臺灣博碩士論文加值系統

三聚氰胺(Melamine)為多胺基所組成，添加於食品中可假性增高蛋白質含量，而三聚氰酸(cyanuric acid)為其結構相似之衍生物。已知兩種物質(melamine and cyanuric acid)混合較單獨三聚氰胺，大幅增加腎臟毒性，目前僅能推測腎衰竭起因於腎臟濃縮尿液，引起腎結晶析出，結晶導致腎小管毒性或阻塞，對於三聚氰胺及三聚氰酸對腎小管細胞之毒性機制仍然尚未明瞭。為了解三聚氰胺及三聚氰酸之急性腎毒性作用機制，以胃管餵食雄性大鼠高劑量400 mg/kg三聚氰胺及三聚氰酸(1:1)混合，在30分鐘、1、3、12、24及48小時不同時間點犧牲，腎臟病理變化結果顯示，自12小時開始近端腎小管上皮細胞變性及死亡量增加，隨時間增長而增加，在48小時發現遠端腎小管腔內有少量黃綠色圓形結晶堆積，血液中嗜中性球、creatinine、BUN及鉀離子顯著上升，腎小管增殖細胞核抗原(PCNA)陽性表現增加伴隨腎損傷增加。分析腎臟中炎症激素及抗氧化表現，發現丙二醛(MDA)、IL-1β及IL-6顯著上升，顯示三聚氰胺混合三聚氰酸使腎臟氧化物質增加及造成急性炎症反應，穿透式電子顯微鏡觀察發現12小時開始，以近端小管細胞為主，開始出現細胞核皺縮、微絨毛消失、粒腺體空泡化及細胞水腫等，腎小管細胞質中發現針狀結晶及腎小管腔中有大型不規則結晶堆積，可直接刺穿細胞膜及對細胞造成物理性傷害，顯示三聚氰胺混合三聚氰酸對近端及遠端腎小管有不同傷害表現，以近端小管受結晶物理性傷害為主。爲探討長時間重覆低劑量攝食三聚氰胺及三聚氰酸之影響，可望作為日後訂定三聚氰胺與三聚氰酸混合毒性之安全性閥值參考依據，進行亞急毒性28天連續餵毒性試驗，以飼料混拌三聚氰胺及三聚氰酸(1:1)劑量分別為0 (control)、100、200及300 ppm連續任食雄性大鼠28或14天，結果顯示，高劑量組大鼠體重下降，中及高劑量組腎臟增重，血液嗜中性球、LDH、Creatinine及BUN上升，組織病理學檢查腎臟局部纖維化及再生，腎小管腔擴張，可見黃綠色圓形結晶堆積，並伴隨有多量炎症細胞浸潤，為腎小管性間質性腎炎(tubulointerstitial nephritis)。在低劑量組則無明顯毒性作用，100、200及300 ppm換算大鼠每日每公斤體重攝食量分別為2.99、4.81及4.06 mg/kg body weight per day，得知三聚氰胺及三聚氰酸(1:1)混合餵食28天之每日無毒害作用劑量(No observed adverse effect level, NOAEL)為2.99 (~3) mg/kg body weight per day，推算人體每日可攝取量(acceptable daily intake, ADI)為0.03 mg/kg weight per day，遠低於WHO (0.2 mg/kg)與USFDA (0.63 mg/kg)訂定之單獨三聚氰胺每日可攝食量，顯示三聚氰胺及三聚氰酸混合可大幅增加腎臟毒性。

Melamine is composed of multi-amine, was added into food to false increase protein contents. Furthermore, cyanuric acid is an aderivarative of melamine. The objective of this study was conducted to evaluate the possible acute toxic mechanisms of melamine and cyanuric acid (MCA) crystals formation related to renal failure. The time course of acute oral toxicity of male rats was singly gavaged with 400 mg/kg MCA (1:1) and observed at different time-course of 30 minutes, 1, 3, 12, 24 and 48 hours, respectively. Results revealed that degeneration/necrosis were found in the proximal tubules starting from 12 hour post-administration and increased severity with timing. After that, a small amount of yellow-greenish crystals were observed in the dilated distal renal tubules at 48 hour. Hematology and serum chemistry parameters showed that acute inflammatory cells, BUN, ceatinine and serum potassium ion values significantly increased. Immunohistochemistry, the numbers of proliferating cell nuclear antigen (PCNA) increased and accompanied with renal tubular injury. Malondialdehyde (MDA), IL-1β and IL-6 levels elevated after MCA (1:1) treatment indicating reduction of antioxidant ability and acute inflammation in kidney. Ultrastructurally, nucleus pyknosis, lost microvilli, mitochondria vesicles and cell swelling were mainly found in the proximal tubular cells. Two kinds of crystals were observed; small needle-like crystals in the cytoplasm were presented in dying cells, and large crystals in the lumen of tubule could induce physical damage or directly penetrated cell membrane. This study suggests that administration of MCA poses different toxicity to the target cells of both the proximal and distal tubules in rats. The proximal tubular cells may be injured directly by MCA crystals. In order to understand the no observed adverse effect level (NOAEL) of MCA combination, three different doses of 100, 200 and 300 ppm MCA in diet were fed to male rats for either 