B3 Carbon Monoxide

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations Research Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Carbon monoxide is a colorless and odorless gas (NRC, 1985).

Formula:

CO

CAS number:

630-08-0

Molecular weight:

28.0

Boiling point:

−192°C

Melting point:

−250°C

Conversion factors at 25°C, 1 atm:

1 ppm = 1.14 mg/m3

1 mg/m3 = 0.87 ppm

OCCURRENCE AND USE

Carbon monoxide (CO) is produced inside the body via hemoglobin metabolism at a rate of 0.4 mL/h resulting in a carboxyhemoglobin (COHb) level of about 0.4% (Coburn et al., 1965). Other than an endogenous source, CO can also be produced in the thermodegradation of materials containing carbon in an atmosphere containing oxygen, so gas stoves and furnaces can be sources of CO indoors. A COHb level of 0.6-1.0% has been reported in nonsmokers in an indoor environment (Radford et al., 1981).

Automobile exhaust is a major source of CO in the environment. The urban atmospheric levels of CO vary with the traffic patterns (Rylander



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants B3 Carbon Monoxide King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Carbon monoxide is a colorless and odorless gas (NRC, 1985). Formula: CO CAS number: 630-08-0 Molecular weight: 28.0 Boiling point: −192°C Melting point: −250°C Conversion factors at 25°C, 1 atm: 1 ppm = 1.14 mg/m3 1 mg/m3 = 0.87 ppm OCCURRENCE AND USE Carbon monoxide (CO) is produced inside the body via hemoglobin metabolism at a rate of 0.4 mL/h resulting in a carboxyhemoglobin (COHb) level of about 0.4% (Coburn et al., 1965). Other than an endogenous source, CO can also be produced in the thermodegradation of materials containing carbon in an atmosphere containing oxygen, so gas stoves and furnaces can be sources of CO indoors. A COHb level of 0.6-1.0% has been reported in nonsmokers in an indoor environment (Radford et al., 1981). Automobile exhaust is a major source of CO in the environment. The urban atmospheric levels of CO vary with the traffic patterns (Rylander

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants and Vesterlund, 1981). On expressways in major metropolitan areas, atmospheric CO levels commonly reach 25 ppm (Stewart, 1975). A second common source of CO is cigarette smoke. Most smokers who smoke a pack a day have a COHb level of 5-6% (Stewart, 1975). There is no known use of CO in spacecraft, but CO has been predicted to be an offgas product in spacecraft (Leban and Wagner, 1989). PHARMACOKINETICS CO is absorbed rapidly in the lung at a rate of about 25.8 mL/min × mm Hg (Jones et al., 1982). The minute volume, partial pressure of oxygen in the pulmonary capillary, and hemoglobin concentration are some of the major factors affecting CO absorption (EPA, 1985). More than 99% of CO in the body is eliminated unchanged via the lung and less than 1% is oxidized to carbon dioxide (Stewart, 1975). CO 's elimination half-life is 4-5 h in resting subjects when breathing ambient air and 24 min when breathing hyperbaric oxygen. TOXICITY SUMMARY CO exerts its toxicity by binding reversibly to the heme group in hemoglobin-forming COHb (Laties and Merigan, 1979). Because the affinity of hemoglobin for CO is 200 times that for oxygen, less oxygen will be carried by hemoglobin to tissues during CO inhalation. The hypoxia is exacerbated by the inhibition of CO on the dissociation of oxygen from hemoglobin as the blood reaches the tissue (Laties and Merigan, 1979). As a result, the main toxicity targets for CO are the brain and heart, two organs with a critical need for oxygen. COHb is cherry-red (Klaassen, 1990). Cherry-red skin has traditionally been regarded as one of the classical signs of CO poisoning, but some modern literature indicates that cherry-red skin might not be evident even in fatal CO intoxication (Findlay, 1988). Acute Toxicity This subsection summarizes the toxicity of CO after an exposure ranging

