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Appendixes

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1 Chloroform Hector D. Garcia, Ph.D. NASA-Johnson Space Center Toxicology Group Habitability ancI Environmental Factors Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Chloroform is a nonflammable, clear, colorless, volatile and mobile, highly refractive, dense liquid with a characteristic pleasant, non-irr~tating odor and a slight, sweet taste (see Table 1-1) (ATSDR 1997~. OCCURRENCE AND USE Chloroform is used as an extractant or solvent for fats, oils, greases, resins, lacquers, rubber, alkaloids, gums, waxes, gutta-percha, penicillin, vitamins, flavors, floor polishes, and adhesives. It is also used as a raw material in the chemical industry for the manufacture of chlorodifluoro- methane (Freon 22), resins, and plastics; as a pharmaceutical solvent; as a dry cleaning spot remover; and as an intermediate in the manufacture of dyes and pesticides (ATSDR 1997; ACGIH 1991~. In the past, chloroform was used as a general anesthetic, in fire extinguishers, and as 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 levels of chloroform are also found almost ubiquitously in the environment. 11

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12 Spacecraft Water Exposure Guidelines TABLE 1-1 Physical and Chemical Properties of Chloroform Formula CHC13 Chemical name Trichloromethane Synonyms Chloroform, trichloroform, formyl bichloride, Cl methenyl chloride, methenyl bichloride, methane tri- chloride, methyl bichloride, NCI-C02686, Freon 20, ~ R-20, TOM Cl C H Cl CAS registry no. 67-66-3 Molecular weight 1 19.38 Boiling point Melting point Liquid density 61.3C -63.2C 1.485 g/cc Vapor density 4.36 (air = 1) Vapor pressure 159 tort at 20C Solubility 1 mL dissolves in 200 mL water at 25C Odor threshold 2.4 ppm (water); 85 ppm (vapor) Miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride, carbon disulfide, and oils. Chloroform was detected in the space shuttle atmosphere in six of 27 mis- sions at levels of 0.002-0.03 milligrams per cubic meter (mg/m3) (Huntoon 1987; Huntoon 1993) and, in more recent missions, in about 10% of air samples at concentrations in the range of 0.01-0.1 mg/m3 (James et al. 1994~. Small amounts of chloroform are sometimes carried on board the space shuttle as part of mid-deck or module experiments. Drinking water on the International Space Station (ISS) will not be chlorinated, but will be iodinated or treated with silver to kill bacteria. It will be generated from recycled hygiene water, urine, and humidity condensate, and supplemented by water from the shuttle or the Russian Progress spacecraft. Thus, it is expected that traces of chloroform may be found occasionally in spacecraft drinking water under normal conditions.

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Chloroform 13 PHARMACOKINETICS AND METABOLISM Considerable data are available on the uptake, metabolism, and elimina- tion of chloroform in several species. The weight of evidence indicates that chloroform is rapidly distributed throughout the body and that its toxic effects have a threshold that is dependent on the dose rate. Absorption Chloroform is rapidly absorbed through the gastrointestinal tract from foodstuffs and drinking water (EPA 1985~. The composition and volume of the vehicle in which it is dissolved may affect the rate of absorption of orally administered chloroform. In female B6C3F, mice, the absorption and tissue dosimetry in blood, liver, and kidneys of a single dose of chloroform administered by gavage was increased in aqueous gavage vehicles com- pared with corn oil, but in male F-344 rats, the gavage vehicle had minimal effects (six et al. l 997~. The absorption rate of chloroform in corn oil was decreased at dosing volumes of 10 milliliters per kilogram (mL/kg) com- pared with 2.5 mL/kg in both rats and mice. In aqueous 2% emuIphor, a large volume of liquid was observed in the stomachs of mice at sacrifice, but not in those of rats. Rate constants for gavage absorption were reported by CorIey et al. (1990) to be Kas~hr~~), corn oil = 0.6; Kas~hr~~), water= 5.0. Absorption of chloroform through the skin is significant (329 ~mol/min/cm2 of skin ex- posed to the liquid) (EPA 1985~. Distribution In humans (Smith et al. 1973) and animals (Cohen 1971; Brown et al. 1974a), chloroform absorbed either by inhalation or orally is distributed to all tissues with relative tissue concentrations of body fat > brain > liver > kidneys > blood, as expected due to the lipophilic nature of chloroform. Partition coefficients in humans were reported by CorIey et al. (1990) as follows: blood/air = 7.43; liver/air = 17.0; kidney/air = 11.0; fat/air = 280; rapidly perfused tissues/air = 17.0; slowly perfused tissues/air = 12.0. In mouse studies, the relative distribution among the organs was de- pendent on the route of administration, the time between dosing and mea- surement, end the metabolism and covalent birding of metabolites to cellu-

