Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation

The hypothesis that hepatocellular proliferative changes give rise to autonomous, neoplastic lesions in rodents was tested in this study in which hepatoproliferative lesions induced in rats by feeding an experimental psychoactive drug, cyproximide, were examined at various times during the course of a 24 month study. A total of 610 male and female rats (Charles River Laboratories COBS®CD®(SD)BR, Wilmington, Mass.) were distributed into three groups. Each of two treatment groups contained 230 rats given 0.1% or 0.4% of cyproximide in the diet. One hundred and fifty rats were given a drug-free diet and served as controls. Five males and five females from each group were sacrificed for postmortem examination after 6, 12 and 20 months of drug diet feeding after which remaining rats were retained for recovery (nontreatment) periods of 18, 12 and 4 months, respectively. An additional 25 males and 25 females from each dose level were treated for 24 months and then sacrificed along with all surviving recovery and control rats. The results of this study demonstrated that the incidence of proliferative lesions was greater in the liver of treated rats (especially females) than in control rats; however, the incidence of hepatocellular neoplasms was the same in treated and control rats.