title: 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.
  
  
  OBJECTIVE
  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.
authors: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.
authors: Weihsueh A
authors: WA
authors: Chiu
authors: Jerry L
authors: JL
authors: Campbell
authors: Harvey J
authors: HJ
authors: Clewell
authors: Yi-Hui
authors: YH
authors: Zhou
authors: Fred A
authors: FA
authors: Wright
authors: Kathryn Z
authors: KZ
authors: Guyton
authors: Ivan
authors: I
authors: Rusyn
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D003999:Dichloroacetic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D014241:Trichloroethylene / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D014241:Trichloroethylene; D003999:Dichloroacetic Acid