THE TRADITIONAL TOXICOLOGIC PARADIGM IS CORRECT - DOSE INFLUENCES MECHANISM

Dose influences mechanism; and over a wide range of doses, one can env ision that mechanism will change with changing dose. This basic concep t in toxicology is juxtaposed with the biologic importance of maintain ing normal DNA methylatiori status to provide the focus of this paper. The idea that altered DNA methylation plays a variety of roles in car cinogenesis is compatible with three key features of this multistage p rocess: clonal selection of abnormal cells in a progressive fashion, t he reversibility of tumor promotion, and the multiplicity of tumor phe notypes. A relatively low capacity to maintain normal methylation stat us appears to explain, in part, the high propensity of the B6C3F1 mous e to develop liver tumors. This observation supports the view that a m ouse liver tumor response is not an appropriate end point for human ri sk assessment. Additionally, it is suggested that altered DNA methylat ion can be viewed as a secondary mechanism underlying carcinogenesis. The knowledge that a chemical is acting by a mode of action involving a secondary mechanism can be used to support a safety factor or multip licity of exposure approach to risk assessment.