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants from several minutes to 8 h. CO's toxicity is generally believed to correlate with the COHb level (Stewart, 1975). Because an exposure to CO at a given concentration for a few hours will yield a COHb level similar to an exposure at a higher concentration for a shorter time (Peterson and Stewart, 1975), to simplify the picture, toxic effects are described based on the COHb level achieved. A COHb level of 70% is lethal, and 50-60% leads to coma and convulsions. Headache, nausea, and vomiting are the most common symptoms of gross intoxication, and they are produced at 15-40% COHb (DiMarco, 1988; Stewart et al., 1970). Myonecrosis has been reported to develop in a case of acute CO poisoning with a COHb level of 16% in the emergency room (Herman et al., 1988). CO, however, is known to produce toxicity at even lower levels. In humans, CO, at a COHb level of 7%, gives a feeling of having to exert more during heavy exercise (Bunnell and Horvath, 1989) and, at 7.5% COHb, it causes a 23% reduction in the duration an individual can exercise maximally (Ekblom and Huot, 1972). At 3.4% or 4% COHb (Horvath et al., 1975; Aronow and Cassidy, 1975), it reduces the maximal-exercise duration by only 5%. A higher heart rate during exercise was detected at 7% or 5% COHb (Bunnell and Horvath, 1989; Gliner et al., 1975), but 2.7% or 3.4% COHb was found not to affect the heart rate during exercise (Horvath et al., 1975; Raven et al., 1974). CO decreases the maximal oxygen uptake during exercise at 20% COHb (Vogel et al., 1972), whereas 5% or 2.7% COHb has no such effect (Gliner et al., 1975; Raven et al., 1974). CO inhalations could affect the heart. An acute CO exposure reduces the ventricular fibrillation threshold in dogs at 6.5 % COHb (Aronow et al., 1979a) and monkeys at 9.3% COHb (DeBias et al., 1976). A COHb level of 6% increases the frequency of ventricular premature depolarization in patients with coronary artery diseases (Sheps et al., 1990). There are contradictory reports on the neurological effects of low-level CO exposures in humans (Laties and Merigan, 1979). CO has been shown to impair vigilance in human subjects at a COHb level of 2, 5, or 6.6% (Beard and Grandstaff, 1975; Putz et al., 1979; Horvath, 1971), but no such impairment was detected at 2.3, 4.8, 7.1, 7.5, 8.2, or 12.6% COHb (Beard and Grandstaff, 1975; Christensen et al., 1977; Davies et al., 1981; Benignus et al., 1987; Benignus and Otto, 1977). Similarly, reaction time is known to be increased in humans by 5, 8.5, 10, or 12% COHb (Putz et al., 1979; Ramsey, 1972, 1973; Ray and Rockwell, 1970), whereas no

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants increase has been detected at 3.9, 7.5, 9, or 12% COHb (Stewart et al., 1970; Beard and Grandstaff, 1975; Aronow et al., 1979b; Luria and McKay, 1979). Studies have shown that CO impairs hand-eye coordination at 5 or 8.2% COHb (Putz et al., 1979; Benignus et al., 1987). On the other hand, 6.6 or 10.4% COHb had no effect on hand-eye coordination in some studies (Mikulka, 1970; O'Donnell et al., 1971). A COHb level of 4.5% has been shown to decrease the light-detection sensitivity in humans (Halperin et al., 1959), but 5, 8.5, 12, or 17% COHb did not affect the light detection sensitivity (Ramsey, 1972, 1973; Hudnell and Benignus, 1989). Finally, 6% COHb was shown in one study not to affect the driving ability (McFarland, 1973), but 5.6, 10, or 11% COHb was found to impair the driving ability in others (Ray and Rockwell, 1970; Wright et al., 1973; McFarland, 1973). There are many neurological functions not affected by low-level CO exposures in human subjects. CO has no effect on visual task performance at 3% COHb (Putz et al., 1976), visual acuity at 17% COHb (Hudnell and Benignus, 1989), night vision at 9% COHb (Luria and McKay, 1979), time perception at 3.9-18% COHb (Stewart et al., 1970; Aronow et al., 1979b; Mikulka, 1970; O'Donnell et al., 1971; Stewart et al., 1973), perceptual speed at 3.9% COHb (Aronow et al., 1979b), depth perception at 5-12% COHb (Ramsey, 1972; Ramsey, 1973), number facility at 3.9 or 7.5% COHb (Beard and Grandstaff, 1975; Aronow et al., 1979b), mental performance at 7-10% COHb (Bender et al., 1972; Ettema and Zielhuis, 1975), short-term memory at 7.5% COHb (Beard and Grandstaff, 1975), and manual dexterity at 5-12% COHb (Stewart et al., 1970; Mihevic et al., 1983). CO can produce latent effects on the nervous system. About 10% of the patients who have apparently recovered from a severe episode of acute CO poisoning might develop neurological sequelae in days or weeks (Smith and Brandon, 1973; Thom and Keim, 1989). In rats, the sciatic nerve conduction velocity is reduced 4 w after an acute CO intoxication in which the COHb level of 19% was reached (Pankow et al., 1975). CO is known to affect oxidative drug metabolism. It inhibits the cytochrome P-450 system in vitro (Estabrook et al., 1970). In rats, 60 ppm of CO reduces the hepatic benzopyrene hydroxylase activity, and an exposure yielding 20% COHb prolongs the hexobarbital sleeping time (Rondia, 1970; Montgomery and Rubin, 1971). COHb at 10-12% has been shown

