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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B11 Trichloroethylene John T. James, Ph.D., Harold L. Kaplan, Ph.D., and Martin E. Coleman, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Trichloroethylene (TCE) is a colorless, nonflammable, volatile liquid, with a sweetish odor resembling chloroform (ACGIH, 1986). Synonyms: Ethylene trichloride, trilene Formula: CHC1=CCl2 CAS number: 79-01-6 Molecular weight: 131.4 Boiling point: 87°C Melting point: -87°C Conversion factors at 25°C, 1 atm: 1 ppm = 5.38 mg/m3 1 mg/m3 = 0.19 ppm OCCURRENCE AND USE TCE is widely used as an industrial solvent, particularly in metal degreasing and extraction processes (Torkelson and Rowe, 1981). Other less toxic chemicals have replaced it in some of its former uses, including that as an anesthetic. Although TCE is not used in the spacecraft, it has been found in numerous atmospheric samples collected from the cabin of the space shuttle (Coleman, 1984). In contact with alkaline materials, especially at high temperatures, TCE can be convert-
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 ed into more toxic compounds. Dichloroacetylene (DCA) is the major product formed from TCE in carbon dioxide scrubbers containing alkaline materials (Saunders, 1967). In an experiment by the Toxicology Laboratory at the National Aeronautics and Space Administration, all the TCE disappeared upon passage over heated alkaline adsorbent, with at least 75% conversion to DCA (Rippstein, 1980). The SMAC limits developed here are only applicable to a spacecraft environment in which an alkaline air scrubber is not present. If an alkaline air scrubber is present, the SMAC values for DCA are applicable to TCE (see Chapter B5). TOXICOKINETICS AND METABOLISM Absorption and Distribution TCE is readily absorbed from the lungs of humans and distributed throughout the body (Waters et al., 1977). Most blood-borne TCE reaches the liver where the majority of its metabolism occurs (Steinberg and DeSesso, 1993). Elimination Approximately 20% to 30% of the absorbed chemical is excreted unchanged in the expired air, mostly during the first 24 h, with the rest metabolized and excreted in the urine (Ogata and Bodner, 1971). Because of its high lipid solubility, a portion of the absorbed TCE is stored in tissues, principally fatty tissues, from which it is slowly released and then metabolized and excreted (Müller et al., 1974). After a 4-h exposure of human volunteers to TCE at 100 ppm, trichloroacetic acid (TCA) and trichloroethanol glucuronide accounted for about 20% and 80%, respectively, of the total urinary trichloro compounds (Sato et al., 1977). In contrast to the rapid excretion of trichloroethanol glucuronide by the kidneys, renal clearance of TCA is delayed because of its high degree of protein-binding (Müller et al., 1974).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Metabolism TCE that is not excreted from the lungs is converted enzymatically in several steps to the principal urinary metabolites, trichloroethanol, trichloroethanol glucuronide, and trichloroacetic acid (Waters et al., 1977), and a minor metabolite, dichloroacetic acid (DCA) (Hathway, 1980). Cytochrome P-450 systems are the primary metabolizing systems in the liver (Steinberg and DeSesso, 1993). In the first metabolic step, TCE is oxidized through intermediates to chloral hydrate, which undergoes reduction to trichloroethanol as well as further oxidation to TCA (Byington and Leibman, 1965; Sellers et al., 1972). Most of the trichloroethanol is conjugated with glucuronic acid in the liver before being excreted in the urine (Waters et al., 1977). Other pathways for trichloroethanol are oxidation to TCA and excretion of unchanged trichloroethanol in the urine. The proportion of urinary metabolites excreted as TCA was predicted to increase in a chronic exposure. TCA and DCA have recently been shown to be complete hepatocarcinogens in male B6C3F1 mice (Herren-Freund et al., 1987; Bull et al., 1990; DeAngelo et al., 1991). Thus, these metabolites might be responsible for hepatic tumors produced in B6C3F1 mice treated with TCE (NCI, 1976). In rodents, DCA can be converted to S-(1, 2-dichlorvinyl)-L-cysteine and subsequently by ß-lyase to the reactive mercaptan (Steinberg and DeSesso, 1993). The pathway to DCA is much more heavily used in rodents than in humans. The biological half-life of trichloroethanol in humans is relatively short compared with that of TCA. In humans exposed to TCE at 50 ppm for 6 h/d for 5 d, the half-lives of trichloroethanol and TCA were approximately 12 h and 99 h, respectively (Müller et al., 1974). For exposures at 100 ppm for 6 h/d for 10 d, the half-lives were 13 h and 86 h, respectively. Physiologically based pharmacokinetic (PB-PK) models of the toxicokinetics and metabolism of TCE in humans (Sato et al., 1977; Fernandez et al., 1977) and in animals (Fernandez et al., 1977; Andersen et al., 1987; Fisher et al., 1989, 1990, 1991; Dallas et al., 1991) have been developed by several groups of investigators. These models have enabled a better understanding of the uptake, distribution, and metabolism of TCE as well as of the kinetics of formation, distribution, and excretion of its metabolites TCA and trichloroethanol. The metabolism and elimination pattern for TCE is conducive to exposure monitoring with the use of biological markers. The parent com-
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 pound can be monitored in the breath, blood, or urine (Stewart et al., 1970; Kimmerle and Eden, 1973; Monster et al., 1979), or the metabolites trichloroacetic acid and trichloroethanol can be monitored in the urine (Inoue et al., 1989). Use of these markers might be confounded by interindividual variation and by the presence of other chlorinated hydrocarbons (Inoue et al., 1989). Air monitoring near the breathing zone of exposed persons is still the best predictor of inhalation exposure to TCE. Biological markers of TCE toxicity have focused on nervous system injury or kidney injury (Feldman et al., 1988; Nagaya et al., 1989); however, those markers do not appear to be widely used and are not specific for TCE exposure. TOXICITY SUMMARY Acute Exposures Many cases of accidental acute poisoning by TCE are described in the literature (Cotter, 1950). The predominant physiological effect is depression of the central nervous system (CNS), with reported symptoms of inebriation, loss of coordination, dizziness, visual disturbances, mental confusion, headache, nausea, vomiting, and loss of consciousness (Waters et al., 1977; Cotter, 1950). In one TCE exposure accident, two workmen rapidly lost consciousness upon re-entry into an atmosphere containing TCE at an estimated 3000 ppm after an earlier, less severe exposure (Longley and Jones, 1963). In a controlled laboratory study with a human volunteer, a 2.75-h exposure to TCE at 100 ppm did not cause any significant effects on psychomotor performance (Stopps and McLaughlin, 1967). At 200 ppm, there was a slight decline in performance, which became more pronounced at 300 and 500 ppm. In another study, a 2-h exposure at 100 or 300 ppm did not affect visual-motor performance, but 1000 ppm significantly impaired performance and resulted in subjective responses of light-headedness and dizziness or lethargy (Vernon and Ferguson, 1969). A longer exposure of 8 h at 110 ppm resulted in a significant decrease in the performance of volunteers in various psychophysiological tests, the greatest decrease being in the more complex tests (Salvini et al., 1971). However, performance decrements were not found in a repeat of this study with an additional concentration of 50 ppm and more end points (Stewart et al.,
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 1974). It has been suggested that drowsiness can occur at 27 ppm during acute exposures and headaches can occur at 81 ppm (Nomiyama and Nomiyama, 1977). Those conclusions were based on subjective reports of three volunteers; however, because no dose-response relationship was shown for drowsiness (i.e., no drowsiness after 3 h in persons exposed at 200 ppm), the observation is suspect. Even though the prevalence of headache shows a dose response, many other symptoms do not show a dose response, so that the findings must be questioned. There are reports that cardiac arrhythmias induced by inhaled TCE have resulted in human deaths (Kleinfeld and Tabershaw, 1954; Bell, 1951). TCE has been shown to be have the capability to cause cardiac sensitization to epinephrine in the dog. After a 10-min exposure to 5000 or 10,000 ppm, a challenge injection of epinephrine produced ventricular fibrillation in 1 of 12 and 7 of 12 dogs, respectively (Reinhardt et al., 1973). Those findings in animals are particularly significant in view of the cardiac dysrhythmias seen periodically in crew members of U.S. spaceflights as well as in at least one Soviet cosmonaut (Bungo, 1989; NASA, 1991). Whether spaceflight-associated conditions, such as gravitational stress, thermal load, electrolyte changes, fluid shifts, or catecholamine alterations, caused those cardiac rhythm irregularities is unknown at this time (NASA, 1991). Short-Term and Subchronic Exposures Repeated exposures for 7 h/d for 5 