similar rats made immunologically tolerant to MBP. They suggest that this mechanism may explain brain damage occurring days after treatment for carbon monoxide poisoning, and be the reason for the observed lack of a simple dose–response relationship between COHb level at presentation and outcome. The use of hyperbaric oxygen following carbon monoxide poisoning in rats prevented deficits in maze-learning performance and MBP immune-mediated neurological dysfunction (165).

In blood obtained from 50 patients who had sustained carbon monoxide poisoning, platelet–neutrophil aggregates were detected and plasma myeloperoxidase concentration was elevated, suggesting that the processes seen in animals also operate in humans (166).

Thus, recent studies suggest that the intracellular uptake of carbon monoxide could be a major cause of neurological damage (i.e. brain damage). When carbon monoxide binds to cytochrome oxidase, it causes mitochondrial dysfunction. The release of nitric oxide from platelets and endothelial cells inside blood vessels, forming the free radical peroxynitrite, further inactivates mitochondrial enzymes and damages the vascular endothelium of the brain. The end result is lipid peroxidation of the brain, which starts during recovery from carbon monoxide poisoning. With reperfusion of the brain, leukocyte adhesion and the subsequent release of destructive enzymes and excitatory amino acids amplify the initial oxidative injury. Such endovascular inflammation may be a major mechanism leading to organ dysfunction.

Other recent studies indicate that carbon monoxide poisoning can cause immune system dysfunction (164) that causes decrements in learning not observed in immunologically tolerant animals. This may be based on adduct formation between MBP and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade. Thus, carbon monoxide poisoning appears to trigger immunological reactions, just as a number of other disease states do. Therefore, a third damaging mechanism of carbon monoxide exposure appears to be through its action on the immune system.

The information summarized above suggests that the damaging effects of carbon monoxide are not only due to its action in binding to haemoglobin and interfering with oxygen delivery, i.e. hypoxic stress. Although this process certainly takes place and is undoubtedly important in higher-level and acute carbon monoxide poisoning, other processes not previously known result in endothelial inflammation and immune activation, causing interference with blood flow and the destruction of cellular machinery. The operation of these pathways and their products explain the effects of carbon monoxide at very low air–carbon monoxide and COHb levels, and what occurs during extended exposure, and finally the seeming lack of a dose–response relationship between air–carbon monoxide concentration, COHb, immediate symptoms and the long-term health effects.

Acute exposure

Effects on exercise duration

There have been no reliable demonstrations of health effects due to acute carbon monoxide exposure in normal, healthy people where exposures resulted in COHb levels below 6%, except for limitation of maximal exercise duration. In laboratory experiments, people exposed to carbon monoxide before maximum exercise tests had reduced exercise duration (167–172). The duration was reduced as an inverse function of COHb level. A linear equation was fitted to the data (167) but the equation should have been curvilinear. This is clear from inspection of the data because the zero COHb point, had it been included in the fitting, would have been plotted well below the intercept of the fitted curve. At higher COHb, however, the curve is nearly linear. An increase in COHb of 4.5% produced a drop in exercise time of about 30 seconds. In the Ekblom & Huot study (167), the baseline mean exercise duration was about 5.2 minutes. Another metric of the effect magnitude was calculated by estimating the maximum total calories expended from the amount of work performed. Here, a 4.5% increase in COHb level reduced the maximum exercise from a total expenditure of about 112 kcal to some 90 kcal.

The exercise effect of carbon monoxide exposure in healthy subjects was produced by reduced oxygen delivery to the exercising muscle. At 20%, COHb reduced the arterial oxygen content from about 19.8% to about 15.8% by volume. Normally, one would expect reduced oxygen dissociation from arterial blood into muscle tissue because of the shift in the dissociation curve, but in the case of exercising muscle the oxygen partial pressure of the tissue is likely to have been so low that the dissociation shift did not matter (167).

Also, at maximum exercise, no further increase in blood flow to the muscle was possible. Thus, in this experiment, the only appreciable determinant of tissue oxygenation was the COHb. No account of the possible role of carboxymyoglobin was possible.

