Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 4 (2000) / Chapter Skim
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B13 Chloroform
B13 Chloroform
Pages 264-306
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From page 264... ...
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 19974. Formula: CHCI3 CAS no.: 67-66-3 Chemical name: Trichioromethane Synonyms: Chiorofo~, trichIorofo~, formy!
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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.
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1988~. High chloroform concentrations in the breath corresponded to high exposure concentrations.
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Approximately 38°/0 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, Coriey et al.
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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~.
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1977~. Chloroform doses that caused liver glutathione depletion produced liver necrosis (Docks and Krishna 1976~.
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, 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.
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in rats exposed for ~ O min to chloroform vapors was 16,000 ppm (CIark and Tinston 1982~. That effect was rapidly reversed on cessation of exposure (Clark and Tinston 1982~.
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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°/O to 80°/O 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.
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for rats exposed for IS min to chloroform vapor was 76,000 ppm (Clark and Tinston 1982~. For a 6-h exposure to chioroforrn vapors, the LCso was 1849 ppm in rats and 1260 ppm in mice (Bonnet et al.
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In case reports of women who died after exposure to chloroform anesthesia during childbirth, autopsy revealed fatty degeneration of the kidneys, indicating chIoroforminduced 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.
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Chloroform is the major byproduct of chlorination of drinking water, and several studies have implicated chlorination by-products in the etiology of specific cancers. A 1992 epidemiological report suggests that consumption of chlorination by-products in drinking water is associated with an increased risk of rectal and urinary bladder cancers (Morris et al.
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Striking differences were observed in the organ specificity between species and between different strains of the same species. Long-term inhalation of high doses of chloroform vapors has been shown to induce kidney cancer in male BDF~ mice (Yamamoto et al.1994~.
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at which the chloroform was delivered, and with the dosing vehicle. Female Wistar rats exposed for a lifetime to chloroform in drinking water at an average concentration of 200 mg/kg/d had an increased incidence of hepatic neoplastic nodules, and Tymphosarcoma was increased in males (Tumasonis et al.
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These effects included dizziness, fatigue, somnolence, insomnia, hypomnesia, anorexia, palpitation, increased scores for depression, anger, and fatigue, and adverse effects on neurobehavioral functions, including increased simple visual reaction time, digit-symbol substitution, digit span, Bentsen retention, and pursuit aiming. The concentration of chIoroforrn in the breathing zones ofthe workers
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Thus, it is inappropriate to ascribe the observed effects to the geometric mean of the measured concentrations. Hepatotoxicity and Pneumonitis There have been several reports of hepatotoxicity due to occupational exposures to chloroform vapors.
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At 25 ppm, mate guinea pigs showed microscopic granular degeneration and foamy vacuolization in the liver, and female guinea pigs showed foamy vacuolization centrally in the liver. Female rabbits showed slight microscopic changes in the lungs, liver, and kidneys.
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. Male BDF~ mice exposed for 6 hid for 4 ~ to chloroform at 0, 0.3,5,30, or 90 ppm had a LOAEL of 30 ppm and a NOAEL of 5 ppm for necrosis of the proximal convoluted tubules, tubule dilation, accumulation of hyaline casts, and focal mineralization ofthe kidneys (Templin et al.
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Female rats were affected less than males. At 25 ppm, mate rats exposed for 7 hid exhibited cloudy swelling of the renal tubular epithelium.
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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 Tymphoma cell, Mitchell et al.
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No studies were found regarding developmental effects in humans after inhalation exposure to chloroform vapors. In rats exposed during gestation, chloroform-induced fetotoxicity and teratogenicity (decreased fetal crown-rump length and delayed ossification ~ were observed by Schwetz et al.
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maleate, that deplete hepatic glutathione can greatly increase the hepatotoxicity of chloroform (Brown et al.
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288 x s .`, ~Cal ~ ~GO ~ct ce Cal Cal ce _ ct ce cd Ct Ct Cd ~C)
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289 ~$ ~ cat ~ ~An ~ ~ ~.
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ACGIH 1991 NIOSH's IDLH 1000 NIOSH 1990 NRC's 1-hEEGL 100 NRC 1984 NRC's 24-h EEGL 30 NRC 1984 NRC's 90-d CEGL 1 NRC 1984 TLV, Theshold Limit Value; TWA, time-weighted average; STEL, short-term exposure limit; PEL, permissible exposure limit; REL, recommended exposure limit; IDLH, immediately dangerous to life and health; EEGL, emergency exposure guidance level; CEGL, continuous exposure guidance level. TABLE 13-3 Spacecraft Maximum Allowable Concentrations Concentration, Concentration, Duration ppm mg/m3 Target Toxicity 1 h 2 10 CNS depression 24 h 2 10 CNS depression 7 da 2 10 CNS depression, hepatotoxicity, nephrotoxicity 30 d 1 5 CNS depression, hepatotoxicity CNS depression, hepatotoxicity 180 d s aPrevious 7-d SMAC= 1 ppm.
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The evidence and logic used to determine the ACs for each adverse effect and exposure duration are documented below. ACs were set for CNS effects, hepatotoxicity, nephrotoxicity, cardiac arrhythmia, and carcinogenicity (Table 13-44.
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To err on the side of conservatism, however, the AC values will be derived assuming that humans might be sensitive to chIoroform-induced hepatocarcinogenisis and basing them on NOAEL values for liver cytotoxicity in rodents inhaling chloroform vapors. A NOAEL for liver cancer can be deduced from the NOAEL of 10 ppm observed for liver cytotoxicity in female and mate B6C3F~ mice exposed to chloroform at 0, 0.3, 2, 10, 30, and 90 ppm for 6 in/d, 71/w for up to 13 w (Larson et al.
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Although mild effects, such as irritation, which would not compromise a crew member's ability to safely perform his duties, might be tolerable for exposures of 24 h or less, mild CNS depression could affect a crew member's judgment and reaction time and thus would compromise safety and wouldbe unacceptable, even for short exposures. Thus, for all exposure durations, AC = 22 ppm- 10 = 2 ppm.
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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.
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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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Pp. 289-291 in Documentation of the Threshold Limit Values and Biological Exposure Indices,Vol 1, 6th Ed.
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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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1997. The association of drinking water source and chlorination byproducts with cancer incidence among postmenopausal women in Iowa: A prospective cohort study.
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1986. Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice.
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Pp. 57-76 in Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol.1.
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1990. Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling.
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1998. Patterns of chloroform-induced regenerative cell proliferation in BDF~ mice correlate with organ specificity and dose-response of tumor formation.
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. Proceedings of the Fifty-third Annual Meeting of the Japanese Cancer Association, 2445 Ohshibahara Hirasawa Hando Kanagawa, 257 Japan.
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