14 or 28 days. Results revealed moderate to severe tubulointerstitial nephritis with yellow-greenish MCA crystals in the median and high dose groups. The NOAEL of MCA subacute toxicity is 2.99 (~3) mg/kg bw/day in male rats and the ADI value of MCA is recommended to equal or less than 0.03 mg/kg bw/day for human. The ADI (0.03 mg/kg bw/day) based on the nephrotoxicity of MCA in rats from the study are lower than published ADI from WHO (0.2 mg/kg bw/day), and suggested that ADI with melamine alone may underestimate the risk from co-exposure to melamine and cyanuric acid.

中文摘要---------------------------------------------------------------------------------- I
英文摘要---------------------------------------------------------------------------------- III
目次---------------------------------------------------------------------------------------- IV
圖目次------------------------------------------------------------------------------------- VI
表目次------------------------------------------------------------------------------------- X
第一章 前言----------------------------------------------------------------------------- 1
第二章 文獻探討----------------------------------------------------------------------- 2
第一節 三聚氰胺及三聚氰酸混合污染之犬貓腎衰竭事件------------- 2
第二節 三聚氰胺單獨污染之中國嬰兒腎衰竭及腎結石事件---------- 3
第三節 三聚氰胺及三聚氰酸文獻探討------------------------------------- 4
第四節 三聚氰胺及三聚氰酸合併加強腎毒性與其作用機制---------- 11
第五節 腎結石與腎衰竭------------------------------------------------------- 14
第六節 生物體內抗氧化系統之作用機制---------------------------------- 20
第七節 目前台灣及全球之三聚氰胺及三聚氰酸管理規範------------- 22
第三章 研究目的與實驗設計-------------------------------------------------------- 23
第一節 研究目的---------------------------------------------------------------- 23
第二節 實驗架構---------------------------------------------------------------- 24
第四章 材料與方法-------------------------------------------------------------------- 25
第一節 實驗材料與儀器------------------------------------------------------- 25
第二節 試驗樣品---------------------------------------------------------------- 26
第三節 大鼠不同時間點之口服急毒性腎毒性試驗---------------------- 27
第四節 大鼠亞急毒性28天餵毒性試驗----------------------------------- 33
第五節 腎組織中氧化狀態分析---------------------------------------------- 36
第六節 腎組織中細胞激素分析(IL-1β, IL-6, TNF-α)-------------------- 40
第五章 結果----------------------------------------------------------------------------- 42
第一節 大鼠不同時間點之口服急毒性腎毒性試驗---------------------- 42
第二節 大鼠亞急毒性28天餵毒性試驗----------------------------------- 79
第三節 腎組織中抗氧化酵素表現------------------------------------------- 113
第四節 腎組織中細胞激素表現---------------------------------------------- 117
第六章 討論----------------------------------------------------------------------------- 119
第一節 大鼠不同時間點之口服急毒性腎毒性試驗---------------------- 120
第二節 大鼠亞急毒性28天餵毒性試驗----------------------------------- 124
第三節 腎組織中抗氧化酵素及細胞激素分析(IL-1β, IL-6, TNF-α)--- 127
第七章 結論----------------------------------------------------------------------------- 130
第八章 參考文獻----------------------------------------------------------------------- 131

吳依璇。三聚氰胺及三聚氰酸混合物之基因毒理及大鼠之腎臟排除研究。碩士論文。國立中興大學獸醫病理生物學研究所。台中。2010。
吳明勳。從毒奶事件--認識三聚氰胺。中化藥訊。台北。2009。
李易帆。三聚氰胺及三聚氰酸合併加強腎小管細胞傷害及大鼠腎毒性作用之研究。碩士論文。國立中興大學獸醫病理生物學研究所。台中。2009。
Abbas AK and Lichtman AH. Cellular and Molecular Immunology 5th: Effector Mechanisms of Immune Responses. Winsland Hose I. P 243-263, 2003.
