Under What Conditions Is Trichloroethylene Likely To Be a Carcinogen in Humans?

Abstract

This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or use recommendation.Exposures to trichloroethylene (TCE) induce several types of cancer in experimental animals. TCE is metabolized in the body to multiple compounds, several of which are carcinogenic at relatively high doses in rodents. Risk assessments can be pursued with any one of the animal cancer endpoints after consideration of their relevance for humans exposed at low environmental concentrations. Among the TCE metabolites, dichloroacetic acid (DCA), trichloroacetic acid (TCA), chloral hydrate (CHL), and 1,2-dichlorovinylcysteine (DCVC) are each considered carcinogenic in rodents. Two of these, DCA and CHL, are used therapeutically in humans, while a third, TCA, has metabolic effects similar to compounds used therapeutically in humans to reduce lipid concentrations in blood. Each of these three compounds produces biological responses that are expected in humans. However, these biological responses, although they serve as precursors for tumor formation in rodents, are not expected to lead to tumors in humans at any environmentally relevant exposure situations. 1,2-DCVC, formed by a minor pathway of TCE metabolism, is further metabolized in kidney to a reactive thioketene. Of the observed animal carcinogenic responses, only the kidney tumors from the DCVC pathway are considered relevant as predictors of human cancer. Factors that increase TCE metabolism to glutathione conjugates or predispose humans to kidney damage should increase risks posed to workers from high-concentration exposures to TCE. Based on our knowledge of the cytotoxic and mutagenic modes of action expected for these active metabolite (s), a nonlinear cancer risk assessment approach is recommended to be used with the kidney tumor data to assess the human risks of TCE.