Nutrition 30 (2014) 380–385
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Nutrition
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Review Urinary melamine: Proposed parameter of melamine adulteration of food
Nitish Rai M.Sc. a, Dibyajyoti Banerjee M.D. a,*, Rajasri Bhattacharyya Ph.D. b a Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala, India article info abstract
Article history: Melamine is widely being reported as a food adulterant. Although its toxicity is currently recog- Received 26 May 2013 nized, melamine adulterations of food items are ongoing for falsely inflating the protein content of Accepted 15 July 2013 the food. Melamine alone or in combination with cyanuric acid or uric acid causes nephrotoxicity, and melamine-induced nephrotoxicity is now a global concern. It has been proven that when Keywords: consumed, melamine is metabolized at a slower rate and excreted unchanged in urine. There is Melamine every possibility that when individuals consume melamine-adulterated food items, the melamine Uric acid may be excreted unchanged in the urine. Therefore, melamine estimation in urine may be a Food adulteration Cyanuric acid yardstick to check for melamine adulteration of food items. In the present review, recent literature Nephropathy on this subject is analyzed justifying. Ó 2014 Elsevier Inc. All rights reserved.
Introduction indication of consumption of adulterated food. But so far, no easy, cost-effective, feasible, point-of-care test has been reported for Melamine is an organic base and a trimer of cyanamide, with such purpose. a 1,3,5-triazine skeleton [1]. It is a chemical compound that A rapid, simple, and sensitive colorimetric detection method for has a number of industrial uses, including the production of melamine has been proposed based on pyridine-3-boronic acid laminates, glues, dinnerware, adhesives, molding compounds, modified gold nanoparticles [7,8]. A similar attempt also was coatings, and flame-retardant materials [2]. Melamine is ille- documented with Chitosan stabilized gold nanoparticles [9]. gally added to inflate the apparent protein content of food Surface-enhanced Raman spectroscopy was recognized as a rapid products. Because it is high in nitrogen, the addition of mel- detection tool for melamine [10,11]. A high-performance liquid amine to a food artificially increases the apparent protein chromatography–based method has been reported to detect mel- content as measured with many standard tests, other than the amine [12]. A capillary electrochromatographic technique with a dye-binding assays [3]. In 2007 and 2008, illegal adulteration of mass spectrometric detection–based method has been described pet food, livestock food, fish feeds, and raw milk used for infant in the context of detection of melamine [13]. formula to falsely boost the apparent protein levels with either These published protocols are neither cost-effective nor melamine alone or “scrap” melamine containing cyanuric acid simple enough for home use for melamine detection. In the resulted in illness and death in infants and companion animals context of worldwide food adulteration, development of such (i.e., cats and dogs) due to the nephrotoxicity associated with tests is of utmost importance. the accumulation of melamine–uric acid or melamine–cyanuric acid crystals in the kidneys [4]. Melamine is widely recognized Food adulteration: some fundamental concepts as a toxic substance and various aspects of melamine toxicity recently have been reviewed [5]. Food adulteration is recognized as a worldwide phenome- After consumption, melamine is mostly excreted unchanged non with high chance of adverse biological consequences [14]. in urine [6]. Therefore, it is highly possible that melamine Contaminated foodstuff is recognized as a cause of serious consumed with adulterated food or milk will be excreted un- health hazards, even in recent times [15]. Almost all types of changed in urine, and if it is detected in urine, it may be an foodstuffs are subjected to adulteration and problems of food authenticity are a reality recognized by all concerned [16]. * Corresponding author. Tel.: þ91 172 2755227; fax:. þ91 172 2744401. Food adulteration is not unique to food for human consump- E-mail address: [email protected] (D. Banerjee). tion; animal (pet) foods also have been contaminated with
