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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
2
Carbon Monoxide1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The recommended exposure levels are applicable to the general population, including infants and children, and other individuals who may be sensitive or susceptible. The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could
1
This document was prepared by the AEGL Development Team composed of Peter Griem (Clariant, Sulzbach, Germany) and Chemical Managers George Rodgers and Iris Camacho (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including sensitive subpopulations, it is recognized that certain individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
Carbon monoxide (CO) is a tasteless, nonirritating, odorless, and colorless gaseous substance. The main source of CO production is the combustion of fuels. Exposure at the workplace occurs in blast-furnace operations in the steel industry and when gasoline- or propane-powered forklifts, chain-saws, or other machines are used in confined spaces, such as companies, tunnels and mines. Environmental exposure to CO can occur while traveling in motor vehicles (9-25 ppm and up to 35 ppm); visiting urban locations with heavily traveled roads (up to 50 ppm); or cooking and heating with domestic gas, kerosene, coal, or wood (up to 30 ppm); as well as in fires and by environmental tobacco smoke. Endogenous CO formation during normal metabolism leads to a background carboxyhemoglobin (COHb) concentration of about 0.5-0.8%. Smokers are exposed to considerable CO concentrations leading to a COHb of about 3-8%.
CO binds to hemoglobin, forming COHb, and thereby renders the hemoglobin molecule less able to bind oxygen. Because of this mechanism, the oxygen transport by the blood and the release of bound oxygen in the tissues are decreased. Tissue damage results from local hypoxia. Organs with a high oxygen requirement, such as the heart and the brain, are especially sensitive for this effect.
AEGL-1 values were not recommended because susceptible persons may experience more serious effects (equivalent to AEGL-2) at concentrations that do not yet cause AEGL-1 effects in the general population.
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Patients with coronary artery disease show health effects at lower COHb concentrations than children, pregnant women, or healthy adults and thus constitute the most susceptible subpopulation. For the derivation of AEGL-2 values, a level of 4% COHb was chosen. At this exposure level, patients with coronary artery disease may experience a reduced time until onset of angina (chest pain) during physical exertion (Allred et al. 1989a, 1991). In the available studies, the CO exposure alone (that is, with subjects at rest) did not cause angina, but exercise alone did so. However, because all studies used patients with stable exertional angina, who did not experience angina while at rest, the possibility cannot be ruled out that CO exposure alone could cause or increase angina symptoms in more susceptible individuals (a part of the patients with unstable angina pectoris might belong to this group). The changes in the electrocardiogram (ST-segment depression of 1 mm [corresponding to 0.1 mV] or greater) associated with angina symptoms were considered reversible, but they are indicative of clinically relevant myocardial ischemia requiring medical treatment. An exposure level of 4% COHb is unlikely to cause a significant increase in the frequency of exercise-induced arrhythmias. Ventricular arrhythmias have been observed at a COHb of 5.3% but not at 3.7% (Sheps et al. 1990, 1991); in another study, no effect of CO exposure on ventricular arrhythmia was found at 3% or 5% COHb (Dahms et al. 1993). This exposure level, which corresponds to COHb values of 5.0-5.6% in newborns and children, was considered protective of acute neurotoxic effects in children, such as syncopes, headache, nausea, dizziness, and dyspnea (Crocker and Walker 1985, Klasner et al. 1998), and long-lasting neurotoxic effects (defects in the cognitive development and behavioral alterations) in children (Klees et al. 1985). A mathematical model (Coburn et al. 1965; Peterson and Stewart 1975) was used to calculate exposure concentrations in air, resulting in a COHb of 4% in adults at the end of exposure periods of 10 and 30 min and 1, 4, and 8 h. A total uncertainty factor of 1 was used. A level of 4% COHb was the no-observed-effect level (NOEL) for AEGL-2 effects in patients with coronary artery disease, and the lowest-observed-effect level (LOEL) was estimated at 6-9%. In comparison, the LOEL was about 10-15% in children and 22-25% in pregnant women. Because AEGL-2 values were based on experimental data on the most susceptible subpopulation, they were considered protective for other subpopulations, and a total uncertainty factor of 1 was used.
It is acknowledged that apart from emergency situations, certain scenarios could result in CO concentrations that might cause serious effects in persons with cardiovascular diseases. These scenarios include extended exposure to traffic fume emissions (e.g., in tunnels or inside cars with defective car exhaust systems), charcoal or wood fire furnaces, and indoor air pollution from tobacco smoke.
The derivation of AEGL-3 values was based on a weight of evidence analysis of human lethal and nonlethal observations. Analysis of lethal cases reported by Nelson (2006a) indicated that most lethal poisoning cases occurred at COHb concentrations higher than 40% and that survival of CO-exposed hu-
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mans was likely to be seen at concentrations below 40%. Thus, a 40% COHb concentration seems to be a reasonable threshold for lethality.
