Hector D. Garcia, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas


Chloroform is a clear, colorless, volatile and mobile, highly refractive, dense liquid with a characteristic pleasant, nonirritating odor and a slight, sweet taste (ATSDR 1997).



CAS no.:


Chemical name:



Chloroform, trichloroform, formyl trichloride, methenyl chloride, methenyl trichloride, methane trichloride, methyl trichloride, NCI-C02686, Freon 20, R-20, TCM

Molecular weight:


Boiling point:


Melting point:


Liquid density:

1.485 g/m3

Vapor density:

4.36 (air = 1)

Vapor pressure:

159 torr at 20°C


1 mL dissolves in 200 mL at 25°C

Odor threshold:

85 ppm (vapor) Miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride, carbon disulfide, oils.

Conversion factors at 20°C, 1 atm:

1 ppm = 4.96 mg/m3


1 mg/m3 = 0.20 ppm

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B13 Chloroform Hector D. Garcia, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Chloroform is a clear, colorless, volatile and mobile, highly refractive, dense liquid with a characteristic pleasant, nonirritating odor and a slight, sweet taste (ATSDR 1997). Formula: CHCl3 CAS no.: 67-66-3 Chemical name: Trichloromethane Synonyms: Chloroform, trichloroform, formyl trichloride, methenyl chloride, methenyl trichloride, methane trichloride, methyl trichloride, NCI-C02686, Freon 20, R-20, TCM Molecular weight: 119.38 Boiling point: 61.3°C Melting point: –63.2°C Liquid density: 1.485 g/m3 Vapor density: 4.36 (air = 1) Vapor pressure: 159 torr at 20°C Solubility: 1 mL dissolves in 200 mL at 25°C Odor threshold: 85 ppm (vapor) Miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride, carbon disulfide, oils. Conversion factors at 20°C, 1 atm: 1 ppm = 4.96 mg/m3   1 mg/m3 = 0.20 ppm

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 OCCURRENCE AND USE Chloroform is used as a raw material in the chemical industry for the manufacture of such materials as fluorocarbons, resins, and plastics; as an extractant for fats, oils, greases, resins, lacquers, rubber, alkaloids, gums, waxes, guttapercha, penicillin, vitamins, flavors, floor polishes, and adhesives; as a pharmaceutical solvent and dry cleaning spot remover; and as an intermediate in the manufacture of dyes and pesticides (ATSDR 1997). In the past, chloroform was used as a general anesthetic, a fire extinguisher, and a flavoring agent in toothpastes and cough syrups (ACGIH 1991). Trace amounts of chloroform are present in drinking water and in wastewater from sewage-treatment plants as a by-product of chlorine treatment to kill bacteria. Trace amounts of chloroform are also found almost ubiquitously in the environment. Small amounts of chloroform are sometimes carried on board the space shuttle as part of mid-deck or module experiments. Chloroform has been detected in the shuttle atmosphere in 6 of 27 missions at concentrations of 0.002 to 0.03 mg/m3 (Huntoon 1987, 1993) and, in more recent missions, in about 10% of air samples at concentrations of 0.01 to 0.1 mg/m3 (James et al. 1994). TOXICOKINETICS AND METABOLISM Considerable data are available on the uptake, processing, and elimination of chloroform in several species. The weight of evidence indicates that chloroform is rapidly distributed throughout the body and that its toxic effects are more dependent on the dose rate than the total dose or the route of administration. Absorption Due to chloroform's relatively high vapor pressure and high blood/air partition coefficient (8 to 10.3 at 37°C), inhalation is a primary route of entry into the body (EPA 1985). Raabe (1988) measured the uptake of ambient concentrations of chloroform (labeled with 14C) in air inhaled through the nose (45.6%) and the mouth (49.6%) by four human subjects. Chloroform is also rapidly absorbed through the gastrointestinal tract from foodstuffs and drinking water (EPA 1985). Absorption of orally administered chloroform might be affected by the vehicle in which it is dissolved. In mice, tissue concentrations of chloroform after gavage dosing were consistently greater for aqueous versus corn-oil vehicles (Dix et al. 1997). Absorption of chloroform through the skin is significant (329 µmoles/min/cm2 of skin exposed to the liquid) (EPA 1985).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Distribution In humans (Smith et al. 1973) and animals (Cohen 1971; Brown et al. 1974), chloroform absorbed either by inhalation or orally is distributed to all tissues with relative tissue concentrations of body fat> brain> liver> kidney> blood, as expected owing to the lipophilic nature of chloroform. In studies in mice, the relative distribution in the organs was dependent on route of administration; oral dosing resulted in the highest concentrations being in the liver, possibly due to a first-pass effect, the time between dosing and measurement, and the metabolism and covalent binding of metabolites to cellular macromolecules (Brown et al. 1974; Taylor et al. 1974). Excretion Chloroform was detected in the exhaled air of volunteers exposed to a normal environment, to heavy automobile traffic, or to 2 h in a dry-cleaning establishment (Gordon et al. 1988). High chloroform concentrations in the breath corresponded to high exposure concentrations. The calculated biological half-time for chloroform was 7.9 h. Excretion of radioactivity in mice and rats was monitored for 48 h following exposure to 14C-labeled chloroform at 10, 89, and 366 ppm (mice) or 93, 356, and 1041 ppm (rats) (Corley et al. 1990). In this study, 92% to 99% of the total radioactivity was recovered in mice, and 58% to 98% was recovered in rats; percentage recovery decreased with increasing exposure. Of the total radioactivity, the percentages recovered as exhaled 14C-labeled carbon dioxide were 80% to 85% for mice and 48% to 85% for rats. The fractions recovered as 14C-labeled chloroform were 0.4% to 8% for mice and 2% to 42% for rats. The fractions recovered as urinary and fecal metabolites were 8% to 11% and 0.6% to 1.4% for mice and 6.4% to 8.9% and 0.6% to 1.1% for rats, respectively. A 4-fold increase in exposure concentration was followed by a 50- and 20-fold increase in the amount of exhaled, unmetabolized chloroform in mice and rats, respectively. Metabolism The metabolism of chloroform has been extensively studied and is fairly well understood. In humans, approximately 50% of an oral dose of 0.5 g chloroform was metabolized to carbon dioxide (Fry et al. 1972). Metabolism was dose