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants to inhibit the metabolism of hemoglobin-haptoglobin in dogs, which could be explained by CO's inhibitory effect on the cytochrome P-450 and its ability to decrease the hepatic blood flow (Coburn and Kane, 1968). The acute toxic effects of CO are summarized in the following table. TABLE 3-1 Acute Toxic Effects of CO Acute Toxic Effects COHb, % 5% reduction in exercise duration 3.4-4.0 Reaction time increases and hand-eye impairment 5 Reduction in ventricular fibrillation threshold in dogs 6.5 Headache, nausea, and vomiting 15-40 Decreases in maximal O2 uptake 20 Convulsions and coma 50-60 Death 70 Adaptation Adaptation to some of the acute effects of CO can develop after repeated CO exposures. A daily 6-h exposure to CO at 230-400 ppm CO for 16 d reduced the severity of headache in humans (Killick, 1936, 1948). After the repeated CO exposures, the buildup rate of COHb during a subsequent acute CO exposure is lowered. The mechanism of this lower buildup rate of COHb is unknown because the repeated CO exposures did not change the hematocrit and blood volume in these human subjects. A lower buildup rate of COHb was also seen in dogs after daily 6-h exposures to CO at 800-1000 ppm for 133 d (Wilks et al., 1959). The lower buildup rate of COHb in this study was probably due to increased hematocrit and hemoglobin concentrations in the blood produced by the repeated CO exposures in these dogs. Even though the repeated CO exposure reduced the buildup rate of COHb during an acute CO challenge, the final COHb level achieved during the acute challenge was not affected by the repeated exposure. There is also evidence of adaptation to the depression effects of CO on the central nervous system (CNS). An acute exposure to CO at 111 ppm (6.6-6.9% COHb) impaired the vigilance of nonsmokers, but not of smokers (O'Hanlon, 1975). CO exposure at 700 ppm decreased the lever-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants pressing response of rats to get food pellets (Ator and Merigan, 1980). However, preconditioning with four daily 75-min exposures to 700 ppm of CO abolished this effect of CO. A 7-d exposure to CO at 4000 ppm for 10-15 min/d increased the time it takes for CO at 4000 ppm to cause coma by 50% in rats and mice (Gorbatow and Noro, 1948). A continuous exposure to CO at 300-2400 ppm for 6 w in mice has been shown to reduce the CNS depression effect of CO (Killick, 1937). In the last two studies, the adaptation could be due to increases in hematocrit and hemoglobin concentrations produced by the repeated or continuous CO exposure. Subchronic and Chronic Toxicity This subsection summarizes the toxicity produced by CO exposures lasting for 7 d or longer. In contrast to the abundance of studies on the acute neurological effects of CO, there are no reports on its neurological effects after an exposure lasting 7 d or more. Stewart et al. (1970), however, reported that a 24-h exposure to 50-ppm CO (yielding 8% COHb) had no effect on response time, time perception, and manual dexterity in humans. In a human study, a 7- or 8-d continuous exposure to CO at 15, 50, or 75 ppm (2.4, 7.1, or 11% COHb) resulted in P-wave changes in the EKG (Davies and Smith, 1980). S-T-segment or T-wave changes were produced by CO at 75 ppm. CO at 75 ppm also produced supraventricular extrasystole in one of nine subjects. Whether CO exposures cause cardiovascular diseases is a question not yet resolved (Kuller and Radford, 1983). Increased mortality from arteriosclerotic heart disease was detected in New York City tunnel officers employed between 1952 and 1981 (Stern et al., 1988). The average CO concentration in the tunnels was 38 ppm in 1981. Although this study provides epidemiological evidence that CO inhalation is associated with cardiac mortality, whether other automobile exhaust pollutants are responsible for the mortality is unclear (Walden and Gottlieb, 1990). In animal studies, the COHb levels produced by a CO concentration varied with the species (Jones et al., 1971), so its toxicity in animals is discussed below mainly in terms of COHb levels rather than its concentrations. Subchronic or chronic CO exposures have been shown to increase the hemoglobin level and hematocrit in several animal species. These

