Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 1 (2004) / Chapter Skim
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Appendix 1: Chloroform
Appendix 1: Chloroform
Pages 9-56
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Appendixes
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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)
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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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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 compared with corn oil, but in male F-344 rats, the gavage vehicle had minimal effects (six et al.
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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 drycleaning establishment (Gordon et al.
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Their results predicted that the "delivered doses" of chloroform, defined as the milligram equivalents 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.
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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~.
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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 H—C C S N `' / H C' 11 o 2-Oxathiazolid ine4-Carboxylic acid Cl HO-C-CI Cl Macromolecule O 11 CO < C -H C1 'jY O\ ~ ~C—O -H .~.0~ Cl Cl Phosoene +H2O 2HCl ~ CO2 G lutath ione Conjugates? FIGURE 1-1 Major pathway (aerobic)
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. Similarly, because of the lower relative rates of chloroform metabolism, ventilation, and cardiac output (per kilogram body weight)
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concentrations 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 eliminates the hepatotoxic effects (Larson et al.
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F-344 rats treated by gavage with a single dose of chloroform at 34,180, or 477 mg/kg in corn oil exhibited a dose-dependent milUto severe necrosis ofthe proximal tubules ofthe kidneys (Larson et al.
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(1994c) found mild degenerative changes in centrilobular hepatocytes of male B6C3F, mice after 4 ~ of treatment with 34 mg/kg/d or 90 mg/kg/d by gavage in corn oil, but these changes were absent at 3 wk of treatment.
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In the 2-wk exposure groups, 40°/O ofthe 30 ppm group and 80°/O ofthe 90 ppm group died with severe kidney damage, indicating that both 30 ppm and 90 ppm exceeded the maximum tolerated dose. Male BDF, mice exposed to chloroform vapors 6 hid for 4 ~ at 0, 0.3, 5, 30, or 90 ppm had a LOAEL (Iowest observed adverse effect level)
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Reduced Water Consumption Female B6C3F~ mice given drinking water containing chloroform at 0, 60,200,400,900, or 1,800 ppm had a transient dose-dependent depression of body weight due to dose-dependent decreases in water consumption at chloroform concentrations of 2 200 ppm (Larson et al.1994b)
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administered in corn oil was toxic to liver cells, producing centrilobular necrosis, swollen hepatocytes, and increased cell proliferation when measured at days 5,12,33, and 159 oftreatment. These results were conf~rmed by Larson et al.
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In a series of studies at CIIT, male F-344 rats and male B6C3F~ mice exposed to chloroform vapors 7 d/wk for 13 wk had LOAELs for kidney toxicity of 30 ppm, whereas female F-344 rats and female B6C3F~ mice had NOAELs of 90 ppm (Larson et al. 1996; Templin et al.
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At 50 ppm, no adverse effects were found in guinea pigs or rabbits, although in rats the effects were similar to but milder than those at 85 ppm, and female rats were affected less than males. At 25 ppm, male rats exposed for 7 hid exhibited cloudy swelling of the renal tubular epithelium.
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1984~. In contrast, a 1981 study of Wisconsin female cancer mortality (Young et al.
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1985~. Rats exposed to chloroform at 160 mg/kg/d in drinking water had an increased incidence of kidney tubular cell adenoma and carcinoma, but those exposed at ~ 1 mg/kg/d did not (Jorgenson et al.
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of liver cells in female and male B6C3F, mice exposed to chloroform at 0,0.3,2,10,30, and 90 ppm for 6 h/d,7 d/wk, for up to 13 wk and proposed that this should also be a NOAEL for liver cancer in female B6C3F~ mice. In other words, chloroform carcinogenicity should have a threshold if tumorigenesis is dependent on regenerative cell proliferation.
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. In contrast, those given chloroform in corn oil at 238 mg/kg or 477 mg/kg had both centrilobular necrosis and markedly elevated regenerative cell proliferation (Larson et al.
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have been reported for induction of sister chromatic exchanges in human lymphocytes in vitro and mouse bone marrow in viva, but some aspects of the procedures used preclude reaching definitive conclusions. In a tightly controlled study of mutation at the thymidine kinase gene in the L5178Y TK+/- mouse lymphoma cell, Mitchell et al.
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(1988) found that fertility was not affected in either of two generations of mice exposedby gavage to chloroform in corn oil et up to 41 mg/kg/d for 105 4, but at those doses, sperm morphology was not affected.
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RATIONALE The spacecraft water exposure guideline (SWEG) listed in Table 1-3 for each exposure duration was set on the basis of the lowest value among the acceptable concentrations (ACs)
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35 it c)
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36 5 Al o V an C)
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38 5 an o V at C)
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ACs were set for reduced water consumption and for hepatotoxicity (see Table 1-5~. No ACs were set for CNS effects, nephro-toxicity, thyroid toxicity, carcinogenicity, reproductive toxicity, or developmental toxicity for the following reasons.
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Reproductive and Developmental Toxicity The clinical significance of Land et al.'s (1981) findings (up to 3.5°/O morphologically abnormal sperm in mice exposed 4 he/d for 5 ~ to chIoroform at 800 ppm)
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43 o o on o o -i O ¢ ~ o ~ ~e Fir b.o o ¢ C)
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report of a NOAEL for hepatic enzyme changes in rats exposed to chloroform at 500 ppm (mg/L) in drinking water for 28 d, yielding a dose of 11 ma/ rat/ d.
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That corresponds to chloroform concentrations of 8.5 mg/L or 24 mg/L in drinking water, respectively. Only a single dose was tested in each study, and there was no LOAEL dose, so it is not known how much higher the NOAELs could be.
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At chloroform concentrations 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.
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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/~)
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1986. Enhancement of the hepatotoxicity of chloroform in B6C3F1 mice by corn oil: Implications for chloroform carcinogenesis.
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1992. Induction of chromosome malsegregation by halogenated organic solvents in Aspergillus nidulans: Quantitative structure activity relationship (QSAR)
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1979. Safety evaluation of toothpaste containing chloroform.
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1994b. Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F 1 mice: Comparison of administration by gavage in corn oil vs ad libitum in drinking water.
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1994. Route of administration determines whether chloroform enhances or inhibits cell proliferation in the liver of B6C3F1 mice.
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1998. Increased frequency of micronucleated kidney cells in rats exposed to halogenated anesthetics.
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Patterns of chloroform-induced regenerative cell proliferation in BDF1 mice correlate with organ specificity and dose-response of tumor formation. Carcinogenesis 19: 187- 193.
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1981. Epidemiologic study of drinking water chlorination and Wisconsin female cancer mortality.
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