Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.
This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1, 2-dichlorovinyl)-l-cysteine (DCVC), and S-(1, 2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE.
Moore
M M
MM
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. moore.martha@epa.gov
Harrington-Brock
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D000818:Animals; D002274:Carcinogens, Environmental / Q000009:adverse effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005796:Genes / Q000187:drug effects; D006801:Humans; D009153:Mutagens / Q000009:adverse effects* / Q000378:metabolism; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics; D018570:Risk Assessment; D014241:Trichloroethylene / Q000009:adverse effects* / Q000378:metabolism; D014481:United States; D014484:United States Environmental Protection Agency
D002274:Carcinogens, Environmental; D009153:Mutagens; D014241:Trichloroethylene