Mechanisms of dioxin tumor promotion: Implications for risk assessment

TCDD is a liver carcinogen in female rats but not male rats. In a two stage model for hepatocarcinogenesis, using a single initiating dose of diethylnitrosamine (DEN) and chronic exposure to TCDD (25 ng/kg/day for 30 weeks), ovariectomy prevented the tumor promoting actions of TCDD. This finding was consistent with data on cell proliferation which demonstrated that TCDD did not induce cell proliferation in the absence of the ovaries. Dose-response data were obtained for a number of responses to TCDD within the framework of a tumor promotion model. These included cell proliferation, number and size of hepatic preneoplastic foci, induction of cytochrome P-450 isozymes (CYP 1A1 and 1A2), TCDD liver and blood concentrations, epidermal growth factor (EGF) receptor, estrogen receptor, histological changes and clinical chemistries. Dose response relationships were markedly different for the different parameters. For example, CYP 1A1 and 1A2 induction occurred at lower doses than effects of cell proliferation and preneoplastic lesions. The relevance of these data to low dose human risks and rodent to human extrapolations of risks are discussed.