THE IMPORTANCE OF BIOLOGICAL REALISM IN DIOXIN RISK ASSESSMENT MODELS

Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the A h, estrogen, and EGF receptors in TCDD hepato-carcinogenicity. Each mo del generates dose-response curves for the expression of biomarker liv er proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expressi on of these proteins. Assuming a constant level of the hepatic Ah rece ptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TC DD in a physiologically realistic dosimetric model produced a linear l ow-dose response of CYP1A1. This behavior was was computed to arise fr om the net effect of sublinear response of CYP1A1 mRNA to the concentr ation of the Ah-TCDD complex and supralinear response of the protein c oncentration to the mRNA level, illustrating the importance of biologi cal realism in dose-response modeling. The dosimetric model also compu ted effects of TCDD on the hepatic estradiol concentration and consequ ent effects on the binding capacity of the EGF receptor and suggests p lausible mechanisms for tumor promotion by TCDD. Setting circulating e stradiol levels in the model to values typical of the male rat indicat ed possible sources of the differences in the responses of the EGF rec eptor and in development of tumors in the two sexes.