This level is supported by experimental studies performed in healthy human subjects. Studies by Haldane (1895), Henderson et al. (1921), and Chiodi et al. (1941) suggest that a COHb of about 34-56% does not cause lethal effects in healthy individuals. Further support come from the studies by Stewart et al. (1970), Nielsen (1971) and Kizakevich et al. (2000), who reported headache as the only symptom when subjects were exposed to 20-33% COHb. A level of 40% COHb was used as the basis for AEGL-3 derivation. This point of departure is supported by studies reporting minimum lethal COHb concentrations in rats and mice of about 50-70% (Rose et al. 1970, E.I. du Pont de Nemours and Co. 1981). A mathematical model (Coburn et al. 1965; Peterson and Stewart 1975) was used to calculate exposure concentrations in air resulting in a COHb of 40% at the end of exposure periods of 10 and 30 min and 1, 4, and 8 h. A total uncertainty factor of 3 was used. A total uncertainty factor of 3 for intraspecies variability was considered adequate based on supporting evidence for susceptible subpopulations: (1) Exposure to the derived AEGL-3 concentrations will result in COHb values of about 14-17% in adults, which, based on case reports, were considered protective of heart patients against CO-induced myocardial infarction. It should be noted, however, that a clear threshold for this end point cannot be defined because myocardial infarction might be triggered at lower COHb in hypersusceptible individuals. (2) COHb concentrations of 14-17% were considered protective of the unborn against lethal effects because, in the case studies available, stillbirths were found only after measured maternal COHb concentrations were about 22-25% or higher (Caravati et al. 1988; Koren et al. 1991). Animal studies support that result. The AEGL values are listed in Table 2-1.
1.
INTRODUCTION
CO is a tasteless, odorless, and colorless gaseous substance (WHO 1999a). CO is produced by both natural and anthropogenic processes. The main source of CO production is the combustion of fuels. The burning of any carbonaceous fuel produces CO and carbon dioxide (CO2) as the primary products. The production of CO2 predominates when the air or oxygen supply is in excess of the stoichiometric needs for complete combustion. If burning occurs under fuel-rich conditions, with less air or oxygen than is needed, CO will be produced in abundance (WHO 1999a). Emission sources include gasoline- and diesel-powered motor vehicles, stationary combustion equipment, such as heating and power-generating plants; industrial processes, such as blast-furnace operation in the steel industry; indoor sources, such as gas ovens, unvented kerosene, and gas space heaters; and coal and wood stoves, as well as wildfires and tobacco smoking. Exposure at the workplace occurs in blast-furnace operations in the steel
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TABLE 2-1 Summary of AEGL Values for Carbon Monoxide
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (Nondisabling)
N.R.a
N.R.
N.R.
N.R.
N.R.
—
AEGL-2b (Disabling)
420 ppm (480 mg/m3)
150 ppm (170 mg/m3)
83 ppm (95 mg/m3)
33 ppm (38 mg/m3)
27 ppm (31 mg/m3)
Cardiac effects in humans with coronary artery disease (Allred et al. 1989a, 1991)
AEGL-3c (Lethal)
1700 ppm (1900 mg/m3)
600 ppm (690 mg/m3)
330 ppm (380 mg/m3)
150 ppm (170 mg/m3)
130 ppm (150 mg/m3)
Lethal poisoning was associated with a COHb ≥40% in most lethal poisoning cases reported by Nelson (2006a); no severe or life-threatening effects in healthy humans at a COHb of 34-56% (Haldane 1895; Henderson et al. 1921; Chiodi et al. 1941)
aN.R., not recommended because susceptible persons may experience more serious effects (equivalent to AEGL-2) at concentrations that do not yet cause AEGL-1 effects in the general population.
bIt was estimated that exposure to the AEGL-2 concentration–time combinations result in COHb concentrations of 5.3-5.6% in newborns, 4.9-5.2% in 5-year-old children, 4.0% in adults, and 6.2-11.5% in adult smokers.
cExposure to the AEGL-3 concentration–time combinations were estimated to result in COHb concentrations of 19.5-20.1% in newborns, 18.1-187% in 5-year-old children, 13.8-17.2% in adults, and 16.1-23.0% in adult smokers.
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industry and when gasoline- or propane-powered forklifts, chain-saws, or other machines are used in confined spaces, such as companies, tunnels, and mines. Low concentrations are produced in the atmosphere by the reactions of hydroxyl radicals with methane and other hydrocarbons as well as by the reactions of alkenes with ozone.
In addition to exogenous sources, humans are also exposed to small amounts of CO produced endogenously. In the process of natural degradation of hemoglobin to bile pigments, oxidation of the tetrapyrrol ring of heme leads to opening of the ring and formation of biliverdin and CO (WHO 1999a). The endogenous CO formation leads to a background COHb concentration in blood of about 0.5-0.8% (NIOSH 1972).
Increased destruction of red blood cells—for example, caused by hematomas, blood transfusion, or intravascular hemolysis—and accelerated breakdown of other heme proteins will lead to increased production of CO. In patients with hemolytic anemia, the CO production rate was 2-8 times higher and blood COHb was 2-3 times higher than in healthy individuals (Coburn et al. 1966).
Smokers are exposed to considerable CO concentrations leading to an average COHb of 4%, with a usual range of 3-8% (Radford and Drizd 1982).
Exposure to CO can also be caused indirectly by exposure to certain halomethanes, particularly dichloromethane (synonym, methylene chloride) because these solvents are at least partly metabolized oxidatively to CO by cytochrome P-450 (Gargas et al. 1986; see ATSDR 2000 for review).
Environmental exposure to CO can occur while traveling in motor vehicles, working, visiting urban locations associated with combustion sources, or cooking and heating with domestic gas, charcoal or wood fires, as well as by environmental tobacco smoke. WHO (1999a) summarized environmental concentrations as follows: CO concentrations in ambient air monitored from fixed-site stations are generally below 9 ppm (8 h average). However, short-term peak concentrations up to 50 ppm are reported on heavily traveled roads. The CO levels in homes are usually lower than 9 ppm; however, the peak value in homes could be up to 18 ppm with gas stoves, 30 ppm with wood combustion, and 7 ppm with kerosene heaters. The CO concentrations inside motor vehicles are generally 9-25 ppm and occasionally over 35 ppm. Similar exposure levels were reported by EPA (2000). The chemical and physical properties of CO are presented in Table 2-2.
