Recent advances in the risk assessment of melamine and cyanuric acid in animal feed

Abstract

Melamine can be present at low levels in food and feed mostly from its legal use as a food contact material in laminates and plastics, as a trace contaminant in nitrogen supplements used in animal feeds, and as a metabolite of the pesticide cyromazine. The mechanism of toxicity of melamine involves dose-dependent formation of crystals with either endogenous uric acid or a structural analogue of melamine, cyanuric acid, in renal tubules resulting in potential acute kidney failure. Co-exposure to melamine and cyanuric acid in livestock, fish, pets and laboratory animals shows higher toxicity compared with melamine or cyanuric acid alone. Evidence for crystal formation between melamine and other structural analogs i.e. ammelide and ammeline is limited. Illegal pet food adulterations with melamine and cyanuric acid and adulteration of milk with melamine resulted in melamine–cyanuric acid crystals, kidney damage and deaths of cats and dogs and melamine–uric acid stones, hospitalisation and deaths of children in China respectively. Following these incidents, the tolerable daily intake for melamine was re-evaluated by the U.S. Food and Drug Administration, the World Health Organisation, and the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA). This review provides an overview of toxicology, the adulteration incidents and risk assessments for melamine and its structural analogues. Particular focus is given to the recent EFSA risk assessment addressing impacts on animal and human health of background levels of melamine and structural analogues in animal feed. Recent research and future directions are discussed.

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.