0899-9007/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2013.07.013 N. Rai et al. / Nutrition 30 (2014) 380–385 381 unwanted substances [17]. With the widespread growth of Mechanism of melamine-induced toxicity food adulteration, food safety has emerged as an important concept, and sophisticated methods have been developed for Melamine is known to stimulate inflammatory response and detection of food adulterants [18–20]. Global standards of food reactive oxygen species (ROS) production in human embryonic quality in the context of food safety is felt to be generated for kidney cell line (HEK293) and macrophage like cell line (RAW attainment of desirable uniform standards of edible food in 264.7). It is known to activate nicotinamide adenine dinucleotide relation to public health issues of food adulteration [21].To phosphate-oxidase (NOX) including NOX1,NOX2, and NOX4, and is attain such gold standards, new concepts are emerging to deal thus associated with an increase of ROS production. It also is shown with food security at international levels, and it is widely to stimulate nuclear factor (NF)-kB by degradation of IkB with recognized that the introduction of novel technologies to deal a corresponding increase of inflammatory molecules like with food security is an urgent need to tackle new food cyclooxygenase-2 and prostaglandin E2 production [36].Inthis adulterants [22]. context, it must be remembered that NF-kB activation is inde- pendently proven to induce subunits of NOX in monocytic and Melamine: a toxic food contaminant microglial cell lines in earlier studies [37,38].Therefore,every possibility exists that melamine induces subunits of the NOX Melamine is an organic base within many industries [23].It through NF-kB activation pathway. Furthermore, ROS is indepen- has high nitrogen content and thus was earlier used as a cheap dently shown to activate the NF-kB pathway in macrophage [39]. alternative for proteins to enrich cattle feed [24]. But as early as So, melamine can activate NOX through NF-kB activation, causing 1978, melamine supplementation of cattle feed was criticized production of ROS, and that in turn can stimulate the NF-kB due to its slow rate of metabolism [25]. Recent knowledge has pathway, resulting in the generation of inflammatory response. paved the path for banning melamine as a source of non- Thus, melamine has the potential to induce a vicious cycle of pro- protein nitrogen in animal feed, because its dose-dependent duction of ROS and mediators of inflammation through NF-kB toxicity has been demonstrated in livestock, laboratory ani- activation. Consequently, melamine is shown to exhibit cytotox- mals, and pets [4,26,27]. Similar results are reported in studies icity in normal rat kidney cell lines (NRK-5e2) by causing excessive involving broilers and fishes [28–31]. In unicellular eukaryotic generation of ROS. It has been shown to decrease antioxidant model systems, melamine toxicity is an established phenome- enzyme activities with corresponding increases of lipid peroxida- non [32]. Analogous toxic effects of melamine also have been tion products in a dose-dependent manner [40]. Based on these observed in in vitro studies involving established cell lines [33]. premises, it appears that melamine induces oxidative stress and Therefore, it has been shown that melamine is a toxic substance inflammatory responses that can account for melamine-induced that should not be added to foodstuff as a source of non-protein toxicity. A proposed pathway of the phenomenon cited here nitrogen. Also, there are recent research pursuits to define no is represented in Figure 1. Such melamine-induced toxicity in observed adverse-effect levels of melamine in animal feeds [34, kidney cells is increased by gut microflora of rats [41]. Every pos- 35]. sibility exists that such mechanisms of melamine-induced renal
