Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 1 (2004) / Chapter Skim
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Appendix 2: Dichloromethane
Appendix 2: Dichloromethane
Pages 57-87
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From page 57... ...
(ATSDR 1998~. OCCURRENCE AND USE DCM is widely used as an industrial solvent and a paint stripper, and it is used in the manufacture of photographic film and in some aerosol products, including spray paints and other household products.
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PHARMACOKINETICS AND METABOLISM Limited data are available on the uptake, metabolism, and elimination of DCM ingested through drinking water by humans or animals. The description below presents data mostly for DCM administered to rodents by gavage in water or corn oil.
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In mice exposed to DCM at 50 mg per kilogram (kg) by gavage in water, DCM was rapidly absorbed from both the upper and lower portions ofthe gut, with 75°/O ofthe dose absorbed within 10 minute (min)
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1996, 1997~. The GST pathway is several times more active in mice than in rats or in humans (Green 1991)
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resulting from exposure to DCM in drinking water. High concentrations of inhaled DCM vapor or ingestion of large amounts of DCM as paint stripper have pronounced CNS effects that are reversible upon cessation of exposure.
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General signs and symptoms of ingestion of large quantities of DCM in these cases included CNS depression, tachypnea, blistering and ulceration of the GI tract, hemogIobinuria, metabolic acidosis, and gastrointestinal hemorrhage. Hepatic and renal failures were reported in two of six cases.
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reported that a 4-h inhalation exposure to DCM at 300 ppm produced subtle but statistically significant CNS effects in human volunteers (including decreased critical flicker frequency and a decrease in auditory vigilance)
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1999~. It should be noted, however, that in many of those cases, blood oxygen levels were monitored during treatments that often included assisted ventilation with 100% oxygen during portions ofthe hospital stays.
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(1986a,b) conducted 2-y drinking water carcinogenicity and toxicity studies in rats and mice administered DCM at target levels of 0, 0, 5, 50, 125, and 250 mg/kg/d in rats and 0, 0, 60, 125, 185, and 250 mg/kg/d in mice.
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, but not those receiving target dose rates of 5 mg/kg/d or 50 mg/kg/d (actual rates: 6 mg/kg/d and 55 mg/kg/~) , had lower body weights and body-weight gains than controls and lower levels of food and water consumption.
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Inhalation of DCM vapors. Epidemiology studies have been performed using large cohorts of workers occupationally exposed to DCM in the photographic film base manufacturing industry and in triacetate fiber production.
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No excess mortality was observed for ischemic heart disease, but statistically significant excess mortality was observed for cancer of the liver and biliary passages. However, in comparing the probabilities of the observed vs the expected death rates, Lanes et al.
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OSHA made the following arguments in rejecting Green's views: · The weight of evidence supports the view that the mechanism of DCM carcinogenesis is through one or more genotoxic metabolites of the GST pathway. Genotoxic metabolites have been shown to cause DNA damage in vitro in cultured CHO cells exposed to DCM in culture medium supplemented with mouse metabolizing enzymes (Graves et al.
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· The available human epidemiological data are of insufficient power to rule out the possibility that DCM exposure causes a low but unacceptable increase in the incidence of tumors in humans. · The lack of tumors in the rodent drinking water studies can be attributed to the much lower doses administered in those studies compared with the rodent inhalation studies.
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l990~. Nevertheless, inhalation of DCM at 4,000 ppm or 8,000 ppm by female B6C3F~ mice for 10 ~ resulted in significant increases in the frequencies of SCEs in lung cells and peripheral blood lymphocytes, chromosome aberrations in lung and bone marrow cells, and micronuclei in peripheral blood erythrocytes (Allen et al.
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That suggests that humans might not be as susceptible to DCM-induced liver cancer, because the mechanism of DCM carcinogenesis is believed to be through genotoxic metabolites of the GST pathway and human metabolic rates for this pathway are much lower than those found in the rat and mouse. Reproductive Toxicity No reliable studies were found regarding reproductive effects in humans after exposure to DCM.
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73 an C)
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74 5 V at C)
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RATIONALE The spacecraft water exposure guideline (SWEG) listed above (Table 2-4)
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(1997) used Winneke's data in a PBPK model to calculate a brain tissue concentration of 3.95 mg/L and extrapolated the inhalation parameters to an exposure to drinking water containing DCM at 562 mg/L, assuming a 70-kg person consuming 2.0 LO Reitz et al.'s calculated LOAEL of 16 mg/kg/d was used to calculate an AC assuming consumption of 2.8 L of water per day by a 70-kg person and using an uncertainty factor of 10 to estimate the NOAEL from the LOAEL.
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's (1986a) NOAEL of 6 mg/kg/d for hepatotoxicity reported for rats consuming DCM in drinking water, and an interspecies factor of 10 was applied.
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rat NOAEL of 55 mg/kg/d for reduced water consumption and reduced weight gain in rats treated with DCM in drinking water, the concentration of DCM that did not reduce water consumption in rats can be estimated. Assuming an average rat weight of 200 g and average consumption of 20 mL/d.
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The SWEG values assume consumption of 2.8 L of water per day and 100% absorption. The daily amounts that would be absorbed during inhalation of air containing the SMACs for DCM vapors assume inhalation of 20 m3/d and retention of 55°/O (NRC 1996~.
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ATSDR.1998. Toxicological Profile for Methylene Chloride (Update)
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Soden 1996. A cohort mortality study of cellulose triacetate fiber workers exposed to methylene chloride.
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2000. Methods for Developing Spacecraft Water Exposure Guidelines.
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1983b. Health evaluation of employees occupationally exposedto methylene chloride: Mortality.
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Mortality of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base. Occup.
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