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 dependent, decreasing with higher exposure. A first-pass effect was observed after oral exposure (Chiou 1975). Approximately 38% of the dose was converted in the liver, and ≤ 17% was exhaled unchanged from the lungs. In a physiologically based pharmacokinetic modeling study of chloroform, Corley et al. (1990) defined in vivo metabolic rate constants (Vmax C = 15.7 mg/kg/h, Km = 0.448 mg) for humans by using experimental results obtained in rats and mice exposed to chloroform by inhalation and enzymatic studies in human tissues in vitro. Their results predicted that metabolic activation of chloroform to its toxic intermediate, phosgene, was slower in humans than in rodents (ATSDR 1997). Chloroform can be metabolized aerobically and anaerobically as shown below: Major Pathway (Aerobic).Source: Adapted from ATSDR (1997)

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Minor Pathway (Anaerobic). Source: Adapted from ATSDR (1997) The production of CO2 by the aerobic pathway accounts for up to 85% of administered chloroform in mice, 65% in rats, and lesser amounts (28%) in squirrel monkeys and humans (50%) (Brown et al. 1974; Taylor et al. 1974). In mice, Brown et al. found greater amounts of radiolabeled chloroform in the kidneys of males than of females. Similarly, Culliford and Hewitt (1957) found that chloroform accumulated and metabolized to a greater extent in the renal cortex of males than of females; the results might have been influenced by testosterone concentrations. This effect was not observed in any other species. These species and sex differences in metabolism, distribution, and binding point out the dangers and difficulties in extrapolating studies in lower animals to humans. Metabolism studies by Pohl (1977) and Stevens and Anders (1981) indicated that chloroform was exhaled from the lungs or was converted to phosgene in the liver and kidneys by cytochrome P-450 (Branchflower et al. 1984; Smith and Hook 1984). Phosgene might react with cellular elements, including lipids and proteins of the endoplasmic reticulum proximate to the cytochrome P-450. In phenobarbital-pretreated Sprague-Dawley rats, chloroform exposure yielded a covalent adduct to a single phospholipid, identified as phosphatidylethanolamine, in liver mitochondria (Guastedisegni et al. 1998). It was further demonstrated that chloroform can induce lipid peroxidation and inactivation of cytochrome P-450 in rat-liver microsomes under aerobic conditions (DeGroot and Noll 1989). This mechanism might also contribute to chloroform-induced hepatotoxicity in rats, although phosgene and other active metabolites are primarily responsible. The conversion of chloroform to reactive metabolites

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 occurs in nuclear preparations, as well as in microsomes (Gomez and Castro 1980). Covalent binding of chloroform to lipids can occur under anaerobic and aerobic conditions; binding to protein occurs only under aerobic conditions (Testai et al. 1987). Covalent binding of chloroform metabolites to microsomal protein in vitro was intensified by microsomal enzyme inducers and prevented by glutathione (Brown et al. 1974). It was proposed that the reaction of chloroform metabolites with glutathione might act as a detoxifying mechanism. Phosgene might combine with two molecules of reduced glutathione (GSH) to form diglutathionyl dithiocarbonate, which is further metabolized in the kidneys (Sipes et al. 1977; Wolf et al. 1977). Chloroform doses that caused liver glutathione depletion produced liver necrosis (Docks and Krishna 1976). Furthermore, chloroform has been found to be more hepatotoxic in fasted animals, possibly due to decreased glutathione content in the liver (Brown et al. 1974; Docks and Krishna 1976; Wang et al. 1995). That might explain the clinical finding of severe acute hepatotoxicity in women exposed to chloroform via anesthesia during prolonged parturition. Evidence that chloroform is metabolized at its carbon-hydrogen bond is provided by experiments using the deuterated derivative of chloroform (McCarty et al. 1979; Pohl et al. 1980; Branchflower et al. 1984). Deuterated chloroform was one-half to one-third as cytotoxic as chloroform, and its conversion to phosgene was much slower. The results confirmed that the toxicity of chloroform is primarily due to its metabolites (ATSDR 1997). A recent in vitro study of mice hepatic microsomes indicated that a reductive pathway might play an important role in chloroform hepatotoxicity (Testai et al. 1990). It was demonstrated that radical chloroform metabolites bind to macromolecules (proteins, lipids) and the process can be inhibited by reduced glutathione (ATSDR 1997). The final product of the aerobic metabolic pathway of chloroform is carbon dioxide (Fry et al. 1972; Brown et al. 1974), which is mostly eliminated through the lung, but some is incorporated into endogenous metabolites and excreted as bicarbonate, urea, methionine, and other amino acids (Brown et al. 1974). Inorganic chloride ion is an end product of chloroform metabolism found in the urine (Van Dyke et al. 1964). Carbon monoxide was a minor product of the anaerobic metabolism of chloroform in vitro (Ahmed et al. 1977) and in vivo in rats (Anders et al. 1978; ATSDR 1997). Interspecies differences in the rate of chloroform conversion were observed in mice, rats, and squirrel monkeys. The conversion of chloroform to carbon dioxide was highest in mice (85%) and lowest in squirrel monkeys (28%) (Brown et al. 1974). Similarly, because of the lower relative rates of chloro-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 form metabolism, ventilation, and cardiac output (per kilogram of body weight) in the larger species, physiologically based pharmacokinetic (PBPK) calculations indicated that exposure to equivalent concentrations of chloroform vapor would lead to a lower delivered dose of active metabolites in humans compared with rats, which would have a lower delivered dose than mice (Corley et al. 1990; ATSDR 1997). TOXICITY SUMMARY Chloroform has pronounced effects on the central nervous system (CNS), most of which are reversible upon cessation of exposure. Short-term exposure to high concentrations causes liver necrosis, kidney degeneration, and cardiac arrhythmias, and possibly nasal lesions and immune-system depression. Exposures to lower concentrations, which do not cause liver or kidney pathology, can still cause cytotoxicity, as evidenced by increases in the labeling indices of these tissues. Long-term exposure to relatively high concentrations might lead to liver or kidney cancer. Acute and Short-Term Exposures Cardiac Effects Chloroform anesthesia is associated with cardiac toxicity. In a 1965 epidemiological study by Whitaker and Jones (1965) of a cohort of 1502 patients (exposures at concentrations of 10,000 to 22,500 ppm), dose-related bradycardia developed in 8% of the cases, and cardiac arrhythmia developed in 1.3% of the cases. Hypotension was observed in 27% of the patients and was related to the duration of the anesthesia and to pretreatment with thiopentone. In 1973, Smith et al. reported that chloroform anesthesia (exposures at 8000 to 10,000 ppm) caused arrhythmia (nodal rhythm, first degree atrioventricular block, or complete heart block) in 50% of the cases from the cohort of 58 patients, and hypotension in 12% (Smith et al. 1973). An EKG study of 66 patients anesthetized for at least 2 h at the State of Wisconsin General Hospital demonstrated that the effect of chloroform on the heart is not to induce ventricular fibrillation but rather depression of the myocardium to the point of asystole (Orth et al. 1951). The EC50 (the concentration that induces a given affect in 50% of the exposed animals of a species in a given time) for sensitization to cardiac ar-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 rhythmia in dogs exposed for 5 min to chloroform vapors was 16,000 ppm (Clark and Tinston 1982). This effect was rapidly reversed on cessation of exposure (Clark and Tinston 1982). CNS Evidence for chloroform's effects on the CNS come from occupational exposures and from the use in the past of chloroform as an inhalation anesthetic. The recommended method to induce anesthesia during surgery or childbirth involved increasing concentrations of chloroform gradually to 25,000 or 30,000 ppm during the first 2 or 3 min, with maintenance at much lower concentrations (ATSDR 1997). Concentrations < 1500 ppm are insufficient to induce anesthesia; 1500 to 2000 ppm causes light anesthesia (Goodman and Gilman 1980). Dizziness and vertigo occur after exposure to 920 ppm for 3 min; headache and slight intoxication occur at higher concentrations (Lehmann and Hasegawa 1910). The EC50 for CNS depression (ataxia and loss of righting reflex) in rats exposed for 10 min to chloroform vapors was 16,000 ppm (Clark and Tinston 1982). That effect was rapidly reversed on cessation of exposure (Clark and Tinston 1982). Hepatotoxicity Several early studies reported acute hepatic necrosis in women exposed to chloroform via anesthesia (Royston 1924; Townsend 1939; Lunt 1953). The effects observed in women included jaundice, liver enlargement and tenderness, delirium, coma, and death. Centrilobular necrosis was found at autopsy in those who died. In 1973, Lieberman reported that there had not been any chloroform jaundice in 30,000 chloroform anesthesias at one hospital since 1942. Lieberman (1973) noted that other studies have documented hepatic necrosis due to all anesthetics, including cyclopropane, ether, ethylene, and nitrous oxide and reported a personal communication from a chief of pathology at a hospital that there had been no cases of chloroform hepatitis over a 15-y period from 1945 through 1960 during which 70,000 ''open-drop" chloroform anesthesias were administered for obstetrics. In the open-drop technique, chloroform was administered on a handkerchief. Until precision vaporizers became available in the late 1950s, anesthetists had no means to measure or control the concentration of chloroform in inspired air, and cases of hepatotoxicity were attributed

