The carcinogenic effect of methapyrilene combined with nitrosodiethylamine given to rats in low doses.

The carcinogenic effects of combinations of methapyrilene hydrochloride (MP), nitrosodiethylamine (NDEA), and phenobarbital (PB) or partial hepatectomy (PH) were examined following sequential treatment of rats. MP is a generally non-genotoxic liver carcinogen of moderate potency, NDEA is a genotoxic liver carcinogen, PB is primarily a liver tumor promoter and PH induces cell proliferation. The dose of each carcinogen was chosen to be below that causing significant liver tumor incidence when given singly. There were 12 protocols involving groups of 28 female rats each. Short treatments with NDEA and MP were followed by 60 weeks of PB promotion or by partial hepatectomy. Each treatment was given separately or in double combination as controls. Several animals of each group were killed at intervals during the experiment for examination of toxic effects and the presence of altered hepatic foci. In only 3 of 12 groups was there a significant incidence of rats with liver neoplasms: the two groups given three treatments: NDEA, MP and PB (86% tumors) or NDEA, MP and PH (33%), and the group receiving NDEA and MP without promotion (46%). The results clearly indicated a co-carcinogenic effect between NDEA and MP. Continuous PB potentiated tumor development, while PH did not. There was no evidence of liver toxicity from any of the treatments, but clear cell foci observed in three groups at weeks 13 and 33 correlated with the later development of liver neoplasms.