2.
HUMAN TOXICITY DATA
On the basis of older literature, the COHb in the blood has been correlated with symptoms in healthy adults, shown in the left half of Table 2-3 (WHO 1999a). Very similar tables or descriptions are found in different publications (e.g., Stewart 1975; Winter and Miller 1976; Holmes 1985; Roos 1994; AIHA 1999). However, with respect to both lethal and nonlethal effects of CO, suscep-
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TABLE 2-2 Chemical and Physical Data for Carbon Monoxide
Parameter
Data
Reference
Synonyms
None
Chemical Name
Carbon monoxide
WHO 1999a
CAS Reg. No.
630-08-0
WHO 1999a
Chemical formula
CO
WHO 1999a
Molecular weight
28.01
WHO 1999a
Physical state
Gaseous
WHO 1999a
Color
Colorless
WHO 1999a
Odor
Odorless
WHO 1999a
Melting point
−199°C
WHO 1999a
Boiling point
−191.5°C
WHO 1999a
Density
1.250 g/L at 0°C
1.145 g/L at 25°C
WHO 1999a
Solubility
35.4 mL/L at 0°C
21.4 mL/L at 25°C
WHO 1999a
Explosive limits in air
12.5% (LEL) to 74.2% (UEL)
WHO 1999a
Conversion factors
1 ppm = 1.145 mg/m3
1 mg/m3 = 0.873 ppm
WHO 1999a
tible subpopulations have been identified, and effects on these are depicted in the right half of Table 2-3 for comparison (see subsequent sections for references). The unborn fetus and adults with coronary artery disease are considerably more susceptible for lethal effects of CO than healthy adults. For nonlethal effects of CO, subjects with coronary artery disease (increased frequency of arrhythmias and reduced time to onset of angina and to changes in the electrocardiogram) and children (syncopes and long-lasting neurotoxic effects) constitute susceptible subpopulations.
2.1.
Acute Lethality
Mortality from CO poisoning is high in England and Wales; 1,365 deaths due to CO exposure were reported in 1985. In the United States, more than 3,800 people annually die from accidental or intentional CO exposure (WHO 1999a).
Immediate death from CO is most likely caused by effects on the heart because the myocardial tissue is most sensitive to hypoxic effects of CO. Severe poisoning results in marked hypotension and lethal arrhythmias, which have been considered responsible for a large number of prehospital deaths. Rhythm disturbances include sinus tachycardia, atrial flutter and fibrillation, premature ventricular contractions, ventricular tachycardia, and fibrillation (WHO 1999a).
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TABLE 2-3 Symptoms Associated with COHb in Healthy Adult Humans and Susceptible Subpopulations
Healthy Adults
Susceptible Subpopulations
COHb (%)
Symptoms
COHb (%)
Symptoms
≈1
Physiologic background concentration
2
During physical exertion reduced time to onset of angina and electrocardiogram signs of myocardial ischemia in subjects with coronary artery disease
5-6
Increase in cardiac arrhythmias in subjects with coronary artery disease
3-8
Background concentration in smokers
7
Headache, nausea in children
10
No appreciable effect, except shortness of breath on vigorous exertion, possible tightness across the forehead, dilation of cutaneous blood vessels
13
Cognitive development deficits in children
15
Myocardial infarction in subjects with coronary artery disease
20
Shortness of breath on moderate exertion, occasional headache with throbbing in temples
25
Syncopes in children
25
Stillbirths
30
Decided headache, irritable, easily fatigued, judgment disturbed, possible dizziness, dimness of vision
40-50
Headache, confusion, collapse, fainting on exertion
60-70
Unconsciousness, intermittent convulsion, respiratory failure, death if exposure is long continued
80
Rapidly fatal
Source: Adapted from WHO 1999a.
The susceptible subpopulations for lethal effects are subjects with coronary artery disease and the unborn fetus (see Section 2.3). The review on death causes by Balraj (1984) shows an association between coronary artery disease and relatively low COHb concentrations. A number of case studies are presented in which CO exposure contributed to myocardial infarction (all cases of infarction are presented in this section irrespective of whether the patients were rescued from death by intensive medical care).
The British Standards Institution (BSI 1989) published the following concentration–time combinations as lethal exposures to CO (used for hazard estimation in fires): 40,000 ppm × 2 min, 16,000 ppm × 5 min, 8,000 ppm × 10 min, 3,000 ppm × 30 min and 1,500 ppm × 60 min. The International Standard Organization (ISO) published lethal exposure concentrations of 12,000-16,000
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ppm for 5 min and 2,500-4,000 ppm for 30 min (for an adult engaged in light activity) (ISO 1989). From the documents, it was concluded that the published values are for normal, healthy adults and that the values were based on animal data (especially monkeys; Purser and Berrill 1983); the documents did not discuss the issue of subpopulations at higher risk for lethal effects.
2.1.1.
