Nongenotoxic Mechanisms Involved in Bromate-Induced Cancer in Rats

摘要

Risk assessments for bromate (BrO3-) in drinking water are based on linear extrapolation from the total incidence of tumors in male rats. The only genotoxic effects that might result from carcinogenic doses of BrO3- in vivo are the formation of 8-oxodeoxyguanosine (8-oxoG) in deoxyribonucleic acid (DNA) and the production of micronuclei. The mutations in tumors are consistent with the 8-oxoG adduct, and both effects are nonlinear with respect to dose. Treatment of rats with BrO3- resulted in bromination of protein tyrosines. The accumulation of these proteins in the kidney appeared to contribute to kidney cancer in male, but not female, rats. BrO3- increased the rate of apoptosis (programmed cell death) in the kidneys of rats of both sexes, an effect associated with increasing expression of antiapoptotic genes and proteins. Consequently, suppression of apoptosis is a likely mechanism for BrO3- induced kidney cancer. More limited data suggest nongenotoxic modes of action for thyroid tumors and mesotheliomas. If these data are confirmed, linear extrapolation of risk to low doses is inappropriate.