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants effects were detected in continuous exposures at 50 ppm (7.3% COHb) for 6 mo in dogs (Musselman et al., 1959), 96 ppm (7.5% COHb) for 90 d in rats (Jones et al., 1971), and 200 ppm (16 to 20% COHb) for 90 d in rats and monkeys (Jones et al., 1971). These effects, however, were absent at generally lower COHb levels, for instance in continuous exposures at 20 ppm (3.4% COHb) for 2 y in monkeys (Eckardt et al., 1972), 51 ppm (5% COHb) for 90 d in monkeys and rats (Jones et al., 1971), and 66 ppm (7.4% COHb) for 2 y in monkeys (Eckardt et al., 1972). Long-term exposures to CO do not seem to have any morphological effects in laboratory animals. Continuous subchronic or chronic CO exposures failed to induce histopathology in dogs at 50 ppm (7.3 % COHb) for 6 mo (Musselman et al., 1959), in rats at 200 ppm (16% COHb) for 90 d (Jones et al., 1971), and in monkeys at 66 ppm (7.4% COHb) for 2 y (Eckardt et al., 1972), at 200 ppm (20% COHb) for 90 d (Jones et al., 1971), or at 400 ppm (32% COHb) for 71 d followed by 500 ppm (33% COHb) for 97 d (Theodore et al., 1971). Finally, continuous exposures to CO in gestation days 6-15 or 18 were not teratogenic in mice and rabbits at 250 ppm (10-15% COHb) (Schwetz et al., 1979) and had no effect on fetal growth in mice at 65 ppm (Singh and Scott, 1984). CO exposures at 125 ppm, however, retarded fetal growth in mice (Singh and Scott, 1984). In addition, a COHb level as low as 10% has been shown to decrease the birth weight and increase the newborn mortality in rabbits (Astrup et al., 1972). Synergistic Effects No evidence that CO acts synergistically with other chemicals was found.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 3-2 Toxicity Summarya Concentration Exposure Duration COHb Species Effects Reference 100 ppm N.S.b 1-2% Human Increases in the completion time and the number of errors in arithmetic and in the t crossing test “should be detectable... when an adequate number of subjects is evaluated.” Schulte, 1963 50 ppm 1 h and 20 min 2% Human Impaired vigilance. No effects on response latency, short-term memory, and ability to mentally subtract numbers. Beard and Grandstaff, 1975 26 ppm 2 h and 15 min 2.3% Human No effect on vigilance, heart rates, and minute volume. Horvath, 1971 50 ppm 80-125 min 2.3-3.1% Human Decrement in vigilance performance. Fodor and Winneke, 1972 15 ppm 24 h/d, 8 d 2.4% Human Changes in P waves (3 of 16 subjects). Marked S-T or T changes in a subject who had had localized myopathy in his heart. Davies and Smith, 1980 50 ppm ca. 25 min 2.5% Human Increased minute volume; reduction in the duration (from 21 rain to 20 min) that the subjects could exercise maximally at 35°C. Drinkwater et al., 1974 50 ppm ca. 25 min 2.7% Human No effects on maximal oxygen uptake, minute volume, and heart rate. Raven et al., 1974 35 ppm 4 h 3% Human No effect on visual task performance. Putz et al., 1976

