Comparative Carcinogenicity of Polybrominated Biphenyls with or without Perinatal Exposure in Rats and Mice

Abstract

Comparative Carcinogenicity of Polybrominated Biphenyls with or without Perinatal Exposure in Rats and Mice. Chhabra, R. S., Bucher, J. R., Haseman, J. K., Elwell, M. R., Kurtz, P. J., and Carlton, B. D. (1993). Fundam. Appl. Toxicol. 21, 451-460.Chronic toxicity and carcinogenicity studies of a polybrominated biphenyl mixture (PBB) were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if exposure to PBB during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of this chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary PBB in rats and mice receiving (i) perinatal exposure up to 8 weeks of age followed by control diet for 2 years, (ii) exposure for 2 years beginning at the age of 8 weeks, and (iii) combined perinatal/adult exposure to PBB (perinatal exposure to 8 weeks of age followed by adult exposure for 2 years). During the perinatal period, rats were exposed to PBB at close levels ranging from 1 to 10 ppm and adult exposure concentrations ranged from 3 to 30 ppm in the diet. In the mice, the dose levels ranged from 3 to 30 ppm in both perinatal and adult exposure portions of the chronic studies. A total of eight dose groups (including controls) were used with 60 animals in each group. Liver was the major target organ of PBB toxicity. Perinatal exposure alone (through dietary administration of 10 ppm PBB to the dams) had no effect on the incidences of neoplasms in female F344/N rats, but in male rats, perinatal exposure was associated with a marginally increased incidence of hepatocellular adenomas that may have been related to chemical administration. In male and female B6C3F1 mice, perinatal exposure to 30 ppm PBB resulted in significantly increased incidences of hepatocellular neoplasms. In adult-only dietary exposure studies, PBB was carcinogenic in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Combined perinatal and adult dietary exposure to PBB confirmed the findings of the adult-only exposures for the increased incidences of hepatocellular neoplasms in rats and mice. In male rats, there were no enhancing effects of combined perinatal and adult exposure. However, perinatal exposure enhanced the susceptibility of female rats receiving adult exposure of 10 or 30 ppm to the induction of liver neoplasms. For male and female rats, a combined analysis of the incidences of leukemia in the adult-only, perinatal-only, and combined perinatal and adult exposure groups revealed an apparent association between increasing incidences of mononuclear cell leukemia and exposure to PBB. In male and female mice, it was not possible to adequately assess the enhancing effects of combined perinatal and adult exposure on hepatocellular tumors, because adult-only exposure to 10 or 30 ppm PBB resulted in high incidences (84-98%) of liver neoplasms. However, with increased perinatal exposure, there were increases in the numbers of mice with hepatocellular carcinomas and in the numbers of mice with multiple hepatocellular adenomas, suggesting that combined perinatal and adult exposure increases PBB-related hepatocellular carcinogenicity relative to adult-only exposure.