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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 3: Carbon Monoxide." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

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/m 3 = 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 endo- genous 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 61

62 SMACS 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 off- gas product in spacecraft (Leban and Wagner, 1989). PHARMA CO KINETICS CO is absorbed rapidly in the lung at a rate of about 25.8 mL/min x 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 hy- poxia 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

CARBON MONOXIDE 63 from several minutes to 8 h. CO's toxicity is generally believed to corre- late 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 Stew- art, 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 con- vulsions. Headache, nausea, and vomiting are the most common symp- toms 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 maxi- mal-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

64 SMACS 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 (McFar- land, 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 perfor- mance 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 conduc- tion 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 cyto- chrome 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

CARBON MONOXIDE 65 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 0 2 uptake 20 Convnlsions 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 smok- ers (O'Hanlon, 1975). CO exposure at 700 ppm decreased the lever-

66 SMACS 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), how- ever, 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 extrasys- tole in one of nine subjects. Whether CO exposures cause cardiovascular diseases is a question not yet resolved (Kuller and Radford, 1983). Increased mortality from arter- iosclerotic 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 re- sponsible 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 concen- trations. Subchronic or chronic CO exposures have been shown to increase the hemoglobin level and hematocrit in several animal species. These

CARBON MONOXIDE 61 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 din rats (Jones et al., 1971), and 200 ppm (16 to 20% COHb) for 90 din 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 yin monkeys (Eckardt et al., 1972), 51 ppm (5% COHb) for 90 din monkeys and rats (Jones et al., 1971), and 66 ppm (7.4% COHb) for 2 yin 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.

TABLE3-2 Toxicity Summarl °' QO Exposure Concentration Duration COHb SEecies Effects Reference 100 ppm N.S.b 1-2% Human Increases in the completion time and the number Schulte, 1963 of errors in arithmetic and in the t crossing test "should be detectable ... when an adt::quate number of subjects is evaluated." 50ppm 1hand20 2% Human Impaired vigilance. No effects on response Beard and mm latency, short-term memory, and ability to Grandstaff, 1975 mentally subtract numbers. 26ppm 2 hand 15 2.3% Human No effect on vigilance, heart rates, and minute Horvath, 1971 mm volume. 50ppm 80-125 min 2.3-3.1% Human Decrement in vigilance performance. Fodor and Winneke, 1972 15 ppm 24 hid, 8 d 2.4% Human Changes in P waves (3of16 subjects). Marked S- Davies and Smith, T or T changes in a subject who had had localized 1980 myopathy in his heart. 50ppm ca. 25 min 2.5% Human Increased minute volume; reduction in the Drinkwater et al., duration (from 21 min to 20 min) that the subjects 1974 could exercise maximally at 35°C. 50ppm ca. 25 min 2.7% Human No effects on maximal oxygen uptake, minute Raven et al., 1974 volume, and heart rate. 35 ppm 4h 3% Human No effect on visual task performance. Putz et al., 1976

100 ppm N.S. 0.03 Human Increases in the time to complete the plural noun Schulte, 1963 underlining test and in the number of errors made in making simple choice ofletter and color "should be detectable ... when an adequate number of subjects is evaluated." 75 iJpm ca. 45 min 0.034 Human A 5% decrease in the duration the subjects can Ho1vath et al., 1975 exercise maximally (from 24 min to 23 min). Reduced minute volume, but no effect on heart rates. 100 ppm N.S. 0.039 Human In cardiac patients: impaired ability to visually Aronow et al., trace a line through a bunch of entangled lines to 1979b the end of that line. No effects on time perception, number facility, reaction time, and perceptual speed. 100 ppm >l h 0.04 Human No ventricular arrhythmia during exercise or at Sheps et al., 1990 (cardiac rest. patients) N.S. ca. 10 min 0.045 Human Decreased ability to detect flashes of light. Halperin et al., 1959 114 ppm 2h 0.048 Human No effect on vigilance and alertness. Christensen et al., 1977 50 ppm 4h 0.049 Human No effect on the speed and precision of motor Fodor and Winneke, performance in the pegboard test, steadiness test, 1972 hand-precision test, and the pursuit-rotor test. 300 ppm 45min ca. 5% Human Increased reaction time to visual stimuli. No Ramsey, 1972 effects on light detection sensitivity and depth perception. C'\ IQ

