DIETHYLNITROSAMINE EXPOSURE-RESPONSES FOR DNA-DAMAGE, CENTRILOBULAR CYTOTOXICITY, CELL-PROLIFERATION AND CARCINOGENESIS IN RAT-LIVER EXHIBIT SOME NONLINEARITIES

The exposure-responses for several effects of limited exposures to die thylnitrosamine (DEN) in the livers of male Fischer 344 rats were meas ured and phenobarbital promotion was used to enhance expression of ini tiation of carcinogenesis. Five doses ranging from a cumulative total of 0.5 to 4 mmol DEN per kg body weight were given as weekly i.p. inje ctions for 10 weeks. This was followed by 4 weeks recovery, after whic h the groups were maintained on either a basal diet or 0.05% phenobarb ital (PB) to promote liver tumor development. All doses of DEN produce d ethylation in liver DNA, which increased with dose. Indicative of to xicity, the centrilobular zone of glutamine synthetase-positive hepato cytes was reduced in relationship to exposure up to a cumulative expos ure of 3 mmol/kg. The two lower exposures to DEN produced no increase in cell proliferation, whereas higher exposures resulted in marked inc reases, similar to 4-fold between 1.0 and 2.0 mmol/kg cumulative, At t he end of the recovery period (14 weeks), hepatocellular altered foci (HAF), which expressed the placental form of glutathione S-transferase , were induced by all exposures, with an increase of similar to 4-fold between the exposures of 1.0 and 2.0 mmol/kg being the greatest. In r ats maintained on basal diet or PB for 24 weeks after exposure. HAF in creased further and with exposures of 2.0 mmol/kg and above, all rats developed hepatocellular carcinomas, With 1.0 mmol/kg, no liver tumor occurred in 12 rats without promotion, whereas in those given PB, two adenomas and two Carcinomas were present in 12 rats, At the lowest exp osure of 0.5 mmol/kg, no tumor occurred in rats on basal diet, althoug h HAF increased similar to 7-fold. With PB promotion, only one adenoma developed in 12 rats and HAF increased another 2-fold. Thus, the find ings document non-linearity for some of the effects of DEN and a near no-effect level for initiation of promotable liver neoplasms at the lo west exposure in spite of a substantial induction of HAF.