consecutive days to TCE at 200 ppm did not adversely affect performance or neurological or biochemical tests in human volunteers, but they elicited a consistent subjective response of a sensation of mild fatigue and sleepiness during the fourth and fifth days (Stewart et al., 1970). In subsequent better-controlled studies, the same investigators did not find objective or subjective adverse effects after repeated 7.5-h daily exposures at 100 or 200 ppm and concluded that 100 ppm probably has a threefold to fourfold margin of safety for most individuals (ACGIH, 1986). According to studies cited by the American Conference of Governmental Industrial Hygienists, daily exposures to TCE at 100 ppm caused no impairment in mental or psychological capabilities in one European study (Triebig et al., 1976), but in a similar study, it caused fatigue, lassitude, and headaches (Ertle et al., 1972).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Several studies of worker complaints have been published involving industrial exposure to TCE; however, the findings are often uncertain and do not agree with results of volunteer exposures. The prevalence of symptoms (e.g., sleepiness, fatigue, nausea, and irritation) was reduced in nine workers after TCE exposures were reduced from 38 ppm TWA (average of 200 ppm for short-term exposure) to 16 ppm TWA (average of 74 ppm for short-term exposures) by improving ventilation and work practices (Landrigan et al., 1987). The reported symptoms probably were elicited by the high-concentration short-term exposures rather than the low-concentration sustained exposures. The National Institute for Occupational Safety and Health (NIOSH) has reviewed a number of work sites because of worker complaints of excess chemical exposure. In one investigation, the TCE exposures were confounded by the presence of other chemicals, and the magnitude of worker complaints did not compare well with the exposure concentrations (Bloom et al., 1974). Three workers reported occasional light-headedness and headache in a degreasing operation, which had a TWA TCE concentration at 47 ppm, with 1-h maximum exposures up to 94 ppm (Hervin et al., 1974). In a study of printed circuit-board processors, average breathing-zone concentrations of TCE ranged from 29 to 62 ppm, and symptoms reported were nausea (71%), headache (54%), and fatigue and drowsiness (25%) (Okawa and Bodner, 1973). The authors concluded that the symptoms were due to toxic exposures to TCE in the workplace. The difficulty of interpreting workplace results is indicated by subjective responses reported by volunteers even when not exposed to TCE. For example, two of two test subjects reported headaches; irritation of the eyes, nose, and throat; and odor when no exposures to TCE had occurred (Stewart et al., 1974). In another group of test subjects, only odor was reported, even at exposure concentrations of 50 and 110 ppm (Stewart et al., 1974). Objectively measurable performance decrements were absent. Chronic Exposures Noncarcinogenicity Neurological symptoms, including vertigo, fatigue, insomnia, and
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 memory loss, have been reported in epidemiological studies of workers chronically exposed to TCE in industry (Grandjean et al., 1955; Bardodej and Vyskocil, 1956). The incidence of these symptoms correlated with the duration of exposure of the workers. Although biochemical tests have also suggested possible hepatic and renal effects in workers chronically exposed to TCE, the evidence is not conclusive (Waters et al., 1977; NIOSH, 1978). In chronic exposure studies with animals, TCE appears to be a weak hepatotoxin and renal toxin because high doses produced mild effects in the liver and kidney. Exposure for 8 h/d, 5 d/w, for 6 w at 730 ppm or for 24 h/d for 90 d at 35 ppm did not result in any evidence of injury to the liver or kidneys of rats, guinea pigs, rabbits, dogs, and monkeys (Prendergast et al., 1967). Exposure of rats, guinea pigs, rabbits, and monkeys for 7 h/d, 5 d/w, for 148 to 178 d at 200 ppm also caused no adverse effects, except decreased growth and body weights in guinea pigs (Adams et al., 1951). Exposure of these species for 7 h/d, 5 d/w, for 161 to 175 d at 400 ppm caused increased liver and kidney weights in rats, increased liver weights in male and female guinea pigs, depressed growth in male guinea pigs, and a slight increase in liver weights of rabbits, but no adverse effects in monkeys (Adams et al., 1951). Carcinogenicity The results of most of the carcinogenicity studies with animals show that TCE is a potential carcinogen. TCE produced an increased