TABLE3-2 (Continued) ~ Exposure Concentration Duration COHb SQecies Effects Reference A bolus of CO, Sh 5% Human No effect on hemoglobin affinity for oxygen Klein et al., 1980 then during exercise. maintained at 30ppm SO ppm 4h 5% Human During exercise, there were higher heart rates, but Horvath et al., 1975 no effects on blood pressures, stroke volume, body temperature, minute volume, oxygen uptake, serum hemoglobin and lactate levels, and hematocrit. 76ppm 4h 5% Human A 30% increase in tracking error and 12% Putz et al., 1979 increase in visual response time. Reduced ability to detect an auditory tone (impaired auditory vigilance) and to simultaneously do two tasks. 100 ppm 2.5 h 5% Human No decrement in motor performance (tapping and Mihevic et al., 1983 digit manipulation). 20,000 ppm Several min 5.6% Human Deficit in driving skills. Wright et al., 1973 200 ppm >l h 6% Human Increased frequency of ventricular premature Sheps et al., 1990 (cardiac depolarization. patients) 700 ppm N.S. 6% Human No effect on driving ability. McFarland, 1973 111 ppm 2 hand 15 6.6% Human Impaired vigilance. No effect on heart rates and Horvath, 1971 mm (non- min. volume. smokers)

111 ppm 2hand15 6.9% Human No effect on vigilance, heart rates, and minute O'Hanlon, 1975 mm (smokers) volume. 125 ppm 15 min to3 6.6% Human No effect on tracking performance or ability to Mikulka, 1970 h estimate time lapse. 100 ppm 2.5 h 7% Human Decrement in visual perception ofletters, manual Bender et al., 1972 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). N.S. N.S. 7% Human Fatigue and a feeling of having to exert more Bunnell and during heavy exercise. Also increased minute Horvath, 1989 volume and heart rate. 50 ppm 24 hid, 8 d 7.1% Human Changes in P waves (6of15 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 1hand20 7.5% Human No effects on vigilance, response latency, short- Beard and mm term memory, and ability to do subtraction. Grandstaff, 1975 N.S. 15 min 7.5% Human A 23% reduction in the duration the subjects can Ekblom and Huot, exercise maximally. 1972 50ppm 24 h 8% Human No symptoms or toxic signs. No effect on manual Stewart et al., 1970 dexterity, hand steadiness, reaction time, and estimation of time lapse. 175 ppm 2.5 h 8-10% Human No effect on mental capacity. Ettema and Zielhuis, 1975 'I "'"'

TABLE3-2 (Continued) ~ Exposure Concentration Duration COHb SEecies Effects Reference 100 ppm 4h 8.2% Human Increases in tracking error, but no effect on ability Benignus et al., to monitor events. 1987 ' 650 ppm 45min 8.5% Human Increased reaction time to visual stimuli. No Ramsey, 1973 effects on depth perception and light detection sensitivity. 200 ppm 3h 9% Human No degradation in night vision sensitivity. No Luria and McKay, effects on reaction time and visually evoked 1979 cortical responses. N.S. 4-6 h 10% Human Increased response time and decreased precision in Ray and Rockwell, maintaining separation distance in driving. 1970 200 ppm 3h 10.4% Human No symptoms. No effects on time perception and O'Donnell et al., tracking performance. 1971 75ppm 24 hid, 7 d 11% Human Changes in the P wave, S-T segment, or T wave Davies and Smith, (6 of9 subjects). Supraventricular extrasystoles (1 1980 of9 subjects). 700 ppm N.S. 11% Human Some decrement in driving performance. McFarland, 1973 100 ppm 8h 12% Human No symptoms or toxic signs. No effect on manual Stewart et al., 1970 dexterity, hand steadiness, reaction time, and estimation of time lapse. 950 ppm 45 min 12% Human Increased reaction time. No effect on depth Ramsey, 1973 perception and light detection sensitivity. 200 ppm 2 hand 40 12.6% Human No effect on vigilance performance. Benignus and Otto, mm 1977

