| الوصف: |
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 mg/kd/day. t 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. he US EPA is re-evaluating 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. his 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. n this model ternary interactions between the Ah receptor, dioxin, and specific DNA binding sites lead to enhanced production of specific hepatic proteins. he model was used to examine the tissue disposition of dioxin and the induction of both a dioxin binding protein (presumably cytochrome P45OIA2), and cytochrome P4501AI. umor promotion correlated more closely with predicted induction of cytochrome P4501AI than with induction of P45OIA2. lthough increased induction of these proteins is not expected to be casually related to tumor formation, these physiological dosimetry and gene induction response models will be important for biologically motivated dioxin risk assessments in determining target tissue doses dioxin of dioxin and gene products to target tissues. |