National Center for Toxicological Research, Jefferson, AR 72079, USA.
Toxicol Sci. 2011 Feb;119(2):391-7. doi: 10.1093/toxsci/kfq333. Epub 2010 Oct 28.
The intentional adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of a large number of cats and dogs in the United States. Although individually these compounds present low toxicity, coexposure can lead to the formation of melamine cyanurate crystals in the nephrons and eventual kidney failure. To determine the dose-response for nephrotoxicity upon coadministration of melamine and cyanuric acid, groups of male and female F344 rats (six animals per sex per group) were fed 0 (control), 7, 23, 69, 229, or 694 ppm of both melamine and cyanuric acid; 1388 ppm melamine; or 1388 ppm cyanuric acid in the diet for 7 days. No toxicity was observed in the rats exposed to the individual compounds, whereas anorexia and a statistically significant increase in blood urea nitrogen and serum creatinine levels was observed in the animals treated with 229 and 694 ppm melamine and cyanuric acid. The kidneys of these animals were grossly enlarged and pale yellow. Large numbers of crystalline structures deposited in the tubules were seen on sections in kidneys from all rats in these treatment groups. No significant changes were detected in the remaining treatment groups exposed to both melamine and cyanuric acid. In the melamine-only treatment group, 5 of 12 rats had scattered crystals present in renal tubules when examined by wet mount. These were not observed by histopathology. The observed adverse effect level (8.6 mg/kg bw [body weight]/day) and benchmark dose modeling data (8.4-10.9 mg/kg bw/day) determined in this study suggest that the tolerable daily intake values derived from studies conducted with melamine alone may underestimate the risk from coexposures to melamine and cyanuric acid.
宠物食品中三聚氰胺和其衍生物（包括三聚氰酸）的蓄意掺假与美国大量猫和狗的肾衰竭和死亡有关。尽管这些化合物单独存在时毒性较低，但共同暴露会导致肾单位中三聚氰胺氰尿酸晶体的形成，最终导致肾衰竭。为了确定三聚氰胺和三聚氰酸共同给药时的肾毒性剂量反应，将雄性和雌性 F344 大鼠（每组 6 只动物）分为 0（对照组）、7、23、69、229 或 694 ppm 的三聚氰胺和三聚氰酸；1388 ppm 的三聚氰胺；或 1388 ppm 的三聚氰酸，在饮食中连续喂养 7 天。单独暴露于这些化合物的大鼠未观察到毒性，而暴露于 229 和 694 ppm 的三聚氰胺和三聚氰酸的动物出现厌食和血尿素氮和血清肌酐水平的统计学显著增加。这些动物的肾脏明显肿大，呈苍黄色。在这些处理组的所有大鼠的肾脏切片中都可以看到大量晶体结构沉积在肾小管中。暴露于三聚氰胺和三聚氰酸的其余处理组未检测到显著变化。在仅接受三聚氰胺处理的组中，12 只大鼠中有 5 只在湿载片检查时肾小管中出现散在晶体，但未通过组织病理学观察到。本研究中确定的观察到的不良效应水平（8.6mg/kg bw[体重]/天）和基准剂量建模数据（8.4-10.9mg/kg bw/天）表明，单独用三聚氰胺进行的研究中得出的可耐受每日摄入量值可能低估了三聚氰胺和三聚氰酸共同暴露的风险。
