MODELING OF THE TOXICOKINETICS OF POLYCHLORINATED DIBENZO-P-DIOXINS AND DIBENZOFURANS IN MAMMALIANS, INCLUDING HUMANS .2. KINETICS OF ABSORPTION AND DISPOSITION OF PCDDS PCDFS/

In the present study, a physiologically based model which describes th e absorption and disposition kinetics of PCDDs/ PCDFs (globally called PCDXs) in mammalian species, including humans, is developed. The mode l integrates the distribution model developed in the first article of this series, which described the fractional distribution of total PCDX s between liver and adipose tissues as a function of overall body conc entration (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Ap pl. Pharmacol. 131, 253-266). In particular it is shown that the liver fraction of the total body burden decreases as overall body concentra tion decreases. Since elimination is principally through the liver, th is leads to lower global elimination rates and Longer half-lives of PC DXs. Absorption and disposition kinetics of PCDXs are captured using n onlinear differential equations with anatomically and biochemically re levant input parameters which are readily available. These are solved to predict the fate of PCDXs in liver, adipose tissues, and the body a s a whole, as a function of time. Model simulations are in agreement w ith published data on absorption and disposition kinetics of these sub stances in rats and in humans. The kinetic profiles are similar for ra ts 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 ma nner to the mass of the adipose tissues; this observation has consider able relevance for interpretation of clinical data for humans. The int erest 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, ta king into account variations in time of anatomical and biochemical par ameters. (C) 1995 Academic Press, Inc.