When laboratory maximal exercise testing was done with patients who exhibited stable angina pectoris due to coronary artery disease, the results were quite different from normal subjects (173–178). Here the subjects were also given maximal exercise tests, but the criterion for stopping was not exhaustion but the onset of angina. Subjects were also exposed to lower levels of carbon monoxide, producing a maximum of nearly 6% COHb. In the baseline (no carbon monoxide) condition, the mean maximum exercise time was around 8.2 minutes. Allred et al. (175) showed that an increase in COHb of 4.5% reduced exercise time by 36 seconds and reduced total maximum energy expenditure from about 64 kcal to about 30 kcal. Thus it is seen that the magnitude of effect produced by an increase in COHb of 4.5% in not dramatically greater than for normal subjects. The difference is that the cardiac impairment has simply reduced the baseline exercise ability.

The angina patient's baseline exercise ability was reduced from a maximum energy expenditure of 112 kcal to 64 kcal by the inability of the heart to supply sufficient blood flow to provide oxygen to the exercising muscles. The further decrease in exercise time was due to the same mechanism as for normal subjects (reduced arterial content of the same magnitude), which produced nearly the same magnitude of effect. To be sure, the percentage exercise reduction is greater for the angina patients than for the normal subjects, but this is simply due to the reduction in baseline exercise ability.

It is not clear whether the slightly greater observed effect of COHb in the patients compared to the normal subjects would be considered statistically significant or physiologically meaningful. Another consideration in the angina data is the fact that COHb was not extended to higher levels as it was for normal subjects. Clearly, this was done for ethical reasons, but the possibility exists that higher exposures would have led to greater magnitudes of effect than for normal subjects.

It might be argued that the data on the effect of carbon monoxide exposure in angina patients contributes little additional information needed for regulatory decisions. However, heart disease is a leading cause of sickness and death worldwide, and it is plausible that coronary artery disease would make patients more susceptible to cardiac failure from increased hypoxic cardiac stress (179), but there are no data to evaluate this hypothesis. On the other hand, individuals with heart disease represent a large fraction of the population and therefore the angina studies do address an issue of public health concern.

Brain function effects

Clinical reports of symptoms of low-level acute carbon monoxide poisoning (headache and nausea) are commonly cited (180) for COHb levels of 10–20% but were not observed in a double-blind study for COHb levels below 20% (181). Head ache and nausea were reported in a double-blind study at COHb levels of 25–30% (182).

A large number of behavioural studies were critically reviewed by Benignus (183,184) involving sensory, psychomotor, vigilance, cognitive and schedule-controlled behaviour in both humans and rats. Human studies were largely unreliable in the sense that they were not replicable, sometimes even by their original authors. Rat studies were highly consistent but demonstrated statistically significant effects only when COHb exceeded about 20%.

Benignus (183) meta-analysed the carbon monoxide literature, fitting dose–effect curves and attempting to relate the rat and human carbon monoxide data and the human hypoxia data. The rat carbon monoxide data were meta-analysed and the internal dose (oxygen delivery by arterial blood) was estimated. The extra behavioural effect of hypothermia (which results from COHb increase) was also estimated and subtracted. The internal dose for humans exposed to carbon monoxide was also calculated, but hypothermia (which does not occur in humans for the duration of acute exposures) was not considered. The internal dose for hypoxic hypoxia in humans was calculated, in addition to the hypocapnia (which occurs due to hyperventilation in hypoxic hypoxia but not carbon monoxide exposure). The carbon monoxide effects were corrected by subtracting the effects of hypocapnia. When all of the internal doses and the behaviourally corrected dose–effect curves were compared, they nearly overlay each other. The conclusion was that, when arterial oxygen content was used as the internal dose and extraneous effects were subtracted, the behavioural effects of carbon monoxide hypoxia and hypoxic hypoxia were of equal magnitude for humans and were equal in rate to the magnitude of carbon monoxide hypoxia. The results were expressed in equivalent of estimated COHb.