incidence of hepatocellular carcinomas in B6C3F1 mice subjected daily for their lifetime to high oral doses of the chemical (NCI, 1976; NTP, 1988, 1990). An increased incidence of these tumors was not detected in rats, but the results indicated the possibility of renal tumorigenic effects in rats. Studies also showed that inhalation exposure to TCE can be carcinogenic in animals (Fukuda et al., 1983; Maltoni et al., 1988). In a recently completed European bioassay, exposure of Swiss and B6C3F1 mice to TCE for 7 h/d, 5 d/w, for 78 w at 100, 300, or 600 ppm resulted in a significant increase in the incidence of pulmonary tumors (from 11.1% in controls to 25.5% in males exposed at 300 ppm and 30.0% in mice exposed at 600 ppm) and hepatomas (from 4.4% in controls to 14.4% in males exposed at 600 ppm) in male Swiss mice (Maltoni et al., 1988). In female B6C3F1 mice, there was a significant
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 increase in the number of total malignant tumors per 100 animals (from 54.4 in controls to 70.0 in mice exposed at 100 ppm, 68.9 at 300 ppm, and 77.7 at 600 ppm) and in the incidence of pulmonary tumors (from 4.4% in controls to 16.7% in mice exposed at 600 ppm). In male and female B6C3F1 mice combined, the increase in incidence of hepatomas from 2.2% in controls to 8.3% in those exposed at 600 ppm was significant. It should be noted that the time of sacrifice of these animals was not specified; however, the reported incidence of hepatomas at 600 ppm appears low compared with the historical lifetime incidences of 20% to 30% and 5%, respectively, in male and female B6C3F1 mice. In rats similarly exposed for 104 w, there were significant dose-related increases in the incidence of Leydig-cell tumors of the testis from 4.4% in controls to 12.3%, 23.1%, and 23.8% in rats exposed at 100, 300, and 600 ppm, respectively (Maltoni et al., 1988). There was also a non-dose-related increase in the incidence of hemolymphoreticular neoplasias as well as a low incidence of renal adenocarcinomas at the highest dose in male rats. In humans, two Scandinavian cohort studies did not find an increase in cancer-related mortality in workers exposed to TCE for up to 13 and 20 y (Axelson et al., 1978; Tola et al., 1980). Genotoxicity TCE was weakly positive or negative in numerous mutagenicity bioassays (Stott et al., 1982). Those results and a low level of in vivo TCE-DNA binding observed in B6C3F1 mice indicate a weak genotoxic potential of TCE (Stott et al., 1982). Many of the studies did not report purity of test material; hence, it is possible that mutagenic epoxide stabilizers caused false positives (Brown et al., 1990). Reproductive and Developmental Effects TCE was found not to be a developmental toxicant in mice or rats exposed to TCE by inhalation at 300 ppm (Schwetz et al., 1975). In more recent studies, administration of TCE to the developing rat fetus in utero and injection into the air sacs of fertilized chick eggs resulted in cardiac teratogenic effects (Dawson et al., 1990; Loeber et al.,
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 1988). Additional evidence of the possible cardiac teratogenicity of TCE was provided by recent epidemiological studies showing a greater-than-expected number of pediatric patients with congenital heart disease in areas where the drinking water of their parents near the time of conception was contaminated by TCE and other halogenated aliphatic hydrocarbons (Goldberg et al., 1990). The authors noted important limitations to their study that preclude the conclusion of a cause-and-effect relationship. Interactions with Other Chemicals Biological interactions between TCE and other chemicals and drugs, such as ethyl alcohol and phenobarbital, have been reported in humans and animals. Degreaser's flush, a transient vasodilation of the skin, occurs in some TCE-exposed workers or subjects after ingestion of even small quantities of ethanol (Müller et al., 1975). Small quantities of ethanol also might increase the concentration of TCE in the blood, suggesting a lower rate of metabolism of TCE in the presence of alcohol (Müller et al., 1975). In Wistar rats, pre-exposure with ethanol or phenobarbital can enhance hepatic damage induced by exposure to TCE vapor (Okino et al., 1991).