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 100 ppm N.S. 0.03 Human Increases in the time to complete the plural noun underlining test and in the number of errors made in making simple choice of letter and color “should be detectable... when an adequate number of subjects is evaluated.” Schulte, 1963 75 ppm ca. 45 min 0.034 Human A 5% decrease in the duration the subjects can exercise maximally (from 24 min to 23 min). Reduced minute volume, but no effect on heart rates. Horvath et al., 1975 100 ppm N.S. 0.039 Human In cardiac patients: impaired ability to visually trace a line through a bunch of entangled lines to the end of that line. No effects on time perception, number facility, reaction time, and perceptual speed. Aronow et al., 1979b 100 ppm >1 h 0.04 Human (cardiac patients) No ventricular arrhythmia during exercise or at rest. Sheps et al., 1990 N.S. ca. 10 min 0.045 Human Decreased ability to detect flashes of light. Halperin et al., 1959 114 ppm 2 h 0.048 Human No effect on vigilance and alertness. Christensen et al., 1977 50 ppm 4 h 0.049 Human No effect on the speed and precision of motor performance in the pegboard test, steadiness test, hand-precision test, and the pursuit-rotor test. Fodor and Winneke, 1972 300 ppm 45 min ca. 5% Human Increased reaction time to visual stimuli. No effects on light detection sensitivity and depth perception. Ramsey, 1972

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants A bolus of CO, then maintained at 30 ppm 5 h 5% Human No effect on hemoglobin affinity for oxygen during exercise. Klein et al., 1980 50 ppm 4 h 5% Human During exercise, there were higher heart rates, but no effects on blood pressures, stroke volume, body temperature, minute volume, oxygen uptake, serum hemoglobin and lactate levels, and hematocrit. Horvath et al., 1975 76 ppm 4 h 5% Human A 30% increase in tracking error and 12% increase in visual response time. Reduced ability to detect an auditory tone (impaired auditory vigilance) and to simultaneously do two tasks. Putz et al., 1979 100 ppm 2.5 h 5% Human No decrement in motor performance (tapping and digit manipulation). Mihevic et al., 1983 20,000 ppm Several min 5.6% Human Deficit in driving skills. Wright et al., 1973 200 ppm >1 h 6% Human (cardiac patients) Increased frequency of ventricular premature depolarization. Sheps et al., 1990 700 ppm N.S. 6% Human No effect on driving ability. McFarland, 1973 111 ppm 2 h and 15 min 6.6% Human (non-smokers) Impaired vigilance. No effect on heart rates and min. volume. Horvath, 1971

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 111 ppm 2 h and 15 min 6.9% Human (smokers) No effect on vigilance, heart rates, and minute volume. O'Hanlon, 1975 125 ppm 15 min to 3 h 6.6% Human No effect on tracking performance or ability to estimate time lapse. Mikulka, 1970 100 ppm 2.5 h 7% Human Decrement in visual perception of letters, manual dexterity in pegboard tests, learning of senseless syllables, the performance in the Amthauer 's Intelligence Structure Test (tests on analogies, communities, calculation, series of numerals, shape selection, and dice tasks). Bender et al., 1972 N.S. N.S. 7% Human Fatigue and a feeling of having to exert more during heavy exercise. Also increased minute volume and heart rate. Bunnell and Horvath, 1989 50 ppm 24 h/d, 8 d 7.1% Human Changes in P waves (6 of 15 subjects). Davies and Smith, 1980 50 ppm 24h/d, 8 d 7.1% Human No effect on auditory vigilance. Davies et al., 1981 250 ppm 1 h and 20 min 7.5% Human No effects on vigilance, response latency, shortterm memory, and ability, to do subtraction. Beard and Grandstaff, 1975 N.S. 15 min 7.5% Human A 23% reduction in the duration the subjects can exercise maximally. Ekblom and Huot, 1972 50 ppm 24 h 8% Human No symptoms or toxic signs. No effect on manual dexterity, hand steadiness, reaction time, and estimation of time lapse. Stewart et al., 1970 175 ppm 2.5 h 8-10% Human No effect on mental capacity. Ettema and Zielhuis, 1975