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14 Spacecraft Water Exposure Guidelines tar macromolecules (Taylor et al. 1974; Brown et al. 1974a). The highest levels were seen in the liver after oral dosing, probably due to a first-pass effect in which most of the chloroform is metabolized by the liver before reaching the general blood circulation. Excretion Chloroform was detected in the exhaled air of volunteers exposed to a normal environment, to heavy automobile traffic, or to 2 hours (h) in a dry- cleaning establishment (Gordon et al. 1988~. Higher chloroform levels in the breath corresponded to higher exposure levels. The calculated biologic half-time for chloroform in breath was 7.9 h. Excretion of radioactivity in mice and rats was monitored for 48 h following exposure to ~4C-labeledtracer chloroform in chloroform at 10, 89, and 366 parts per million (ppm) in mice or 93, 356, and 1,041 ppm in rats (CorIey et al. 1990~. In this study, 92-99% of the absorbed radioactivity was recovered in mice, and 58-98/O was recovered in rats; percent recovery decreased with increasing exposure. Ofthe total radioactivity absorbed, the percentages recovered as exhaled ~4C-labeled carbon dioxide were 80-85/O for mice and 48-85/O for rats. After exposure, the fractions recovered as ~4C-labeled chloroform were 0.4-~/O for mice and 2-42% for rats. The fractions recovered as urinary and fecal metabolites were S-11% and 0.6- 1.4%, respectively, for mice and 0.1% and 0.6%, respectively, for rats. A 4-fold increase in exposure concentration was followed by 50- and 20-fold increases in the amount of exhaled, unmetabolized chloroform in mice and rats, respectively. This indicates that the higher concentrations exceeded the capacity of the body to metabolize chloroform. Metabolism The metabolism of chloroform has been studied extensively and is understood fairly well. In humans, approximately 50/O of an oral dose of 0.5 g chloroform was metabolized to carbon dioxide (Fry et al. 1972~. Me- tabolism was dose dependent, decreasing with higher exposure. A first-pass effect was observed after oral exposure (Chiou 1975~. Approximately 38/O of the dose was converted in the liver, and < 17% was exhaled unchanged from the lungs. In a physiologically based pharmacokinetic (PBPK) modeling study of chloroform, CorIey et al. (1990) derived in viva metabolic rate constants

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Chloroform 15 (VmaxC = 15.7 mg/hL/kg, Km = 0.448 mg per liter [L]) for humans on the basis of experimental results obtained in rats and mice exposed to chioro- form by inhalation and enzymatic studies in human tissues in vitro. The order of activity of liver microsomes was hamster > mouse > rat > human. Microsomes obtained from the kidneys of the various species were less active than those obtained from the livers. Virtually no activity could be detected from the three samples of human kidney tissues available; there- fore, for the PBPK model, Coriey et al. (1990) assumed that activity in human kidney was present at the limit of detection. Their results predicted that the "delivered doses" of chloroform, defined as the milligram equiva- lents of phosgene bound to macromolecules per liter of liver tissue per day, were about 10-fold lower in humans than in mice and about 5-fold lower in humans than in rats exposed to the same concentrations of chloroform in drinking water. They assume that equivalent levels of macromolecular binding produce equivalent toxicities in target tissues. The relative sensitivi- ties of the three species (mouse > rat > human) predicted by the Coriey et al. (1990) PBPK model differ markedly from those predicted by the default assumptions used by EPA. In the absence of experimental data, EPA as- sumes that equal concentrations in the air or water produce a 10-fold greater risk in humans than in the most sensitive tested species (mice). The Coriey et al. data show that humans should have a 10-fold lower risk than mice exposed at equal chloroform concentrations. Chloroform can be metabolized both aerobically and anaerobically as shown below (Figures 1 - 1 and 1 -2~. The production of CO2 by the aerobic pathway accounts for up to 85/O of administered chloroform in mice, 65% in rats, and lesser amounts in humans (50/O) and squirrel monkeys (28%) (Brown et al. 1974a; Taylor et al. 1974~. In mice, Brown et al. (1974a) found greater levels of radiolabeled chloroform in the kidneys of male mice than in females. Similarly, Culliford and Hewitt (1957) found that chloro- form accumulated and metabolized in the renal cortex of males to a greater extent than in females; however, the results may have been influenced by testosterone levels. This effect was not observed in any other species. These species and gender differences in metabolism, distribution, and bind- ing point out the limitations and difficulties in extrapolating studies in lower animals to humans. Metabolism studies by Pohl (1979) and Stevens and Anders (1981) indicated that chloroform was exhaled from the lungs or was converted to phosgene (Pohl 1979; Stevens end Anders 1981) in the river end kidneys by cytochrome P-450 (Branchflower et al.1984; Smith and Hook 1984~. Phos- gene may react with cellular elements, inducing cytotoxicity to lipids and proteins ofthe endoplasmic reticulum proximate to the cytochrome P-450.