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 11-1 Toxicity Summarya Concentration, ppm Exposure Duration Species Effects Reference NS Up to 13 y Human (workers) No increase in mortality or cancer-related mortality Tola et al., 1980 NS Up to 20 y Human (workers) No increase in cancer-related mortality Axelson et al., 1978 1-335 Up to 15 y Human (workers) Nervous disorders increased with exposure duration and levels greater than 40 ppm Grandjean et al., 1955 5-630 0.5-25 y Human (workers) Various symptoms; some correlated with exposure duration Bardodej and Vyskocil, 1956 29-62 (averages) Work site Workers Nausea, headache, dizziness Okawa and Bodner, 1973 20, 100, or 200 7.5 h/d, 5 d Human No adverse subjective or objective behavioral effects ACGIH, 1986 50 or 110 8 h Human No impairment of performance Stewart et al., 1974 100 h/d NS, 5 d Human No impairment in mental performance ACGIH, 1986 100, 200, 300, or 500 165 min Human Slight decrease in psycho-motor performance at 200 ppm, more pronounced at 300 and 500 ppm Stopps and McLaughlin, 1967 100, 300, or 1000 2 h Human Impairment of visual-motor performance, dizziness, lightheadedness at 1000 ppm Vernon and Ferguson, 1969 110 average (90-130) 8 h Human Significant decrease in psychomotor performance; slight dizziness at 130 ppm Salvini et al., 1971 200 7 h/d, 5 d Human (n = 5) No adverse effects on performance, neurological or clinical chemistry tests Stewart et al., 1970
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Concentration, ppm Exposure Duration Species Effects Reference 1000 2 h Human CNS effects indicated by optokinetic nystagmus test Kylin et al., 1967 3000 10 min Human (workers) Unconsciousness in two workers exposed previously Longley and Jones, 1963 10 or 600 6 h Rat (O-M), mouse (B6C3F1) Reactive metabolite formation and hepatic macromolecular binding greater in mouse than rat Stott et al., 1982 35 24 h/d, 90 d continuous Monkey, dog, rabbit, guinea pig, rat No deaths, hematological changes, or toxic signs except depressed body-weight gain in rabbits Prendergast et al., 1967 100 7 h/d, 5 d/w, 132 d Guinea pig No adverse effects Adams et al., 1951 100, 300, or 600 7 h/d, 5 d/w, 78 w Mouse (Swiss, B6C3F1) In Swiss males, significant increase in incidence of pulmonary tumors from 11.1% (controls) to 25.5% (300 ppm) and 30.0% (600 ppm), and of hepatomas from 4.4% (controls) to 14.4% (600 ppm); in B6C3F1, females significant increase in total number of malignant tumors per 100 animals from 54.4 (controls) to 70.0 (100 ppm), 68.9 (300 ppm) and 77.7 (600 ppm) and in incidence of pulmonary tumors from 4.4% (controls) to 16.7% (600 ppm); significant increase in hepatomas at 600 ppm in male plus female mice Maltoni et al., 1988
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Some studies used mutagenic epoxide stabilizers in the TCE test material. Some studies used unconventional protocols and incomplete reporting methods or did not comply (apparently) with good laboratory practices. Some tumors appear to be due to metabolic pathways in the test species that differ from those in human beings. Some tumors might involve cytotoxic mechanisms and are not relevant to risk at much lower human exposures. Despite those uncertainties, we have chosen to calculate a cancer risk based on an estimate by the U.S. Environmental Protection Agency (EPA, 1987). A continuous lifetime exposure to TCE at 1 µg/m3 (0.00019 ppm) was estimated to yield an excess tumor risk of 1.7 × 10-6 in humans. Using the approach of the National Research Council (NRC, 1992) and setting k = 3 (stages in process), t = 25,550 d (70-y lifetime), and s1 = 10,950 d (earliest exposure, 30 y of age), the adjustment factor was calculated to be 26,082 for a near instantaneous exposure concentration that would yield the same excess tumor risk as a continuous lifetime exposure. The 24-h TCE exposure concentration that would yield an excess tumor risk of 10-4 was equal to the following: 1.9 × 10-4 ppm × 26082 × 10-4 ÷ (1.7 × 10-6) or 290 ppm. For the 7-d, 30-d, and 180-d SMACs, adjustment factors were calculated on the basis of the NRC (1992) approach and setting k = 3, t = 25,550 d, and s1 = 10,950 d. The adjustment factors are 3728, 871, and 146.7 for continuous 7-d, 30-d, and 180-d exposures, respectively, that would yield the same excess tumor risk of 1.7 × 10-6 as a continuous lifetime exposure. The 7-d, 30-d, and 180-d exposure concentrations that would yield an excess tumor risk of 10-4 are equal to the following: 1.9 × 10-5 ppm × 3728 × 10-4 ÷ (1.7 × 10-6) = 42 ppm (7 d). 1.9 × 10-5 ppm × 871 × 10-4 ÷ (1.7 × 10-6) = 9.7 ppm (30 d). 1.9 × 10-5 ppm × 146.7 × 10-4 ÷ (1.7 × 10-6) = 1.6 ppm (180 d).