SOOppm 1h 13% Human Mild headache. Stewart et al., 1970 200ppm 4h 16% Human Mild headache. Stewart et al., 1970 11,600 ppm 2hand15 17% Human No effects on thresholds to visually detect motion, Hudnell and bolus, 142 ppm mm pattern, and contrast. No effect on luminance Benignus, 1989 maintenance threshold. 200 ppm Sh 18% Human No impairment on ability to estimate time lapse. Stewart et al., 1973 100 ppm N.S. 20% Human Headache in 1149 subjects. No other symptoms. Schulte, 1963 No changes in spinal and cranial nerve reflexes, heart rate, systolic and diastolic blood pressure, respiratory rate, muscle persistence time. No effect on static steadiness and on the response time in making simple choices ofletter and color. 11,000 ppm ca. 1 h 20% Human Reduced maximal oxygen uptake. Vogel et al., 1972 bolus, 225 ppm maintenance 860 ppm N.S. 37% Human Severe headache, dizziness, difficulty in DiMarco, 1988 concentrating, and polycythemia. 50 ppm 1.5 h N.S. Human Impaired ability to estimate time lapse. Beard and Wertheim, 1967 100 ppm 4.5 h N.S. Human No effect on tracking performance. Hanks, 1970 20ppm 22 hid, 7 3.4% Monkey No changes in hematocrit, hemoglobin level, and Eckardt et al., 1972 dlw,2 y RBC count. No histopathology in heart, brain, and lung. 51 ppm 24 hid, 90 d 5% at48 Monkey, Rat No toxic signs and histopathology. No changes in Jones et al., 1971 h hematocrit and hemoglobin level. -....l ~

TABLE3-2 (Continued) ... -...I Exposure Concentration Duration COHb S~cies Effects Reference 100 ppm 2h 6.5% Dog Decreased ventricular fibrillation threshold. Aronow et al., 1979a 50ppm 24 h/d,6 mo 7.3% Dog A 12% increase in hemoglobin concentration. No Musselman et al., change on EKG or histology. 1959 66ppm 22 hid, 7 7.4% Monkey No changes in hematocrit, hemoglobin level, and Eckardt et al., 1972 d/w,2 y RBC count. No histopathology in heart, brain, and lung. 96ppm 24 hid, 90 d 7.5% at Rat No toxic signs and histopathology. Increased Jones et al., 1971 48 h hematocrit and hemoglobin level. 96ppm 24 hid, 90 d 10% at Monkey No toxic signs and histopathology. No effects on Jones et al., 1971 48 h hematocrit and hemoglobin levels. 100 ppm 6h 9.3% Monkey Decreased ventricular fibrillation threshold. DeBias et al., 1976 200 ppm 24 h/d, 90 d 16-20% Monkey, rat No toxic signs and histopathology. Increased Jones et al., 1971 hematocrit and hemoglobin level. 400 ppm 0.5 h on/0.5 18-23% Monkey Did not cause atherosclerosis. Bing et al., 1980 h off, I 0 h/d, for 7 h/d for 12 mo 100 ppm 5 3/4 h/d, 6 20% Dog Increases in RBC counts after 8 w, but returned to Brieger, 1944 d/w, 11 w normal after 11 w. 100 ppm 5 3/4 h/d, 6 20% Dog T-wave changes (4 dogs). Myocardial Ehrich et al., 1944 d/2, 11 w degeneration.

100 ppm 5 3/4 hid, 6 20% Dog Disturbance of postural and position reflexes and Lewey and Drabkin, d/w, 11 w of gait. Histologic changes in the cortex, white 1944 matter of the cerebral hemispheres, globus pallibus, and brain stem 3 mo after exposure. 400 ppm 4h 27% Rat No effect on unconditioned reflex and conditioned Mullin and avoidance tests. Krivanek, 1982 380 ppm 24 hid, 99 d 31% Monkey No decrement on operant behavior (visual and Theodore et al., auditory response times and learned pressing of a 1971 lever). 400 ppm for 71 24 hid, 71 32-33% Monkey, 40% increases in hemoglobin concentration, 30% Theodore et al., d, then 500 and 97 d dog, rat, increases in hematocrit and blood volume. No 1971 ppm for97 d mouse effect on plasma volume, body weight, and survival. No histopathology in the brain and heart. In rats, heart and spleen increased in weight. 800 ppm 4h 34% Rat Failure of unconditioned reflex, decrements in Mullin and conditioned avoidance. Krivanek, 1982 500 ppm 21 hid, 62 d 42% Rat Enhanced development of NaCl-induced Shiotsuka et al., hypertension, cardiomegaly, splenomegaly, 1984 elevated hemoglobin, level and hematocrit. 2000 ppm 30min 75% Rat Increased in time to traverse a maze. Annau, 1987 25 ppm 24 h/d,2 mo N.S. Rat No effects on serum corticosterone and thyroxine, Vyskocil et al., 1986 hypothalamic norepinephrine level, adrenal catecholamines levels, organ weights and body weight. 50ppm 24 hld,2 mo N.S. Rat Reduced serum thyroxine level, increased adrenal Vyskocil et al., 1984 catecholamine concentration. No effects on organ weights. ~