Case Studies
Nelson (2006a) reported data on unvented space heaters related to human lethality and CO poisoning. Sixteen of 22 lethal cases had COHb concentrations more than 40%. Six of 22 cases had COHb concentrations of ≤40%, and two of six cases had pre-existing conditions, such as arteriosclerotic disease and cardiorespiratory failure. A 1942 fatality study reported by Nelson (2006a) summarized COHb data for 68 victims that were found dead in a gas-filled room or in a garage containing exhaust gases at high concentrations. CO concentrations were not provided. Sixty-seven percent of the 68 lethal cases had COHb concentrations of 40-88%. Three-percent of those cases had concentrations of 30-40%. A summary of another fatality study from Poland showed a similar trend of COHb concentrations (Nelson 2006a). Individual data were not provided, and the CO source was not discussed. However, the Polish study considered 321 lethal CO poisonings from 1975 to 1976 and provided COHb concentrations for 220 survivors and 101 fatal cases. The survivors had a mean COHb level of 28.1% (standard deviation [SD] = 14.1), whereas the lethal cases showed an average COHb level of 62.3% (SD = 10.1). Over 80% of the survivors had COHb levels below 40%. In contrast, about 90% of the deceased had COHb levels above 50%. Similar percentages of survivors and deceased were observed at COHb levels of 40-50%, with a slight increase in the number of survivors when compared with that of the deceased. These three studies showed a trend that most lethal cases occurred at COHb concentrations higher than 40% and that survivorship was likely to be seen at concentrations below 40%.
Another study from the Center of Forensic Sciences in Canada evaluated 304 fatal cases from 1965 to 1968 (Nelson 2006a). The mean lethal COHb level was 51 ± 12% with a majority range between 40% and 59% and the highest single frequency range at 45-59%. A report on CO exposure from exhaust fumes in the state of Maryland during 1966-1971 showed COHb levels in the 40-79% range for 98% of lethal cases (Nelson 2006a). The Institute of Forensic Medicine in Oslo reported a study of COHb levels in 54 automobile-exhaust victims. The mean fatal COHb level was 70%, and 40% was the minimum COHb level exhibited by less than 2% of the cases (Nelson 2006a). Another forensic study (Nelson et al. 2006) examining 2,241 fatalities from 1976 to 1985 found that the mean COHb level of all the cases was 64.20% with a SD of 17.47. The data showed that 34% of victims had COHb levels of less than 60%. Of those who died in fires, 41% had COHb levels of less than 60% compared with 22% of the nonfire deaths.
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Pach et al. (1978; 1979) reviewed cases of CO poisoning in the Toxicological Clinic, Cracow, Poland, in the years 1975-1976. Excluded from this study were mixed intoxications (e.g., by CO and medicaments). Group A comprised 101 persons (60 men and 41 women, mean age 48 ±15 years) who had died from CO poisoning before arrival at the clinic. Measurement of COHb and autopsy was done on these subjects. Group B comprised 220 subjects (95 men and 125 women, mean age 38 ±18 years) who were treated for CO poisoning. COHb was determined upon arrival at the clinic. Patients were excluded from further analysis if more than 120 min elapsed between the end of exposure and the blood drawing at the clinic (n = 62). For the patients, the COHb level was recalculated at the end of exposure. Mean COHb values for Groups A and B were 62% ± 10% and 28% ± 14%, respectively. In Group A, the percentages of subjects with COHb levels of 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90% were 2%, 6%, 26%, 44%, 21%, and 2%, respectively, and 3%, 25%, 32%, 24%, 12%, 3%, 0.6%, and 0.6% of the patients in the corrected Group B had COHb values of 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, and 70-80%, respectively. Within each group, no correlation between COHb and either sex, blood alcohol above 0.1%, or poisoning circumstances (accidental or suicidal) were found. Group A showed a higher percentage (34%) of subjects who were 60 years or older than Group B (13%); Group B had a higher percentage of subjects younger than 30.
Grace and Platt (1981) reported two cases of myocardial infarction due to CO poisoning. In the first case, a 67-year-old man was exposed to increased CO concentrations for about a few weeks in his home due to a rusted-out flue of a gas furnace. The man presented to the emergency room after 3 days of persistent light-headedness with vertigo, brief stabbing anterior chest pain that worsened with deep inspiration, a dry cough, chills, and a mild headache. His wife experienced similar malaise and dizziness that had been resolving over the past week. At the hospital, his symptoms were explained with a diagnosis of viral syndrome, hypokalemia of unclear origin, and diabetes mellitus with diabetic peripheral and autonomic neuropathy. Ten days after discharge he was seen in the emergency room with true vertigo, palpitations, and nausea but was sent home to be followed up as an outpatient. Four days later he returned to the emergency room after development of rectal urgency and an explosive incontinent diarrheal stool, followed by a severe crushing anterior chest pain. With the pain he collapsed on the floor. The electrocardiogram showed an acute myocardial infarction. His COHb (measured on arterial blood gases) was 15.6%; the level of the patient’s wife was 18.1%. The patient survived and recovered completely.
In the second case, a 69-year-old man came to the emergency room after awakening 2 days earlier with confusion, nausea, and vomiting. He then passed out and awoke the next day in the bathroom. He crawled to the living room, where he again passed out for an undetermined amount of time, awoke to open his door for fresh air, and then went to bed. He later experienced auditory and visual hallucinations and phoned his neighbor for help. An acute inferior myocardial infarction with secondary mild congestive heart failure and chronic ob-
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structive pulmonary disease was diagnosed. During his hospitalization, his sister and daughter-in-law spent a night in his mobile home. They arrived at the emergency room early the next morning with throbbing headaches, vomiting, and vertigo. Their COHb values were 28% and 32%. A faulty gas water heater had caused CO exposure. The patient survived and recovered completely.