Fig. 1. Proposed mechanism of melamine-induced oxidative stress and inflammatory response-mediated toxicity. Melamine is known to stimulate inflammatory response and ROS production in human embryonic kidney cell lines (HEK293) and macrophage like cell lines (RAW 264.7) by NF-kB–mediated expression of COX-2 and activation of NOX, respectively [37]. Moreover, ROS produced as a result of NOX activation is expected to counter-stimulate NF-kB activity, which in turn induces subunits of NOX [38–40]. Melamine also increases the ROS and lipid peroxidation products in NRK-5e2 cell lines, which may be by inhibition of the antioxidant enzymes. Melamine in the presence of cyanuric acid is reported to produce more ROS in NRK 5e2 cell lines [41]. Furthermore, in silico studies have shown that melamine can directly bind with proteins like glutathione peroxidase 1, which can be a potential mechanism of melamine-mediated inhibition of antioxidant enzymes [43]. 382 N. Rai et al. / Nutrition 30 (2014) 380–385 injury may work in human or other subhuman species, but con- studies that report neurotoxicity of melamine causing cognitive crete evidence of this issue is presentlylacking, and this issue needs impairment and hippocampal injury [58]. Selective melamine- to be addressed as melamine adulteration of human food items is induced hippocampal neurotoxicity is believed to be due to increasingly being reported worldwide. Moreover, in silico studies reduction in adenosine triphosphate and oxidative damage [59]. have shown various target proteins (i.e., glutathione peroxidase 1) Unfortunately, this aspect of melamine toxicity is currently, to that can account for melamine-induced nephrotoxicity [42] and our knowledge, unexplored in humans, and warrants immediate these potential targets need urgent experimental validation in the study. context of melamine-induced human nephrotoxicity. Non-enzymatic modifications of melamine with various Melamine combines with cyanuric acid and uric acid to form sugars are reported in vitro, but its toxicologic relevance in crystals that are known to be nephrotoxic. By forming such normal and diabetic individuals is yet to be determined [60]. crystals, melamine can contribute to the formation of renal The potential toxicity-causing mechanisms of melamine stones. Other than nephrolithiasis, melamine also contributes to other than oxidative stress and inflammation are presented in chronic kidney inflammation and bladder cancer [43–45]. Mel- Figure 2. amine causes sperm cell abnormality without any observed ev- idence of genotoxicity in prokaryotic or eukaryotic cells [46]. Melamine adulteration of human food However, in vitro studies have suggested the binding of mel- amine with DNA by electrostatic interactions and by hydrogen Melamine-induced nephrotoxicity is emerging as a global bond formation [47,48], and urinary tract tumors are reported epidemic [61]. The sole reason for this can be linked to melamine more frequently in individuals who are exposed to melamine via adulteration of foodstuffs for profit-earning motifs resulting in contaminated or adulterated milk [49]. Corroborating with these pandemics [62]. Melamine is added to foodstuff, including milk, observations, male laboratory animals also exhibit reproductive due to its high nitrogen content, and because it produces false- toxicity due to melamine in a dose-dependent manner that is positive results for protein when estimated by the Kheldhals or enhanced in the presence of cyanuric acid [50,51]. In vitro studies Dumas methods. Both methods are widely employed to examine have shown the potential for transplacental transfer of mel- the protein content of milk. These methods rely on the liberation amine, and such conclusions also are derived from in vivo studies of ammonia from the protein by concentrated sulphuric acid in animal model systems [52,53]. Lactational transfer of mel- or heat treatment, respectively [63,64]. Because melamine con- amine from mother to neonates has been reported in animals tains a high percentage of non-protein nitrogen, it causes a [54]. Although melamine toxicity has been reported in humans, false-positive result, particularly when protein is measured by to the best of