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 to overdosing by inexperienced anesthetists. Whitaker and Jones (1965) studied over 1500 patients receiving chloroform anesthesia administered by a precision vaporizer at nominal inspired concentrations of no greater than 22,500 ppm for durations of less than 30 min (1164 patients) to over 120 min (24 patients). The only case of hepatotoxicity found was transient jaundice in one patient 36 h after exposure to chloroform for 6 min, but the patient was believed to have been incubating infectious hepatitis before anesthesia. Increased sulfobromophthalein retention was observed in some patients exposed to chloroform via anesthesia (exposures at 8000 to 10,000 ppm), indicating impaired liver function (Smith et al. 1973). Brown et al. (1974) found that exposure of rats for 2 h to chloroform at 5000 or 10,000 ppm produced hepatic necrosis and destruction of microsomal enzymes. Treatment of rats with phenobarbital to induce microsomal enzyme activity before exposure to chloroform markedly increased the hepatotoxic response to anesthesia and produced a 70% to 80% decrease in hepatic glutathione concentrations. In rats in which microsomal enzyme activity was not induced with phenobarbital, chloroform exposure did not result in depletion of glutathione or in hepatic necrosis 24 h after exposure (Brown et al. 1974). Experimental depletion of hepatic glutathione by pretreatment with diethyl maleate also resulted in centrilobular necrosis after exposure to chloroform (Brown et al. 1974). These results suggest that much or all of the hepatotoxicity of chloroform is due to the production of reactive chloroform metabolites (e.g., phosgene). Studies at the Chemical Industry Institute of Toxicology (CIIT) found large species-specific differences in the dose-related hepatotoxicity of chloroform inhaled 6 h/d for 7 d by B6C3F1 mice and Fischer 344 (F344) rats, with lowest-observed-adverse-effect levels (LOAELs) of 10 ppm and 300 ppm and no-observed-adverse-effect levels (NOAELs) of 3 ppm and 100 ppm, respectively (Larson et al. 1994b). They later tested for hepatotoxicity in male and female BDF1 mice exposed to chloroform for 6 h/d for 4 d at 0, 0.3, 5, 30, or 90 ppm or males exposed for 6 h/d, 5 d/w for 2 w at 0, 30, or 90 ppm (Templin et al. 1996a). Mild centrilobular hepatocyte vacuolization was seen in one of five male mice exposed at 30 ppm for 2 w, and centrilobular vacuolization and focal areas of hepatocyte necrosis were seen in three of four male mice and three of five female mice exposed at 90 ppm for 4 d. Significant increases in hepatocyte labeling index (LI) were seen in male mice exposed to chloroform at 30 and 90 ppm and in female mice exposed at 90 ppm (Templin et al. 1996a). Unpublished results from CIIT indicated that similar dose responses were obtained for increases in hepatocyte LIs in B6C3F1 mice exposed for periods of 7 d to 180 d (Butterworth 1997). The observed species-specific differences in sensitivity to the hepatotoxic

