Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.
A physiologically based pharmacokinetic model for trichloroethylene (TCE) in rodents and humans was calibrated with published toxicokinetic data sets. A Bayesian statistical framework was used to combine previous information about the model parameters with the data likelihood, to yield posterior parameter distributions. The use of the hierarchical statistical model yielded estimates of both variability between experimental groups and uncertainty in TCE toxicokinetics. After adjustment of the model by Markov chain Monte Carlo sampling, estimates of variability for the animal or human metabolic parameters ranged from a factor of 1.5-2 (geometric standard deviation [GSD]). Uncertainty was of the same order as variability for animals and higher than variability for humans. The model was used to make posterior predictions for several measures of cancer risk. These predictions were affected by both uncertainties and variability and exhibited GSDs ranging from 2 to 6 in mice and rats and from 2 to 10 for humans.
Bois
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Institut National de L'Environnement Industriel et des Risques, INERIS, Verneuil-en-Halatte, France. frederic.bois@ineris.fr
D000818:Animals; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D015233:Models, Statistical; D051381:Rats; D012680:Sensitivity and Specificity; D014241:Trichloroethylene / Q000008:administration & dosage / Q000493:pharmacokinetics*
D002274:Carcinogens, Environmental; D014241:Trichloroethylene