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 24-h SMAC There is only one report on the neurological effects of CO exposures lasting over 8 h in humans. A 24-h exposure to 50 ppm, yielding 8% COHb, led to no effects on response time, manual dexterity, and time perception in human subjects (Stewart et al., 1970). Unfortunately, there are no data on the effect of a 24-h CO exposure on hand-eye coordination, so 5% COHb, which impairs hand-eye coordination in 4 h (Putz et al., 1979), is also assumed to impair hand-eye coordination in 24 h. The same target COHb of 3% is, therefore, used to set the 24-h SMAC. With a minute volume of 20 m3/d used by NRC (1990) and the inflight hemoglobin level obtained in Skylabs (Kimzey, 1977), 20 ppm is calculated to be the CO concentration required to yield a COHb of 3% in 24 h (Peterson and Stewart, 1975). The 24-h SMAC is, therefore, set at 20 ppm. 7-d SMAC There is only one report on CO toxicity on humans for a continuous exposure lasting 7 d or more. In that study, an 8-d CO exposure at 15 ppm (2.4% COHb) or 50 ppm (7.1% COHb) resulted in P-wave changes in 3 of 16 subjects or 6 of 15 subjects, respectively (Davies and Smith, 1980). The investigators concluded that the P-wave changes reflects CO toxicity on atrial pacemaking or conducting tissue. At a higher concentration of 75 ppm (11% COHb), even more EKG changes, such as S-T-segment or T-wave changes and supraventricular extrasystole, were detected (Davies and Smith, 1980). From these findings, it is decided that the 7-d SMAC will yield a COHb level less than 2.4%. Because the EPA's NAAQS of 9 ppm for 8 h will yield 1.6% COHb in an exercising individual (Rylander and Vesterlund, 1981), 1.6% is selected to be the target COHb level for the 7-d SMAC. With the use of the Coburn-Forster-Kane equation (Peterson and Stewart, 1975), the minute volume of 20 m3/d recommended by NRC (1990), and the inflight hemoglobin concentration obtained in Skylabs (Kimzey, 1977), 10 ppm is calculated to be the 7-d SMAC. There are no data on the neurological effects of continuous CO exposures lasting 7 d or more. It is believed that a target COHb of 1.6% should be able to prevent any significant neurological effects on the crew for 7 d. The reason is that 1.6% is not much higher than the 0.7-1.0% COHb detected in nonsmokers in their everyday lives (Radford et al.,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 1981), but it is lower than the 2.8-3.2% (O'Hanlon, 1975) or 4-5% (Horvath et al., 1975) detected in smokers. It is also quite a bit lower than the threshold of 5% COHb for significant neurological effects in acute CO exposures discussed above. In addition, CO at 111 ppm (6.6-6.9% COHb) was shown to impair the vigilance ability of nonsmokers, but not smokers (O'Hanlon, 1975). That suggests that tolerance to CO's neurological toxicity may develop after repeated exposures. There are also data indicating that tolerance develops toward the effect of CO in causing headache in humans (Killick, 1936, 1948) and coma in mice (Gorbatow and Noro, 1948; Killick, 1937) after repeated exposures. Taken together, these studies point out that 1.6% COHb should provide sufficient margin of safety toward potential CO's neurological effects in subchronic exposures. It has been pointed out earlier that, in general, astronauts are hyposusceptible to the toxic effects of CO compared with the general population because of their physical fitness. So using the COHb levels achievable in an exposure to the EPA's NAAQS usually will provide enough protection in setting the SMACs of CO. On the other hand, based on the cardiotoxicity of CO, the astronauts could be considered a hypersusceptible population. The reason is that cardiac arrhythmias were occasionally detected inflight during the Skylab missions (Smith et al., 1977). Nevertheless, a COHb level of 1.6% should be sufficiently low to prevent cardiac toxicity of CO even in the “hypersusceptible ” astronauts because 1.6% is only slightly higher than the COHb level in nonsmokers and is lower than the COHb level in smokers. It should be noted that coronary disease patients are also considered hypersusceptible to the cardiotoxic effect of CO. Sheps et al. (1990) showed that it takes a COHb of 6% to increase the frequency of ventricular premature depolarization in patients with coronary artery disease, whereas 4% fails to cause any increase. That indicates that a target COHb of 1.6% should prevent arrhythmia even in a hypersusceptible population, such as the astronauts. The Subcommittee on Guidelines for Developing SMACs of the NRC's Committee on Toxicology also agreed with this assessment. 30-d SMAC and 180-d SMAC There are no data on CO's toxicity in humans after a continuous exposure lasting more than 8 d. Although there are several subchronic or chronic studies in animals, very few of them used neurological or EKG

