Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. II. Kinetics of absorption and disposition of PCDDs/PCDFs

Abstract

In the present study, a physiologically based model which describes the absorption and disposition kinetics of PCDDs/PCDFs (globally called PCDXs) in mammalian species, including humans, is developed. The model integrates the distribution model developed in the first article of this series, which described the fractional distribution of total PCDXs between liver and adipose tissues as a function of overall body concentration (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 253-266). In particular it is shown that the liver fraction of the total body burden decreases as overall body concentration decreases. Since elimination is principally through the liver, this leads to lower global elimination rates and longer half-lives of PCDXs. Absorption and disposition kinetics of PCDXs are captured using nonlinear differential equations with anatomically and biochemically relevant input parameters which are readily available. These are solved to predict the fate of PCDXs in liver, adipose tissues, and the body as a whole, as a function of time. Model simulations are in agreement with published data on absorption and disposition kinetics of these substances in rats and in humans. The kinetic profiles are similar for rats and humans, but the varying half-lives differ considerably in both species: weeks with rats, years with humans. For a given body burden, the adipose tissue concentrations vary in an inversely proportional manner to the mass of the adipose tissues; this observation has considerable relevance for interpretation of clinical data for humans. The interest of the proposed model rests upon the fact that it is generalized and broadly applicable: it allows the study of the kinetics of PCDXs for any pattern of exposure from background to highly toxic levels, taking into account variations in time of anatomical and biochemical parameters.