Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

Abstract

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456–463; http://dx.doi.org/10.1289/ehp.1307623

Comparative Analysis of the Relationship Between Trichloroethylene Metabolism and Tissue-Specific Toxicity Among Inbred Mouse Strains: Kidney Effects

“…These findings are consistent with the TCE metabolite data in mouse serum (Kim et al 2009b; Bradford et al 2011; Chiu et al 2014). However, our findings differ from those reported in one rat study where kidney levels of TCE metabolites were evaluated (Lash et al 2006).…”

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

“…For individual variability, genetic polymorphisms exist for CYP2E1, GSTs, CCBL, and FMO, which need to be taken into account when making predictions for humans. Likewise, considerable variability in TCE metabolism has been observed among mouse inbred strains and understanding whether the inter-strain variability in TCE metabolism is associated with the differences in toxicity outcomes may provide important clues as to the quantitative underpinnings of various toxic effects of TCE, including mutagenicity [190]. Finally, the complexities of using epidemiology studies for understanding TCE metabolism and mechanisms of action are illustrated by a recent retrospective cohort study [191].…”

Comparative Analysis of the Relationship Between Trichloroethylene Metabolism and Tissue-Specific Toxicity Among Inbred Mouse Strains: Liver Effects

“…First, we performed a sub-acute study where vehicle (10 mL/kg, 5% Alkamuls EL-620 in saline) or TCE (600 mg/kg/d, in vehicle) was administered by gavage to mice from 7 inbred strains (129S1/SvImJ, A/J, BTBR T+tf/J, C57BL/6J, CAST/EiJ, NOD/ShiLtJ, and NZW/LacJ) for 5 consecutive days. These strains were selected to maximize inter-strain differences in metabolism of TCE based on the previous study of TCE metabolism in a panel of inbred strains (Bradford et al 2011) and the results of the statistical modeling of the effect of time and strain on TCE metabolite concentrations which supports the sample size used in this study (Chiu et al 2014). Second, based on the data from the sub-acute study, we selected two inbred strains (C57BL/6J and NZW/LacJ) that represented widely varying degrees of formation of oxidative metabolites of TCE for a subsequent sub-chronic study.…”