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 It must be pointed out that the original EPA estimate was withdrawn, and a revised estimate has not been determined as of this writing (EPA, 1993). Some authors suggest that a threshold model might be more appropriate than a linear extrapolation to low doses to set exposure limits (Steinberg and DeSesso, 1993). Summary The 1-h SMAC of 50 ppm was based on cardiac sensitization in dogs and the occurrence of arrhythmias in some crew members during missions. The 24-h SMAC of 12 ppm was based on CNS and neurobehavioral effects in humans rather than on cardiac sensitization in dogs. The 7-d and 30-d SMACs of 9 and 4 ppm, respectively, were set to protect against liver and kidney injury. Those concentrations protect against cancer at a risk predicted to be below 0.01%. The 180-d SMAC of 2 ppm protects against liver and kidney injury and against cancer at the 95% limit of 0.01% risk per mission.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 11-4 Acceptable Concentrations Uncertainty Factors Small n To NOAEL Spaceflight Acceptable Concentrations, ppm Effect, Data, Reference Species Species Time 1 h 24 h 7 d 30 d 180 d CNS effects NOAEL = 300 ppm, 2 h (Vernon and Ferguson, 1969) Human 3.5 1 1 - 1 90 - - - - NOAEL = 100 ppm, 8 h (Stewart et al., 1974) Human 3.0 1 1 3 (HR) 1 - 11 - - - Cardiac arrhythmia 1/12 at 5000 ppm, 10 min (Reinhardt et al., 1973) Dog - 2 10 1 5 50 50 50 50 50 Hepatotoxicity and nephrotoxicity Rat, guinea - 1 10 - 1 - - - 4 2 NOAEL = 35 ppm, 7 h/d, 5 d (Stewart et al., 1970) pig, monkey, rabbit, dog NOAEL = 200 ppm, 7 h/d, 5 d (Stewart et al., 1970) Human 4.5 1 1 5 (HR) 1 - - 9 - - Carcinogenesis 1.7 × 10-6 a at 0.00019 ppm, life continuous (EPA, 1987) Human - NA 1 NA 1 - 300 40 10 2 SMACs 50 11 9 4 2 a Excess tumor risk of 1.7 × 10-6. —, Data not considered applicable to the exposure time; HR, Haber's rule.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 REFERENCES ACGIH. 1986. Trichloroethylene. In Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH. 1991. Guide to Occupational Exposure Values—1991. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH. 1995. 1995-1996 Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Adams, E. M., H. C. Spencer, V. K. Rowe, D. D. McCollister, and D. D. Irish. 1951. Vapor toxicity of trichloroethylene determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med. 4:469-481. Andersen, M. E., M. L. Gargas, H. J. Clewell III, and K. M. Severyn. 1987. Quantitative evaluation of the metabolic interactions between trichloroethylene and 1, 1-dichloroethylene in vivo using gas uptake methods. Toxicol. Appl. Pharmacol. 89:149-157. Annau, Z. 1981. The neurobehavioral toxicity of trichloroethylene. Neurobehav. Toxicol. Teratol. 3:417-424. Axelson, O., K. Andersen, C. Hogstedt, B. Holberg, G. Molina, and A. de Verdier. 1978. A cohort study on trichloroethylene exposure and cancer mortality. J. Occup. Med. 20:194-196. Bardodej, Z., and J. Vyskocil. 1956. The problem of trichloroethylene in occupational medicine. AMA Arch. Ind. Health 13:581-592. Battig, K., and E. Grandjean. 1963. Chronic effects of trichloroethylene on rat behavior. Arch. Environ. Health 7:694-699. Bell, A. 1951. Death from trichloroethylene in a dry-cleaning establishment. N. Z. Med. J. 50:119-126. Bloom, T. F., R. S. Kramkowski, and J. Cromer. 1974. Health Hazard Evaluation/Toxicity Report 73-151-141. National Institute for Occupational Safety and Health, Cincinnati, Ohio. 8 pp. Available from NTIS, Springfield, Va., Doc. No. PB-246-461. Brown, L. P., D. G. Farrar, and C. G. DeRooij. 1990. Health risk assessment of environmental exposure to trichloroethylene. Regul. Toxicol. Pharmacol. 11:24-41. Bull, R. J., I. M. Sanchez, M. A. Nelson, J. L. Larson, and A. J. Lan-
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 sing. 1990. Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology 63:341-359. Bungo, M. W. 1989. The cardiopulmonary system. Pp. 179-199 in Space Physiology and Medicine, 2nd Ed. Philadelphia: Lea & Febiger. Byington, K. H., and K. C. Leibman. 1965. Metabolism of trichloroethylene in liver microsomes. II. Identification of the reaction product as chloral hydrate. Mol. Pharmacol. 1:247-254. Coleman, M. 1984. Summary Report of Postflight Atmospheric Analysis for STS-1 to STS-41-C. JSC Memo. SD4-84-351. National Aeronautics and Space Administration, Johnson Space Center, Houston, Tex. Cotter, L. H. 1950. Trichloroethylene poisoning. Arch. Ind. Hyg. Occup. Med. 1:319-322. Dallas, C. E., J. M. Gallo, R. Ramanathan, S. Muralidhara, and J. V. Bruckner. 1991. Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats. Toxicol. Appl. Pharmacol. 110:303-314. Dawson, B. V., P. D. Johnson, S. J. Goldberg, and J. B. Ulreich. 1990. Cardiac teratogenesis of trichloroethylene and dichloroethylene in a mammalian model. J. Am. Col. Cardiol. 16:1304-1309. DeAngelo, A. B., F. B. Daniel, J. A. Stober, and G. R. Olson. 