The Dose Dependence and Sequential Appearance of Putative Preneoplastic Populations Induced in the Rat Liver by Stop Experiments with N-nitrosomorpholine

Different doses of N-nitrosomorpholine (NNM) (80, 120, 160, 200 mg/l drinking water) were administered for various periods of time (1, 4, 7, 14, 20 weeks) to male Sprague-Dawley rats in order to investigate the dose dependence and sequential appearance of preneoplastic and neoplastic lesions in the liver. With all dose levels studied a sequence was established leading from clear cell and acidophilic cell glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. The first appearance and frequency of the different lesions investigated proved dependent on dose of carcinogen administered. Morphometric analysis demonstrated that the rare small clear cell foci apparent after 7 weeks treatment with NNM increase in number and size with progression through the sequence to carcinomas without further administration of carcinogen. No evidence was found to suggest that pronounced focal populations were reversible upon cessation of NNM-treatment under the present experimental conditions.