Physiologically based pharmacokinetic models for trichloroethylene and its oxidative metabolites.
Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metabolism of TCE and the production, distribution, metabolism, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE and its metabolites have focused on the major metabolic pathway for metabolism of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental and PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principle metabolite responsible for TCE-induced liver cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. Environmental Protection Agency for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood and plasma measurements of TCA are reported in mice and humans. To reduce confusion about disparately measured and model-predicted levels of TCA in plasma and whole blood, model-predicted outcomes are compared for first-generation (plasma) and second-generation (whole blood) PBPK models published by Fisher and colleagues. Qualitatively, animals and humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE and its metabolites are important tools for providing dosimetry comparisons between experimental animals and humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE.
Fisher
J W
JW
Air Force Research Laboratory, Operational Toxicology Branch, Human Effectiveness Directorate, Wright-Patterson AFB, OH 45433, USA. jeffrey.fisher@wpafb.af.mil
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015386:Hazardous Substances / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D010084:Oxidation-Reduction; D014238:Trichloroacetic Acid / Q000493:pharmacokinetics; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics*
D015386:Hazardous Substances; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003577:Cytochrome P-450 Enzyme System