our knowledge its specific dose-dependent ammonia-liberating assays, making melamine an attractive milk reproductive toxicity has not yet been documented in humans. adulterant; it is now recognized that food protein evaluation Research is urgently needed in this area because, in the context methods require a thorough revision [65]. Following a recent of observations from animal studies and in vitro studies relevant devastating incidence of melamine adulteration of milk in China to the context, there is a high potential for reproductive toxicity that caused significant pathos in vulnerable individuals con- in humans exposed to melamine. suming melamine-contaminated milk, including infants, the Melamine–cyanurate complex has been observed to damage issue of evaluation methods received considerable interest [66]. erythrocyte membranes [55], and melamine is shown to exhibit Melamine adulteration of food has been a well-known phe- inhibition of certain haem groups containing peroxidase [56]. nomenon worldwide over the past thirty years, especially after Some peroxidase activation also is reported in the presence of the recent melamine scandal reported in China. However, mel- melamine [57]. These aspects should be looked into in the amine adulteration of milk still is reported from other parts of context of melamine toxicity in humans. There are animal the world [67]. Due to consideration of the global adverse effect
Fig. 2. Melamine toxicity: possible mechanisms are highlighted with ball and stick structure of melamine [47–58]. Other than toxicity by producing oxidative stress, melamine is known for neurotoxicity causing hippocampal injury by adenosine triphosphate depletion, and it also damages erythrocyte membranes in the presence of cyanuric acid. Melamine alters the activity of many haem-containing enzymes. Moreover, it is known for lactational and transplacental transfer, making it a potential teratogenic agent. Melamine also causes sperm cell abnormality, possibly by interacting with sperm cell DNA. Furthermore, melamine has the potential to alter various carbohydrate molecules by non-enzymatic modifications. N. Rai et al. / Nutrition 30 (2014) 380–385 383
Table 1 Established methods of melamine detection from various samples
Method Sample Lower limit of detection Reference Electrochemical accumulation coupled with enzyme Infant formula powders and fish feed samples 1 10 11 M [72] colorimetric assay Colloidal gold-based lateral flow immunoassay Foods of animal origin 25 mg/g [73] DNA-labeled immunosensor-based assay Milk 0.3 fg/g [74] Monoclonal antibody–based inhibition ELISA Milk and pet food 0.35 ng/mL [75] Immunogold chromatographic strip test based on a Raw milk 0.05 ng/mL [76] monoclonal antibody Silver nanoparticle-based “oxidative etching-aggregation” Raw milk 0.08 mM (when hydrogen [77] based colorimetricsensor peroxide is the electron acceptor) Dopamine-stabilized silver nanoparticle-based colorimetric Raw milk 10 ppb [78] detection r-nitroaniline–modified silver nanoparticle-based colorimetric Infant formula samples 0.1 ppm [79] detection Fluorescence turn on of oligonucleotide-stabilized silver Milk samples 1 10 8 M [80] nanoclusters by melamine Gold nanoparticle-based colorimetric detection Milk 40 ppb [81] Pyridine-3-boronic acid–modified gold nanoparticle-based Liquid milk products 3 10 8 M [82] colorimetric sensing 4-mercaptopyridine–modified gold nanoparticles by Dairy products 0.1 ppb [83] surface-enhanced Raman scattering Citrate-coated gold nanoparticles by surface-enhanced Raman Milk powder, infant formula, lactose, 100 mg/L [84] spectroscopy in presence of isopropanol povidone, wheat bran, wheat gluten, whey protein Capillary electrochromatography mass spectrometry–based Dairy products 0.1 mg/L [85] detection Molecularly imprinted matrix solid-phase dispersion coupled Milk samples 0.24 mg/g [86] with liquid chromatography UV detection Hydrophilic interaction liquid chromatography Eggs and meat 2 mg/kg [87] Cation–exchange–based HPLC coupled with tandem mass Human urine 0.66 mg/mL [88] spectrometry Mid and near-infrared spectroscopy-based method Milk, infant formula, milk powder 0.76 0.11 ppm [89] Matrix-assisted laser desorption/ionization time-of-flight Kidney stone 0.41 g/mL [90] mass spectrometry High-performance gold nanofinger coupled with surface- Infant formula 100 ppb [91] enhanced Raman scattering-based detection