1991. The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. Fundam. Appl. Toxicol. 16:337-347. EPA. 1987. Addendum to the Health Assessment Document for Trichloroethylene: Update Carcinogenicity Assessment for Trichloroethylene. Review draft. EPA 600/8-82/006FA. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Washington, D.C. EPA. 1993. Trichloroethylene. Integrated Risk Information System. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Washington, D.C. Ertle, T., D. Henschler, G. Müller, and M. Spassowski. 1972. Metabolism of trichloroethylene in man. I. The significance of trichloroethanol in long-term exposure conditions. Arch. Toxikol. 29:171-188. Feldman, R. G., J. Chirico-Post, and S. P. Proctor. 1988. Blink reflex latency after exposure to trichloroethylene in well water. Arch. Environ. Health 43:143-147.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Fernandez, J. G., P. O. Droz, B. E. Humbert, and J. R. Caperos. 1977. Trichloroethylene exposure. Simulation of uptake, excretion, and metabolism using a mathematical model. Br. J. Ind. Med. 34:43-55. Fisher, J. W., T. A. Whittaker, D. H. Taylor, H. J. Clewell III, and M. E. Andersen. 1989. Physiologically based pharmacokinetic modeling of the pregnant rat: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Toxicol. Appl. Pharmacol. 99:395-414. Fisher, J. W. , T. A. Whittaker, D. H. Taylor , H. J. Clewell III, and M. E. Andersen. 1990. Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Toxicol. Appl. Pharmacol. 102:497-513. Fisher, M. L. Gargas, B. C. Allen, and M. E. Andersen. 1991. Physiologically based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse. Toxicol. Appl. Pharmacol. 109:183-195. Fukuda, K., K. Takemoto, and H. Tsuruta. 1983. Inhalation carcinogenicity of trichloroethylene in mice and rats. Ind. Health 21:243-254. Goldberg, S. J., M. D. Lebowitz, E. J. Graver, and S. Hicks. 1990. An association of human congenital cardiac malformations and drinking water contaminants. J. Am. Col.. Cardiol. 16:155-164. Grandjean, E., R. Müchinger, V. Turrian, P. A. Haas, H. K. Knoepfel, and H. Rosenmund. 1955. Investigations into the effects of exposure to trichloroethylene in mechanical engineering. Br. J. Ind. Med. 12:131-142. Hathway, D. E. 1980. Consideration of the evidence for mechanisms of 1, 1, 2-trichloroethylene metabolism, including new identification of its dichloroacetic acid and trichloroacetic acid metabolites in mice. Cancer Lett. 8:263-269. Henschler, D., W. Romen, H. M. Elsasser, D. Reichert, E. Eder, Z. Radwan. 1980. Carcinogenicity study of trichloroethylene by longterm inhalation in three animal species. Arch. Toxicol. 43:237-248. Herren-Freund, S. L., M. A. Pereira, M. D. Khoury, and G. Olson. 1987. The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol. Appl. Pharmacol. 90:183-189.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Hervin, R. L, J. W. Cromer, and G. J. Butler. 1974. Health Hazard Evaluation/Toxicity Determination Report 74-2/8-164. Prepared by the Vendo Company, Kansas City, Mo., for the National Institute for Occupational Safety and Health, Cincinnati, Ohio. 17 pp. Available from NTIS, Springfield, Va., Doc. No. PB-246-479. Inoue, O., K. Seiji, T. Kawai, C. Jin, Y. T. Liu, Z. Chen, S. X. Cai, S. N. Yin, G. L. Li, and H. Nakatsuka. 1989. Relationship between vapor exposure and urinary metabolite excretion among workers exposed to trichloroethylene. Am. J. Ind. Med. 15:103-110. Kimmerle, G., and A. Eden. 1973. Metabolism, excretion and toxicity of trichloroethylene after inhalation. Experimental human exposure. Arch Toxicol 30:127-138. Kjellstrand, P., L. M. Ansson, B. Holmquist, and I. Jonsson. 1990. Tolerance during inhalation of organic solvents. Pharmacol. Toxicol. 66:409-414. Kleinfeld, M., and I. R. Tabershaw. 1954. Trichloroethylene toxicity report five fatal cases. AMA Arch. Ind. Hyg. Occup. Med. 10:134-141. Kylin, B., K. Axell, H. E. Samuel, and A. Lindborg. 1967. Effect of inhaled trichloroethylene on the CNS. As measured by optokinetic nystagmus. Arch. Environ. Health 15:48-52. Landrigan, P. J., G. F. Stein, J. R. Kominsky, R. L. Ruhe, and A. S. Watanabe. 1987. Common source community and industrial exposure to trichloroethylene. Arch. Environ. Health 42:327-332. Loeber, C. P. M. J. Hendrix, S. Diez de Pinos, and S. J. Goldberg. 1988. Trichloroethylene: A cardiac teratogen in developing chick embryos. Pediatr. Res. 24:740-744. Longley, E. O., and R. Jones. 1963. Acute trichloroethylene narcosis. Arch. Environ. Health 7:249-252. Maltoni, C., G. Lefemine, G. Cotti, and G. Perino. 