This article is a US Government work and, as such, is in the public domain in the United States of America.
Article first published online: 31 OCT 2007
Published 2007 Wiley-Liss, Inc.
Environmental and Molecular Mutagenesis
Volume 49, Issue 2, pages 142–154, March 2008
How to Cite
Caldwell, J. C., Keshava, N. and Evans, M. V. (2008), Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures. Environ. Mol. Mutagen., 49: 142–154. doi: 10.1002/em.20350
This manuscript has been reviewed by the U.S. Environmental Protection Agency and approved for publication. The views expressed in this manuscript are those of the author[s] and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.
- Issue published online: 19 FEB 2008
- Article first published online: 31 OCT 2007
- Manuscript Accepted: 19 SEP 2007
- Manuscript Revised: 28 JUN 2007
- Manuscript Received: 11 APR 2007
- dichloroacetic acid;
- trichloroacetic acid;
The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by coexposure to pollutants that have similar targets or affected pathways. Trichloroethylene (TCE) can be an useful example for illustration of the complexity coexposure can present to elucidation of the MOA of an agent. TCE exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. There are a number of TCE metabolites that could play a role in the induction of these effects. Coexposures of other chemicals with TCE typically occurs as a result of environmental cocontamination that include its own metabolites, such as trichloroacetic acid, dichloroacetic acid, and other pollutants with similar metabolites such as perchloroethylene. Behaviors such as alcohol consumption can also potentially modify TCE toxicity through similar MOAs. The U.S. Environmental Protection Agency (EPA)'s 2001 draft TCE risk assessment, Trichloroethylene (TCE) Health Risk Assessment: Synthesis and Characterization, concluded that it was difficult to determine which of the metabolites of TCE may be responsible for these effects, what key events in their hypothesized MOAs are involved, and the relevance of some of the hypothesized MOAs to humans. Since the publication of U.S. EPA's draft TCE assessment, several studies have been conducted to understand the effects of coexposures to TCE. They cover both pharmacodynamic and pharmacokinetic considerations. This article highlights some of the recently published scientific literature on toxicological interactions between TCE, its metabolites, and other coexposures, including solvents, haloacetates, and ethanol. These studies give insight into both the potential MOAs of TCE exposure itself and putative modulators of TCE toxicity, and illustrate the difficulties encountered in determining the MOAs and modulators of toxicity for pollutants with such complex metabolism and coexposures. Environ. Mol. Mutagen., 2007. Published 2007 Wiley-Liss, Inc.