Atkins and Baker (1985) described two fatal cases of workers with severe atherosclerotic coronary artery disease. The first worker (age not stated) was a shipping employee in a plant that reconditioned steel dyes. A gas-fired furnace was used for tempering the dyes but also for heating the plant. One day the worker was found unconscious, and resuscitation efforts at a nearby hospital were unsuccessful. Autopsy showed a severe two-vessel coronary artery disease and old scarring and a COHb of 30%. Four other workers of the plant complaining of nausea were seen in the emergency room, but COHb was not obtained. The second worker (age not stated) was operating a bale press in a used-clothing company. As well as gas- and oil-fired heaters, there were a number of propane-fueled forklifts used to transport bales of clothing, and ventilation was poor. Resuscitation was unsuccessful after his collapse. Autopsy revealed three-vessel coronary artery disease and global subendocardial ischemia. Two blood samples showed COHb of 24.1% and 21.5%. Five other workers from the same company were also seen, complaining of light nausea, lightheadedness, and headache. One was hospitalized with a COHb of 35%; the others had levels from 4.1% to 12.8%. CO measurement was performed in the company the next day and revealed concentrations of 135-310 ppm. Concentrations were highest near fork-lifts (250-310 ppm) and near the bale press (120-230 ppm), which was where the patient had been working at the time of his death.
Ebisuno et al. (1986) reported a case of myocardial infarction after acute CO poisoning in a healthy young man. A 28-year-old male ironworker was admitted to the emergency room complaining of precordial pain. Two hours before admission the patient had been exposed accidentally to CO for about 1 h while working at a blast furnace. After the exposure he experienced a sense of fullness of the head and precordial pain following transient unconsciousness. Blood samples 2 h after the exposure contained COHb of 21%. The electrocardiogram was interpreted as an acute anterior myocardial infarction. The coronary arteriogram 1 month after onset of infarction showed no significant narrowing on both left and right coronary arteries. The left ventriculogram showed a giant aneurysm in the apical portion. During ventricular aneurysmectomy, a massive transmural myocardial necrosis was observed. After surgical treatment, the patient was free of symptoms.
Marius-Nunez (1990) reported the case of a 46-year-old man who suffered an acute myocardial infarction after CO exposure. He was found unconscious in a doorway of a burning apartment. Artificial respiration was initiated until arrival at the emergency room. The electrocardiogram showed sings of myocardial infarction, which was confirmed by high levels of cardiac enzymes in the patient’s serum. Blood gas analysis revealed a COHb concentration of 52.2%.
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APPENDIX B
Mathematical Model for Calculating COHb and Exposure Concentrations
Studies describing model: Coburn et al. (1965); Peterson and Stewart (1975)
Model: For the calculation of concentration-time combinations that result in a certain COHb, the model of Coburn, Forster, and Kane (CFK model) (see Section 4.4.4) was used.
Since this model in the formulation of Peterson and Stewart (1975) calculates COHb larger than 100% at high-exposure concentrations, the following correction proposed by Peterson and Stewart (1975) was used: the amount of bound oxygen is actually not constant but is dependent on the COHb; therefore,
Because, in this case, the CFK equation can only be solved iteratively, calculations were done using time steps (Δt) of 1 min for the period of 0-10 min, steps of 5 min between 10 and 60 min, steps of 15 min between 60 and 240 min, and steps of 20 min between 240 and 480 min. In each step, the COHb of the step before was used to calculate Ohbt. For the first step, a background COHb of 0.75% was assumed.
The alveolar ventilation rate was calculated as
VA = VE − fVD (Peterson and Stewart 1975) with
VE = total rate of ventilation (mL/min),
f = respiration rate (min−1), and
VD = dead space (mL).
Derivations were done for a 70-kg man, assuming a blood volume of 5,500 mL (Coburn et al. 1965) and a daily inhalation volume (VE) of 23 m3 (8 h resting and 16 h light/nonoccupational activity; WHO 1999b), a respiration rate (f) of 18 min−1 and a dead space (VD) of 2.2 mL/kg (Numa and Newth 1996). Calculations using the following equation were carried out in a spreadsheet computer program:
where
COHbt = mL of CO per mL blood at time t (min)
Conversion: % COHb = COHb 100/Ohbmax
VCO = rate of endogenous CO production, VCO = 0.007 mL/min
Vb = blood volume, Vb (70-kg man) = 5,500 mL, Vb (5-yr child, 20 kg) = 1,500 mL
Vb (newborn, 3.5 kg) = 400 mL
M = ratio of affinity of blood for CO to that for O2, M = 218 (newborn: M = 240)
B = 1/DL + PL/VA with DL = diffusivity of the lung for CO, DL = 30 mL/min mm Hg
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PL = barometric pressure minus the vapor pressure of water at body temperature
PL = 713 mm Hg
VA = alveolar ventilation rate, VA (70-kg man) = 23 m3/d * 1 • 106 mL/m3 * 1/1,440 min/d − 18/min * 2.2 mL/kg * 70 kg, VA (70-kg man) = 13,200 mL/min
VA (5-y child) = 3,580 mL/min, VA (newborn) = 1,250 mL/min
Ohbmax = mL of O2 per mL blood under normal conditions, Ohb = 0.2
PO2 = average partial pressure of oxygen in the lung capillaries, PO2 = 100 mm Hg
PCO = partial pressure of CO in the air inhaled (mm Hg)
Conversion: PCO (mm Hg) = PCO (ppm)/1,316
t = exposure duration (min)
Calculations: For the derivation of AEGL-2 values, exposure concentrations were calculated that would result in a COHb of 4%. A representation of the spreadsheet for the 60-min AEGL-2 is shown in Figure B-1. Results are shown in Table B-1.
For children, newborns, and adult smokers, the end-of-exposure COHb values for exposure to the concentrations calculated in Table B-1 were computed using the CFK model in Table B-2.
