The influence of sex, dose, time, and cross on neoplasia in mice given benzidine dihydrochloride

Abstract

Mice were provided ad libitum water containing 0, 30, 60, 120, 200, or 400 ppm benzidine dihydrochloride for 40, 60, or 80 weeks. Initially there were 864 mice of both sexes of two crosses, monohybrid cross and F-1 cross. The monohybrid cross was genetically heterogeneous and was produced from the genetically homogenous F-1 cross. Groups of mice from both crosses and both sexes were terminated at 40, 60, and 80 weeks for pathological evaluation. Statistical analyses of animal weights, water consumption, hepatic cellular alteractions, liver tumor incidence, liver tumor survival, and time-to-first appearance of a liver tumor were performed. Average animal weights decreased as the dose of benzidine increased. There was a corresponding decrease in water consumption with increased dose. Positive associations between incidences of basophilic and acidophilic hepatic foci of cellular alterations, hepatocellular adenomas, and hepatocellular carcinomas were noted in females but similar associations were not noted in males. ED50s calculated from liver tumor incidence for the three termination periods ranged from a low of 54 ppm (F-1 cross and monohybrid cross 80-week females) to a high of 2799 ppm (F-1 cross 40-week males). There were significant differences among the liver tumor survival distributions for all four cross-sex combinations, attributable in all four cases to significant dose-related trends. The estimated time-to-first appearance of a liver tumor was also dose related. The estimated mean time-to-liver tumor ranged from 9 months at 400 ppm to 18 months at 60 ppm in females and 15 months at 400 ppm to 23 months at 60 ppm in males. Five months was estimated for an animal to die of a tumor following the first appearance of the tumor for both sexes and both crosses, irrespective of dose. In all responses mentioned above there were minor differences observed between the two crosses but major differences in response were observed between the sexes for both crosses.