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 effects of chloroform are not due to differences in the sensitivity of hepatocyte cells to the cytotoxic effects of chloroform or to differences in their ability to metabolize chloroform. When freshly isolated hepatocytes from B6C3F1 mice and F344 rats were exposed to solutions of chloroform for up to 3 h, concentration-dependent cytotoxicity (lactate dehydrogenase release) was seen in culture at concentrations higher than 1 mM (Ammann et al. 1998). Cotreatment with the cytochrome P-450 inhibitor 1-phenylimidazole prevented both cytolethality and glutathione depletion, indicating that metabolism is necessary for chloroform-induced cytotoxicity. These results correlate well with simulations of a physiologically based dosimetry model for chloroform. The simulations indicated that after hepatotoxic oral bolus doses of chloroform at 477 mg/kg of body weight, the livers of mice and rats were exposed to chloroform at concentrations up to 5 mM for 3 h (Ammann et al. 1998). Hepatocytes from the two species exhibited similar sensitivity toward chloroform toxicity, indicating that toxicity is not sufficient to explain different susceptibility to heptocarcinogenicity. Lethality Acute exposures to relatively high concentrations of chloroform can cause immediate death due to cardiovascular toxicity or delayed death (1 to 4 d after exposure) due to hepatotoxicity or nephrotoxicity. In humans, obstetric use of chloroform anesthesia earlier in this century occasionally caused fatal toxicity (Royston 1924). Obstetric deaths occurred either during anesthesia, due to cardiac arrhythmias, or a few days after anesthesia, due to hepatotoxicity. A 1973 report by an anesthesiologist stated that there had been no deaths at one hospital in 30 y from over 30,000 chloroform anesthesias for obstetrics since 1942 (Lieberman 1973) and attributed previous reports of chloroform-related deaths to use by inexperienced anesthetists of the crude open-drop technique of administering chloroform on a handkerchief, which made it difficult to control exposure concentrations. The LC50 (lethal concentration for 50% of the exposed animals) for rats exposed for 15 min to chloroform vapor was 76,000 ppm (Clark and Tinston 1982). For a 6-h exposure to chloroform vapors, the LC 50 was 1849 ppm in rats and 1260 ppm in mice (Bonnet et al. 1980). Nausea A frequent side effect of chloroform anesthesia (8000 to 22,500 ppm) was

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 nausea (Royston 1924; Townsend 1939; Whitaker and Jones 1965; Smith et al. 1973). Nausea was also reported by women employed in a lozenge factory while working in an atmosphere with chloroform concentrations ranging from 23 to 1163 ppm (average = 128 ppm) for a period of 3 to 10 y (Challen et al. 1958). Thirteen workers exposed to chloroform at >400 ppm for 1 to 5 mo and 18 workers exposed at 14.4 to 50.4 ppm for 1 to 4 mo developed nausea in association with toxic hepatitis (Phoon et al. 1983). The data available are insufficient to establish a NOAEL or LOAEL or a dose-response relationship for nausea. Nephrotoxicity Chloroform induces kidney toxicity, which, depending on the species and strain, can be more or less severe than the liver toxicity induced by the same dose. Reports of chloroform-induced kidney toxicity in humans are few and sketchy but always associated with severe liver toxicity. In case reports of women who died after exposure to chloroform anesthesia during childbirth, autopsy revealed fatty degeneration of the kidneys, indicating chloroform-induced damage (Royston 1924). Those deaths are most likely attributable to hepatotoxicity in fasted individuals rather than nephrotoxicity, because the same women were reported to have jaundice, liver enlargement and tenderness, and, at autopsy, centrilobular necrosis. In laboratory animals, susceptibility to chloroform-induced nephrotoxicity varies greatly with species, strain, and sex. In BDF1 mice, Templin et al. (1996a) found degenerative lesions and an increase of 7- to 10-fold in the percentage of cells in the S phase in the kidneys of males, but not of females, inhaling chloroform at 30 or 90 ppm, 6 h/d, 5 d/w for 2 w. In males exposed for 2 w, 40% of the 30-ppm group and 80% of the 90-ppm group died with severe kidney damage, indicating that 30 and 90 ppm exceeded the maximum tolerated dose. The NOAEL for male BDF1 mice inhaling chloroform for 4 d, 6 h/d was 5 ppm. In contrast, B6C3F1 mice were more resistant to chloroform nephrotoxicity and had a NOAEL of 100 ppm for a 6-h/d, 7-d exposure (Larson et al. 1994b). Similarly exposed F344 rats had a LOAEL of 30 ppm and a NOAEL of 10 ppm for exposure-induced kidney-cell proliferation (Larson et al. 1994b). In certain strains of mice, renal tubular necrosis was reported in 100% of males after exposure to chloroform at ≤ 240 ppm for 2 h (Derringer et al. 1953; Culliford and Hewitt 1957). Mice surviving the exposure were found to have tubular calcifications when examined 12 mo after exposure. The kidneys of female mice of the susceptible strains and of both male and female mice of other strains were completely unaffected. Females of the susceptible strains

