Bayesian Analysis of a Lipid-Based Physiologically Based Toxicokinetic Model for a Mixture of PCBs in Rats

Abstract

A lipid-based physiologically based toxicokinetic (PBTK) model has been developed for a mixture of six polychlorinated biphenyls (PCBs) in rats. The aim of this study was to apply population Bayesian analysis to a lipid PBTK model, while incorporating an internal exposure-response model linking enzyme induction and metabolic rate. Lipid-based physiologically based toxicokinetic models are a subset of PBTK models that can simulate concentrations of highly lipophilic compounds in tissue lipids, without the need for partition coefficients. A hierarchical treatment of population metabolic parameters and a CYP450 induction model were incorporated into the lipid-based PBTK framework, and Markov-Chain Monte Carlo was applied to in vivo data. A mass balance of CYP1A and CYP2B in the liver was necessary to model PCB metabolism at high doses. The linked PBTK/induction model remained on a lipid basis and was capable of modeling PCB concentrations in multiple tissues for all dose levels and dose profiles.

Considerations for Assessing the Risks of Combined Exposure to Multiple Chemicals

“…Various PB-TK and PB-TK-TD models have been developed, taking into consideration a number of important metabolic steps, population variability in enzyme induction and metabolic rates, that are applicable for binary mixtures in the field of pesticides (Timchalk and Poet, 2008;Lee et al, 2010) and more complex mixtures such as solvents (Cheng and Bois, 2011;Bois et al, 2010;Fan et al, 2010) and polychlorinated biphenyls (PCBs) (Sasso et al, 2012). So far, these models have not yet been used by regulatory authorities for combined exposure assessment because of a number of limitations such as the lack of detailed knowledge on TK/TD data for multiple chemicals, the fact that they are resource intensive, need specialised expertise and may not always fit the purpose of a specific risk assessment.…”

International Frameworks Dealing with Human Risk Assessment of Combined Exposure to Multiple Chemicals

“…Recently, a lipid-based bayesian PB-TK model has been developed for a mixture of six polychlorinated biphenyls (PCBs) in rats to incorporate an internal exposure-response model applied to in vivo data linking population variability in enzyme induction (cytochrome P-450: CYP1A and CYP1B) and metabolic rate. Such models can simulate concentrations of highly lipophilic compounds in tissue lipids, without the need for partition coefficients and in this context can model PCB concentrations in multiple tissues for all dose levels and dose profiles (Sasso et al, 2012).…”