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Chemical carcinogens can be classified into two categories (i.e. mutagenic and non-mutagenic) on the basis of positive or negative evidence of DNA In 1971, the International Agency for Research on Cancer (IARC), initiated a program for the evaluation of the carcinogenic risk of chemicals to humans based on the epidemiological evidence and evidence of carcinogenicity studies in animals (1). Recently, the IARC attempted to evaluate data from numerous short term tests for additional evidence of carcinogenicity (1). The foregoing is based on the observation that more than 80% of the carcinogens tested were mutagenic in the Salmonella/microsome assay (2-4). The end-points interpreted as positive in the short-term test systems are based on the hypothesis that damage to DNA is possibly a central event in the initiation of carcinogenesis and the neoplastic transformation of mammalian cells (2, [5][6][7][8][9][10][11][12] Carcinogens With and Without Mutagenic ActivityA positive correlation between positivity in short-term mutagenic assays and carcinogenicity has been established (2-5, 13) for a variety of chemicals, which are both carcinogens and mutagens. However, certain chemicals, which are carcinogenic in traditional animal bioassay studies, do not appear to yield positive results in the presently available short-term tests (3, 5, 6, 13-15). Accordingly, carcinogens can be classified into t w o broad types: mutagenic, when there is sufficient evidence for such activity in short term assays, and non-mutagenic, when there is no evidence for activity in mutagenesis assays. The IARC Working Group considered a minimum of three positive results obtained in two of three test systems measuring DNA damage, mutagenicity or chromosomal effects (1) as sufficient evidence for mutagenic activity in short-term tests. Although the IARC Group did not define the criteria for "negative" evidence, we feel that at least three negative results in three test systems measuring DNA damage, mutagenicity or chromosomal aberrations are necessary be-

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Cells morphologically indistinguishable from hepatic parenchymal cells are inducible in hamster pancreas by the administration of a pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine at the peak of acinar cell regeneration (29). Such hepatocytelike cells in pancreas contain albumin and glycogen ; undergo cell division after partial hepatectomy, and respond to the peroxisome proliferative effect of methyl clofenapate in a manner identical to liver parenchymal cells (22,23,29). In view of these properties, it seemed reasonable to consider these cells with stable phenotypic features, as true hepatocytes rather than "hepatocyte-like" cells (23). Because the hamster pancreatic hepatocyte model system involves regenerating pancreas, in which acinar cell constitutes the major replicating cell population, it was suggested that regenerating acinar cells in adult hamster pancreas might be susceptible to redirection into a new pathway of differentiation (29). However, unequivocal identity of the precursor cell(s) and the nature of changes in gene expression responsible for the conversion remain at present unknown . Attempts to induce hepatocytes in regeneratingpancreas ofrats and guinea pigs following manipulations such as those outlined for hamster (29) have been unsuccessful, thereby prompting speculation that pancreatic hepatocyte transdifferentiation might be species-specific . Although the hamster regenerating pancreas model appears to be highly promising for the study of ABSTRACT 2-[4(2,2-Dichlorocyclopropyl)phenoxy]2-methyl propionic acid (ciprofibrate), a peroxisome proliferator, induced hepatocytes in the pancreas of adult male F-344 rats when added to their diet at a dosage of 10 mg/kg body weight for 60-72 wk. These cells are morphologically indistinguishable from hepatic hepatocytes and were usually localized adjacent to islets of Langerhans with extensions into surrounding acinar tissue . A significant increase in the volume density of peroxisomes, together with immunochemically detectable amounts of two peroxisome-associated enzymes, was observed in pancreas with hepatocytes of rats maintained on ciprofibrate . Uricase-containing crystalloid nucleoids, specific for rat hepatocyte peroxisomes, were present in pancreatic hepatocytes . These structures facilitated the identification of cells with hybrid cytoplasmic features characteristic of pancreatic acinar and endocrine cells and hepatocytes . Such cells are presumed to represent a transitional state in which pancreas specific genes are being repressed while liver specific ones are simultaneously expressed . The presence of exocrine and/or endocrine secretory granules in transitional cells indicates that acinar/intermediate cells represent the precursor cell from which pancreatic hepatocytes are derived .complexities of transdifferentiation, availability of other systems would further facilitate study of critical aspects of gene activation and repression involved in the hepatocyte conversion. We now report the induction of hepatocytes in the pancreas of Fi...

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