TABLE B-1 Concentration–Time Combinations Resulting in 4% COHb
Exposure Time (min)
For a 70-kg Adult Man
Exposure Concentration (ppm)
Exposure Concentration (ppm), Rounded
10
424
420
30
150
150
60
83
83
240
33
33
480
27
27
TABLE B-2 COHb Values for AEGL-2 Concentration–Time Combinations in Different Subpopulations
Exposure Time (min)
Exposure Concentration (ppm)
5-y-old Child
Newborn
Healthy Adult
Adult Smoker (3% COHb)
Adult Smoker (8% COHb)
10
420
5.2
5.5
4.0
6.2
11.2
30
150
5.2
5.6
4.0
6.3
11.3
60
83
5.2
5.6
4.0
6.4
11.4
240
33
5.0
5.4
4.0
6.6
11.5
480
27
4.9
5.3
4.0
6.7
11.5
For the derivation of AEGL-3 values, exposure concentrations were calculated that would result in a COHb of 40%. A representation of the spreadsheet for the 60-min value is shown in Figure B-2. Results are shown in Table B-3.
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FIGURE B-1 COHb vs. exposure time plots. Data are shown for CO exposure concentrations indicated (70-kg man).
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FIGURE B-2 Calculation of 60-min exposure concentration that would result in 40% COHb in a healthy adult.
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TABLE B-3 Concentration–Time Combinations Resulting in 40% COHb
Exposure Time (min)
Concentration for a 70-kg Adult Man
Exposure Concentration (ppm)
Exposure Concentration (ppm), Rounded
10
5,120
5,100
30
1,810
1,800
60
998
1,000
240
439
440
480
403
400
For children, newborns, healthy nonsmoking adults, and smokers, the end-of-exposure COHb values for exposure to the AEGL-3 exposure concentration–time combinations were computed using the CFK model. For all subpopulations, the endogenous CO production rate was adjusted so that the starting level of 0.75% for children and newborn and 3% and 8% for smokers were constant without additional CO exposure (Table B-4).
The following end-of-exposure COHb values were calculated for the series of experiments reported by Haldane (1895) (Table B-5). Since exposure occurred while the subject was sitting on a chair, a ventilation rate of 7.5 L/min was used for the calculation (WHO 1999b). The alveolar ventilation rate was calculated as
VA (70-kg man) = 3,600 L/8 h * 1 • 103 mL/L* 1/480 min/8 h − 18/min *
2.2 mL/kg * 70 kg
VA (70-kg man) = 4,700 mL/min
TABLE B-4 COHb Values for AEGL-3 Concentration–Time Combinations in Different Subpopulations
Exposure Time (min)
Exposure Concentration (ppm)
5-yr Child
Newborn
Healthy Adult
Smoker (3% COHb)
Smoker (8% COHb)
10
1,700
18.7
19.9
13.8
16.1
21.1
30
600
18.5
19.8
14.0
16.2
21.1
60
330
18.3
19.6
14.1
16.4
21.2
240
150
18.6
20.1
16.4
18.6
22.7
480
130
18.1
19.5
17.2
19.2
23.0
TABLE B-5 Comparison of Reported and Calculated COHb Values for the Data by Haldane (1895)
Experiment Number
Concentration (ppm)
Time (min)
COHb Measured (%)
COHb Calculated (%)
1
5,000
11.5
Not done
22
2
3,900
30.5
39
43
3
4,000
24
27
35
4
3,600
29
37
38
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
Experiment Number
Concentration (ppm)
Time (min)
COHb Measured (%) COHb
Calculated (%)
5
4,100
29
35
43
6
1,200
120
37
46
7
2,100
71
49
50
8
Irregular
35
56
—
9
270
210
14
17
10
210
240
13
15
11
460
240
23
30
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
APPENDIX C
ACUTE EXPOSURE GUIDELINE LEVELS FOR CARBON MONOXIDE
Derivation Summary for Carbon Monoxide
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
N.R.a
N.R.
N.R.
N.R.
N.R.
aN.R., not recommended because susceptible persons may experience more serious effects (equivalent to AEGL-2) at concentrations that do not yet cause AEGL-1 effects in the general population.
Reference: Not applicable.
Test Species/Strain/Number: Not applicable/not applicable/not applicable.
Exposure Route/Concentrations/Durations: Not applicable/not applicable/not applicable.
Effects: Not applicable.
End Point/Concentration/Rationale: CO is the classical example of a tasteless, nonirritating, odorless and colorless toxic gas. Until very severe symptoms occur (inability to walk) none or only nonspecific symptoms were noted in monkeys and healthy humans (Haldane 1895; Purser and Berrill 1983). In patients with coronary artery disease, which constitutes the most susceptible subpopulation, effects, such as significant electrocardiogram changes, reduced time to the onset and increased cardiac arrhythmia, start occurring at exposure concentrations little higher than current ambient air quality guidelines, e.g., the U.S. national air quality guideline of 9 ppm for 8 h (National Air Pollution Control Administration 1970; 65 Fed. Regist. 50201[2000]; EPA 2000), the WHO air quality guideline of 10 mg/m3 (9 ppm) for 8 h (based on 2.5% COHb) (WHO 1999a) and the designated European Union limit value of 10 mg/m3 (9 ppm) for 8 h (EC 1999). These effects were considered above the AEGL-1 effect level and thus would not constitute a suitable basis for the derivation of AEGL-1 values. AEGL-1 values were not recommended because susceptible persons may experience more serious effects (equivalent to AEGL-2) at concentrations, which do not yet cause AEGL-1 effects in the general population. In addition, CO exposures encountered frequently in everyday life are at or above the concentration range, in which AEGL-1 would have to be set: smokers have COHb in the range of 3-8% (Radford and Drizd 1982) and CO concentrations between about 10 and 50 ppm, which can be found on heavily traveled roads, inside motor vehicles and in homes with gas-, coal-, wood- or kerosene-fired heaters and stoves, correspond to an equilibrium COHb of 1.8-7.5% (see Figures 2-2 and B-1).