The above-mentioned dose–effect curves reached the 10% effective dose (ED-10) at mean COHb ∼ 20%, with upper and lower 95% confidence limits of about 22.2% and 18.8% (184). The ED-10 was selected as a point of interest because in the behavioural literature, and with the typical number of subjects, the ED-10 is about the magnitude of effect that becomes statistically significant or behaviourally important. A continuous non-linear function was fitted to the data and thus there is a continuum of magnitude of effect estimates, which may be used to estimate severity of effects between zero and about 30% COHb and higher by extrapolation from rats. It may not be inferred from these results that effects be low a COHb of 20% are absent; they gradually diminish towards zero at a COHb of zero.

These results provide an example of compensatory physiological action, i.e. the increased arterial blood flow to the brain sufficient to keep tissue oxygen supply nearly constant (73,185). It was observed by these workers that brain energy metabolism remained statistically unchanged until COHb exceeded 20%, because up to that point blood flow could increase sufficiently to offset the carbon-monoxide-induced hypoxia. At COHb levels of around 30%, the brain metabolism fell precipitously. These physiological results agree almost exactly with the behavioural data.

It is interesting that small decreases in mean brain energy metabolism as well as in mean behaviour are estimated to occur below 20% COHb. This could be attributed to an actual small effect or to some small fraction of susceptible subjects having larger effects or to an inappropriate statistical model for the dose–effect curves. This is an area requiring additional study, since at the present stage of knowledge the question cannot be resolved.

An implication of the above analysis is that if, owing to some pre-existing cardiovascular or pulmonary disease, the compensatory increase in blood flow were impaired, small increases in COHb could produce larger decreases in tissue oxygen and thus larger behavioural effects. No data have been reported to test this hypothesis.

Compromised brain function, in addition to being an adverse effect in itself, can contribute to sensory impairment that could result in failure to detect signs of danger or could impair decision-making capabilities, leading to an inability to respond appropriately to danger. The ability to avoid or flee danger could also be impaired by carbon-monoxide-induced limitations on exercise. Such effects of acute exposure can potentially lead to consequences ranging from minor injuries to serious injuries and death. Behaviourally or physically impaired people exposed to carbon monoxide could also endanger others in their vicinity.

Quality of the exposure and effects measures

It has been customary to specify the “dose” of carbon monoxide as either the amount in blood as COHb or as the concentration in the inhaled air. The effects of carbon monoxide are, however, not strictly determined by either of these metrics. The health effects are a product of tissue functioning and these, in turn, are functions of some tissue dose metric. An effort is made below to specify tissue dosimetry where knowledge permits and to point to gaps in knowledge when appropriate.

Susceptible populations and effect modifiers

Any person with some form of impaired oxygen uptake and delivery would be more sensitive to the acute hypoxic effects of carbon monoxide exposure. Thus, hypothetically, any cardiac, vascular or pulmonary disease would have such an effect, as would other factors that limit the blood's ability to transport oxygen, such as anaemia. Also, presumably, multiple diseases in a particular person could increase that individual's risk of greater effects; the potential interaction need not necessarily be simply additive. The severity of a given disease state would influence the maximum COHb, possibly before adverse effects became noticeable, and could determine the maximum amount of effort that could be expended. The magnitude of a carbon monoxide effect would depend on the amount of oxygen available for metabolism in the tissue under consideration. Because multiple cardiac, vascular and pulmonary diseases in one person are not uncommon, it would not be surprising if some impaired people were adversely affected by even small increases in COHb. No data are available to evaluate this conjecture, but quantitative physiological analyses to further delimit the range of effects would be possible.

Other possible sensitive groups are pregnant women, whose endogenous COHb is greater, and fetuses, whose haemoglobin has somewhat greater affinity to carbon monoxide than that of adults.

There are numerous situations in which carbon monoxide is not the only source of hypoxia. Until a person is adapted to high altitude, the resulting arterial hypoxia is directly additive (in terms of arterial oxygen content) to carbon monoxide hypoxia (178), and the increased pulmonary ventilatory response also increases carbon monoxide uptake. Increased inhaled carbon dioxide increases pulmonary ventilation and thus carbon monoxide uptake. Hydrogen cyanide inhibits tissue respiration and thus adds to hypoxic effects, in addition to strongly stimulating increased pulmonary ventilation. These effects are of interest because all of the above pollutants are combustion products. These effects are enumerated in detail by Benignus (184) and physiological effects and interactions have also been quantitatively estimated in interesting cases by Benignus (186) using computerized mathematical models of physiological function. Thus, the presence of any or all of the above combustion gases would exacerbate the effects of carbon monoxide exposure.

