Recent work has established that the nucleolus is a specific gene site which is visibly engaged in synthesis and processing of ribosomal precursor RNA. Many carcinogenic agents, such as aflatoxin, ethionine and laziocarpine, bring about disruption of nucleolar structure as an early response to administration of these agents. Similar patterns are seen with agents such as actinomycin D which are inhibitors of RNA synthesis. While probably a carcinogen, actinomycin does not produce malignant change in the liver. Our project is directed toward (a) an understanding of the fundamental changes in structure and function of the nucleolus brought about by these carcinogens and metabolic inhibitors, and (b) what relationship these changes may have to subsequent transformation of the cells. We are working with intact rats, concentrating on the liver, and are developing an in vitro system for the study of hepatic parenchymal cells.