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16 Spacecraft Water Exposure Guidelines In phenobarbital-pretreated Sprague-Dawley rats, chloroform treatment yielded a covalent abduct to a single phospholipid, identified as phospha- tidylethanolamine, in liver mitochondria (Guastedisegni et al. l 998~. 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 may also contribute to chloroform-induced hepatotoxicity in rats, although phosgene and other active metabolites are primarily responsible. The conversion of chloroform to reactive metabolites occurs in nuclear preparations as well as in micro- somes (Gomez and Castro 1980~. Covalent binding of chloroform to lipids can occur under anaerobic and aerobic conditions, although binding to protein occurs only under aerobic conditions (Testai et al. 1987~. Covalent binding of chloroform metabolites to microsomal protein in vitro was increased by microsomal enzyme inducers and prevented by glutathione (GSH) (Brown et al. 1974b). It was proposed that the reaction of chloroform metabolites with GSH might act as a detoxifying mechanism. Phosgene may combine with two molecules of GSH to form diglutathiony! dithiocarbonate, which is further metabolized in the kidneys (Sipes et al. 1977; Wolfet al. l977~. Chloroform doses that caused liver GSH depletion produced liver necrosis (Docks and Krishna 1976~. Furthermore, chioro- form has been found to be more hepatotoxic in fasted animals, possibly due to decreased GSH content in the liver (Brown et al. 1974b; Docks and Krishna 1976; Wang et al. 1995~. Evidence that chloroform is metabolized at its carbon-hydrogen bond is provided by experiments that used the deuterated derivative of chioro- form (McCarty et al. 1979; Poh! et al. 1980; Branchflower et al. 1984~. Deuterated chloroform is one-half to one-third as cytotoxic as chloroform, and its conversion to phosgene is much siower. The results confirmed that the toxicity of chloroform to the liver and kidneys is due primarily to its metabolites (ATSDR 1997~. The final product of the aerobic metabolic pathway of chloroform is carbon dioxide (Fry et al.1972; Brown et al.1974a), which is mostly elimi- nated through the lungs, but some is incorporated into endogenous metabo- lites and excreted as bicarbonate, urea, methionine, and other amino acids (Brown et al. 1974a). Inorganic chloride ion is an end-product of chioro- form metabolism found in the urine (Van Dyke et al. 1964~. Carbon mon- oxide was a minor product of the anaerobic metabolism of chloroform in rats in vitro (Ahmed et al. 1977) and in vivo (Anders et al. 1978; ATSDR 1997~.

