Umemura Takashi, Kurokawa Yuji
Division of Pathology, National Institute of Health Scineces, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Toxicology. 2006 Apr 17;221(2-3):154-7. doi: 10.1016/j.tox.2006.01.007. Epub 2006 Feb 13.
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.
给雄性和雌性大鼠饮用含250和500mg/L溴酸钾的水后，肾细胞肿瘤显著增加。在至少另一项研究中，给雄性大鼠饮用125mg/L溴酸钾可诱发肾细胞肿瘤。在给予750mg/L溴酸钾的雄性小鼠中，试验88周后，处理组和对照组之间肾细胞肿瘤无显著差异。在氧化DNA损伤试验中，500mg/L时，雄性大鼠肾脏DNA在1周内诱导产生8-氧代脱氧鸟苷（8-oxodG，也称为8-羟基脱氧鸟苷8-OH-dG），雌性大鼠在3周后诱导产生；250mg/L时，雄性和雌性大鼠均在1周后诱导产生，但125mg/L时未诱导产生。DNA加合物被认为是致癌过程的初始步骤，然而，给药剂量并不总是足以引起突变，这可能是由于DNA修复。在以N-乙基-N-羟乙基亚硝胺（EHEN）为启动剂的两步大鼠肾癌发生模型中，使用BrdU标记指数测量溴酸钾的促癌活性。溴酸钾对雄性大鼠的促癌活性更强，低至60mg/L时对雄性大鼠仍有促癌作用，而对雌性大鼠的反应仅限于250和500mg/L。因此，得出结论，雄性大鼠致癌的机制比雌性大鼠更复杂。暴露于溴酸钾的雄性大鼠肾脏中α2μ球蛋白的积累可能是雄性大鼠相对于雌性大鼠标记指数更高的原因。化学物质处理导致α（2μ）球蛋白积累是雄性大鼠特有的，确实会导致致癌反应。人类和雌性大鼠均无此反应。然而，由于雌性大鼠有反应，必须认为溴酸钾具有致癌性。8-oxodG形成与肿瘤反应之间更好的相关性表明，雌性大鼠的剂量反应信息与人类风险评估更相关。雌性大鼠肾脏中BrdU-LI升高这一事实与雌性大鼠中观察到的细胞增殖可能是由肾脏中的氧化应激和/或细胞毒性反应引起的可能性一致。因此，氧化应激很可能是人类癌症风险的相关机制。
