Comparative nephrotoxicitiy induced by melamine, cyanuric acid, or a mixture of both chemicals in either Sprague-Dawley rats or renal cell lines.
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.
Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
Lan
L
Choi
Min Young
MY
Kwak
Eun Hwa
EH
Kwak
Dong Hyun
DH
Kim
Eun Young
EY
Han
Taehyun
T
Roh
Jung Yun
JY
Bae
Il Young
IY
Ahn
Jea Yeon
JY
Jung
Mi Jung
MJ
Kwon
Dong Eun
DE
Jang
Seong Kwang
SK
Lim
Seung Jun
SJ
Kwack
Soon Young
SY
Han
Tae Seok
TS
Kang
Seung Hee
SH
Kim
Hyung Sik
HS
Kim
Byung Mu
BM
Lee
D000208:Acute Disease; D000818:Animals; D001774:Blood Chemical Analysis; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004338:Drug Combinations; D004785:Environmental Pollutants / Q000633:toxicity*; D005503:Food Additives / Q000633:toxicity*; D005506:Food Contamination; D006403:Hematologic Tests; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007669:Kidney Calculi / Q000139:chemically induced* / Q000473:pathology; D007677:Kidney Function Tests; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000633:toxicity*
D004338:Drug Combinations; D004785:Environmental Pollutants; D005503:Food Additives; D014227:Triazines; C004632:cyanuric acid; D015232:Dinoprostone; C011907:melamine