Adams LG and Syme HM. Textbook of Veterinary Internal Medicine Sixth Edition: Canine Lower Urinary Tract . Los Angeles. 1858-1872, 2005.
Allen LM, Briggle TV and Pfaffenberger CD. Absorption and excretion of cyanuric acid in long-distance swimmers. Drug Metab Rev. 13(3): 499-516, 1982.
Andersen WC, Turnipseed SB, Karbiwnyk CM, Clark SB, Madson MR, Gieseker CM, Miller RA, Rummel NG and Reimschuessel R. Determination and confirmation of melamine residues in catfish, trout, tilapia, salmon, and shrimp by liquid chromatography with tandem mass spectrometry. J Agric Food Chem. 56(12): 4340-4347, 2008.
Asselman M, Verhulst A, De Broe ME and Verkoelen CF. Calcium oxalate crystal adherence to hyaluronan-, osteopontin-, and CD44-expressing injured/regenerating tubular epithelial cells in rat kidneys. J Am Soc Nephrol. 14(12): 3155-3166, 2003.
Bingham EC, B.; Powell, C.H. Patty''s Toxicology Volumes 1-9 5th ed. John Wiley & Sons. 2001.
Borges F, Fernandes E and Roleira F. Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem. 9(2): 195-217, 2002.
Brown CA, Jeong KS, Poppenga RH, Puschner B, Miller DM, Ellis AE, Kang KI, Sum S, Cistola AM and Brown SA. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest. 19(5): 525-531, 2007.
Burns K. Recall shines spotlight on pet foods. J Am Vet Med Assoc. 230(9): 1285-1288, 2007.
Chen KC, Chen FP and Liao JW. Genotoxic effects of suspected feed in canine renal failure case. Symposium on 9th. Chinese Laboratory Animal Science. P 66, 2006.
Chen KC, Liao CW, Cheng FP, Chou CC, Chang SC, Wu JH, Zen JM, Chen YT and Liao JW. Evaluation of subchronic toxicity of pet food contaminated with melamine and cyanuric acid in rats. Toxicol Pathol. 37(7): 959-968, 2009.
Cianciolo RE, Bischoff K, Ebel JG, Van Winkle TJ, Goldstein RE and Serfilippi LM. Clinicopathologic, histologic, and toxicologic findings in 70 cats inadvertently exposed to pet food contaminated with melamine and cyanuric acid. J Am Vet Med Assoc. 233(5): 729-737, 2008.
DHHS/NTP. NTP Carcinogenesis Bioassay of Melamine (CAS No. 108-78-1) in F344/N Rats and B6C3F1 Mice (Feed Study). Natl Toxicol Program Tech Rep Ser. 245(1-171), 1983.
Dobson RL, Motlagh S, Quijano M, Cambron RT, Baker TR, Pullen AM, Regg BT, Bigalow-Kern AS, Vennard T, Fix A, Reimschuessel R, Overmann G, Shan Y and Daston GP. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci. 106(1): 251-262, 2008.
Dominguez-Estevez M, Constable A, Mazzatorta P, Renwick AG and Schilter B. Using urinary solubility data to estimate the level of safety concern of low levels of melamine (MEL) and cyanuric acid (CYA) present simultaneously in infant formulas. Regul Toxicol Pharmacol. 57(2-3): 247-255, 2010.