ELISA, enzyme-linked immunosorbent assay; HPLC, high-performance liquid chromatography; UV, ultraviolet of melamine adulteration of milk, particularly in the context of important that such a test can be used in a clinical laboratory in development of nephrotoxicity, specialized bodies like the US times of need. Development of such a test will also pave the path FDA have advocated for a maximum tolerable daily intake of of renal calculi analysis in melamine-induced nephrotoxicity melamine, which may be required to undergo screening for where nephrolithiasis is common. certification of food safety in days to come [68]. In areas where uncontrollable massive adulteration of mel- amine in food items is still ongoing, point-of-care test develop- Urinary melamine as a proposed parameter of melamine ment for melamine in urine or spot-test development for adulteration detection of melamine from milk and other food items will aid easy detection by even untrained personal. This will assist in the Melamine detection in food and biological research has consumption of melamine-free foodstuffs for all practical pur- received considerable interest. Many technologies already have poses and help eliminate melamine adulteration of food items. been explored for detection of melamine in food and biologic samples, and the matter has been reviewed from the melamine References detection point of view [69–71]. Particulars of some recently used methods for melamine detection are presented in Table 1. [1] National Center for Biotechnology Information. PubChem Compound However, as of 2013, to our knowledge, there are no available Database, CID¼7955,
[7] Yang L, Huo D, Jiang Y, Hou C, Zhang S. Monitoring the adulteration of milk [37] Anrather J, Racchumi G, Iadecola C. NF-kappaB regulates phagocytic with melamine: a visualised sensor. Array approach. Food Addit Contam NADPH oxidase by inducing the expression of gp91phox. J Biol Chem 2006; Part A Chem Anal Control Expo Risk Assess 2013;30:786–95. 281:5657–67. [8] Wu Z, Zhao H, Xue Y, Cao Q, Yang J, He Y, et al. Colorimetric detection of [38] Gauss KA, Nelson-Overton LK, Siemsen DW, Gao Y, DeLeo FR, Quinn MT. melamine during the formation of gold nanoparticles. Biosens Bioelectron Role of NF-kappaB in transcriptional regulation of the phagocyte NADPH 2011;26:2574–8. oxidase by tumor necrosis factor-alpha. J Leukoc Biol 2007;82:729–41. [9] Guan H, Yu J, Chi D. Label-free colorimetric sensing of melamine based on [39] Gwinn MR, Vallyathan V. Respiratory burst: role in signal transduction in chitosan-stabilized gold nanoparticles probes. Food Control 2013;32:35–41. alveolar macrophages. J Toxicol Environ Health B Crit Rev 2006;9:27–39. [10] Chen LM, Liu YN. Surface-enhanced Raman detection of melamine on [40] Guo C, He Z, Wen L, Zhu L, Lu Y, Deng S, et al. Cytoprotective effect of trolox silver-nanoparticle-decorated silver/carbon nanospheres: effect of metal against oxidative damage and apoptosis in the NRK-52e cells induced by ions. ACS Appl Mater Interfaces 2011;3:3091–6. melamine. Cell Biol Int 2012;36:183–8. [11] Lin M, He L, Awika J, Yang L, Ledoux DR, Li H, et al. Detection of melamine in [41] Zheng X, Zhao A, Xie G, Chi Y, Zhao L, Li H, et al. Melamine-induced renal gluten, chicken feed, and processed foods using surface enhanced Raman toxicity is mediated by the gut microbiota. Sci Transl Med 2013;5:172ra22. spectroscopy and HPLC. J Food Sci 2008;73:T129–34. [42] Ma C, Kang H, Liu Q, Zhu R, Cao Z. Insight into potential toxicity mecha- [12] Venkatasami G, Sowa JR Jr. A rapid, acetonitrile-free, HPLC method for nisms of melamine: an in silico study. Toxicology 2011;283:96–100. determination of melamine in infant formula. Anal Chim Acta 2010;665: [43] Hau AK, Kwan TH, Li PK. Melamine toxicity and the kidney. J Am Soc 227–30. Nephrol 2009;20:245–50. [13] Li X, Wang Y, Gu X, Chen Y, Yan C. Preparation of hydrophilic interaction [44] Dalal RP, Goldfarb DS. Melamine-related kidney stones and renal toxicity. monolithic column and its application in the analysis of melamine in dairy Nat Rev Nephrol 2011;7:267–74. products using pressurized capillary electrochromatography. Chinese [45] Skinner CG, Thomas JD, Osterloh JD. Melamine toxicity. J Med Toxicol Journal of Chromatography (Se Pu) 2010;28:231–5. 