The concomitant behaviour of people exposed to carbon monoxide can also make them more sensitive to its effects. Higher rates of physical exercise increase pulmonary ventilation, thereby increasing the COHb formation rate, and increase oxygen metabolism, exacerbating the hypoxia. Increased body temperature from external heat or inappropriate clothing would increase pulmonary ventilation. Those who are anxious owing to emotional or psychological conditions have increased pulmonary ventilation.

Clearly, impaired persons could be exposed to multiple hypoxic toxicants while engaged in situations in which pulmonary ventilation would be elevated. Even though the carbon monoxide in these environments might be insufficient to produce effects in controlled laboratory experiments, the real world is much more complicated and the possibility of such complex multiple effects cannot be dismissed.

Health risk evaluation

There are several health concerns associated with exposure to carbon monoxide. The best understood health effects appear to be produced by hypoxia due to the binding of carbon monoxide to haemoglobin, which reduces the oxygen-carrying capacity of the blood as well as decreasing the dissociation of oxygen into extravascular tissue. COHb is widely used as a biomarker for carbon monoxide exposure. Carbon monoxide also binds with myoglobin and cytochrome oxidase and P-450, but the magnitude and the effects of such binding are less well explored.

High-level exposures (over several hundred mg/m3) can cause unconsciousness and death. There can be severe and permanent CNS damage, even in cases where individuals do not experience loss of consciousness. Evidence is also mounting that carbon monoxide can produce a cascade of cellular events leading to adverse effects that are not necessarily ascribable to hypoxia (i.e. COHb may be a less reliable biomonitor for these effects).

Acute exposure

Acute laboratory exposure to carbon monoxide in healthy young people has been shown to decrease duration of maximum exercise tests in a COHb (dose)-related manner. The same phenomena were demonstrated in patients with stable angina, but only at a lower range of COHb. The latter effect is presumably due to limitation of heart oxygen supply because of an inability to increase blood flow in the presence of, for example, stenoses in the coronary arteries.

In early acute laboratory exposures of healthy young people, brain function (as measured by reduced behavioural performance) was reported to be impaired in a COHb-related manner when COHb ranged from 2.5% to around 10%. These studies were, however, not replicable in any case where such replication was attempted. It has been suggested, based on physiological analysis and extrapolation, that brain function should not be reduced by more than 10% until COHb approaches around 18%. With laboratory carbon monoxide exposures of a few hours' duration, no symptoms were reported, even for COHb approaching 20%. Such high effect thresholds were attributed to the compensatory effect of the increased brain blood flow that accompanies increased COHb.

As COHb due to acute exposure increases above 25–30%, people begin to lose consciousness and eventually, as COHb reaches 60% and above, death ensues. Exact COHb values depend on individual susceptibilities, the underlying state of health and, to some extent, the activity level of the individuals concerned.

The above data have been considered as evidence that carbon monoxide hypoxia produced the effects. It may not be assumed, however, that non-hypoxic physiological events do not contribute to the effects, because such non-hypoxic effects might be correlated in time and magnitude with COHb. Evidence exists that non-hypoxic events are responsible for impairments that sometimes develop several days after reduction of COHb due to high-level acute carbon monoxide exposure.

Chronic, low-level exposure

There is a growing consensus that for carbon monoxide, as with ionizing radiation, a NOAEL exists. Effectively, a so-called “safe level” is arbitrarily set at a point at which a level of health effects is deemed acceptable. Thus, the setting of a guideline for indoor carbon monoxide involves other considerations than simply scientific considerations of carbon monoxide's toxicity.

