An Example of Model Structure Differences Using Sensitivity Analyses in Physiologically Based Pharmacokinetic Models of Trichloroethylene in Humans

Abstract

Trichloroethylene (TCE) is an industrial chemical and an environmental contaminant. TCE and its metabolites may be carcinogenic and affect human health. Physiologically based pharmacokinetic (PBPK) models that differ in compartmentalization are developed for TCE metabolism in humans, and the focus of this investigation is to evaluate alternative models. The two models formulated differ in the compartmentalization of metabolites; more specifically, one model has compartments for all chemicals and the other model has only a generalized body compartment for each the metabolites and contains multiple compartments for the parent, TCE. The models are compared through sensitivity analyses in order to selectively discriminate with regards to model structure. Sensitivities to a parameter of cardiac output (Qcc) are calculated, and the more compartmentalized model predictions for excretion show lower sensitivity to changes in this parameter. Values of Qcc used in the sensitivity analyses are specifically chosen to be applicable to adults of ages into the low 60s. Since information about cardiac output across a population is not often incorporated into a PBPK model, the more compartmentalized ("full") model is probably a more appropriate mathematical description of TCE metabolism, but further study may be necessary to decide which model is a more reasonable option if distributional information about Qcc is used. The study is intended to illustrate how sensitivity analysis can be used in order to make appropriate decisions about model development when considering physiological parameters than vary across the population.

Exposure estimation using repeated blood concentration measurements

“…framework for exposure estimation A number of PBTK models and analyses of TCE with differences in compartmentalization of metabolites have appeared in the literature (Bois 2000;Clewell et al 2000;Fisher et al 1998;Fisher 2000;Yokley and Evans 2007). For the present study, however, only the parent chemical concentration of TCE in blood was considered, and no metabolites of TCE or their pathways were involved.…”

A computational investigation of the ventilation structure and maximum rate of metabolism for a physiologically based pharmacokinetic (PBPK) model of inhaled xylene

“…Physiologically based pharmacokinetic (PBPK) modeling uses ordinary differential equations to describe absorption, distribution, metabolism, and excretion of toxicants following exposure. PBPK models have been developed to estimate internal doses for various toxicants in rodents [1] [9] [11] [14] [17] [18] [25] [34] [37] [40] and in humans [2] [3] [8] [10] [13] [15] [23] [26] [35] [36] [39] [38] [43] [48]. Most PBPK model equations use the same basic structure and assumptions, such as the assumption that compartments are well-mixed and that the transfer of some chemicals is at equilibrium.…”