Promotion of spontaneous preneoplastic cells in rat liver as a possible explanation of tumor production by nonmutagenic compounds.

Foci of putative preneoplastic cells were detected in the livers of untreated aged Wistar rats of both sexes. The foci exhibited markers similar to those of their counterparts in carcinogen-treated rats such as increased cytoplasmic basophilia, clearness of cytoplasm, or expression of gamma-glutamyltransferase. Rates of DNA synthesis in foci were higher than in normal liver and were further increased by single doses of liver mitogens assumed to promote liver tumor development (phenobarbital, alpha-hexachlorocyclohexane, cyproterone acetate, nafenopin). Thus, cells in the spontaneous foci appear to possess a defect in growth control, rendering them more susceptible to endogenous and exogenous growth stimuli. This defect has been found previously in carcinogen-induced foci and may be used as a marker for putative preneoplastic cells. The spontaneous foci are present at low incidence in 8-month-old rats; at 2 years, all of 50 rats studied possessed foci. These observations suggest that nongenotoxic compounds can produce liver tumors if they promote tumor development from preneoplastic foci. Therefore, long-term bioassay for carcinogenicity will not discriminate between initiating and promoting compounds if preneoplastic lesions develop in control animals.