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Thus, Nephrotoxicity ACs for nephrotoxicity are set based on data from animal experiments because few or no data exist on the nephrotoxic effects of inhalation exposures to chloroform in humans other than autopsy reports on women who died as a result of chloroform anesthesia during childbirth. Those reports found fatty degeneration of kidneys believed to be due to chloroform exposure in some of the patients (Royston 1924), but the exposure concentrations that produced such toxicity were not reported. In males of the most sensitive species of mice, Templin et al. (1996a) found an experimental NOAEL of 5 ppm for kidney necrosis after exposures of 6-h/d for 4 d or for 2 w (5 d + 4 d). Their NOAEL is used to derive an AC for nephrotoxicity. A species extrapolation factor of 1 is used because PBPK modeling of the rate at which inhaled chloroform reaches the liver shows that, at any given atmospheric concentration, humans will achieve lower hepatic (and, by extension, kidney) chloroform concentrations than will mice. In addition, the data available suggest that the susceptibility of human tissues to injury by the active metabolites of chloroform does not exceed that of mouse tissues (Reitz et al. 1990). The total exposure time in the Templin et al. (1996a) experiment was 54 h, (6 h/d × 9 d). Thus, for exposure durations shorter than 54 h, (i.e., 1 h and 24 h), the ACs are set equal to the 5-ppm NOAEL, and for the 7-d AC, the NOAEL is adjusted for exposure duration using Haber's rule. Thus, No 30-d or 180-d AC was set using these data because they would require a time extrapolation of greater than 10-fold.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Reproductive and Developmental Toxicity ACs are not calculated for chloroform's ability to cause changes in sperm morphology, because Land et al. (1981) stated that the clinical significance of their findings (up to 3.5% abnormal sperm in mice exposed 4 h/d for 5 d at 800 ppm) cannot be evaluated because they did not study mating outcomes. ACs are also not calculated for decreased ability to maintain pregnancy, decreased conception rates in females, or teratogenic effects because NASA policy does not permit pregnant astronauts to fly. Spaceflight Effects Spaceflight is believed to increase the susceptibility of crew members to noncritical cardiac arrhythmias and could amplify the arrhythmogenic effects of chloroform.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 13-4 Acceptable Concentrations End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species NOAEL Species Time Spaceflight 1 h 24 h 7 d 30 d 180 d Carcinogenicity (liver cytotoxicity) Mouse 1 1 1 1 NS NS 10 10 10 NOAEL, 10 ppm (Larson et al. 1996)                     Cardiac arrhythmia Human 10 1 1 5 160 160 160 160 160 8000 ppm = EC50 (Smith et al. 1973)                     CNS depression Human 10 1 1 1 2 2 2 2 2 LOAEL, 22 ppm (Challen et al. 1958)                     Hepatotoxicity Human 10 1 HR 1 NS NS 3 1 NS LOAEL 32 ppm, 8 h/d, 6 d/w, 1 mo (Phoon et al. 1983)                     LOAEL, 22 ppm, 4 h/d, 5 d/w for 24 mo (Challen et al. 1958) Human 10 1 HR 1 NS NS NS NS 1 Nephrotoxicity Mouse, BDF1, male 1 1 1 1 5 5 1.6 NS NS NOAEL increases in LI, 5 ppm, 6 h/d, 4 d (Templin et al. 1996a)                     SMACs           2 2 2 2 1 —, not applicable; NS, not set; HR, Haber's rule.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RECOMMENDATIONS Because chloroform's toxicity to the liver, kidney, and possibly the respiratory tract is due to its metabolites produced by cytochrome P-450, research is needed to quantitate the organ-specific levels of metabolism in humans and to elucidate factors, such as glutathione concentrations, which could modulate the threshold concentration of chloroform required for toxicity. Once those are determined, a PBPK model incorporating these values would be useful. REFERENCES ACGIH. 1991. Chloroform. Pp. 289-291 in Documentation of the Threshold Limit Values and Biological Exposure Indices, Vol 1, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1991. Guide to Occupational Exposure Values—1991. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1997. P. 19 in 1997 TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Agustin, J.S., and C.Y. Lim-Sylianco. 1978. Mutagenic and clastogenic effects of chloroform. Bull. Phil. Biochem. Soc. 1:17-23. Ahmed, A.E., V.L. Kubic and M.W. Anders. 1977. Metabolism of haloforms to carbon monoxide. I. In vitro studies . Drug Metab. Dispos. 5:198-204. Ammann, P., C.L. Laethem, and G.L. Kedderis. 1998. Chloroform-induced cytolethality in freshly isolated male B6C3F1 mouse and F-344 rat hepatocytes. Toxicol. Appl. Pharmacol. 149:217-225. Anders, M.W., J.L. Stevens, R.W. Sprague, Z. Shaath, and A.E. Ahmed. 1978. Metabolism of haloforms to carbon monoxide. II. In vivo studies. Drug Metabol. Dispos. 6:556-560. Aranyi, C., W.J. O'Shea, J.A. Graham, and F.J. Miller. 1986. The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fundam. Appl. Toxicol. 6:713-720. ATSDR. 1997. Toxicological Profile for Chloroform. TP-92-07. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Baeder, C., and T. Hofmann. 1988. Inhalation Embryotoxicity Study of Chloroform in Wistar Rats. Frankfurt: Pharma Research Toxicology and Pathology, Hoechst Aktiengesellschaft. Bomski, H., A. Sobolewska, and A. Strakowski. 1967. Toxic damage of the liver by chloroform in chemical industry workers. Int. Arch. F. Gewerbepathol. Gewerbehyg. 24:127-134. Bonnet, P., J.M. Francin, D. Gradiski, G. Raoult, and D. Zissu. 1980. Determination

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 of the median lethal concentration of principal chlorinated aliphatic hydrocarbons in the rat. Arch. Mal. Prof. Med. Trav. Secur. Soc. 41:317-321. Branchflower, R.V., D.S. Nunn, R.J. Highest, J.H. Smith, J.B. Hook, and L.R. Pohl. 1984. Nephrotoxicity of chloroform: Metabolism to phosgene by the mouse kidney. Toxicol. Appl. Pharmacol. 72:159-168. Brown, B.R., Jr., I.G. Sipes, and A.M. Sagalyn. 1974. Mechanisms of acute hepatic toxicity: Chloroform, halothane, and glutathione. Anesthesiology 41:554-561. Brown, D.M., P.F. Langley, D. Smith, and D.C. Taylor. 1974. Metabolism of chloroform—I. The metabolism of [14C]-chloroform by different species. Xenobiotica 4:151-163. Butterworth, B.E., M.V. Templin, A.A. Constan, C.S. Sprankle, B.A. Wong, L.J. Pluta, J.I. Everitt, and L. Recio. 1998. Long-term mutagenicity studies with chloroform and dimethylnitrosamine in female lacI transgenic B6C3F1 mice. Environ. Mol. Mutagen. 31:248-256. Callen, D.F., C.R. Wolf, and R.M. Philpot. 1980. Cytochrome P-450 mediated genetic activity and cytotoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat. Res. 77:55-63. Challen, P.J.R., D.E. Hickish, and J. Bedford. 1958. Chronic chloroform intoxication. Br. J. Ind. Med. 15:243-249. Chiou, W.L. 1975. Quantitation of hepatic and pulmonary first-pass effect and its implications in pharmacokinetic study. I. Pharmacokinetics of chloroform in man. J. Pharmacokinet. Biopharm. 3:193-201. Clark, D.G., and D.J. Tinston. 1982. Acute inhalation toxicity of some halogenated and nonhalogenated hydrocarbons. Hum. Toxicol. 1:239-247. Cohen, E.N. 1971. Metabolism of the volatile anesthetics. Anesthesiology 35:193-202. Corley, R.A., A.L. Mendrala, F.A. Smith, D.A. Staats, M.L. Gargas, R.B. Conolly, M.E. Andersen, and R.H. Reitz. 1990. Development of a physiologically based pharmacokinetic model for chloroform. Toxicol. Appl. Pharmacol. 103:512-527. Crebelli, R., C. Andreoli, A. Carere, G. Conti, M. Cotta-Ramusino, and R. Benigni. 1992. Induction of chromosome malsegregation by halogenated organic solvents in Aspergillus nidulans: Quantitative structure activity relationship (QSAR) analysis with chlorinated aliphatic hydrocarbons. Mutat. Res. 266:117-134. Crebelli, R., R. Benigni, J. Franekic, G. Conti, L. Conti, and A. Carere. 1988. Induction of chromosome malsegregation by halogenated organic solvents in Aspergillus nidulans: Unspecified or specified mechanism? Mutat. Res. 201:401-411. Culliford, D., and H.B. Hewitt. 1957. The influence of sex hormone status on the susceptibility of mice to chloroform-induced necrosis of the renal tubules. J. Endocrinol. 14:381-393. DeGroot, H., and T. Noll. 1989. Halomethane hepatotoxicity: Induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver microsomes under low oxygen partial pressures. Toxicol. Appl. Pharmacol. 97:530-537. Derringer, M.K., T.B. Dunn and W.E. Heston. 1953. Results of exposure of strain C3H mice to chloroform. Proc. Soc. Exp. Biol. Med. 83:474-479. Dix, K.J., G.L. Kedderis, and S.J. Borghoff. 1997. Vehicle-dependent oral absorption

