Incorporation of the glutathione conjugation pathway in an updated physiologically-based pharmacokinetic model for perchloroethylene in mice


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Abstract

Background:Perchloroethylene (perc) induced target organ toxicity has been associated with tissue-specific metabolic pathways. Previous physiologically-based pharmacokinetic (PBPK) modeling of perc accurately predicted oxidative metabolites but suggested the need to better characterize glutathione (GSH) conjugation as well as toxicokinetic uncertainty and variability.Objectives:We updated the previously published “harmonized” perc PBPK model in mice to better characterize GSH conjugation metabolism as well as the uncertainty and variability of perc toxicokinetics.Methods:The updated PBPK model includes expanded models for perc and its oxidative metabolite trichloroacetic acid (TCA), and physiologically-based sub-models for conjugative metabolites. Previously compiled mouse kinetic data in B6C3F1 and Swiss-Webster mice were augmented to include data from a recent study in male C57BL/6J mice that measured perc and metabolites in serum and multiple tissues. Hierarchical Bayesian population analysis using Markov chain Monte Carlo was conducted to characterize uncertainty and inter-strain variability in perc metabolism.Results:The updated model fit the data as well or better than the previously published “harmonized” PBPK model. Tissue dosimetry for both oxidative and conjugative metabolites was successfully predicted across the three strains of mice, with estimated residuals errors of 2-fold for majority of data. Inter-strain variability across three strains was evident for oxidative metabolism; GSH conjugation data were only available for one strain.Conclusions:This updated PBPK model fills a critical data gap in quantitative risk assessment by predicting the internal dosimetry of perc and its oxidative and GSH conjugation metabolites and lays the groundwork for future studies to better characterize toxicokinetic variability.Graphical abstractHighlightsUncertainty in perchloroethlyene (perc) toxicokinetics (TK) hampers risk assessment.An updated physiologically-based (PBPK) model was developed to address this gap.This is the first model to predict perc glutathione conjugation in mice.Modeling results show interstrain variability in mouse oxidative metabolism of perc.This model reduces perc TK uncertainty and allows for characterizing TK variability.

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