Estimating the risk of human cancer associated with exposure to methylene chloride.
Dichloromethane (methylene chloride, CH2Cl2) has been shown to significantly increase the incidence of malignant lung and liver tumors in B6C3F1 mice inhaling high concentrations of CH2Cl2 vapor for the majority of their natural lifetime. CH2Cl2 is extensively metabolized in mammalian species through two competing pathways: (1) oxidation by the mixed function oxidase enzymes, and (2) conjugation with glutathione catalyzed by glutathione-S-transferase(s)(GST). Since elevated tumor incidences have not been observed in B6C3F1 mice exposed to 1,1,1-trichloroethane, a halogenated solvent with similar physical-chemical properties (but only minor amounts of mammalian metabolism), it appeared that biologically reactive intermediates (BRIs) from one or both of the pathways of CH2Cl2 metabolism were involved in the tumorigenic process. Development of an integrated pharmacokinetic model incorporating quantitative measures of mammalian physiology, chemical solubility, and metabolic rate constants permitted formulation of a plausible hypothesis for the tumorigenic effects of CH2Cl2: namely that BRIs formed by the CH2Cl2/GST(s) may react with critical molecules in the target organs. This hypothesis is consistent with the dose-dependency, route-dependency, and species-specificity of CH2Cl2 for the induction of lung and liver tumors. Based on this hypothesis as well as in vivo and in vitro measurements of CH2Cl2 metabolism in humans, it was possible to prepare quantitative estimates of the cancer risk in human populations. Examination of these risk estimates indicates that development of quantitative procedures for describing the production of BRI in target tissues may cause significant changes in the levels of estimated risk.
Reitz
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Health and Environmental Sciences, Dow Chemical Company, Midland, Michigan.
D000280:Administration, Inhalation; D000818:Animals; D001711:Biotransformation; D015197:Carcinogenicity Tests; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000139:chemically induced*; D008752:Methylene Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D008815:Mice, Inbred Strains; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D012307:Risk Factors; D013045:Species Specificity
D008752:Methylene Chloride; D006899:Mixed Function Oxygenases; D005982:Glutathione Transferase