Ejaz AA, Mu W, Kang DH, Roncal C, Sautin YY, Henderson G, Tabah-Fisch I, Keller B, Beaver TM, Nakagawa T and Johnson RJ. Could uric acid have a role in acute renal failure? Clin J Am Soc Nephrol. 2(1): 16-21, 2007.
Emmerson BT, Cross M, Osborne JM and Axelsen RA. Reaction of MDCK cells to crystals of monosodium urate monohydrate and uric acid. Kidney Int. 37(1): 36-43, 1990.
Finlayson B and Reid F. The expectation of free and fixed particles in urinary stone disease. Invest Urol. 15(6): 442-448, 1978.
Fridovich I. Superoxide dismutases. Annu Rev Biochem. 44(147-159), 1975.
Gardner R, Salvador A and Moradas-Ferreira P. Why does SOD overexpression sometimes enhance, sometimes decrease, hydrogen peroxide production? A minimalist explanation. Free Radic Biol Med. 32(12): 1351-1357, 2002.
Gokhale JA, Glenton PA and Khan SR. Characterization of Tamm-Horsfall protein in a rat nephrolithiasis model. J Urol. 166(4): 1492-1497, 2001.
Hau AK, Kwan TH and Li PK. Melamine toxicity and the kidney. J Am Soc Nephrol. 20(2): 245-250, 2009.
Hilts C and Pelletier L. Background paper on occurrence of melamine in foods and feed. Prepared for the WHO Expert Meeting on Toxicological and Health Aspects of Melamine and Cyanuric Acid In collaboration with FAO and supported by Health Canada. 2008.
Hirose M, Tozawa K, Okada A, Hamamoto S, Shimizu H, Kubota Y, Itoh Y, Yasui T and Kohri K. Glyoxylate induces renal tubular cell injury and microstructural changes in experimental mouse. Urol Res. 36(3-4): 139-147, 2008.
HSDB. HSDB number: 2648. Hazardous Substances Data Bank. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB, 2008.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer. 1972.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. . Geneva: World Health Organization, International Agency for Research on Cancer. 73, 1999.
Jacob CC, Reimschuessel R, Von Tungeln LS, Olson GR, Warbritton AR, Hattan DG, Beland FA and Gamboa da Costa G. Dose-response assessment of nephrotoxicity from a 7-day combined exposure to melamine and cyanuric acid in f344 rats. Toxicol Sci. 119(2): 391-397, 2011.
Jeong WI, Do SH, Jeong da H, Chung JY, Yang HJ, Yuan DW, Hong IH, Park JK, Goo MJ and Jeong KS. Canine renal failure syndrome in three dogs. J Vet Sci. 7(3): 299-301, 2006.
JMPR. Cyromazine. http://www.fao.org/ag/AGP/AGPP/Pesticid/JMPR/Download/2006_rep/Cyromazine.pdf, 2006.
Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L and Johnson RJ. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 41(6): 1287-1293, 2003.
Karbiwnyk CM, Andersen WC, Turnipseed SB, Storey JM, Madson MR, Miller KE, Gieseker CM, Miller RA, Rummel NG and Reimschuessel R. Determination of cyanuric acid residues in catfish, trout, tilapia, salmon and shrimp by liquid chromatography-tandem mass spectrometry. Anal Chim Acta. 637(1-2): 101-111, 2009.
Khan SR. Calcium oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion and its impact on stone development. Urol Res. 23(2): 71-79, 1995.
Khan SR. Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. Clin Exp Nephrol. 8(2): 75-88, 2004.
Khan SR and Thamilselvan S. Nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. Mol Urol. 4(4): 305-312, 2000.
Kitchen DN, Carlton WW and Tuite J. Ochratoxin A and citrinin induced nephrosis in Beagle dogs. I. Clinical and clinicopathological features. Vet Pathol. 14(2): 154-172, 1977.
Kitchen DN, Carlton WW and Tuite J. Ochratoxin A and citrinin induced nephrosis in Beagle dogs. II. Pathology. Vet Pathol. 14(3): 261-272, 1977.
