Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues

Abstract

Mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans, globally called PCDXs, are ubiquitously present in the environment. They accumulate in the human organism, especially through uptake from food. In view of their long residence time in the body and their potential adverse health effects for humans, it is therefore important to develop toxicokinetic models capable of predicting their distribution in human tissues. In the present study a physiologically based model which describes the distribution kinetics of PCDXs in various mammalian species is proposed. The approach is both theoretical and empirical. First, a plausible and general dynamical model that takes into account intercellular diffusion, PCDX-receptor and PCDX-protein binding, and PCDX-dependent enzyme induction in the liver is developed. Simplified formulas are proposed to predict the functional dependencies fh(Cb) and f(at)(Cb), which establish the fractions of the total PCDX body burden contained in liver and adipose tissues as a function of overall body concentration at any one moment. These formulas have fewer free parameters that can be determined for various species with the use of already available data. Model simulations are in agreement with published data on the distribution kinetics of PCDXs in rodents and monkeys and clinical data in humans. In rodents and monkeys as well as in humans, the respective relations fh(Cb) and f(at)(Cb) follow a similar nonlinear pattern. These varying distribution functions constitute the basis for a generalized toxicokinetic model of absorption and disposition described in a companion article (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 267-276).