2010;6:50–5. [14] Lawrence MS, Mia VG, Katsi C. What’s NOT to eatdfood adulteration in the [46] Zhang QX, Yang GY, Li JT, Li WX, Zhang B, Zhu W. Melamine induces sperm context of human biology? Am J Hum Biol 2012;24:139–48. DNA damage and abnormality, but not genetic toxicity. Regul Toxicol [15] Wu MT, Wu CF, Wu JR, Chen BH, Chen EK, Chao MC, et al. The public Pharmacol 2011;60:144–50. health threat of phthalate-tainted foodstuffs in Taiwan: the policies the [47] Sun Y, Liu R, Chi Z, Qin P, Fang X, Mou Y. Spectroscopic investigation on the government implemented and the lessons we learned. Environ Int 2012; toxic interaction of melamine with herring sperm DNA. J Biochem Mol 44:75–9. Toxicol 2010;24:323–9. [16] Czerwiecki L. Problems of food authenticity. Rocz Panstw Zakl Hig [48] Shen HY, Liu YQ, Gao J, Zhen HM, Zhu N, Li J. In vitro study of DNA inter- 2004;55:9–19. action with melamine and its related compounds. DNA Cell Biol 2011; [17] Bischoff K, Rumbeiha WK. Pet food recalls and pet food contaminants in 30:255–64. small animals. Vet Clin North Am Small Anim Pract 2012;42:237–50. [49] Vara Messler M, Cremonezzi DC, Soria EA, Eynard AR. Nutritional chemo- [18] Rodriguez-Saona LE, Allendorf ME. Use of FTIR for rapid authentication prevention of urinary tract tumors (UTT) induced by lithogenic agents: risk and detection of adulteration of food. Annu Rev Food Sci Technol 2011; for UTT in children exposed to melamine-contaminated milk formulas. J 2:467–83. Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2012;30:174–87. [19] Feng YZ, Sun DW. Application of hyperspectral imaging in food safety [50] Yin RH, Wang XZ, Bai WL, Wu CD, Yin RL, Li C, et al. The reproductive inspection and control: a review. Crit Rev Food Sci Nutr 2012;52:1039–58. toxicity of melamine in the absence and presence of cyanuric acid in male [20] Zhang Z, Li P, Hu X, Zhang Q, Ding X, Zhang W. Microarray technology for mice. Res Vet Sci 2013;94:618–27. major chemical contaminants analysis in food: current status and pros- [51] Lv Y, Liu Z, Tian Y, Chen H. Effect on morphology, oxidative stress and pects. Sensors (Basel) 2012;12:9234–52. energy metabolism enzymes in the testes of mice after a 13-week oral [21] Vojir F, Schübl E, Elmadfa I. The origins of a global standard for food quality administration of melamine and cyanuric acid combination. Regul Toxicol and safety: Codex Alimentarius Austriacus and FAO/WHO Codex Ali- Pharmacol 2013;65:183–8. mentarius. Int J Vitam Nutr Res 2012;82:223–7. [52] Partanen H, Vähäkangas K, Woo CS, Auriola S, Veid J, Chen Y, et al. [22] Iyengar V, Elmadfa I. Food safety security: a new concept for enhancing Transplacental transfer of melamine. Placenta 2012;33:60–6. food safety measures. Int J Vitam Nutr Res 2012;82:216–22. [53] Jingbin W, Ndong M, Kai H, Matsuno K, Kayama F. Placental transfer of [23] Bann B, Miller SA. Melamines and derivatives of melamine. Chem Rev melamine and its effects on rat dams and fetuses. Food Chem Toxicol 1958;58:131–72. 2010;48:1791–5. [24] Colby WR, Jackson L, Tex, Mesler RJ Jr., Midland et al. United States Patent [54] Chan JY, Lau CM, Ting TL, Mak TC, Chan MH, Lam CW, et al. Gestational and Office [Internet] US; 1958, Jan 14. Available from. http://www. lactational transfer of melamine following gavage administration of a freepatentsonline.com/2819968.pdf. single dose to rats. Food Chem Toxicol 2011;49:1544–8. [25] Newton GL, Utley PR. Melamine as a dietary nitrogen source for ruminants. [55] Wang C, Qin X, Huang B, He F, Zeng C. Hemolysis of human erythrocytes J Anim Sci 1978;47:1338–44. induced by melamine-cyanurate complex. Biochem Biophys Res Commun [26] Pang J, Li GQ, Li CR, Yang XY, Lu X, Hu XX, et al. Toxicokinetic study of 2010;402:773–7. melamine in the presence and absence of cyanuric acid in rats. J Appl [56] Vanachayangkul P, Tolleson WH. Inhibition of heme peroxidases by mel- Toxicol 2013;33:444–50. amine. Enzyme Res 2012;2012:416062. [27] Dobson RL, Motlagh S, Quijano M, Cambron RT, Baker TR, Pullen AM, et al. [57] Karaseva EI, Naumchik IV, Metelitsa DI. Noncompetitive activation of Identification and characterization of toxicity of contaminants in pet food peroxidase oxidation of o-phenylenediamine by melamine. Bioorg Khim leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci 2003;29:49–56. 