Uncertainty Factors/Rationale: Not applicable.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
Time Scaling: Not applicable.
Data Adequacy: Not applicable.
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AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
420 ppm
150 ppm
83 ppm
33 ppm
27 ppm
References: Allred, E.N., E.R. Bleecker, B.R. Chaitman, T.E. Dahms, S.O. Gottlieb, J.D. Hackney, M. Pagano, R.H. Selvester, S.M. Walden, and J. Warren. 1989a. Short-term effects of carbon monoxide exposure on the exercise performance of subjects with coronary artery disease. N. Engl. J. Med. 321(21):1426-1432; Allred, E.N., E.R. Bleecker, B.R. Chaitman, T.E. Dahms, S.O. Gottlieb, J.D. Hackney, D. Hayes, M. Pagano, R.H. Selvester S.M. Walden, and J. Warren. 1989b. Acute Effects of Carbon Monoxide Exposure on Individuals with Coronary Artery Disease. Research Report No. 25. Health Effects Institute, Cambridge, MA.; Allred, E.N., E.R. Bleecker, B.R. Chaitman, T.E. Dahms, S.O. Gottlieb, J.D. Hackney, M. Pagano, R.H. Selvester, S.M. Walden, and J. Warren. 1991. Effects of carbon monoxide on myocardial ischemia. Environ. Health Perspect. 91:89-132.
Test Species/Strain/Sex/Number: Humans with coronary artery disease/not applicable/male/63.
Exposure Route/Concentrations/Durations: Inhalation/mean concentrations of 0, 117 or 253 ppm for 50-70 min were used, adjusted individually to reach COHb concentrations of 2.2% or 4.4% at the end of exposure (about 2 or 4% COHb in the subsequent exercise tests).
Effects:
When potential exacerbation of the exercise-induced ischemia by exposure to CO was tested using the objective measure of time to 1-mm ST-segment change in the electrocardiogram, exposure to CO levels producing COHb of 2% resulted in a overall statistically significant 5.1% decrease in the time to attain this level of ischemia. For individual centers (patients were tested in one of three centers), results were significant in one, borderline significant in one and nonsignificant in one center. At 4% COHb, the decrease in time to the ST criterion was 12.1% (statistically significant for all patients, the effect was found in 49/62 subjects) relative to the air-day results. Significant effects were found in all three test centers. The maximal amplitude of the ST-segment change was also significantly affected by the CO exposures: at 2% COHb the maximal increase was 11% and at 4% COHb the increase was 17% relative to the air day.
At 2% COHb, the time to exercise-induced angina was reduced by 4.2% in all patients (effects were significant in two test centers and nonsignificant in one center). At 4% COHb, the time was reduced by 7.1% in all patients (effects were significant in one, borderline significant in one and nonsignificant in one center). The two end-points (time to angina and time to ST change) were also significantly correlated. Only at 4% COHb a significant reduction in the total exercise time and in the heart rate-blood pressure product was found (this double product provides a clinical index of the work of the heart and myocardial oxygen consumption).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
420 ppm
150 ppm
83 ppm
33 ppm
27 ppm
End Point/Concentration/Rationale:
Patients with coronary artery disease show health effects at lower COHb levels than children, pregnant women or healthy adults and, thus, constitute the most susceptible subpopulation. For the derivation of AEGL-2 values a level of 4% COHb was chosen. At this exposure level, patients with coronary artery disease may experience a reduced time until onset of angina (chest pain) during physical exertion (Allred et al. 1989a,b; 1991). In the available studies, the CO exposure alone (that is, with subjects at rest) did not cause angina, while exercise alone did so. However, it should be noted that all studies used patients with stable exertional angina, who did not experience angina while at rest. Thus, it cannot be ruled out that in more susceptible individuals (a part of the patients with unstable angina pectoris might belong to this group) CO exposure alone could increase angina symptoms. The changes in the electrocardiogram (ST-segment depression of 1 mm or greater) associated with angina symptoms were considered reversible, but is indicative of clinically relevant myocardial ischemia requiring medical treatment. An exposure level of 4% COHb is unlikely to cause a significant increase in the frequency of exercise-induced arrhythmias. Ventricular arrhythmias have been observed at COHb of 5.3%, but not at 3.7% (Sheps et al. 1990; 1991), while in another study no effect of CO exposure on ventricular arrhythmia was found at 3 or 5% COHb (Dahms et al. 1993). An exposure level of 4% COHb was considered protective of acute neurotoxic effects in children, such as syncopes, headache, nausea, dizziness and dyspnea (Crocker and Walker 1985; Klasner et al. 1998), and long-lasting neurotoxic effects (defects in the cognitive development and behavioral alterations) in children (Klees et al. 1985).
It is acknowledged that apart from emergency situations, certain scenarios could lead to CO concentrations which may cause serious effects in persons with cardiovascular diseases. These scenarios include extended exposure to traffic fume emissions (e.g., in tunnels or inside cars with defect car exhaust systems), charcoal or wood-fire furnaces, and indoor air pollution by tobacco smoking.
Uncertainty Factors/Rationale:
Total uncertainty factor: 1
Interspecies: Not applicable.
