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 periodsof time (1, 4, 7, 14, 20 weeks) to male Sprague-Daw-ley ratsin order to investigate the dose dependence and sequential appearanceof preneoplastic and neoplastic lesions in the liver. With alldose levels studied a sequence was established leading fromdear cell and acidophilic cell glycogen storage foci throughmixed cell foci and neoplastic nodules to hepatocellular carcinomas.The first appearance and frequency of the different lesionsinvestigated proved dependent on dose of carcinogen administered.Morphometric analysis demonstrated that the rare small clearcell foci apparent after 7 weeks treatment with NNM increasein number and size with progression through the sequence tocarcinomas without further administration of carcinogen. Noevidence was found to suggest that pronounced focal populationswere reversible upon cessation of NNM-treatment under the presentexperimental conditions.