||Health Effects Research Lab., Research Triangle Park, NC. ;Chemical Industry Inst. of Toxicology, Research Triangle Park, NC. ;North Carolina Univ. at Chapel Hill. Center for Environmental Medicine and Lung Biology. ;Purdue Univ., Lafayette, IN. Dept. of Pharmacology and Toxicology. ;Freie Univ. Berlin (Germany, F.R.). Inst. fuer Toxikologie und Embryonalpharmakologie.
Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a widespread polychlorinated aromatic hydrocarbon, caused tumors in the liver and other sites when administered chronically to rats at doses as low as 0.0l microgram/kg/day. It functions in combination with a cellular protein, the Ah receptor, to alter gene regulation, and this resulting modulation of gene expression is believed to be obligatory for both dioxin toxicity and carcinogenicity. The paper describes a receptor-mediated physiologically based pharmacokinetic model for the tissue distribution and enzyme-inducing properties of dioxin and discusses the potential role of these models in a biologically motivated risk assessment. In the model, ternary interactions between the Ah receptor, dioxin, and specific DNA binding sites lead to enhanced production of specific hepatic proteins. The model was used to examine the tissue disposition of dioxin and the induction of both a dioxin-binding protein (presumably cytochrome P4501A2), and cytochrome P4501A1.