Emerging issues in mouse liver carcinogenesis.
The mouse liver is the primary target site for carcinogenesis of more than 200 chemicals (including pesticides, food additives, pharmaceuticals, and industrial intermediates) tested in long-term toxicity safety assessment assays. Mouse liver tumors develop through defined morphological stages (similar to those found in other species) whether their origin is of undetermined etiology (spontaneous) or induced by chemicals. The morphologic type of hepatocytes in the various stages of hepatocarcinogenesis is sometimes associated with the specific inducing agent. Liver tumors developing in toxic livers often have more benign appearances and may progress to carcinomas at a slower rate than tumors developing in histologically normal livers. Specific tumors, dependent on the inducing chemical, may regress under defined protocols. Genotoxic and nongenotoxic mouse hepatocarcinogens each may induce tumors of either high malignant or low malignant potential. Liver tumors with specific H-ras oncogene mutations may appear morphologically and biologically similar to those without proven ras mutations. Thus, distinguishing mechanism of carcinogenesis by liver tumor morphology and mutation spectra may be difficult. Additionally, the presence of liver tumors with a morphology and a ras oncogene mutation spectrum characteristic of spontaneous tumors in histologically normal livers of mice exposed to a nongenotoxic test chemical may indicate promotion of spontaneous hepatocarcinogenesis by one of several potential mechanisms. Further research into the mechanisms responsible for the increased incidences of liver tumors in mice exposed to test chemicals could enhance human cancer risk assessments.