...:a TABLE3-2 (Continued) C\ Exposure Concentration Duration COHb S~cies Effects Reference 65ppm 24 hid, N.S. Mouse No effect on fetal growth. Singh and Scott, gestation 1984 days 7-18 75ppm 24 hid, N.S. Rat Elevations in DNA and dopamine in the striatum. Fechter et al., 1987 conception to postnatal day 11 100 ppm 24 h/d,2 mo N.S. Rat Reductions in serum thyroxine and hypothalamic Vyskocil et al., 1986 norepinephrine levels; increases in adrenal catecholamines and serum cortocosterone; no effect on body organ weights except for a slight decrease in liver weight. 100 ppm 24 h/d,6 wk N.S. Rat No toxic signs or death. No effect on the weights McGrath, 1988 of the body, heart, right ventricle, adrenal, spleen, and kidneys. Increases in the weight of the left ventricle and septum, and in hematocrit. 125 ppm 24 hid, N.S. Mouse Retarded fetal growth. Singh and Scott, gestation 1984 days 7-18 250 ppm 24 h/d, N.S. Rabbit, No teratogenesis. Schwetz et al., 1979 gestation mouse days 6-15 or 6-18 ~nly the results from inhalation studies were included . .S. = not specified.

CARBON MONOXIDE 77 TABLE 3-3 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 50 ACGIH's STEL 400 OSHA's PEL 50 NIOSH's REL 35 (TWA) 200 (ceiling) NIOSH's IDLH 1500 NRC's IDLH 1500 NRC's 10-min EEGL 1500 NRC's 30-min EEGL 750 NRC's 60-min EEGL 400 NRC's 24-h EEGL 50 NRC's 90-d EEGL 20 EPA's NAAQS 35 for 1 h 9 for 8 h FAA's standard 50 TLV = threshold limit value. TWA = time-weighted average. PEL permissible exposure limit. STEL = short-term exposure limit. REL recommended exposure limit. IDLH = immediately dangerous to life and health. EEGL = emergency exposure guidance level. NAAQS = national ambient air quality standard. FAA = Federal Aviation Administration. TABLE 3-4 S~cecraft Maximum Allowable Concentrations Target Duration eEm m~/m3 COHb, % Tar~et Toxici~ 1 ha 55 63 3 Heart, CNS 24h 20 23 3 Heart, CNS 7 db 10 11 1.6 Heart, CNS 30d 10 11 1.6 Heart, CNS 180 d 10 11 1.6 Heart, CNS aRefer to "Rationale" section for a discussion of lowering the 1-h SMAC in the unlikely event that the 1-h exposure immediately follows a 24-h exposure at the ~4-h or 7-d SMAC. Current 7-d SMAC = 25 ppm.