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 and target tissue dosimetry of chloroform in male rats and female mice. Toxicol. Lett. 91:197-209. Docks, E.L., and G. Krishna. 1976. The role of glutathione in chloroform-induced hepatotoxicity. Exp. Mol. Pathol. 24:13-22. Doyle, T.J., W. Zheng, J. R. Cerhan, C.-P. Hong, T.A. Sellers, L.H. Kushi, and A.R. Folsom. 1997. The association of drinking water source and chlorination by-products with cancer incidence among postmenopausal women in Iowa: A prospective cohort study. Am. J. Public Health 87:1168-1176. EPA. 1985. Health Assessment Document for Chloroform. PB86-105004. U.S. Environmental Protection Agency, Washington, DC. NTIS Publ. Doc. PB86-105004. Eschenbrenner, A.B., and E. Miller. 1945. Induction of hepatomas in mice by repeated oral administration of chloroform, with observations on sex differences. J. Natl. Cancer Inst. 5:251-255. Fry, B.J., R. Taylor, and D.E. Hathaway. 1972. Pulmonary elimination of chloroform and its metabolite in man. Arch. Int. Pharmacodyn.Ther. 196:98-111. Gocke, E., M.T. King, K. Eckhardt, and D. Wild. 1981. Mutagenicity of cosmetics ingredients licensed by the European Communities. Mutat. Res. 90:91-109. Golden, R.J., S.E. Holm, D.E. Robinson, P.H. Julkunen, and E.A. Reese. 1997. Chloroform mode of action: Implications for cancer risk assessment. Regul. Toxicol. Pharmacol. 26:142-155. Gomez, M.I.D., and J.A. Castro. 1980. Nuclear activation of carbon tetrachloride and chloroform. Res. Commun. Chem. Pathol. Pharmacol. 27:191-194. Goodman, L.S., and A. Gilman, eds. 1980. The Pharmacological Basis of Therapeutics. New York: Macmillan. Gordon, S.M., L.A. Wallace, E.D. Pellizzari, and H.J. O'Neill. 1988. Human breath measurements in a clean-air chamber to determine half-lives for volatile organic compounds. Atmos. Environ. 22:2165-2170. Guastedisegni, C., L. Guidoni, M. Balduzzi, V. Viti, E. DiConsiglio, and L. Vittozi. 1998. Characterization of a phospholipid adduct formed in Sprague Dawley rats by chloroform metabolism: NMR studies. J. Biochem. Mol. Toxicol. 12:93-102. Gulati, D.K., E. Hope, R.C. Mounce, S. Russell, and K.B. Poonacha. 1988. Chloroform: Reproduction and fertility assessment in CD-1 mice when administered by gavage. NTP 89-018; PB89-148639. Prepared by Environmental Health Research and Testing, Inc., Lexington, KY, for National Toxicology Program, Research Triangle Park, NC Hathaway, G.J., N.H. Proctor, J.P. Hughes, and M.L. Fishman, eds. 1991. Chloroform Pp. 168-169 in Proctor and Hughes' Chemical Hazards of the Workplace, 3rd Ed. New York: Van Nostrand Reinhold. Heywood, R., R.J. Sortwell, P.R.B. Noel, A.E. Street, D.E. Prentice, F.J.C. Roe, P.F. Wadsworth, A.N. Worden, and N.J. Van Abbe. 1979. Safety evaluation of toothpaste containing chloroform. III. Long-term study in beagle dogs. J. Environ. Pathol. Toxicol. 2:835-851. Huntoon, C.L. 1987. Introduction Summary Report of Postflight Atmospheric Analysis

