The overall objective of our research is to discern mechanisms that can facilitate the aberrant expression of oncogenes involved in carcinogenesis. We are testing the hypothesis that hypomethylation of DNA is a nongenotoxic mechanism underlying the aberrant expression of oncogenes involved in carcinogenesis. Hypomethylation may be a mechanism underlying the role of cell proliferation in carcinogenesis, and hypomethylation could possibly result from an enzymatic replacement of 5-methylcytosine (5MeC) with cytosine that is not linked to DNA replication. The testing of this hypothesis can serve as a focal point for a mechanism of action-oriented approach for considering key aspects of carcinogenesis: aberrant gene expression, heritable epigenetic events, species-to-species extrapolation/unique species sensitivity, tumor promotion, and thresholds. DNA methylation plays a role in the regulation of gene activity. There is a persuasive body of evidence indicating that differential methylation of DNA (ie, 5-methylcytosine v. cytosine) is a determinant of chromatin structure and that the methyl group provides a chemical signal which is recognized by trans-acting factors that regulate transcription. Hypomethylation of a gene is necessary but not sufficient for its expression and, therefore, a hypomethylated gene can be considered to possess an increased potential for expression as compared to a hypermethylated gene. Changes in the methylation status of a gene provide a mechanism by which its potential for expression can be altered in an epigenetic heritable manner, and it is expected that modifications in DNA methylation would result from threshold-exhibiting events. Our experimental model is liver tumorigenesis, we focus upon oncogenes (eg, Ha-ras and raf) relevant to mouse liver tumorigenesis, employ the liver tumor prone B6C3F1 (C57BL/6 x C3H/He) mouse, and make relevant comparisons with the sensitive C3H/He paternal strain and the resistant C57BL/6 maternal strain. A unique aspect of this research is that it offers the potential to provide insight regarding molecular mechanisms that underlie promotion of carcinogenesis while at the same time the results can provide the type of information that is required in order to take a more rational approach towards carcinogen risk assessment. Specifically, the practical significance of our research is that it addresses the areas of dose-response relationships, eg, the existence of threshold-exhibiting mechanisms, and species-to-species extrapolation issues. This is discussed within the context of the requirement for a rational approach to risk assessment.