Carcinogenesis Risk Assessment Model for Environmental Chemicals

Abstract

A Monte Carlo computer simulation model was created incorporating the pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the stochastic pharmacodynamics of resulting carcinogenesis. The animal model was the female Sprague-Dawley rat. The model was calibrated to the observed tumor formation probabilities from a carcinogenesis bioassay. TCDD tissue distribution was modeled with a four-compartment physiologically based pharmacokinetic model, using compartments of liver, fat, muscle/skin, and richly perfused tissue. The model includes TCDD binding to two liver compartment sites, a cytosolic receptor and a microsomal binding protein. The concentration bound to the cytosolic receptor was used as the basis for dose-response in a stochastic pharmacodynamic model. Using a Monte Carlo approach, the stochastic model was calibrated to the bioassay controls, and then to the bioassay high and medium dose data using a two parameter fitting function. Fitting to low dose results was impossible because the bioassay had an anomalous decreased response relative to controls. The overall model is capable of predicting human carcinogenesis in response to environmental TCDD exposure through substitution of human biological parameters for those of Sprague-Dawley rats.