Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

摘要

A physiologically based pharmacokinetics (PBPK) model was developed which provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH). and trichloroacetic acid (TCA), in the mouse, rat, and human, for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Dose metrics that can be calculated with the model for cancer risk assessment include the area under the concentration curve (AUC) for TCA in the plasma or liver, the peak concentration and AUC for chloral (CHL) in the tracheo-bronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine (DCVC) in the kidney. Additional dose metrics that can be calculated for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. There is currently no adequate' data available with which to confidently parameterize a description for another metabolite of interest, dichloroacetic add (DCA). Model predictions of TCE, TCA, and TCOH concentrations in rodents and humans are consistent with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations for these dose metrics are highly uncertain.