Dobson Roy L M, Motlagh Safa, Quijano Mike, Cambron R Thomas, Baker Timothy R, Pullen Aletha M, Regg Brian T, Bigalow-Kern Adrienne S, Vennard Thomas, Fix Andrew, Reimschuessel Renate, Overmann Gary, Shan Yuching, Daston George P
The Procter & Gamble Company, Cincinnati, Ohio 45253, USA.
Toxicol Sci. 2008 Nov;106(1):251-62. doi: 10.1093/toxsci/kfn160. Epub 2008 Aug 9.
This paper describes research relating to the major recall of pet food that occurred in Spring 2007 in North America. Clinical observations of acute renal failure in cats and dogs were associated with consumption of wet pet food produced by a contract manufacturer producing for a large number of companies. The affected lots of food had been formulated with wheat gluten originating from China. Pet food and gluten were analyzed for contaminants using several configurations of high-performance liquid chromatography (HPLC) and mass spectrometry (MS), which revealed a number of simple triazine compounds, principally melamine and cyanuric acid, with lower concentrations of ammeline, ammelide, ureidomelamine, and N-methylmelamine. Melamine and cyanuric acid, have been tested and do not produce acute renal toxicity. Some of the triazines have poor solubility, as does the compound melamine cyanurate. Pathological evaluation of cats and dogs that had died from the acute renal failure indicated the presence of crystals in kidney tubules. We hypothesized that these crystals were composed of the poorly soluble triazines, a melamine-cyanuric acid complex, or a combination. Sprague dawley rats were given up to 100 mg/kg ammeline or ammelide alone, a mixture of melamine and cyanuric acid (400/400 mg/kg/day), or a mixture of all four compounds (400 mg/kg/day melamine, 40 mg/kg/day of the others). Neither ammeline nor ammelide alone produced any renal effects, but the mixtures produced significant renal damage and crystals in nephrons. HPLC-MS/MS confirmed the presence of melamine and cyanuric acid in the kidney. Infrared microspectroscopy on individual crystals from rat or cat (donated material from a veterinary clinic) kidneys confirmed that they were melamine-cyanuric acid cocrystals. Crystals from contaminated gluten produced comparable spectra. These results establish the causal link between the contaminated gluten and the adverse effects and provide a mechanistic explanation for how two apparently innocuous compounds could have adverse effects in combination, that is, by forming an insoluble precipitate in renal tubules leading to progressive tubular blockage and degeneration.
本文描述了与2007年春季在北美发生的宠物食品大规模召回事件相关的研究。猫和狗急性肾衰竭的临床观察结果与食用由一家为多家公司生产的合同制造商生产的湿宠物食品有关。受影响的批次食品是用源自中国的小麦面筋配制的。使用几种高效液相色谱（HPLC）和质谱（MS）配置对宠物食品和面筋中的污染物进行了分析，结果显示存在多种简单的三嗪化合物，主要是三聚氰胺和氰尿酸，还有较低浓度的蜜胺、三聚氰酸一酰胺、脲基三聚氰胺和N-甲基三聚氰胺。三聚氰胺和氰尿酸经测试不会产生急性肾毒性。一些三嗪化合物以及三聚氰胺氰尿酸化合物的溶解度都很差。对死于急性肾衰竭的猫和狗进行的病理评估表明肾小管中存在晶体。我们推测这些晶体由难溶性三嗪、三聚氰胺-氰尿酸复合物或两者的组合构成。给斯普拉格-道利大鼠单独喂食高达100mg/kg的蜜胺或三聚氰酸一酰胺，或三聚氰胺和氰尿酸的混合物（400/400mg/kg/天），或所有四种化合物的混合物（400mg/kg/天三聚氰胺，其他化合物40mg/kg/天）。单独的蜜胺或三聚氰酸一酰胺都未产生任何肾脏影响，但这些混合物导致了严重的肾脏损伤和肾单位中的晶体形成。HPLC-MS/MS证实肾脏中存在三聚氰胺和氰尿酸。对来自大鼠或猫（来自兽医诊所的捐赠材料）肾脏的单个晶体进行的红外显微光谱分析证实它们是三聚氰胺-氰尿酸共晶体。受污染面筋中的晶体产生了类似的光谱。这些结果确立了受污染面筋与不良反应之间的因果联系，并为两种看似无害的化合物如何联合产生不良反应提供了一种机制解释，即通过在肾小管中形成不溶性沉淀物导致肾小管逐渐堵塞和变性。
