Non-linearity of neoplastic conversion induced in rat liver by low exposures to diethylnitrosamine

Neoplastic conversion induced in rat liver by diethylnitrosamine(DEN) was quantified by measuring preneoplastic and neoplasticlesions over a 34 week period in the beginning of which thecarcinogen was given at three dose levels and two dose ratesfor the first 10 weeks, after which animals were maintainedfor 24 weeks with either no further exposure or were fed phenobarbital(PB) to promote neoplastic development of cells converted byDEN. DEN was injected s.c. inmale F344 rats at weekly or biweeklyintervals for total doses of 1, 2 or 4 mmol/kg body wt and thenthe rats were maintained on basal diet alone or diet containing0.05% PB. At the end of exposure, DEN had produced a dose-relateddecrease in centrilobular glutamine synthetase-expressing (GS⁺)hepatocytes which is indicative of mild cytotoxicity. All dosesinduced foci that were