Long-term exposures to lower levels of carbon monoxide have far wider-ranging implications for human health than do acute carbon monoxide exposures. There are many hundreds of millions, indeed billions of people around the world who are currently chronically exposed to carbon monoxide indoors. Such exposure has been reported to alter health in a number of ways, including physical symptoms, sensory–motor changes, cognitive memory deficits, emotional–psychiatric alterations, cardiac events and low birth weight. The evidence for this is derived from clinical toxicological, medical and neuropsychological case reports, case series and other retrospective studies. It is established that many cases of carbon monoxide toxicity are misdiagnosed because the symptoms mimic other health problems.

Epidemiological studies involving large population groups, where exposures are generally at relatively low carbon monoxide levels, have demonstrated increased incidences of low birth weight, congenital defects, infant and adult mortality, cardiovascular admissions, congestive heart failure, stroke, asthma, tuberculosis, pneumonia, etc. In both accidental exposure and epidemiological studies, toxic substances other than carbon monoxide were often present in the exposed person's inhaled air. Dose–effect relationships are suggested in some epidemiological studies. The body of literature from both kinds of study is large and growing, and is consistent with subtle but often profound health effects at low carbon monoxide levels.

Health damage resulting from chronic, lower-level exposure has been difficult to fully explain on the basis of hypoxia, hypoxaemia and measured COHb, since various physiological mechanisms should quickly compensate. This leads to the conjecture that non-hypoxic mechanisms may be responsible for some of the effects. The lack of good dose–effect relationships in the accidental exposure case study reports also suggests alternative mechanisms of causation. The cellular mechanisms described above from recent experimental studies may well be the avenues by which this health damage occurs.

If COHb and hypoxia are not important factors in chronically generated health effects, then an alternative means of referencing severity of exposure must be used. Since COHb level only recognizes initial carbon monoxide uptake, a better measure is arguably to use the product, carbon monoxide concentration × time (i.e. duration of exposure). This parameter more accurately represents the total dose of carbon monoxide received in long-term carbon monoxide exposure, since duration of exposure is explicitly present.

Specially sensitive people

Groups at highest risk from carbon monoxide exposure include the unborn and those adults, elderly or not, with coronary artery disease, congestive heart failure or potential stroke, those at risk of sudden death, etc. There is almost certainly also a group of individuals who are extraordinarily sensitive to carbon monoxide but who have no obvious health or unusual physiological conditions and thus cannot be readily identified. They represent that fraction of individuals who lie at the left end of the standard curve when health effects are determined in any population with known exposure history. All of these higher risk groups must be considered when setting carbon monoxide guidelines for indoor air or, for that matter, outdoor air, i.e. the guideline must be low enough to protect all those at highest risk.

Quality and weight of evidence

Compelling evidence of carbon-monoxide-induced adverse effects on the cardiovascular system is derived from a series of controlled human exposure studies of individuals with cardiovascular disease at COHb levels relevant to ambient conditions. Carbon monoxide exposure caused decreases the time to angina and ST-segment changes with COHb levels on the range of 2 to 6%.

Recent epidemiological studies of chronic environmental exposures are coherent with the results of the controlled human exposure studies. Positive associations between ambient carbon monoxide exposure and ED visits and hospital admissions for ischemic heart disease, congestive heart failure and cardiovascular disease are seen in multiple locations where ambient carbon monoxide concentrations ranged from 0.6 to 10.9 mg/m3. These carbon monoxide associations generally remained robust in multiple pollutant models. In addition, newer data on pathophysiological mechanisms offer an eventual possible explanation of the chronic effects. These two lines of data support a direct effect of carbon monoxide exposure on cardiovascular morbidity and are considered to have a high weight of evidence.

The toxicological studies of carbon monoxide effects on human birth outcomes and fetal development have been critically reviewed. There is evidence that carbon monoxide exposure during pregnancy is associated with reduced fetal growth and low birth weight. Because of inconsistencies in data reporting, exposure assessment and possible confounding of effects by co-pollutants the weight of this evidence is considered limited but suggestive of important health effects.

At the present time, the strength of the evidence for important health outcomes is as summarized in Table 2.4.

Table 2.4. Strength of evidence.

Table 2.4

Strength of evidence.

