In 2008, 300 000 children became ill and six of them died after consuming contaminated infant formula. The infant formula had been illegally stretched with melamine, because the substance mimics higher protein content. Melamine made from carbamide and one of the side products that is formed during production is cyanuric acid. Melamine is used as a monomer in the production of melamine resin. Melamine resin can be used as surface coating for paper, board and beverage cans and jar lids as well as in the production of body panels and household appliances. Secondly, it may be blended with other additives for the manufacture of dinnerware, chopsticks and electrical equipment. Other applications are furniture, the construction industry, banknotes, printed textiles, concrete additives and flame retardants. In 2004, the global capacity amounted to about 1 million ton annually, with approximately 10% being used in food contact materials. Melamine may migrate from coatings, table ware and household appliances into food. The migration process is influenced by the temperature of the heat treatment and to some extend by the time of the heating and the acidity of the food [1, 2]. Migration levels up to 332 µg/kg food were observed by Bradley and colleagues [1]. Melamine has a half live of approximately 6 hours in humans and undergoes renal clearance.

Melamine is not classifiable as to its carcinogenicity to humans due to a lack of toxicological data, and has been found not to be genotoxic in vitro or in vivo [3, 4]. In vitro melamine has been shown to lead to renal tubular cell injury via apoptosis, inflammation and fibrosis at concentrations up to 1000 µg/mL [5]. Melamine is of increased toxicity when fed in combination with cyanuric acid leading to the development of severe renal dysfuntion [6, 7, 8]. In mammals, melamine can also be converted to cyanuric acid by the gut bacterium Klebsiella terrigena (FPF reported) [9]. Considering that the presence of cyanuric acid increases the risk of kidney stone formation, this recent finding induces further caution. Further, studies have found melamine to have adverse effects on the male reproduction system at doses between 5 and 25 mg/kg bodyweight including testes, sperm morphology and increased apototic index of spermatogenic cells at the higher dose [10]. Melamine may induce neurotoxicity [11, 12], altered TCA cycle, and gut microflora structure [13]. Melamine can pass the placenta and can be transferred via breast milk.

The infant formula scandal in 2008 let the WHO to convene an expert meeting in 2009 [14]. The report subsequently published by the WHO set the lower benchmark dose (BMDL10) at 35 mg/kg body weight/day based on the development of urinary bladder stones [15]. A TDI of 0.2 mg/kg body weight was derived from that estimate. In the European Union where melamine is authorized as a monomer and an additive in plastic food contact materials, the TDI was subsequently also lowered to 0.2 mg/kg body weight and the specific migration limit set at 2.5 mg/kg food (Commission Regulation 1282/2011). The TDI is not applicable in case of significant concomitant exposure to cyanuric acid or another substance increasing the risk of urinary crystal formation. Melamine is listed on the Swiss inventory list of substances authorized for the use in printing inks. In the U.S., melamine is authorized as adhesive and component of coatings in food packaging. In 2008, the U.S. FDA lowered the TDI from 0.63 to 0.063 mg/kg body weight.

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References

  1. Bradley, E.L. et al. (2011). “Migration of melamine from can coatings cross-linked with melamine-based resins into food simulants and foods.” Food Addit Contam A 28:243-50.
  2. Bradley, E.L. et al. (2010). “Comparison of the migration of melamine from melamine-formaldehyde plastics (‘melaware’) into various food simulants and foods themselves.” Food Addit Contam A 27:1755-64.
  3. EFSA, CEF (2006). “Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food on a request from the Commission related to 2,2-bis(4-hydroxyphenyl)propane (Bisphenol A).
  4. IARC (1999). “Melamine – Summaries & evaluations.”
  5. Hsieh, T.J. et al. (2012). “Melamine induces human renal proximal tubular cell injury via transforming growth factor and oxidative stress.” Toxicol Sci 130:17-32.
  6. Puschner, B. et al. (2007). “Assessment of melamine and cyanuric acid toxicity in cats.” J Vet Diagn Invest 19:616-24.
  7. Kim, T.H. et al. 2012. “Evaluation of metabolomic profiling against renaltoxicity in Sprague-Dawley rats treated with melamine and cyanuric acid.” Arch Toxicol 86:1885-97.
  8. Reimschuessel, R. et al. (2010). “Renal crystal formation after combined or sequential oral administration of melamine and cyanuric acid.” Food Chem Toxicol. 48:2898-906.
  9. Zheng, X. et al. (2013). “Melamine-induced renal toxicity is mediated by the gut microbiota.” Sci Transl Med 5:172ra22.
  10. Yang, Y. et al. (2012). “Acute low-dose melamine affects hippocampal synaptic plasticity and behavior in rats.” Toxicol Lett 214:63-8.
  11. Yang, J.J. et al. (2010). “Effect of melamine on potassium currents in rat hippocampal CA1 neurons.” Toxicol In Vitro 24:397-403.
  12. USDA. (2007). “Disposition of hogs and chickens from farms identified as having received pet food scraps contaminated with melamine and melamine-related compounds and offered for slaughter.
  13. Xie, G. et al. (2010). “Metabonomic evaluation of melamine-induced acute renal toxicity in rats.”J Proteome Res 9:125-33.
  14. Chen JS. 2009. “A worldwide food safety concern in 2008 – melamine-contaminated infant formula in China caused urinary tract stone in 290,000 children in China.” Chin Med J (Engl) 122:243-4.
  15. WHO (2009). “Toxicological and health aspects of melamine and cyanuric acid.