Kobayashi T, Okada A, Fujii Y, Niimi K, Hamamoto S, Yasui T, Tozawa K and Kohri K. The mechanism of renal stone formation and renal failure induced by administration of melamine and cyanuric acid. Urol Res. 38(2): 117-125, 2010.
Kogika MM, Hagiwara MK and Mirandola RM. Experimental citrinin nephrotoxicosis in dogs: renal function evaluation. Vet Hum Toxicol. 35(2): 136-140, 1993.
Lam CW, Lan L, Che X, Tam S, Wong SS, Chen Y, Jin J, Tao SH, Tang XM, Yuen KY and Tam PK. Diagnosis and spectrum of melamine-related renal disease: plausible mechanism of stone formation in humans. Clin Chim Acta. 402(1-2): 150-155, 2009.
Lusby AF, Simmons Z and McGuire PM. Variation in mutagenicity of s-triazine compounds tested on four Salmonella strains. Environ Mutagen. 1(3): 287-290, 1979.
Mast RW, Jeffcoat AR, Sadler BM, Kraska RC and Friedman MA. Metabolism, disposition and excretion of [14C]melamine in male Fischer 344 rats. Food Chem Toxicol. 21(6): 807-810, 1983.
Melnick RL, Boorman GA, Haseman JK, Montali RJ and Huff J. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol. 72(2): 292-303, 1984.
Moriyama MT, Glenton PA and Khan SR. Expression of inter-alpha inhibitor related proteins in kidneys and urine of hyperoxaluric rats. J Urol. 165(5): 1687-1692, 2001.
Murakami K, Shimizu T and Irie K. Formation of the 42-mer Amyloid β Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer’s Disease. Journal of Amino Acids. 2011.
OECD. Screening Information Data Set for Melamine, CAS No. #108-78-1. http://www.chem.unep.ch/irptc/sids/OECDSIDS/108781.pdf, 1998.
OECD. Screening Information Data Set for Melamine, CAS #108-78-1. http://www.inchem.org/pages/sids.html ,1999.
Ogasawara H, Imaida K, Ishiwata H, Toyoda K, Kawanishi T, Uneyama C, Hayashi S, Takahashi M and Hayashi Y. Urinary bladder carcinogenesis induced by melamine in F344 male rats: correlation between carcinogenicity and urolith formation. Carcinogenesis. 16(11): 2773-2777, 1995.
Okumura M, Hasegawa R, Shirai T, Ito M, Yamada S and Fukushima S. Relationship between calculus formation and carcinogenesis in the urinary bladder of rats administered the non-genotoxic agents thymine or melamine. Carcinogenesis. 13(6): 1043-1045, 1992.
Osborne CA, Clinton CW, Kim KM and Mansfield CF. Etiopathogenesis, clinical manifestations, and management of canine silica urolithiasis. Vet Clin North Am Small Anim Pract. 16(1): 185-207, 1986.
Puschner B, Poppenga RH, Lowenstine LJ, Filigenzi MS and Pesavento PA. Assessment of melamine and cyanuric acid toxicity in cats. J Vet Diagn Invest. 19(6): 616-624, 2007.
Ranganathan AC, Nelson KK, Rodriguez AM, Kim KH, Tower GB, Rutter JL, Brinckerhoff CE, Huang TT, Epstein CJ, Jeffrey JJ and Melendez JA. Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation. J Biol Chem. 276(17): 14264-14270, 2001.
Reimschuessel R, Gieseker CM, Miller RA, Ward J, Boehmer J, Rummel N, Heller DN, Nochetto C, de Alwis GK, Bataller N, Andersen WC, Turnipseed SB, Karbiwnyk CM, Satzger RD, Crowe JB, Wilber NR, Reinhard MK, Roberts JF and Witkowski MR. Evaluation of the renal effects of experimental feeding of melamine and cyanuric acid to fish and pigs. Am J Vet Res. 69(9): 1217-1228, 2008.
Sarica K, Yagci F, Bakir K, Erbagci A, Erturhan S and Ucak R. Renal tubular injury induced by hyperoxaluria: evaluation of apoptotic changes. Urol Res. 29(1): 34-37, 2001.
