BIOCHEMICAL-MECHANISMS AND CANCER RISK ASSESSMENT MODELS FOR DIOXIN

Biologically realistic mechanistic models of carcinogenesis by TCDD are composed of equations representing biochemical events leading to altered expression of proteins involved in the response or equations representing the kinetics of proliferation of clones of mutant cells. A biochemically augmented physiological dosimetry model reproduces the observed altered expression of liver proteins in female rats exposed to dioxin. The model suggests that oxidation of estradiol to DNA reactive quinones or semiquinones by CYP1A2 protein induced by TCDD may contribute to an increased mutational rate. It suggests that TCDD-stimulated production of a peptide ligand of the epidermal growth factor (EGF) receptor and subsequent activation of the receptor's tyrosine kinase activity may increase the rate of proliferation of susceptible cells. These calculated quantities can serve as indices of toxicity and can be used to predict tumor incidence as a function of exposure.