1988. Long-term carcinogenicity bioassays on trichloroethylene administered by inhalation to Sprague-Dawley rats and Swiss and B6C3F1 mice. Ann. N.Y. Acad. Sci. 534:316-342. Monster, A. C., G. Boersma, and W. C. Duba. 1979. Kinetics of trichloroethylene in repeated exposure of volunteers. Int. Arch. Occup. Environ. Health 42:283-292. Müller, G., M. Spassowski, and D. Henschler. 1974. Metabolism of trichloroethylene in man. II. Pharmacokinetics of metabolites. Arch. Toxicol. 32:283-295.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Okino, T., T. Nakajima, and M. Nakano. 1991. Morphological and biochemical analyses of trichloroethylene hepatotoxicity: Differences in ethanol—and phenobarbital—pretreated rats. Toxicol. Appl. Pharmacol. 108:379-389. Prendergast, J. A., R. A. Jones, L. J. Jenkins, and J. Siegel. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270-289. Reinhardt, C. F., L. S. Mullin, and M. E. Maxfield. 1973. Epinephrine-induced cardiac arrhythmia potential of some common industrial solvents. J. Occup. Med. 15:953-955. Rippstein, W. J. 1980. Halogenated Hydrocarbon Conversions in Lithium Hydroxide Beds. NASA Memo. SD4-80-61. National Aeronautics and Space Administration, Johnson Space Center, Houston, Tex. Salvini, M., S. Binaschi, and M. Riva. 1971. Evaluation of the psychophysiological functions in humans exposed to trichloroethylene. Br. J. Ind. Med. 28:293-295. Sato, A., T. Nakajima, Y. Fujiwara, and N. Murayama. 1977. A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. Br. J. Ind. Med. 34:56-63. Saunders, R. A. 1967. A new hazard in closed environmental atmospheres. Arch. Environ. Health 14:380-384. Schwetz, B. A., B. K. J. Leong, and P. J. Gehring. 1975. The effect of maternally inhaled trichloroethylene, perchloroethylene, methyl chloroform, and methylene chloride on embryonal and fetal development in mice and rats. Toxicol. Appl. Pharmacol. 32:84-96. Sellers, E. M., M. Lang, J. Koch-Wesser, E. LeBlanc, and H. Kalant. 1972. Interaction of chloral hydrate and ethanol in man. I. Metabolism. Clin. Pharmacol. Ther. 13:37-48. Spirtas, R., P. A. Stewart, J. S. Lee, D. E. Marano, C. D. Forbes, D. J. Grauman, H. M. Pettigrew, A. Blair, R. N. Hoover and J. L. Cohen. 1991. Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br. J. Ind. Med. 48:515-530. Steinberg, A. D., and J. M. DeSesso. 1993. Have animal data been used inappropriately to estimate risks to humans from environmental
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 trichloroethylene? Regul. Toxicol. Pharmacol. 18:137-153. Stewart, R. D., H. H. Gary, D. S. Erley, C. L. Hoke, and J. E. Peterson. 1962. Concentrations of Trichloroethylene in blood and expired air following exposure of humans. Am. Ind. Hyg. Assoc. J. 23:167-170. Stewart, R. D., H. C. Dodd, H. H. Gay, and D.S. Erley. 1970. Experimental human exposure to trichloroethylene. Arch. Environ. Health 20:64-71. Stewart, R. D., C. L. Hake, A. J. Lebrun, J. H. Kalbfleisch, P. E. Newton, J. E. Peterson, H. H. Cohen, R. Struble, and K. A. Busch. 1974. Effects of trichloroethylene on behavioral performance capabilities. Pp. 96-129 in Behavioral Toxicology: Early Detection of Occupational Hazards, C. Xintaras and B. Johnson, and I. de Groot, eds. HEW Publ. No. (NIOSH) 74-126. National Institute for Occupational Safety and Health, Cincinnati, Ohio. Stewart, P. A., J. S. Lee, D. E. Marano, R. Spirtas, C. D. Forbes, and A. Blair. 1991. Retrospective cohort mortality study of workers at an aircraft maintenance facility. II. Exposures and their assessment. Br. J. Ind. Med. 48:531-537. Stopps, G. J., and M. McLaughlin. 1967. Psychophysiological testing of human subjects exposed to solvent vapors. Am. Ind. Hyg. Assoc. J. 28:43-50. Stott, W. T., J. F. Quast, and P. G. Watanabe. 1982. The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats. Toxicol. Appl. Pharmacol. 82:137-151. Tola, S., R. V. Lhuuen, E. J. Arvinen, and M. L. Korkala. 1980. A cohort study on workers exposed to trichloroethylene. J. Occup. Med. 22:737-740. Torkelson, T. R., and V. K. Rowe. 1981. Halogenated aliphatic hydrocarbons containing chlorine, bromine and iodine. Pp. 3553-3560 in Patty's Industrial Hygiene and Toxicology, 3rd Rev. Ed., Vol. 2B, G. D. Clayton and F. E. Clayton, eds. New York: John Wiley & Sons. Triebig, G., H. G. Essing, K. H. Schaller, and H. Valentin. 1976. Biochemical and psychological examinations of trichloroethylene exposed volunteers [translation from German]. Zentralbl. Bakteriol. Abt. 1 Orig. B 163:383-416. U.S. Department of Labor. 1995. Air Contaminants—Permissible Exposure Limits. Title 29, Code of Federal Regulations, Part 1910,
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Representative terms from entire chapter: