| Key Issues in the Modes of Action and Effects of Trichloroethylene Metabolites for Liver and Kidney Tumorigenesis Jane C. Caldwell and Nagalakshmi Keshava National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA Abstract
Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs) , and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA) , trichloroacetic acid (TCA) , and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl) -l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans. Key words: chloral hydrate, dichloroacetic acid, S-(1, 2-dichlorovinyl) -l-cysteine, trichloroacetic acid, trichloroethanol, trichloroethylene. Environ Health Perspect 114:1457–1463 (2006) . doi:10.1289/ehp.8692 available via http://dx.doi.org/ [Online 9 May 2006]
This article is part of the mini-monograph "Trichloroethylene Health Risks: Key Scientific Issues." Address correspondence to J.C. Caldwell, U.S. EPA, 1200 Pennsylvania Ave., Mail Code 8623D, Washington, DC 20460 USA. Telephone: (919) 541-4477. Fax: (919) 541-5541. E-mail: Caldwell.Jane@epa.gov We thank J. Blancato, C. Chen, M. Evans, J. Jinot, J. Lipscomb, M. Okino, F. Power, J. Schaum, and C. Siegel Scott for their insightful, constructive input. We especially thank W. Chiu, TCE team chemical manager, for key assistance in completing this review and coordinating this mini-monograph. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. The authors declare they have no competing financial interests. Received 27 September 2005 ; accepted 28 March 2006.
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