The role of oncogenes, chronic toxicity and aging on carcinogenesis in mouse liver was studied. Activation of the H-ras oncogene by point mutation was found in a proportion of hepatocellular adenomas and carcinomas induced in B6C3F1 mice by N-nitrosodiethylamine or occurring spontaneously in C3H mice. The three types of mutations found at Codon 61 of H-ras was similar in type and incidence to those occurring spontaneously in B6C3F1 mice. The incidence of H- ras activation in liver tumors of C3H mice, a strain with a high spontaneous rate, was significantly lower than for B6C3F1 mice. These findings provide evidence for the role of H-ras in tumor initiation rather than promotion and suggest other factors play a major role in the multistage process of mouse hepatocarcinogenesis. Aging mouse hepatocytes were shown to he significantly more sensitive to phenobarbital carcinogenesis than those of young mice. Age-related changes in metabolism of phenobarbital and oncogene activation are possible mechanisms of this interesting phenomenon. We found similar findings for rats. Chronic toxicity in mouse liver and kidney was induced by acetaminophen or di(2- ethylhexyl)phthalate as measured by tritiated thymidine or Brdu uptake and histopathology. These studies provided evidence that chronic hyperplasia does not always lead to organ-specific carcinogenesis or tumor promotion.
