BIOLOGICALLY-BASED MODELS OF DIOXIN PHARMACOKINETICS

Significant advances have been made in the development of physiologically-based models of dioxin pharmacokinetics (PBPK) in the last 5-6 years. These models incorporate explicit descriptions of biological factors which determine tissue dosimetry of dioxin and include some description of dioxin-mediated pharmacodynamic events. Biological determinants of dioxin disposition include fat solubility, specific and inducible binding in the liver, diffusion-limited tissue distribution and metabolic elimination. PBPK models have been successfully used to predict the dose and time-dependent chemical disposition and protein induction properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a wide variety of experimental data sets with rodents. The models have also been extended to describe the disposition of a brominated dioxin, 2,3,7,8-tetrabromodibenzo-p-dioxin. As these quantitative descriptions of disposition are more fully refined, particularly with regard to pharmacodynamic descriptions of dioxin-mediated alterations in gene expression, more accurate predictions of tissue dosimetry and tissue responses will be performed across dose, species and related polyhalogenated aromatic hydrocarbons. Accurate, mechanistic dosimetry models will facilitate biologically-based approaches to the human risk assessment of these important and ubiquitous environmental contaminants.