Recent advances in the risk assessment of melamine and cyanuric acid in animal feed
Introduction
Melamine (2,4,6-triamino-1,3,5-triazine; Fig. 1) is produced in high volumes mainly for the synthesis of melamine–formaldehyde resins, one of the uses of which includes the manufacture of contact materials such as plastics, laminates and coatings. Additionally, melamine is present as a trace contaminant in nitrogen supplements used in animal feeds (e.g. urea), and can be found as a metabolite and degradation product of the pesticide and the veterinary drug, cyromazine (EFSA, 2010). Depending on the purification process, melamine may contain a number of structurally related by-products, including cyanuric acid (2,4,6-trihydroxy-1,3,5-triazine), ammeline (4,6-diamino-2-hydroxy-1,3,5-triazine), and ammelide (6-amino-2,4-dihydroxy-l,3,5-triazine). These 3 melamine analogues keto-enol tautomerise and their keto forms are depicted in Fig. 1. In soil and in the GI tract, ammeline, ammelide, and cyanuric acid may also be produced by microbial degradation of melamine by sequential hydrolysis to replace one, two, or three amino groups, respectively. Dichloroisocyanurates used in disinfection of water (e.g. swimming pools) and food contact materials can also be hydrolysed into cyanuric acid (WHO, 2004). In this context, the occurrence of melamine and its structural analogues is from authorised use in plastics or from impurities in authorised nitrogen-containing feed supplements or pesticides and can be considered as background levels. In 2007 and 2008, illegal adulteration of pet food, livestock food, fish feeds and raw milk used for infant formula to falsely boost the apparent protein levels with either melamine alone or “scrap” melamine containing cyanuric acid has resulted in illness and deaths of human infants and companion animals (cats and dogs) due to the nephrotoxicity associated with the accumulation of melamine–uric acid or melamine–cyanuric acid crystals in the kidneys (Reimschuessel and Puschner, 2010, Reimschuessel et al., 2010a, US-FDA (U.S. Food and Drug Administration), 2007, WHO (World Health Organization), 2009a, WHO (World Health Organization), 2009b). Following these incidents, a number of risk assessments have been performed by the US-Food and Drug Administration (US-FDA), the expert consultation of the World Health Organization (WHO), and the Scientific Panel on Contaminants in the Food Chain (CONTAM) of the European Food Safety Authority (EFSA). This review provides an overview of the toxicity, exposure assessment in food and feed to melamine and its structural analogues, including a brief historical account of adulteration incidents, metabolism and disposition, toxicology, and recent risk assessments, with particular emphasis on the EFSA assessment of the animal and human health implications of background levels of melamine and its structural analogues in animal feed.
Section snippets
Toxicology of melamine and cyanuric acid
While the toxicokinetics and toxicology of melamine have been the subjects of a number of reviews, this section aims to present key toxicokinetic and toxicological data used in hazard identification and hazard characterisation of melamine and its structural analogues (cyanuric acid, ammelide, ammeline) in laboratory animals, farm animals and humans (Bhat et al., 2010, EFSA, 2010, Gossner et al., 2009). The mode of action of melamine with regard to complex formation with uric acid and cyanuric
Toxicological data in laboratory animals, farm animals, pets, fish and shrimp
The major target organ for the toxic effects of melamine, alone and in combination with cyanuric acid, is the kidney in fish and many mammalian species, including humans. While other types of adverse effects could occur (e.g., developmental or neurotoxicity), they either occur at higher doses than, or subsequent to nephrotoxicity. Therefore, the focus of this overview is on melamine-associated kidney toxicity.
Historical perspectives on fraudulent adulterations of food and feed with melamine
Melamine has been fraudulently added to pet food, livestock feed, fish feeds and raw milk used for human consumption to enhance the apparent protein concentration because of its high nitrogen content (67% of nitrogen on a weight-basis). Few reports of adulteration of foodstuffs with melamine are available from the 1980s: potato meal in Germany and meat and fish meals in Italy. Over the last four years, a number of incidents of adulteration or contamination have been reported from North America,
Derivation of health-based guidance values for melamine: a historical perspective
A brief historical account is given below to summarise the scientific basis for the derivation of health-based guidance values for melamine by the European Scientific Committee for Food, US FDA, WHO and EFSA.
Animal health aspects
The potential health risks associated with melamine and cyanuric acid exposure from identifiable “background” sources, as opposed to adulteration, were recently evaluated by EFSA (EFSA, 2010). The exposure to melamine has been estimated in livestock based on three scenarios: (1) an impurity in urea-based commercial feed additive in ruminants; (2) a metabolite of cyromazine used as a feed additive in poultry; (3) hypothetical contamination of melamine in feed at 0.5, 2.5, and 10 mg/kg feed.
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Conclusions and future research
This review focused on the lessons learnt from the fraudulent adulterations of food and feed with melamine, the toxicology of melamine and its structural analogues (cyanuric acid, ammelide, ammeline) in laboratory animals, farm animals and pets. Additionally, recent risk assessments performed by the US-FDA, the WHO and EFSA as a direct consequences of the 2007 and 2008 adulteration incidents in China have been reviewed with special focus on the latter regarding animal and human health
Conflict of interest
No conflict of interests between the authors was identified.
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