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Melamine came to public attention in 2007, following reports of acute renal failure in cats and dogs through consumption of contaminated pet food (1). In 2008, reports from China began to emerge of at least 150 cases of renal failure and six confirmed deaths in young children among more than 300,000 with urinary tract ailments as a result of melamine contamination in Chinese infant formula. Fortunately, no related cases in Canadian children have been reported thus far, and no evidence of intentional melamine contamination has occurred in any other country. Infant formula manufactured in China is not approved in Canada, and formula companies do not use milk ingredients from China in the manufacture of Canadian formula (2). There has, however, been a recall of imported Chinese food products including candies, cookies and coffee drinks because the Canadian Food Inspection Agency found concentrations of melamine in them that were above the established tolerance concentration of 2.5 parts per million (ppm) (2).
In China, melamine was illegally added to raw milk to give the appearance of a higher protein content (3). There is no evidence to date that this has occurred in other countries. Because 66% of melamine mass is nitrogen, which is used as a surrogate to measure food protein content, it was used as a solution to falsely indicate an increased protein content in infant formula, and combat marasmus that was appearing in formula-fed Chinese infants (4). Melamine is a metabolite of an agricultural pesticide, cryomazine. It is also a decomposition product of a food equipment sanitizer, trichloromelamine. Melamine is manufactured from cyanic acid for industrial applications and used in the production of resins and foams for industrial coatings, paper, flame retardants and plastic tableware. Leaching from plastics into food may occur, but amounts measured are very small and are considered to be nontoxic. Melamine is added to crop fertilizers and by this route may be absorbed into foods. The extent of this contamination is unknown (4). It is estimated that these sources of exposure contribute negligible amounts of melamine to food products but can be detected (5). In China, melamine has been found in food products containing contaminated milk and eggs (6). Although melamine is not approved for use in foods in Canada, the trace amounts measured have left both Health Canada and the United States Food and Drug Administration (FDA) grappling with an evidence base that is limited for defining a safe level of melamine in infant formula, given the potential vulnerability of the developing renal system (7). Nonetheless, Health Canada had recently established an interim tolerance for infant formula of 1 ppm, and 2.5 ppm for all other foods, using standard risk assessment approaches shared by food regulatory agencies in the United States, the European Union, Australia, New Zealand and Hong Kong (2). Moreover, on December 11, 2008, Health Canada announced that it was adopting a recommendation from the World Health Organization to drop its allowable level of melamine in infant formula to 0.5 ppm (8). The FDA has recently reported trace concentrations of melamine in infant formula manufactured in the United States of up to 10,000 times below the concentration in Chinese formula, which is associated with infant illness, and approximately 10-fold below the 1 ppm tolerance. Health Canada, likewise, found trace levels of melamine below the new lower allowable limits of 0.5 ppm in infant formula sold in Canada (8).
Melamine is considered to have low-acute toxicity; however, when present with cyanuric acid, which is an analogue and common co-contaminant, large crystal complexes may form in the urine. Melamine has a plasma half-life of approximately 3 h and is not metabolized in the body but rapidly excreted in the urine. However, the formation of a highly insoluble melamine cyanurate complex is not only a urinary tract lining irritant, but may also cause uroliths leading to obstruction and renal failure (9). Health effects of long-term low-level melamine consumption are unknown at this time due to a lack of longitudinal data. Long-term chronic dosing studies (10,11) in animals suggest that chronic urinary tract epithelial irritation and inflammation from crystals and stones can result in urinary tract cancer.
Cyanuric acid, a recognized impurity and structural analogue of melamine, is an FDA-approved animal feed additive and a dissociation product of swimming pool water disinfectant, dichloroisocyanurates. Human exposure may occur through drinking swimming pool water. Sodium dichloroisocyanurate, when used to disinfect drinking water, may be dechlorinated to cyanurate, another possible source of exposure. Cyanurates may also accumulate in fish and provide a dietary source. Also recognized for low-acute toxicity and rapid excretion through the kidneys, cyanuric acid may cause tubular crystallization and subsequent renal tissue damage at high doses (12).
Infants receiving contaminated formula as their main food source are likely to receive more melamine per kilogram of body weight. Older children or adults who rely on a wider variety of food sources and not infant formula have a much lower level of potential exposure. The identified toxicity of melamine rests in the deposition of crystals and uroliths in the kidney collecting system and ureters. Because the diameters of the renal structures are small in infants, proportionate degrees of inflammation or obstruction are more likely to result in renal compromise. In addition, the lower glomerular filtration rate in infants may predispose to the development of uroliths due to decreased flow of urine through their tubules. Finally, because infants excrete more uric acid (13), this may be a contributing factor to the formation of uroliths. Animal studies have demonstrated that melamine may co-crystallize with uric acid (10). There is currently no information available regarding the composition of uroliths in affected Chinese babies.
Because the pathogenesis of melamine toxicity is that of urolithiasis, the presenting symptoms may include irritability, crying while urinating, vomiting, failure to thrive, polyuria, polydipsia, visible stones in the diaper, flank tenderness and eventually anuria, high blood pressure and death. Testing for melamine in blood or urine is not routinely available through clinical or public health laboratories and is of limited utility given the short half-life.
Identifying infants at risk for exposure to melamine-contaminated formula and removing the exposure is the first priority. Infants who are likely to be exposed to melamine-containing formula and exhibit signs or symptoms consistent with renal tract disease should be evaluated for melamine toxicity. This may include microscopic urinalysis for hematuria, plasma electrolytes, urea and creatinine, as well as a renal ultrasound to rule out obstruction. The necessity of evaluation of healthy and asymptomatic children who have a history of exposure is not clear. An expert panel of the American Society of Pediatric Nephrologists provided specific recommendations for evaluation of symptomatic infants (14). They do not currently recommend evaluation of healthy infants who may have been living in areas where other infants were exposed and suffered melamine toxicity. The Public Health Agency of Canada recommends a plasma creatinine and renal ultrasound in asymptomatic young children who have recently arrived from China, and in whom a history of consumption of contaminated milk is suspected (5).
The Public Health Agency of Canada, in their statement on October 28, 2008, stated that paediatric chairs, paediatric surgical chairs and paediatric health care institutions have been contacted to provide information on any apparent increase in cases of renal illness in very young children. The Canadian Paediatric Surveillance Program has undertaken a survey of Canadian paediatricians to ask whether they had seen potentially related cases (refer to page 218). Surveillance activities in other countries are being examined and will help guide further efforts in Canada (5).
Although there are no reported cases thus far of melamine toxicity in Canadian children, given the diverse Canadian ethnic population, travel of Canadians to China and adoption of Chinese infants, paediatricians and other health care professionals need to maintain vigilance for infants and children who may have had access to Chinese infant formula or recalled food products. An index of suspicion should be raised in the setting of symptoms or signs of renal illnesses, particularly urolithiasis. The question of health effects from long-term low-dose melamine and/or cyanuric acid exposure will only be answered through ongoing animal toxicological research and longitudinal observational cohorts of those infants who have already been exposed.
The authors wish to thank Bronia Heilik for her library assistance, Melissa Wiens for her administrative assistance, and Dr Maury Pinsk and Dr Robin Walker for their review and comments on the paper. The authors sincerely thank the authors of “Melamine: Information for pediatric health professionals,” especially Dr A Miodovnik, Dr T Guidotti, Dr J Paulson, Dr J Lowry, Dr M Miller, Dr A Woolf and Ginger Ellingson because the foundation of this paper rested on the work of this cohesive and committed group.