Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
J Toxicol Environ Health A. 2010;73(21-22):1407-19. doi: 10.1080/15287394.2010.511540.
Acute nephrotoxicities of melamine (MEL), cyanuric acid (CA), and a mixture of both melamine and cyanuric acid (MC) were comparatively investigated in male Sprague-Dawley rats at 5 doses each with 10-fold dose interval as follows: MEL at 0.0315, 0.315, 3.15, 31.5, and 315 mg/kg; CA at 0.025, 0.25, 2.5, 25, and 250 mg/kg, and MC: [1×: (0.0315 + 0.025), 10×: (0.315 + 0.25), 100×: (3.15 + 2.5), 1000×: (31.5 + 25), and (315 + 250) mg/kg]. No marked adverse effects in renal function were observed in animals treated with MEL alone or CA alone, but evidence related to nephrotoxicity was noted in rats administered MC. Renal calculi and increased kidney weights were found in rats 7 d after daily oral administration of MC. Blood urea nitrogen (BUN) and creatinine were significantly elevated in the high dose MC groups at 100× or 1000×. In addition, elevated numbers of white blood cells (WBC), neutrophils, and lymphocytes in vivo and increased levels of prostaglandin E(2) (PGE(2)) in vitro were found in the MC group. Based on these data, the NOAEL (no-observed-adverse-effect level) for nephrotoxicity for MC was estimated to be 3.15 mg/kg body weight (bw)/d (MEL) plus 2.5 mg/kg bw/d (CA). If a safety factor of 1000 or more were applied to NOAEL, tolerable daily intake (TDI) would be 0.00315 and 0.0025 mg/kg/d or less for MEL and CA, respectively, which is far below the TDI of 0.2 mg/kg/d set by World Health Organization (WHO). In addition, in vitro cytotoxicity assays showed that the ACHN human renal adenocarcinoma cell line was more sensitive to MEL, CA, and MC than the MDCK canine kidney epithelial cell line. The 24-h half maximal inhibitory concentration (IC(50)) values for MEL (4792, 2792 μg/ml) were less than those of CA (9890, 6725 μg/ml, respectively) in MDCK and ACHN cell lines, suggesting that MEL may be more cytotoxic than CA. Furthermore, the 24-h IC(50) value for MC was found to be 208 μg/ml in ACHN cells. Data suggest that NOAELs based upon acute nephrotoxic parameters for MC were low, which might require further reassessment of the current TDI.
三聚氰胺（MEL）、三聚氰酸（CA）和三聚氰胺与三聚氰酸混合物（MC）的急性肾毒性在雄性 Sprague-Dawley 大鼠中进行了比较研究，每个剂量组有 5 个剂量，剂量间隔为 10 倍，如下所示：MEL 分别为 0.0315、0.315、3.15、31.5 和 315mg/kg；CA 分别为 0.025、0.25、2.5、25 和 250mg/kg，MC：[1×：（0.0315 + 0.025），10×：（0.315 + 0.25），100×：（3.15 + 2.5），1000×：（31.5 + 25），和（315 + 250）mg/kg]。单独使用 MEL 或 CA 处理的动物未观察到肾功能的明显不良反应，但在给予 MC 的大鼠中观察到与肾毒性相关的证据。在每日口服 MC 7 天后，大鼠发现肾结石和肾脏重量增加。在 MC 的高剂量 100×或 1000×组中，血尿素氮（BUN）和肌酐显著升高。此外，体内白细胞（WBC）、中性粒细胞和淋巴细胞数量增加，体外前列腺素 E2（PGE2）水平升高，MC 组中发现这些情况。根据这些数据，MC 的肾毒性无观察到不良效应水平（NOAEL）估计为 3.15mg/kg 体重（BW）/d（MEL）加 2.5mg/kg BW/d（CA）。如果将安全系数应用于 NOAEL 超过 1000，则可耐受每日摄入量（TDI）将分别为 MEL 和 CA 为 0.00315 和 0.0025mg/kg/d 或更低，远低于世界卫生组织（WHO）设定的 0.2mg/kg/d 的 TDI。此外，体外细胞毒性测定表明，ACHN 人肾腺癌细胞系比 MDCK 犬肾上皮细胞系对 MEL、CA 和 MC 更敏感。MEL（4792、2792μg/ml）在 MDCK 和 ACHN 细胞系中的 24 小时半最大抑制浓度（IC50）值小于 CA（9890、6725μg/ml），表明 MEL 可能比 CA 更具细胞毒性。此外，在 ACHN 细胞中发现 MC 的 24 小时 IC50 值为 208μg/ml。数据表明，基于 MC 的急性肾毒性参数的 NOAEL 较低，这可能需要进一步重新评估当前的 TDI。