Schepers MS, van Ballegooijen ES, Bangma CH and Verkoelen CF. Crystals cause acute necrotic cell death in renal proximal tubule cells, but not in collecting tubule cells. Kidney Int. 68(4): 1543-1553, 2005.
Schmidt KN, Amstad P, Cerutti P and Baeuerle PA. The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-kappa B. Chem Biol. 2(1): 13-22, 1995.
Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G and Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 12(8): 3095-3104, 1993.
Suzuki K, Tanaka T, Miyazawa K, Nakajima C, Moriyama M, Suga K, Murai M and Yano J. Gene expression of prothrombin in human and rat kidneys: basic and clinical approach. J Am Soc Nephrol. 10 Suppl 14(S408-411), 1999.
Suzuki YJ, Forman HJ and Sevanian A. Oxidants as stimulators of signal transduction. Free Radic Biol Med. 22(1-2): 269-285, 1997.
Thamilselvan S, Hackett RL and Khan SR. Lipid peroxidation in ethylene glycol induced hyperoxaluria and calcium oxalate nephrolithiasis. J Urol. 157(3): 1059-1063, 1997.
Thompson ME, Lewin-Smith MR, Kalasinsky VF, Pizzolato KM, Fleetwood ML, McElhaney MR and Johnson TO. Characterization of melamine-containing and calcium oxalate crystals in three dogs with suspected pet food-induced nephrotoxicosis. Vet Pathol. 45(3): 417-426, 2008.
Tsujihata M. Mechanism of calcium oxalate renal stone formation and renal tubular cell injury. Int J Urol. 15(2): 115-120, 2008.
Turnipseed SB, Andersen WC, Karbiwnyk CM, Madson MR and Miller KE. Multi-class, multi-residue liquid chromatography/tandem mass spectrometry screening and confirmation methods for drug residues in milk. Rapid Commun Mass Spectrom. 22(10): 1467-1480, 2008.
Umekawa T, Chegini N and Khan SR. Increased expression of monocyte chemoattractant protein-1 (MCP-1) by renal epithelial cells in culture on exposure to calcium oxalate, phosphate and uric acid crystals. Nephrol Dial Transplant. 18(4): 664-669, 2003.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M and Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 39(1): 44-84, 2007.
Verhulst A, Asselman M, Persy VP, Schepers MS, Helbert MF, Verkoelen CF and De Broe ME. Crystal retention capacity of cells in the human nephron: involvement of CD44 and its ligands hyaluronic acid and osteopontin in the transition of a crystal binding- into a nonadherent epithelium. J Am Soc Nephrol. 14(1): 107-115, 2003.
Vervaet BA, D''Haese PC, De Broe ME and Verhulst A. Crystalluric and tubular epithelial parameters during the onset of intratubular nephrocalcinosis: illustration of the ''fixed particle'' theory in vivo. Nephrol Dial Transplant. 24(12): 3659-3668, 2009.
Vervaet BA, Verhulst A, Dauwe SE, De Broe ME and D''Haese PC. An active renal crystal clearance mechanism in rat and man. Kidney Int. 75(1): 41-51, 2009.
Waisman J, Mwasi LM, Bluestone R and Klinenberg JR. Acute hyperuricemic nephropathy in rats. An electron microscopic study. Am J Pathol. 81(2): 367-378, 1975.
Westropp JL, Buffington CAT and Chew DJ. Textbook of Veterinary Internal Medicine Sixth Edition: Feline Lower Urinary Tract Diseases. Los Angeles. 1843-1850, 2005.
WHO. Evaluation of certain food additives and contaminants (Sixty-first report of th Toint FAO/WHO Expert Committee on Food Additives). WHO Technical Report Series. 922, 2004.
WHO. Toxicological and Health Aspects of Melamine and Cyanuric Acid, Report of a WHO Expert Meeting, In collaboration with FAO and supported by Health Canada. Health Canada. 2009.
Yhee JY, Brown CA, Yu CH, Kim JH, Poppenga R and Sur JH. Retrospective study of melamine/cyanuric acid-induced renal failure in dogs in Korea between 2003 and 2004. Vet Pathol. 46(2): 348-354, 2009.