In rats, single glutathione S-transferase, placental form (GSTP)- immunoreactive hepatocytes were found to be putative initiated hepatocytes after carcinogen (N-nitrosodiethylamine) (NDEA) exposure. Single cells, doublets and multiple cell foci, were evaluated in rat liver at various time intervals after carcinogen and promoter exposure. Computerized image analysis and stereology was used to provide three dimensional data for group comparison. Although single cells and foci decreased in number after initial expression, apoptosis may explain the cause of this phenomenon. Phenobarbital enhanced the progression of the single cells to foci and neoplasms, while rats exposed only to NDEA had a constant number of single cells and small foci. Thus, the promoter enhanced clonal expansion of the putative initiated GSTP-immunoreactive hepatocytes. In contrast, mice given diets containing di(2- ethylhexyl)phthalate (DEHP) developed novel hepatocellular foci and adenomas that differed from those in untreated B6C3F1 mice. The mouse study provided evidence that DEHP induces these novel preneoplastic and neoplastic lesions instead of promoting spontaneous foci and tumors. A dose relationship with the level of cell proliferation was found for the number of hepatocellular foci and not for the number of tumors. The pathogenesis of renal tubular tumors induced or promoted by barbital sodium was studied retrospectively in F344 rats. Induction of dysplastic tubules of the basophilic phenotype was followed by the development of renal tubular cell adenomas of identical phenotype. Spontaneous tumors were of the same phenotype but often were found to arise in a different segment of the nephron.