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 for STS-41-D to 61-C. SD4/87-253. National Aeronautics and Space Administration, Lyndon B. Johnson Space Center, Houston, TX. Huntoon, C.L. 1993. Summary Report of Preflight and Postflight Atmospheric Analyses for STS-26 through STS-41. SD4-93-021. National Aeronautics and Space Administration, Lyndon B. Johnson Space Center, Houston, TX. James, J.T., T.F. Limero, H J. Leaño, J.F. Boyd, and P.A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the Space Shuttle: STS-26 to STS-55. Aviat. Space Environ. Med 65:851-857. Jorgenson, T.A., E.F. Meierhenry, C.J. Rushbrook, R.J. Bull, and M. Robinson. 1985. Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fundam. Appl. Toxicol. 5:760-769. Kirkland, D.J., K.L. Smith, and N.J. Van Abbe. 1981. Failure of chloroform to induce chromosome damage or sister chromosome exchanges in cultured human lymphocytes and failure to induce reversion in Escherichia coli. Food Cosmet. Toxicol. 19:651-656. Klaunig, J.E., R.J. Ruch, and M.A. Periera. 1986. Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice. Environ. Health Perspect. 69:89-95. Land, P.C., E.L. Owen, and H.W. Linde. 1981. Morphological changes in mouse spermatozoa after exposure to inhalational anesthetics during early spermatogenesis. Anesthesiology 54:53-56. Larson, J.L., M.V. Templin, D.C. Wolf, K.C. Jamison, J.R. Leininger, S. Méry, K.T. Morgan, B.A. Wong, R.B. Conolly, and B.E. Butterworth. 1996. A 90-day chloroform inhalation study in female and male B6C3F 1 mice: Implications for cancer risk assessment. Fundam. Appl. Toxicol. 30:118-137. Larson, J.L., D.C. Wolf, and B.E. Butterworth. 1994a. Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage. Fundam. Appl. Toxicol. 23:537-543. Larson, J.L., D.C. Wolf, K.T. Morgan, S. Méry, and B.E. Butterworth. 1994b. The toxicity of 1-week exposures to inhaled chloroform in female B6C3F1 mice and male F-344 rats. Fundam. Appl. Toxicol. 22:431-446. Lehmann, K.B., and D. Hasegawa. 1910. Absorption of chlorinated hydrocarbon compounds from the air in animals and man. Arch. Hyg. 72:327-342. Li, L.H., X.Z. Jiang, Y.X. Liang, .Z.Q. Chen, Y.F. Zhou, and Y.L. Wang. 1993. Studies on the toxicity and maximum allowable concentration of chloroform. Biomed. Environ. Sci. 6:179-186. Liang, J.C., T.C. Hsu, and J.E. Henry. 1983. Cytogenetic assays for mitotic poisons: The grasshopper embryo system for volatile liquids. Mutat. Res. 113:467-479. Lieberman, S.L. 1973. Chloroform anesthesia. Anesth. Analg. 52:673-675. Lundberg, I., M. Ekdahl, T. Kronevi, V. Lidums, and S. Lundberg. 1986. Relative hepatotoxicity of some industrial solvents after intraperitoneal injection or inhalation exposure in rats. Environ. Res. 40(2):411-420. Lunt, R.L. 1953. Delayed chloroform poisoning in obstetric practice. Br. Med. J. 1:489-490.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 McCarty, L.P., R.S. Malek, and E.R. Larsen. 1979. The effects of deuteration on the metabolism of halogenated anesthetics in the rat. Anesthesiology 51:106-110. Melnick, R.L., M.C. Kohn, J.K. Dunnick, and J.R. Leininger. 1998. Regenerative hyperplasia is not required for liver tumor induction in female B6C3F1 mice exposed to trihalomethanes. Toxicol. Appl. Pharmacol. 148:137-147. Mersch-Sundermann, V., U. Schneider, G. Klopman, and H.S. Rosenkranz. 1994. SOS induction in Eschericia coli and Salmonella mutagenicity: A comparison using 330 compounds. Mutagenesis 9:205-224. Mery, S., J.L. Larson, B. E. Butterworth, D. C. Wolf, R. Harden, and K. T. Morgan. 1994. Nasal toxicity of chloroform in male F-344 rats and female B6C3F1 mice following a 1-week inhalation exposure. Toxicol. Appl. Pharmacol. 125:214-227. Mitchell, A.D., B.C. Myhr, C.J. Rudd, W.J. Caspary, and V.C. Dunkel. 1988. Evaluation of the L5178Y mouse lymphoma cell system: Methods used and chemicals evaluated. Environ. Mol. Mutagen. 12 (Suppl 13):1-18. Morimoto, K., and A. Koizumi. 1983. Trihalomethanes induce sister chromatid exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo. Environ. Res. 32:72-79. Morris, R.D., A.M. Audet, I.F. Angelillo, T.C. Chalmers, and F. Mosteller. 1992. Chlorination, chlorination by-products, and cancer: A meta-analysis. Am. J. Public Health 82:955-963. Murray, F.J., B.A. Schwetz, J.G. McBride, and R.E. Staples. 1979. Toxicity of inhaled chloroform in pregnant mice and their offspring. Toxicol. Appl. Pharmacol. 50:515-522. NCI. 1976. Report on Carcinogenesis Bioassay of Chloroform. Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, MD. NIOSH. 1990. NIOSH Pocket Guide to Chemical Hazards. Publication No. 90-117 . National Institute for Occupational Safety and Health, Cincinnati, OH. NRC. 1984. Chloroform. Pp. 57-76 in Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. Orth, O.S., R.R. Liebenow, and R.T. Capps. 1951. The Effect of Chloroform on the Cardiovascular System. Pp. 39-75 in Chloroform. A Study after 100 Years, R.M. Waters, ed. Madison: University of Wisconsin Press. Palmer, A.K., A.E. Street, J.C. Roe, A.N. Worden, and N.J.V. Abbé. 1979. Safety evaluation of toothpaste containing chloroform. II. Long term studies in rats. J. Environ. Pathol. Toxicol. 2:821-833. Pegram, R.A., M.E. Anderson, S.H. Warren, T.M. Ross, and L.D. Claxton. 1997. Glutathione S-transferase-mediated mutagenicity of trihalomethanes in Salmonella typhimurium: Contrasting results with bromodichloromethane and chloroform. Toxicol. Appl. Phamacol. 144:183-188. Phoon, W.H., K.T. Goh, and L.T. Lee. 1983. Toxic jaundice from occupational