2008;106:251–62. [58] Yang Y, Xiong GJ, Yu DF, Cao J, Wang LP, Xu L, et al. Acute low-dose mel- [28] Ding XM, Zhang KY, Wang L, Bai SP. Toxicity of melamine and cyanuric acid amine affects hippocampal synaptic plasticity and behavior in rats. Toxicol in broilers and residues in tissues. Hum Exp Toxicol 2012;31:174–84. Lett 2012;214:63–8. [29] Pirarat N, Katagiri T, Chansue N, Ponpornpisit A, Endo M, Maita M. The [59] An L, Li Z, Yang Z, Zhang T. Melamine induced cognitive impairment Pathological Effects of Melamine and Cyanuric Acid in the Diet of Walking associated with oxidative damage in rat’s hippocampus. Pharmacol Bio- Catfish (Clarius batrachus). J Comp Pathol 2012;147:259–66. chem Behav 2012;102:196–202. [30] Brand LM, Murarolli RA, Gelven RE, Ledoux DR, Landers BR, Bermudez AJ, [60] Liu W, Cohenford MA, Frost L, Seneviratne C, Dain JA. Non-enzymatic et al. Effects of melamine in young broiler chicks. Poult Sci 2012;91:2022–9. glycation of melamine with sugars and sugar like compounds. Bioorg Chem [31] Phromkunthong W, Nuntapong N, Boonyaratpalin M, Kiron V. Toxicity of 2013;46:1–9. melamine, an adulterant in fish feeds: experimental assessment of its ef- [61] Bhalla V, Grimm PC, Chertow GM, Pao AC. Melamine nephrotoxicity: an fects on tilapia. J Fish Dis 2013;36:555–68. emerging epidemic in an era of globalization. Kidney Int 2009;75:774–9. [32] Wang Z, Chen L, Al-Kasir R, Han B. In vitro toxicity of melamine against [62] Chan EY, Griffiths SM, Chan CW. Public-health risks of melamine in milk Tetrahymena pyriformis cells. J Vet Sci 2011;12:27–34. products. Lancet 2008;372:1444–5. [33] Guo C, Yuan H, He Z. Melamine causes apoptosis of rat kidney epithelial [63] Thompson M, Owen L, Wilkinson K, Wood R, Damant A. A comparison cell line (NRK-52e cells) via excessive intracellular ROS (reactive oxygen of the Kjeldahl and Dumas methods for the determination of protein in species) and the activation of p38 MAPK pathway. Cell Biol Int 2012;36: foods, using data from a proficiency testing scheme. Analyst 2002;127: 383–9. 1666–8. [34] Stine CB, Reimschuessel R, Gieseker CM, Evans ER, Mayer TD, Hasbrouck NR. [64] Lynch JM, Barbano DM. Kjeldahl nitrogen analysis as a reference method A No Observable Adverse Effects Level (NOAEL) for pigs fed melamine and for protein determination in dairy products. J AOAC Int 1999;82:1389–98. cyanuric acid. Regul Toxicol Pharmacol 2011;60:363–72. [65] Wiles PG, Gray IK, Kissling RC. Routine analysis of proteins by Kjeldahl and [35] Early RJ, Yu H, Mu XP, Xu H, Guo L, Kong Q, et al. Repeat oral dose toxicity Dumas methods: review and interlaboratory study using dairy products. J studies of melamine in rats and monkeys. Arch Toxicol 2013;87:517–27. AOAC Int 1998;81:620–32. [36] Kuo FC, Tseng YT, Wu SR, Wu MT, Lo YC. Melamine activates NF-kB/COX-2/ [66] Wei Y, Liu D. Review of melamine scandal: still a long way ahead. Toxicol PGE2 pathway and increases NADPH oxidase-dependent ROS production Ind Health 2012;28:579–82. in macrophages and human embryonic kidney cells. Toxicol In Vitro [67] Hassani S, Tavakoli F, Amini M, Kobarfard F, Nili-Ahmadabadi A, 2013;27:1603–11. Sabzevari O. Occurrence of melamine contamination in powder and liquid N. Rai et al. / Nutrition 30 (2014) 380–385 385
milk in market of Iran. Food Addit Contam Part A Chem Anal Control Expo [82] Wu Z, Zhao H, Xue Y, He Y, Li X, Yuan Z. Colorimetric determination of Risk Assess 2013;30:413–20. melamine by pyridine-3-boronic acid modified gold nanoparticles. J [68] World Health Organization. Toxicological and health aspects of melamine Nanosci Nanotechnol 2012;12:2412–6. and cyanuric acid,