Persistent proliferation of normal hepatocytes and promotion of preneoplastic development by N-nitrosodibenzylamine in rats.

In a traditional long-term study N-nitrosodibenzylamine (NDBzA) was proven to be noncarcinogenic, but recently the substance was found to produce genotoxic lesions in hepatocytes. Our own experiments have shown that relatively low single doses of NDBzA cause liver hypertrophy and additive proliferation of hepatocytes in rats. Both effects are known from well-documented promoters and non-genotoxic carcinogens, respectively, in rodents. Investigation of NDBzA in an initiation-promotion assay (IP assay) showed it to cause an increase in the number and size of preneoplastic liver cell foci. This occurred only after initiation with diethylnitrosamine, but not when 2-acetylaminofluorene was used. Another property of NDBzA is its sustained mitotic stimulation of extrafocal hepatocytes. This is inconsistent with their adaptive loss of susceptibility to mitogens in IP assays using other promoters of hepatocarcinogenesis. The following conclusions can be drawn. First, "differential inhibition" of the proliferation of extrafocal hepatocytes, in contrast to the selective mitostimulation of preneoplastic cells, is obviously no prerequisite for cancer development. Second, primary mitogenicity of a compound in short-term studies can be a useful indicator for tumorigenic potential. In the case of NDBzA the data available at present are still insufficient to classify it unequivocally in terms of genotoxic or nongenotoxic carcinogenicity.