Factors modulating benzidine carcinogenicity bioassay

Abstract

An integrated series of studies was presented in which several factors were assessed as to their capability to influence the outcome of carcinogenicity of benzidine dihydrochloride in mice. In all studies C57BL/6J X C3HeB/FeJ F1 mice of both sexes were utilized. Animals were either 6 or 1 week of age at the beginning of carcinogenic treatment. Six-week-old mice were exposed to p.o. administration of carcinogen delivered either in food (50 or 100 ppm daily) or by stomach intubation at equivalent dose levels at twice-weekly intervals. In addition, a 150-ppm dose level in food was administered for 39, 54, or 84 weeks. A limited 3-week, daily intubation of benzidine (30 or 100 mug/mouse) was also explored in 1- and 6-week-old mice. Animals were killed in all studies at 90 weeks of age, at which time their tumor incidence was evaluated. Depending upon experimental conditions, benzidine treatment effected development of liver tumors, lung adenomas. Harderian gland cystadenomas, and lymphoreticular neoplasms. Continuous feeding of adult mice for 84 weeks at three dose levels of benzidine resulted in development of liver tumors with a positive dose-response relationship in both sexes. The analysis of data revealed a greater susceptibility of females than of males (94% versus 44% at 150 ppm). Twice-weekly administration of benzidine by stomach intubation was shown to be less hepatocarcinogenic than continuous feeding of equivalent amounts. In the series in which male mice were fed food containing 150 ppm of benzidine for only 34 or 54 weeks, in contrast to the above 84-week schedule, a negative relationship was observed between the incidence of liver tumors and the duration of treatment. Daily administration of 30 mug of benzidine to infants by stomach intubation for a 3-week period significantly enhanced development of liver tumors only in males (66%). Introduction of 150 ppm of benzidine into food offered to mother and offspring from delivery to weaning led to development of liver tumors in 95% of male mice and in 5% of females. No liver tumors developed following similar 3-week treatment of 6-week-old adults.