Trichloroethylene risk assessment: A review and commentary

Abstract

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (μg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The final guidelines emphasized a “weight-of-evidence” approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors’ (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.

Keywords::

• Trichloroethylene
• risk assessment
• peroxisome proliferation
• presystemic elimination
• carcinogenesis
• PBPK modeling

Acknowledgement

This research was supported by funding from the US Department of Energy cooperative agreement DE-FC09-02CH11109.

Declaration of interest: This review was prepared during the normal course of the authors’ employment. Their employment affiliations are included on the first page. The authors had sole responsibility for writing the paper, without input from the Department of Energy (DOE) or any other governmental agency, corporation, or trade group. The review’s content does not necessarily reflect the views of DOE or any other group. J.V.B., J.W.F., and D.G.H. have served on US government advisory panels dealing with trichloroethylene (TCE) health effects. D.G.H. testified before the Senate in May, 2008, about EPA and its TCE risk assessment considerations. J.W.F. was previously employed by the US Air Force, where he conducted research to develop PBPK models for TCE and its metabolites. He is currently funded by the Henry Jackson Foundation for the Advancement of Military Medicine to develop a PBPK model for chloral hydrate, a TCE metabolite. The authors have not testified for plaintiffs or defendants in litigation concerned with allegations of adverse health effects by TCE within the last 5 years.