Intraspecies: 1
A level of 4% COHb was the NOEL for AEGL-2 effects in patients with coronary artery disease, while the LOEL was estimated at 6-9%. In comparison, the LOEL was about 10-15% in children and 22-25% in pregnant women. Since AEGL-2 values were based on experimental data on the most susceptible subpopulation, they were considered protective also for other subpopulations and a total uncertainty factor of 1 was used.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
420 ppm
150 ppm
83 ppm
33 ppm
27 ppm
Time Scaling: A mathematical model (Coburn et al. 1965; Peterson and Stewart 1975) was used to calculate exposure concentrations in air resulting in a COHb of 4% at the end of exposure periods of 10 and 30 min and 1, 4 and 8 h.
Data Adequacy: AEGL-2 values were based on cardiac effects in subjects with coronary artery disease, which constitute the most susceptible subpopulation. Several high quality studies are available addressing end points such as time to the onset of exercise-induced angina, time to the onset of exercise-induced 1-mm ST-segment changes in the electrocardiogram and frequency of exercise-induced arrhythmias. However, no experimental studies in heart patients are available that used significantly higher levels of COHb than about 5% COHb.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
1,700 ppm
600 ppm
330 ppm
150 ppm
130 ppm
Key Reference: Haldane, J. 1895. The action of carbonic acid on man. J. Physiol. 18:430-462; Henderson, Y., H.W. Haggard, M.C. Teague, A.L. Prince, and R.M. Wunderlich. 1921. Physiological effects of automobile exhaust gas and standards of ventilation for brief exposures. J. Ind. Hyg. 3(3):79-92; Chiodi, H., D.B. Dill, F. Consolazio, and S.M. Horvath. 1941. Respiratory and circulatory responses to acute carbon monoxide poisoning. Am. J. Physiol. 134:683-693; Nelson, G. 2006a. Effects of carbon monoxide in man. Pp. 3-62 in Carbon Monoxide and Human Lethality: Fire and Non-fire Studies, M.M. Hirschler, ed. New York: Taylor and Francis.
Test Species/Strain/Sex/Number: Nelson (2006a): Humans/not applicable/both sexes/~3,010 subjects (Haldane 1895; Henderson et al. 1921; Chiodi et al. 1941: Humans (healthy young males)/not applicable/males/4 (total)
Exposure Route/Concentrations/Durations: Inhalation/Nelson (2006a) reported COHb levels in deceased subjects poisoned by inhalaling CO; Chiodi et al. (1941): repeated test on three subjects that reached COHb of 27-52% at the end of exposure; individual COHb values were 31, 32, 32, 33, 39, 41, 42, 43, 45 and 52% in subject H.C., 27, 35, 41, 43 and 48% in subject F.C. and 41, 42 and 44% in subject S.H.; Haldane (1895): repeated exposure of one subject reaching the following COHb at the end of exposure (time in min): 13% (240 min), 14% (210 min), 23% (240 min), 27% (24 min), 35% (29 min), 37% (29 min), 37% (120 min), 39% (30.5 min), 49% (71 min), 56% (35 min).
Effects: At a COHb of about 40-56%, Haldane (1895) described symptoms included hyperpnea, confusion of mind, dim vision and unsteady/inability to walk. Chiodi et al. (1941) found no effect on oxygen consumption, ventilation, pulse rate, blood pressure and blood pH; the cardiac output increased 20-50% at COHb >40%, while the changes were negligible at COHb of <30%. Nelson (2006a) reported COHb measurements in lethal poisoning human cases and the data indicated that most lethal poisoning cases occurred at COHb levels higher than 40% and that survival of CO-exposed humans were likely to be seen at levels below 40%.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
1,700 ppm
600 ppm
330 ppm
150 ppm
130 ppm
End Point/Concentration/Rationale: The derivation of AEGL-3 values was based on observations in humans. Analysis of lethal cases reported by Nelson (2006a) indicated that most lethal poisoning cases occurred at COHb levels higher than 40% and that survival of CO-exposed humans were likely to be seen at levels below 40%. Thus, 40%COHb level seems a reasonable threshold for lethality. This level is supported by experimental studies suggest that a COHb of about 34-56% does not cause lethal effects in healthy individuals. Further support come from the studies by Kizakevich et al. (2000), Stewart et al. (1970), and Nielsen (1971) that reported headache as the only symptom when subjects were exposed to 20-33% COHb. The point of departure of 40% COHb is also supported by studies in animals reporting minimum lethal COHb levels in rats and mice of about 50-70% (E.I. du Pont de Nemours and Co., 1981; Rose et al., 1970). Further support comes from published cases of myocardial infarction that measured COHb levels after transport to the hospital: 52.2% (Marius-Nunez 1990), 30%, 22.8% (Atkins and Baker 1985), 21% (Ebisuno et al., 1986), 15.6% (Grace and Platt 1981).
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applicable.
Intraspecies: 3
An intraspecies uncertainty factor of 3 was supported by information on effects, such as myocardial infarction and stillbirths, reported in more susceptible subpopulations.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
Time Scaling: A mathematical model (Coburn et al. 1965; Peterson and Stewart 1975) was used to calculate exposure concentrations in air resulting in a COHb of 40% at the end of exposure periods of 10 and 30 min and 1, 4 and 8 h.
Data Adequacy: AEGL-3 values were based on 40% COHb levels derived from the analysis of clinical cases of lethal and nonlethal poisoning. The AEGL-3 values derived using an intraspecies uncertainty factor of 3 (corresponding to an COHb of about 15%) are supported by the available case reports of lethal effects (myocardial infarction, stillbirths) in more susceptible subpopulations. Lethal effects from myocardial infarction in hypersusceptible patients with coronary artery disease at even lower CO concentrations, which could be at the upper end of the range of CO concentrations found inside buildings and in ambient air outside, cannot be excluded.