EFFECTS OF LOW-DOSES OF N-NITROSOMORPHOLINE ON THE DEVELOPMENT OF EARLY STAGES OF HEPATOCARCINOGENESIS

Male Sprague-Dawley rats received the hepatocarcinogen N-nitrosomorpho line (NNM) in the drinking water at low dose levels ranging from 6 mg/ l to 60 mg/l for 6 and 12 weeks, respectively. Foci of altered hepatoc ytes (FAH) were demonstrated histochemically using changes in the acti vities of glucose-6-phosphate dehydrogenase and glycogen phosphorylase , and in the glycogen content as markers. Proliferating cells were det ected by the immunohistochemical reaction for proliferating cell nucle ar antigen (PCNA), The number and size of foci of altered hepatocytes increased in a time and dose-related manner, The dose-effect curves we re non-linear with a slight positive slope at the low doses and a mark edly increased slope at higher doses, The number of PCNA positive hepa tocytes showed a dose-dependent increase, In addition to the granular distribution of PCNA in the nuclei, hepatocyte nuclei with homogeneous ly distributed PCNA occurred in animals exposed to 60 mg/l NNM, It is proposed that these cells are related to the occurrence of hepatocytes with higher ploidy induced by NNM and may be regarded as cells in the G2 phase of the cell cycle, The non-linear shape of the dose-response -curve of the FAH suggests that some mechanisms contribute to carcinog enesis over the whole dose range, whereas other mechanisms enhance car cinogenesis only at higher doses. The relevance of the non-linear dose -effect curve for the risk assessment of carcinogens is discussed.