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Chloroform Cl P-450, 0 2 H C C I NADPH I M c oso es Cl 1 r m Acce pto r H HC C S N `' / H C' 11 o 2-Oxathiazolid ine- 4-Carboxylic acid Cl HO-C-CI Cl Macromolecule O 11 CO < C -H C1 'jY O\ ~ ~CO -H .~.0~ Cl Cl Phosoene +H2O 2HCl ~ CO2 G lutath ione Conjugates? FIGURE 1-1 Major pathway (aerobic). Source: Redrawn from ATSDR 1997. C I Anaerobic H C C I Reduce~ > P-450-Fe :C C 12 ~ H C I C I M icroso m es +H2O P-450-Fe++ C O < CO ~ 2HCI FIGURE 1-2 Minor pathway (anaerobic). Source: Redrawn from ATSDR 1997. 17

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18 Spacecraft Water Exposure Guidelines A recent in vitro study of hepatic microsomes in mice indicated that a reductive pathway might play an important role in chloroform hepatotoxic- ity (Testai et al. 1990~. It was demonstrated that radical chloroform metabo- lites bind to macromolecules (i.e., proteins, lipids), and the process can be inhibited by reduced GSH (ATSDR 1997). Interspecies differences in the rate of chloroform conversion were ob- served in mice, rats, and squirrel monkeys. The conversion of chloroform to carbon dioxide was highest in mice (85/O) and lowest in squirrel mon- keys (28%) (Brown et al. 1974a). Similarly, because of the lower relative rates of chloroform metabolism, ventilation, and cardiac output (per kilo- gram body weight) in the larger species, physiologically based pharmaco- kinetic (PBPK) calculations indicated that exposure to equivalent concen- trations of chloroform vapor would lead to a lower delivered dose of active metabolites in humans compared with rats; rats would have a lower deliv- ered dose than mice (Coriey et al. 1990; ATSDR 1997~. TOXICITY SUMMARY Although high concentrations of inhaled chloroform vapor have pro- nounced effects on the central nervous system (CNS), most of which are reversible upon cessation of exposure, there are no reports of CNS effects resulting from exposure to chloroform in drinking water. This is true even at concentrations high enough to render the water unpalatable to very thirsty rodents. This lack of CNS effects is due to a first-pass effect in which most of the chloroform is metabolized by the liver before reaching the general blood circulation. Other reported effects of exposure to high vapor concen- trations include cardiac arrhythmias, immune system depression, and, in rats, nasal lesions. None of these effects have been reported for oral expo- sures. Short-term exposure to high levels by various routes, including oral, causes liver necrosis and kidney degeneration. Long-term exposure to levels high enough to cause cytotoxicity may lead to liver or kidney cancer. Acute Toxicity (<1 d) Hepatotoxicity The liver has been shown to be the primary toxicity target of ingested chloroform in humans. Ingestion of chloroform at approximately 3,755 mg/kg produced jaundice, liver enlargement and tenderness, increased

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Chloroform 19 levels of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and lactate dehydrogenase activities, and increased bilirubin levels in an individual who died of chloroform poisoning (Pierso! et al. 1933~. Autopsy revealed fatty degeneration and extensive centrilobular necrosis. The hepatotoxicity of chloroform is believed to be due to the production of reactive chloroform metabolites (e.g., phosgene) by cytochrome P-450 and is modulated by hepatic GSH. Brown et al. (1974b) found that expo- sure of rats to chloroform for 2 h at either 5,000 or 10,000 ppm produced hepatic necrosis and destruction of microsomal enzymes. Pretreatment of rats with phenobarbital to induce microsomal enzyme activity before expo- sure to chloroform markedly increased the hepatotoxic response to anesthe- sia. It also produced a 70-80/0 decrease in hepatic GSH levels compared with uninduced rats in which chloroform exposure resulted in neither deple- tion of GSH nor in hepatic necrosis at 24 h after exposure (Brown et al. 1974b). Experimental depletion of hepatic GSH by pretreatment with di- ethy! maleate also resulted in centrilobular necrosis after exposure to chio- roform (Brown et al. 1974b). In cytotoxicity studies at CIIT, freshly isolated hepatocytes cultured from B6C3F, mice and F-344 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 then 1 millimolar (mM) (Ammann et al. 1998~. Co-treatment with the cytochrome P-450 inhibitor 1-phenylimidazole prevented both cytolethality and GSH depletion, indicat- ing that metabolism is necessary for chloroform-induced cytotoxicity. These results correlate well with simulations of a physio-Iogically based dosimetry model for chloroform, which indicated that the livers of mice and rats were exposed to chloroform concentrations up to 5 mM for 3 h after hepatotoxic doses of chloroform (Ammann et al. l 998~. The high (>1 mM) concentra- tions of chloroform necessary to produce hepatotoxicity can be achieved only by bolus dosing, such as gavage. Drinking water exposure results in much lower hepatic chloroform concentrations than bolus gavage and elimi- nates the hepatotoxic effects (Larson et al. 1994b). Nephrotoxicity Unpublished studies at CIIT (B. Butterworth, CIIT, personal commun., Sept.21,1998) using mice in which the CYP-450 IIE1 gene had been inac- tivated showed that the metabolism of chloroform was completely elimi- nated. Thus, chloroform metabolism in mice is entirely dependent on cyto-

