potassium-bromate and Cocarcinogenesis

Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

Topics: Adenocarcinoma; Administration, Oral; Animals; Bread; Bromates; Bromides; Carcinogenicity Tests; Carcinogens; Carcinoma, Renal Cell; Chromosome Aberrations; Cocarcinogenesis; Cricetinae; Cysteine; Dose-Response Relationship, Drug; Fish Products; Food Additives; Food Handling; Glutathione; Hair Preparations; Hearing Loss; Humans; Japan; Kidney Diseases; Kidney Neoplasms; Maximum Allowable Concentration; Mesocricetus; Mesothelioma; Mice; Mutagenicity Tests; Occupational Diseases; Peritoneal Neoplasms; Potassium; Potassium Compounds; Rats; Rats, Inbred F344; Species Specificity; Thyroid Neoplasms; United Kingdom; United States

Renal cell tumors were significantly increased in male and female rats given potassium bromate at 250 and 500 mg/L in drinking water. In at least one other study renal cell tumors were produced in male rats at 125 mg/L. Among male mice given 750 mg/L of potassium bromate, there were no significant differences in renal cell tumors between treated and control groups after 88 weeks on test. In oxidative DNA damage tests 8-oxodeoxyguanosine (8-oxodG also referred to as 8-OH-dG) was induced in DNA in the male rat kidney in 1 week, and in females after 3 weeks at 500 mg/L, and also in both male and female rats at 250 mg/L, but not at 125 mg/L. DNA adducts are considered to be an initial step in the carcinogenesis process, however, the administered doses are not always sufficient to cause mutations, possibly due to DNA repair. In the two-step rat renal carcinogenesis model using N-ethyl-N-hydroxyethylnitrosamine (EHEN) as initiator, promotion activity by potassium bromate was measured using the BrdU labeling index. The promoting activity of bromate in male rats was much greater and extended to doses as low as 60 mg/L in male rats, whereas in females the response was limited to 250 and 500 mg/L. Therefore, it was concluded that the mechanisms contributing to cancer in the male rat were more complex than in the female rat. The accumulation of alpha2mu-globulin in the kidneys of male rats exposed to potassium bromate probably accounts for the greater labeling index in the male rat relative to the female rat. Accumulation of alpha(2mu)-globulin as a result of treatment with chemicals is unique to the male rat and does contribute to carcinogenic responses. Neither humans nor female rats display this response. Nevertheless, bromate must be considered carcinogenic because of the response of the female rats. The better correlation between 8-oxodG formation and tumor response indicates that dose-response information from the female rat would be much more relevant to human risk assessment. The fact that an elevation of BrdU-LI in the kidney of the female rat is consistent with the possibility that cell proliferation observed in female rats resulted from oxidative stress and/or cytotoxic responses in the kidney. Therefore, oxidative stress is most likely the mechanism of interest for cancer risk in humans.

Topics: Administration, Oral; Alpha-Globulins; Animals; Bromates; Carcinogens, Environmental; Carcinoma, Renal Cell; Cell Proliferation; Cocarcinogenesis; Diethylnitrosamine; DNA Adducts; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Drinking; Female; Japan; Kidney; Kidney Neoplasms; Male; Mice; Mice, Inbred Strains; Mutagenicity Tests; Mutagens; Oxidative Stress; Rats; Rats, Inbred F344; Sex Factors

Dose-response studies were undertaken to investigate the enhancing activity of potassium bromate (KBrO3), a food additive, on renal tumorigenesis initiated by N-ethyl-N-hydroxyethylnitrosamine (EHEN). A total of 180 male 6-week-old F344 rats were divided into 12 groups. EHEN was given in the drinking water for the first 2 weeks at a concentration of 500 ppm for initiation of carcinogenesis. Thereafter, the rats were treated orally either with KBrO3 at a concentration of 500, 250, 125, 60, 30 or 15 ppm, or with potassium bromide (KBr) at a concentration of 1750 or 350 ppm for 24 weeks. The mean numbers of kidney dysplastic foci were significantly increased in a dose-related manner in rats treated with more than 30 ppm KBrO3. The mean number of renal cell tumors was significantly higher after treatment with KBrO3 at the highest concentration of 500 ppm. On the other hand, KBr had no effect. It was concluded that KBrO3 at doses higher than 30 ppm in the drinking water has an enhancing effect on renal tumorigenesis.

Topics: Animals; Bromates; Bromine; Carcinogens; Cocarcinogenesis; Diethylnitrosamine; Dose-Response Relationship, Drug; Food Additives; Kidney Neoplasms; Male; Nitrosamines; Rats; Rats, Inbred F344