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants effects as the end point (Jones et al., 1971; Musselman et al., 1959; Eckardt et al., 1972; Theodore et al., 1971). One study did show that a 6-mo continuous exposure to CO at 50 ppm (7.3% COHb) produced no EKG changes in dogs (Musselman et al., 1959). This finding is not used to set the 30- and 180-d SMACs because EKG changes were produced in humans by a 7-d continuous CO at a much lower COHb of 2.4% (Davies and Smith, 1980). A 99-d continuous exposure to CO at 380 ppm (31% COHb) did not cause any decrement in operant behavior in monkeys (Theodore et al., 1971). This study is also not relied on in setting the 30- and 180-d SMACs because significant neurological effects were detected in humans in acute CO exposure at a much lower COHb of 5% (Putz et al., 1979; Ramsey, 1972). We also know that rats are up to 10-fold less sensitive than humans toward the acute behavioral effects of CO (Ehrich et al., 1944). It is likely that behavioral testing in monkeys also underestimates the no-behavioral-effect level for humans. The target COHb level of 1.6% for 7-d SMAC would also be appropriate for the 30- and 180-d SMACs because the same rationale for the 7-d SMAC should apply for a 30- or 180-d CO exposure. With 1.6% being lower than the COHb levels commonly detected in smokers and the possibility of tolerance, 1.6% COHb should provide a sufficient margin of safety toward the neurological and cardiac effects of CO in a continuous 30- or 180-d exposure. Using the Coburn-Forster-Kane equation (Peterson and Stewart, 1975), both the 30- and 180-d SMACs are calculated to be 10 ppm. Exposures at these long-term SMACs also should not lead to any detrimental effect on tissue morphology because none was detected in monkeys with continuous CO exposures resulting in 3.4% COHb for 2 y or 32-33% COHb for 168 d (Eckardt et al., 1972; Theodore et al., 1971). Finally, the potential effect of microgravity-induced hematological changes on CO's toxicity can be accounted for by using the inflight hemoglobin concentration obtained in Skylabs to calculate the CO SMAC required to yield a given target COHb level. Therefore, no further adjustments of the SMACs are needed. 1-h and 24-h SMACs Immediately Following CO Exposure The SMACs were calculated assuming a baseline COHb of 0.6%.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants However, it was pointed out by the NRC's Subcommittee on Guidelines for Developing SMACs that NASA should also consider the impact on the 1-h and 24-h SMACs when the beginning COHb is not 0.6% (e.g., immediately after the COHb level has been raised by an exposure to CO at one of its SMACs). Because the COHb level reaches equilibrium 24 h into a CO exposure (Peterson and Stewart, 1975), we need only consider the impact on the 1-h and 24-h SMACs 24 h into a CO exposure at the 24-h or 7-d SMAC. If a 1-h “spike” of 55-ppm CO occurs immediately after a 24-h CO exposure at the 24-h SMAC of 20 ppm, the 1-h spike will lead to a COHb of 4.7%, which is too close to the 5% threshold of the CNS depression effects of CO. Therefore, the 1-h SMAC should be reduced to 20 ppm if a 1-h exposure follows a 24-h CO exposure at the 24-h SMAC. Following a 24-h CO exposure at the 24-h SMAC, a 1-h CO exposure at 20 ppm will result in a COHb level of 3%, which is acceptable. A 1-h spike of 55 ppm following a 24-h exposure of CO at the 7-d SMAC of 10 ppm will lead to a COHb level of 3.8%. Consequently, the 1-h SMAC should be lowered to 40 ppm in the special situation in which a 1-h spike follows a CO exposure at the 7-d SMAC for 24 h or longer. In that situation, CO at 40 ppm will lead to an acceptable COHb level of 3.1%. A similar analysis was done for a spike at the 24-h SMAC. As shown before, a 24-h exposure at the 24-h SMAC of 20 ppm will result in a COHb of only 3% starting from a COHb of 0.6%. If the 24-h exposure at 20 ppm follows a 24-h exposure at the 7-d SMAC of 10 ppm (a starting COHb of 1.6%), the 24-h exposure at 20 ppm will only produce a COHb of only 3.2%, which is acceptable. Therefore, 20 ppm is low enough as the 24-h SMAC for all CO exposure scenarios. REFERENCES Annau, Z. 1987. Complex maze performance during carbon monoxide exposure in rats. Neurotoxicol. Teratol. 9:151-155. Aronow, W.S. and J. Cassidy. 1975. Effect of carbon monoxide on maximal treadmill exercise. Ann. Intern. Med. 83:496-499. Aronow, W.S., E.A. Stemmer, and S. Zweig. 1979a. Carbon monoxide and ventricular fibrillation threshold in normal dogs. Arch. Environ. Health 34:184-186.

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