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46 Spacecraft Water Exposure Guidelines Reduced Water Consumption ACs for reduced water consumption for 1-d and 10-d exposures are based on Larson et al.'s (1994b) results in mice given chloroform in drink- ing water at 0, 60,200,400, 900, or 1,800 ppm. At chloroform concentra- tions of 200 ppm and above, the average daily doses were lower for the first 4 ~ of exposure than for the entire 3 wk of exposure because ofthe mice's initial aversion to the drinking water. The 1-d and 10-d ACs are set at the 60 ppm (mg/L) NOAEL for reduced water consumption during the initial exposure period. No adjustment was made for potential species differences in taste aversion. 1-d and 10-d ACs = 60 mg/L. Spaceflight Effects Spaceflight is believed to increase the susceptibility of crew members to noncritical cardiac arrhythmias and could amplify the arrhythmogenic effects of chloroform. The blood levels of chloroform that can be achieved by ingesting drinking water are too low, however, to pose a concern for induction of cardiac arrhythmia. Comparison of SWEG Values with Inhalation Limits for Chloroform The amount of chloroform to which an individual would be exposed through drinking water at the SWEG values is compared in Table 1-6 with the exposures experienced through inhalation of the recommended space- craft maximum allowable concentrations (SMACs) for chloroform vapors. The daily amounts ingested using the SWEG values assume consumption of 2.8 L of water per day and 100% absorption. Calculation of the daily amounts that would be absorbed during inhalation of air containing the SMACs for chloroform assumes inhalation of 20 m3 of chloroform vapor per day end retention of 45/O (NRC 2000, pp.264-306~. Forty-f~ve percent is probably low because it was estimated from experiments with humans inhaling much higher concentrations. At concentrations near the SMACs, the retention could approach 100%, and the values in Table 1 -6 for milli- grams per day at the SMAC values would need to be adjusted.

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Chloroform TABLE 1-6 Comparison of Daily Amounts of Chloroform Exposure Allowable Under SWEGs and SMACs 47 F,xnos,~,re SWEGs SMACs ~--r ~ Duration mg/L mg/d Effect 1 h mg/m3 mg/d Effect 10 90 CNS depression 10 90 CNS depression 24h 1 d 60 120 Reduced water consumption 7 d 10 90 CNS depression, hepatotoxicity, nephrotoxicity, car- cinogenicity 10 d 60 120 Reduced water consumption 30 d 5 45 Hepatotoxicity, CNS depression 100 d 18 36 Hepatotoxicity 180 d 5 45 Hepatotoxicity 1,000 d 6.5 13 Hepatotoxicity Abbreviations: SMACs, spacecraft maximum allowable concentrations; SWEGs, spacecraft water exposure guidelines. The daily amounts absorbed (mg/~) are comparable for the two routes of exposure. At SMAC values for durations of <7 4, inhalation leads to CNS depression, whereas, due to the first-pass effect, similar amounts in- gested from drinking water do not reach the CNS because much of the chloroform is metabolized by the liver before it reaches the general circula- tion. Comparison of SWEG Values with Standards Set by Other Organizations The daily amounts ingested using the ACs recommended above and assuming consumption of 2.8 L of drinking waterper day and 100% absorp- tion are compared, in Table 1-7, with the drinking water standards set by other organizations.