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 exposure to chloroform. Med. J. Malaysia 38:31-34. Pohl, L.R., B. Bhooshan, N.F. Whittaker, and G. Krishna. 1977. Phosgene: A metabolite of chloroform. Biochem. Biophys. Res. Commun. 79:684-691. Pohl, L. R., ed. 1979. Biochemical toxicology of chloroform. Rev. Biochem. Toxicol. 1:79-107. Pohl, L. R., J.L. Martin, A.M. Taburet, and J.W. George. 1980. Oxidative bioactivation of haloforms into hepatotoxins. Microsomes Drug Oxid. Chem. Carcinog. 2:881-884. Raabe, O.G. 1988. Inhalation Uptake of Xenobiotic Vapors by People. ARB-R-88/338. 94 pp. Gov. Rep. Announce. Index (U.S.) 1988, 88(16), Abstr. No. 842, 087. University of California at Davis. NTIS Publ. Doc. PB88-202726. Reitz, R.H., A.L. Mendrala, R.A. Corley, J.F. Quast, M.L. Gargas, M.E. Andersen, D.A. Staats, and R.B. Conolly. 1990. Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling. Toxicol. Appl. Pharmacol. 105:443-459. Robbiano, L., E. Mereto, A. Migliazzi Morando, P. Pastore, and G. Brambilla. 1998. Increased frequency of micronucleated kidney cells in rats exposed to halogenated anesthetics. Mutat. Res. 413:1-6. Roe, F.J.C., A.K. Palmer, and A.N. Worden. 1979. Safety evaluation of toothpaste containing chloroform. I. Long-term studies in mice. J. Environ. Pathol. Toxicol. 2:799-819. Roldan-Arjona, T., and C. Pueyo. 1993. Mutagenic and lethal effects of halogenated methanes in the Ara test of Salmonella typhimurium: Quantitative relationship with chemical reactivity. Mutagenesis 8:127-131. Rosenthal, S.L. 1987. A review of the mutagenicity of chloroform. Environ. Mol. Mutagen. 10:211-226. Royston, G.D. 1924. Delayed chloroform poisoning following delivery. Am. J. Obstet. Gynecol. 10:808-814. Schwetz, B.A., B.K.J. Leong, and P.J. Gehring. 1974. Embryo-and fetotoxicity of inhaled chloroform in rats. Toxicol. Appl. Pharmacol. 28:442-451. Sipes, I.G., G. Krishna, and J.R. Gillette. 1977. Bioactivation of carbon tetrachloride, chloroform and bromotrichloromethane: Role of cytochrome P-450. Life Sci. 20:1541-1548. Smith, A.A., P.P. Volpitto, Z.W. Gramling, M.B. DeVore, and A.B. Glassman. 1973. Chloroform, halothane, and regional anesthesia: A comparative study. Anesth. Analg. 52:1-11. Smith, J.H., and J.B. Hook. 1984. Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol. Appl. Pharmacol. 73:511-524. Stevens, J.L., and M.W. Anders. 1981. Effect of cysteine, diethyl maleate, and phenobarbital treatments on the hepatotoxicity of [1H]- and [2H] chloroform. Chem. Biol. Interact. 37:207-217. Stoner, G.D., P.B. Conran, E.A. Greisiger, J. Stober, M. Morgan, and M.A. Periera. 1986. Comparison of two routes of chemical administration on the lung adenoma

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 response in strain A/J mice . Toxicol. Appl. Pharmacol. 82:19-31. Sturrock, J. 1977. Lack of mutagenic effect of halothane or chloroform on cultured cells using the 8-azaguanine test system. Br. J. Anaesth. 49:207-210. Taylor, D.C., D.M. Brown, R. Keeble, and P. F. Langley. 1974. Metabolism of chloroform—II. A sex difference in the metabolism of [14C]-chloroform in mice. Xenobiotica 4:165-174. Templin, M.V., A.A. Constan, D.C. Wolf, B.A. Wong, and B.E. Butterworth. 1998. Patterns of chloroform-induced regenerative cell proliferation in BDF1 mice correlate with organ specificity and dose-response of tumor formation. Carcinogenesis 19:187-193. Templin, M.V., K.C. Jamison, C.S. Sprankle, D.C. Wolf, B.A. Wong, and B.E. Butterworth. 1996a. Chloroform-induced cytotoxicity and regenerative cell proliferation in the kidneys and liver of BDF1 mice. Cancer Lett. 108:225-231. Templin, M.V., K.C. Jamison, D.C. Wolf, K.T. Morgan, and B.E. Butterworth. 1996b. Comparison of chloroform-induced toxicity in the kidneys, liver, and nasal passages of male Osborne-Mendel and F-344 rats. Cancer Lett. 104:71-78. Templin, M.V., J.L. Larson, B.E. Butterworth, K.C. Jamison, J.R. Leininger, S. Méry, K.T. Morgan, D.C. Wolf, and B.A. Wong. 1996c. A 90-day chloroform inhalation study in F-344 rats: Profile of toxicity and relevance to cancer studies. Fundam. Appl. Toxicol. 32:109-125. Testai, E., S. DiMarzio, and L. Vittozzi. 1990. Multiple activation of chloroform in hepatic microsomes from uninduced B6C3F1 mice. Toxicol. Appl. Pharmacol. 104:496-503. Testai, E., F. Gramenzi, S. DiMarzio, and L. Vittozzi. 1987. Oxidative and reductive biotransformation of chloroform in mouse liver microsomes. Mechanisms and models in toxicology. Arch. Toxicol. Suppl. 11:42-44. Topham, J.C. 1980. Do induced sperm head abnormalities specifically identify mammalian mutagens rather than carcinogens? Mutat. Res. 74:379-387. Torkelson, T.R., F. Oyen, and V.K. Rowe. 1976. The toxicity of chloroform as determined by single and repeated exposure of laboratory animals . J. Am. Ind. Hyg. Assoc. 37:697-705. Townsend, E. 1939. Acute yellow atrophy of the liver. Two cases, with one recovery. Br. Med. J. 2:558-560. Tumasonis, C.F., D.N. McMartin, and B. Bush. 1987. Toxicity of chloroform and bromodichloromethane when administered over a lifetime in rats. J. Environ. Pathol. Toxicol. Oncol. 7:55-64. Van Dyke, R.A., M.B. Chenoweth, and A.V. Poznak. 1964. Metabolism of volatile anesthetics—I. Conversion in vitro of several anesthetics to 14CO2 and chloride. Biochem. Pharmacol. 13:1239-1247. Wang, P.-Y., T. Kaneko, A. Sato, M. Charboneau, and G.L. Plaa. 1995. Dose and route dependent alteration of metabolism and toxicity of chloroform in fed and fasting rats. Toxicol. Appl. Pharmacol. 135:119-126. Whitaker, A.M., and C.S. Jones. 1965. Report of 1500 chloroform anesthetics administered with a precision vaporizer. Anesth. Analg. 44:60-65.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 White, A.E., S. Takehisa, E. Shin, I. Edmond II, S. Wolff, and W.C. Stevens. 1979. Sister chromatid exchanges induced by inhaled anesthetics. Anesthesiology 50:426-430. Wolf, C.R., D. Mansuy, W. Nastainczyk, G. Deutschmann, and V. Ullrich. 1977. The reduction of polyhalogenated methanes by liver microsomal cytochrome P-450. Mol. Pharmacol. 13:698-705. Wolf, D.C., and B.E. Butterworth. 1997. Risk assessment of inhaled chloroform based on its mode of action. Toxicol. Pathol. 25:49-52. Yamamoto, S., S. Aiso, N. Ikawa, and T. Matsushima. 1994. Carcinogenesis studies of chloroform in F344 rats and BDF1 mice [abstract]. Proceedings of the Fifty-third Annual Meeting of the Japanese Cancer Association, 2445 Ohshibahara Hirasawa Hando Kanagawa, 257 Japan.