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The promoting activity of the commercial PCB mixture Clophen A 50 on preneoplastic, enzyme-altered islands in rat liver was investigated. Female Sprague-Dawley rats, 3 and 6 weeks old, were pretreated with nitrosamines for island initiation. Thereafter Clophen A 50 was administered repeatedly. Island development was examined between 2 and 12 weeks. Clophen A 50 by itself initiated few enzyme-altered islands, indicating a weak carcinogenicity. In Clophen A 50-treated adult rats, the majority of nitrosamine-initiated islands persisted. Without Clophen A 50 more than 80% of the islands disappeared between 6 and 12 weeks. Moreover, PCBs caused a striking increase in island number and total area during the last 2 weeks. In weanlings, islands persisted with or without the promoting stimulus. However, treatment with Clophen A 50 caused an earlier appearance and a higher number and total area of islands. The increase in the yield of DEN-initiated islands in both age groups is suggested to be due to the promotion of initiated but dormant cells. By pretreatment with N-NM instead of DEN, a shift to larger islands was observed additionally. The data indicate that weanlings are highly susceptible to initiation and promotion and may thus provide a sensitive tool to screen for tumor initiating and promoting agents.

The promoting effect of Clophen A 50, a commercial mixture of polychlorinated biphenyls (PCBs) on preneoplastic islands, initiated by diethylnitrosamine (DEN), was studied in male and female Sprague-Dawley rats. The islands were identified histochemically by loss of adenosine-5'-triphosphatase (ATPase) and/or emergence of gamma-glutamyltranspeptidase (GGTase). Treatment with 12 X 8 mg DEN/kg body wt./day initiated a similar number and total area of islands in males and females. Additional weekly application of Clophen A 50 (50 or 100 mg/kg body wt./week, for 7 weeks) enhanced the number of ATPase-deficient islands 3-fold in males and 9-fold in females. The total area was increased 4-fold in males and 15-fold in females. Number and area of GGTase-positive islands were similarly enhanced. The emergence of a small number of islands after application of Clophen A 50 alone may indicate a weak carcinogenic potency. PCB treatment caused an increase in liver weight, which amounted to approximately 55% in males and 20% in females compared to controls. This increase is partly due to cell hypertrophy, as indicated by determination of cell size. The mitogenic activity of Clophen A 50 was evaluated by measurement of the mitotic index of unaltered hepatocytes at 24, 48 h, and 7 days after application of a single dose (100/mg/kg body wt.) of Clophen A 50. The mitotic index in control animals of both sexes was approximately 0.3%, and was enhanced approximately 8-fold in males, 24 h after PCB treatment. In females only a slight, non-significant increase was observed. The results indicate that the sex-dependent promoting effect of Clophen A 50 is independent from its mitogenic action.

Cyproterone acetate (CPA) is a synthetic steroid which is used in oral contraceptive and anti-androgen formulations. It has previously been classified as a tumor promoter in rat liver. Recent studies have shown that CPA induces DNA repair synthesis in isolated hepatocytes, and this implies that CPA is genotoxic. We studied the initiating activity of CPA in vivo by means of a rat liver foci bioassay, using weanling female Sprague-Dawley rats. The results show that CPA induces adenosine-triphosphatase-deficient and gamma-glutamyltranspeptidase-positive putative preneoplastic foci in a dose-dependent manner. This indicates that CPA has not only promoting but also initiating activity and may therefore act as a complete carcinogen in rat liver.