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首页> 外文期刊>Archives of Toxicology >Repeat oral dose toxicity studies of melamine in rats and monkeys.
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Repeat oral dose toxicity studies of melamine in rats and monkeys.

机译：重复大鼠和猴子三聚氰胺的口服剂量毒性研究。

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摘要

Melamine is an important and widely used organic industrial chemical. Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula. To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine. Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations. The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period. The dose levels were 140, 700, and 1,400?mg/kg/day (lowered to 1,000?mg/kg/day subsequently due to mortality). Oral administration of melamine at 700?mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium). The kidney was identified as the target organ. Oral administration at 1,400?mg/kg/day (subsequently lowered to 1,000?mg/kg/day) resulted in animal death and moribundity. There were no treatment-related findings in the 140?mg/kg/day group. There were no compound-related findings in the high-dose recovery animals. The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues. At the top dose of 1,050?mg/kg/day, similar clinical and anatomical pathology findings as described above were observed. The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold). These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury. A 3-month oral study with 4-week recovery in monkeys was also conducted. In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700?mg/kg/day. The administration of 700?mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis. Nephrotoxicity was also noted at 200?mg/kg/day. It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140?mg/kg/day in rats following a 14-day oral administration and 60?mg/kg/day in the monkey study.
机译：三聚氰胺是一种重要而广泛使用的有机工业化学品。最近，婴儿肾功能衰竭和肾结石的临床发现与聚酰胺受污染的婴儿配方的摄入有关。为了了解三聚氰胺暴露的毒性和临床结果，进行大鼠和猴子的重复口服剂量研究，表征三聚氰胺的副浓度毒性。毒性评估是基于死亡率，临床症状，体重，眼科发现，临床病理学，病理学，器官重量和微观观测。第一个RAT研究旨在是14天的口腔研究，然后是8天的回收期。剂量水平为140,700和1,400？mg / kg /天（随后由于死亡率降低至1,000？mg / kg /天）。在大鼠中连续14天在700℃/千克/天的口服给药产生复合相关的临床症状（红尿），减少体重，以及临床病理学的变化（增加血清尿素氮和肌酐）和解剖病理学（肾小管细胞碎片，晶体沉积和肾小管上皮的多活性再生）。肾脏被鉴定为靶器官。口服给药在1,400？mg / kg /天（随后降至1,000？mg / kg /天）导致动物死亡和荒诞地。 140毫克/千克/天组中没有治疗有关的发现。高剂量回收动物中没有复合相关的发现。第二大鼠研究是肾组织中测定的基因组生物标志物的5天口服毒性研究。在1,050℃的顶剂量，观察到如上所述的类似临床和解剖病理学发现。测量的基因，Kim-1，Clu，SPP1，A2M，LCN2，TCFRSF12A，GPNMB和CD44显着上调（五倍至550倍），而TFF3显着下调（五倍）。这些结果表明，基因组标志物可以敏感地诊断蛋白酶诱导的肾损伤。还进行了3个月的猴子恢复了3个月的口语研究。在这项猴子研究中，将这些动物用60,200，200或700×mg / kg /天的剂量用三聚氰胺处理。通过鼻胃饲养给700克/千克/天三聚草的给药导致猴子导致测试物文章相关的临床症状，包括浑浊和白色尿液，尿液，红细胞变化，增加血清丙氨酸氨基转移酶和肾脏和/或肝脏重量和微观调查结果，包括肾毒性，心包炎和血液缺血增加。肾毒性也注明了200μlmg/ kg /天。得出结论是，肾脏是初级靶器官，诺埃尔估计在14天口服给药后大鼠的140毫克/千克/天，60？Mg / kg /天在猴子研究中。

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