| Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites Weihsueh A. Chiu,1 Miles S. Okino,2 John C. Lipscomb,3 and Marina V. Evans4 1National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA; 2National Exposure Research Laboratory, U.S. Environmental Protection Agency, Las Vegas, Nevada, USA; 3National Center for Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, Ohio, USA; 4National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA Abstract
Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE) . Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases. Key words: metabolism, pharmacokinetics, physiologically based pharmacokinetic model, risk assessment, trichloroethylene. Environ Health Perspect 114: 1450–1456 (2006) . doi:10.1289/ehp.8691 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 W. Chiu, U.S. EPA, 1200 Pennsylvania Ave., Mail Code 8623D, Washington, DC 20460 USA. Telephone: (202) 564-7789. Fax: (202) 565-0079. E-mail: chiu.weihsueh@epa.gov Supplemental Material is available online at http://www.ehponline.org/members/2006/8691/suppl.pdf We thank H. Barton, J. Blancato, J. Caldwell, C. Chen, N. Keshava, F. Power, and C. Siegel Scott for their critical comments on earlier versions of this paper, and P. Preuss, D. Bussard, P. White, C. Dary, L. Sheldon, M. DeVito, and L. Birnbaum for their management support. 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 4 April 2006.
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