Repeat oral dose toxicity studies of melamine in rats and monkeys.
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.
WuXi AppTec, 1318 Wuzhong Avenue, Wuzhong District, Suzhou, 215104, China.
Richard J
RJ
Early
Hong
H
Yu
Xueyan Peter
XP
Mu
Haiyan
H
Xu
Lei
L
Guo
Qingxue
Q
Kong
Junma
J
Zhou
Bruce
B
He
Xiuying
X
Yang
Hailiang
H
Huang
Edward
E
Hu
Ying
Y
Jiang
D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005506:Food Contamination; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests; D014227:Triazines / Q000008:administration & dosage* / Q000633:toxicity*
D015415:Biomarkers; D005819:Genetic Markers; D014227:Triazines; C011907:melamine