The traditional toxicologic paradigm is correct: dose influences mechanism.

Dose influences mechanism; and over a wide range of doses, one can envision that mechanism will change with changing dose. This basic concept in toxicology is juxtaposed with the biologic importance of maintaining normal DNA methylation status to provide the focus of this paper. The idea that altered DNA methylation plays a variety of roles in carcinogenesis is compatible with three key features of this multistage process: clonal selection of abnormal cells in a progressive fashion, the reversibility of tumor promotion, and the multiplicity of tumor phenotypes. A relatively low capacity to maintain normal methylation status appears to explain, in part, the high propensity of the B6C3F1 mouse to develop liver tumors. This observation supports the view that a mouse liver tumor response is not an appropriate end point for human risk assessment. Additionally, it is suggested that altered DNA methylation 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 multiplicity of exposure approach to risk assessment.