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48 o . - .~ o o D an V] 5 5 V] .~ ~0 so ~0 V so ~0 V] o o .~ o V 1 o C) Ct .i C) no C) V so o .~ Ct m Ct Ct Ct C) Fit t0 ,~ ~ Fat ~ Ct 1 .~ lo A .~ C) E- zo .~ C) VO o an C) 53- VO o ~ En vow o .= Ct o o ~ .~ .~ .~ .~ ~ c) c) c) c) c) ~ ~ ~ ~ ~ ~ s~ x x x x x ~ o o o o o ~ o o o o o E~ ~ ~ ~ ~ ~ .~ c) x o o ~10 o ~o o o o o o o ~ o . . . e 'e 'e o ~ o ~t s~ ~ s~ ~ s~ ~ cO O. cO o o vO z ~ ~ ~ o ~ vO E~ vO z o o o ~ ~ o vO oo ~ ~ o ~ ~ o ~ ~ o 3 ~ '; ~ VO E~ VO V~ E~ Z o ~ Ct Ct VO F~ . . ~ o ~ ~ o 3 Al ~ ~ ~ = Z F~ . ~ ~ .= ~ .~0 m) C) a~ O U, Ct O (= . C) V) . ^o .^ V) ~ ~ .~ o a~ cq, := .~ ~ a~ a~ c) -O .O v) ~ x o O a~ E~ . ~ >l .-o . = .= ~ -~) = ~ e

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Chloroform 49 RECOMMENDATIONS FOR FUTURE RESEARCH Research is needed to quantitate the organ-specific (liver and kidney) levels of chloroform metabolism in humans, compare them with those in rodents, and elucidate factors, such as glutathione levels, that could modu- late the threshold level of chloroform required for toxicity. Once all ofthat is determined, a PBPK model incorporating those values and addressing both oral and inhalation exposures would be users. REFERENCES 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. ACGIH. 1991. Chloroform. Pp.198-204 in Documentation ofthe Threshold Limit Values and Biological Exposure Indices, Vol. 1, 6 Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Ammann, P., C.L. Laethem, and G.L. Kedderis. 1998. Chloroform-induced cyto- lethality 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. ATSDR. 1997. Toxicological Profile for Chloroform. TP-92-07. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Sub- stances and Disease Registry, Washington, DC. Baeder, C., and T. Hotmann.1988. Inhalation Embryotoxicity Study of Chloroform in Wistar Rats. Frankfurt: Pharma Research Toxicology and Pathology, Hoechst Aktiengesellschaft. Branchflower, R.V., D.S. Nunn, R.J. Highet, J.H. Smith, J.B. Hook, and L.R. Pohl. 1984. Nephrotoxicity of chloroform: Metabolism to phosgene by the mouse kidney. Toxicol. Appl. Pharmacol. 72:159-1168. Brown, D.M., P.F. Langley, D. Smith, and T.D.C. 1974a. Metabolism of chloro- form.I. ThemetabolismofE14C]-chloroformbydifferentspecies.Xenobiotica 4:151-163. Brown, B.R., Jr., I.G. Sipes, and A.M. Sagalyn. 1974b. Mechanisms of acute hepatic toxicity: Chloroform, halothane, and glutathione. Anesthesiology 41 :554-561. Bull, R.J., J.M. Brown, E.A. Meierhenry, T.A. Jorgenson, M. Robinison, and J.A. Stober. 1986. Enhancement of the hepatotoxicity of chloroform in B6C3F1 mice by corn oil: Implications for chloroform carcinogenesis. Environ. Health Perspect. 69:49-58.

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so Spacecraft Water Exposure Guidelines Butterworth, B.E., M.V. Templin, A.A. Constan, C.S. Sprankle, B.A. Wong, L.J. Pluta, J.I. Everitt, and L. Recio. 1998a. 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 Sacchaaromyces cerevisiae. Mutat. Res. 77:55-63. 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. Chu, I., D.C. Villenueve, V.E. Secours, and G.C. Becking. 1982a. Toxicity of trihalomethanes. I. The acute and subacute toxicity of chloroform, bromodi- chloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health B 17:205-224. Chu, I., D.C. Villenueve, V.E. Secours, and G.C. Becking. 1982b. Toxicity of trihalomethanes. II. Reversibility oftoxicological changes producedby chloro- form, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health B17:225-240. Cohen, E.N.1971. Metabolism ofthe 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, andR.H. Reitz. 1990. Development ofa 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 sol- vents 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, end A. Carere. 1988. In- duction 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. De Salva, S., A. Volpe, G. Leigh, and T. Regan.1975. Long-term safety studies of a chloroform-containing dentifrice and mouth rinse in man. Fd. Cosmet. Toxicol. 13:529. 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 and

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