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 0.01 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 U.S. EPA is reevaluating its
dioxin risk assessment and, as part of this process, will be developing risk assessment approaches for chemicals, such as
dioxin, whose toxicity is receptor-mediated. This paper describes a receptor-mediated physiologically based pharmacokinetic (PB-PK) 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 this model, ternary interactions among the
Ah receptor,
dioxin, and
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.
Tumor promotion correlated more closely with predicted induction of P4501A1 than with induction of hepatic
binding proteins. Although increased induction of these
proteins is not expected to be causally related to
tumor formation, these physiological dosimetry and gene-induction response models will be important for biologically motivated
dioxin risk assessments in determining both target tissue dose of
dioxin and gene products and in examining the relationship between these gene products and the cellular events more directly involved in
tumor promotion.