78 SMACS FOR SELECTED AIRBORNE CONTAMINANTS RATIONALE The effects of acute CO exposures at low concentrations on mental functions are controversial (Stewart, 1975). The lowest effective level is 2% COHb, which was found to impair vigilance in normal subjects (Beard and Grandstaff, 1975). The practical significance of that finding is ques- tionable because the same study showed that 7.5% COHb did not impair vigilance. A COHb level of 3.4 or 4% has been shown to reduce the duration subjects can exercise until exhaustion by 5 % (Horvath et al., 1975; Aronow and Cassidy, 1975). The SMACs are not set to protect against this effect because a reduction of the duration an individual can exercise maximally, from 24 to 23 min (Horvath et al., 1975), will not significantly affect the ability of astronauts to achieve the mission objectives. The next lowest effective level is 3.9% COHb, which was discovered to cause "impairment" of the ability of cardiac patients to visually trace a line through several tangled lines (Aronow et al., 1979b). This finding is disregarded because of an uncertainty of whether the effect detected was indeed an impairment. The score of that visual test represented the number of lines correctly traced (Aronow et al., 1979b), so the higher the score the better the ability to visually trace the lines. In that study, the CO exposure increased the score, compared with the pre-exposure baseline score, and the air exposure decreased the score. Therefore, 3.9% COHb appeared not to impair that ability in cardiac patients. The fourth lowest effective level is 4.5% COHb, which was found to reduce the ability to detect flashes of light (Halperin et al., 1959). That finding is not relied on to set the SMACs because no parallel control group was used in that study (Hudnell and Benignus, 1989). 1-h SMAC The studies of Ramsey (1972) and Putz, et al. (1979) are relied on to set the 1-h SMAC. In these studies, 5% COHb was found to increase the reaction time (about 30%) and to impair hand-eye coordination (a 12 % increase in tracking errors). Even though there are conflicting reports on the effects of COHb levels higher than 5 % on reaction time and hand-eye

CARBON MONOXIDE 19 coordination (Stewart et al., 1970; Beard and Grandstaff, 1975; Benignus et al., 1987; Ramsey, 1973; Ray and Rockwell 1970; Luria and McKay, 1979; Mikulka, 1970; O'Donnell et al., 1971), prudence dictates that we have to assume that 5 % COHb would slow down the reaction and impair the coordination of the crew. These impairments would clearly interfere with the crew's ability to deal with a contingency. To prevent the interfer- ence, the 1-h SMAC is aimed at a target COHb level of 3 % . Three percent is chosen for three reasons. First, 5 % COHb appears to be the threshold of neurological detriments significant to mission's objec- tives. Second, EPA, NIOSH, and some scientists believed that CO causes no significant CNS toxicity below 5% COHb (Rylander and Vesterlund, 1981; EPA, 1985; NIOSH, 1972). Third, a safety margin of 2% COHb should be sufficient, considering that a 1-h exposure at the 1-h NAAQS produces 3% COHb during exercise (Rylander and Vesterlund, 1981) and 2% COHb during moderate activity (EPA, 1985). Because the NAAQS is aimed at protecting the entire population, including potentially highly sensitive individuals, such as the old and the infirm, a SMAC that achieves a COHb level comparable to that achieved at the NAAQS should protect the astronauts also. This is because astronauts, being physically fit, are a hyposusceptible group compared with the general population. The CO concentration required to yield 3% COHb in 1 h was calculated using the Coburn-Forster-Kane equation (Peterson and Stewart, 1975). A minute volume of 20 L/min, corresponding to the minute volume of an adult at light activity (NRC, 1990), was used in calculating the CO concen- tration. A higher minute volume was not used, even though the crew is expected to exercise more than 1 h/d, because NASA will issue a flight rule that disallows exercise when the CO level in the spacecraft approaches the 1-h SMAC. In addition, a pre-exposure COHb level of 0.6% and the intlight hemoglobin concentration measured in Sky labs were used (Kimzey, 1977) in calculating the CO concentration. Under these conditions, CO at 55 ppm will yield 3% COHb in 1 h; therefore, 55 ppm becomes the 1-h SMAC. The 1-h SMAC will also protect against the cardiotoxicity of CO. Because an exposure to CO at 100 ppm for over 1 h yielding 4% COHb failed to increase the frequency of ventricular premature depolarization in cardiac patients (Sheps et al., 1990), 3% COHb should not lead to EKG changes in a healthy crew.

80 SMACS 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 ex- posures 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.,

CARBON MONOXIDE 81 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 neurolog- ical 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 hyposus- ceptible 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 cardiotoxi- city of CO, the astronauts could be considered a hypersusceptible popula- tion. 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 ex- posure lasting more than 8 d. Although there are several subchronic or chronic studies in animals, very few of them used neurological or EKG

82 SMACS 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 appro- priate 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 possi- bility 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 hemo- globin concentration obtained in Skylabs to calculate the CO SMAC re- quired to yield a given target COHb level. Therefore, no further adjust- ments of the SMACs are needed. 1-h and 24-h SMACs Immediately Following CO Exposure The SMAC~ were calculated assuming a baseline COHb of 0.6%.

CARBON MONOXIDE 83 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., immedi- ately 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 lOppm will lead to a COHb level of3.8%. 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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