Guidelines

The 24-hour guideline

Chronic carbon monoxide exposure is different from acute exposure in several important respects, as noted above. Thus, a separate guideline is needed to address minimal exposure over 24 hours, rather than the 8-hour period used in the acute guidelines. The latest studies available to us in 2009, especially those epidemiological studies using very large databases and thus producing extremely high-resolution findings, suggest that the appropriate level for carbon monoxide in order to minimize health effects must be positioned below the 8-hour guideline of 10.5 mg/m3, possibly as low as 4.6–5.8 mg/m3. This is also essential since the minimal exposure time for this guideline is three times longer.

Derivation of a concentration–response factor

Exposure to carbon monoxide reduced maximum exercise ability in healthy, young individuals and reduced the time to angina and, in some cases, the time to ST-segment depression in subjects with cardiovascular disease, albeit at a concentration that was lower than that needed to reduce exercise ability in healthy individuals.

The relationship of carbon monoxide exposure and the COHb concentration in blood can be modelled using the differential Coburn-Forster-Kane equation (3), which provides a good approximation to the COHb concentration at a steady level of inhaled, exogenous carbon monoxide. Based on the laboratory studies of reduction in exercise capacity in both healthy individuals and volunteers with cardiovascular disease, it was determined that COHb levels should not exceed 2%. The CFK equation is used below to determine the levels of carbon monoxide to which a normal adult under resting conditions for various intervals can be exposed without exceeding a COHb level of 2%.

The previous WHO guidelines were established for 15 minutes to protect against short-term peak exposures that might occur from, for example, an unvented stove; for 1 hour to protect against excess exposure from, for example, faulty appliances; and for 8 hours (which is relevant to occupational exposures and has been used as an averaging time for ambient exposures). We do not recommend changing the existing guidelines. However, chronic carbon monoxide exposure appears different from acute exposure in several important respects. Thus, a separate guideline is recommended to address 24-hour exposures. This is also relevant because the epidemiological studies (based on 24-hour exposures) using very large databases and thus producing extremely high-resolution findings are now available and indicate important population-level effects at levels that might be lower than the current 8-hour limit. We recommend a series of guidelines relevant to typical indoor exposures, as shown in Table 2.5.

Table 2.5. Indoor carbon monoxide guidelines.

Table 2.5

Indoor carbon monoxide guidelines.

The guidelines section was formulated and agreed by the working group meeting in November 2009.

Summary of main evidence and decision-making in guideline formulation

Critical outcome for guideline definition

Acute exposure-related reduction of exercise tolerance and increase in symptoms of ischaemic heart disease (e.g. ST-segment changes).

Source of exposure–effect evidence

Laboratory dose–effect experiments with human subjects with stable angina exposed to carbon monoxide (173–178). COHb elevated above 2% caused ST-segment changes and decreased time to angina. The CFK equation (3) was used to calculate exposure levels to which a normal adult under resting conditions can be exposed for various intervals without exceeding 2% COHb to calculate guideline levels.

Supporting evidence

–

Laboratory dose–effect exercise experiments in non-angina (normal) subjects (167–172).

–

Numerous epidemiological studies on effects of acute and chronic exposure to carbon monoxide, including studies on health effects when daily mean levels were in the range 0.6–10.9 mg/m3, provide sufficient evidence of a relationship between long-term exposure and cardiovascular morbidity (145–157).

Results of other reviews

–

Air quality guidelines for Europe, 2nd ed. Chapter 5.5, carbon monoxide. The guidelines were established for 15 minutes (100 mg/m3), for 1 hour (35 mg/ m3) and for 8 hours (10 mg/ m3) (41,42).

–

European Commission's INDEX project proposed guidelines: for 1 hour, 30 mg/m3; for 8 hours, 10 mg/m3(78).

Guidelines

15 minutes – 100 mg/m3.

1 hour – 35 mg/ m3.

8 hours – 10 mg/ m3.

24 hours – 7 mg/m3.

Comments

The addition of a guideline for 24 hours (7 mg/m3) to the WHO 2000 guidelines (41) to address the risk of long-term exposure.

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