Toxicology of melamine
Based on the previous incidents of melamine contaminated pet food and the development of kidney stones and subsequent acute kidney failure in cats and dogs, it appears that melamine and its structural analogues, such as cyanuric acid, may act together to form crystals. This crystal formation occurs at very high-dose levels and is a threshold and concentration dependent phenomenon, which would not be relevant at low levels of exposure (US FDA/CFSAN Interim Melamine and Analogues safety/risk assessment http://www.cfsan.fda.gov/~dms/melamra.html).
Consumer exposure to melamine is considered to be low, but may occur through the extraction of melamine from compression moulds by acidic foods, such as lemon or orange juice or curdled milk, at high temperature. Taking into account these sources the estimated oral uptake of melamine is around 0.007 mg melamine/kg/day (OECD 1998).
Toxicity of melamine
Melamine is not metabolized and is rapidly eliminated in the urine. No human data could be found on the oral toxicity of melamine but there are data from animal studies. These show the compound to have a low acute toxicity, with an oral LD50 in the rat of 3161 mg/kg body weight. In animal feeding studies, high doses of melamine have an effect on the urinary bladder, in particular causing inflammation, the formation of bladder stones and crystals in the urine. Analysis of the bladder stones has shown that these are a mixture of melamine, protein, uric acid and phosphate. Animal studies have shown signs of renal toxicity only after long-term and high dose exposure.
The International Agency for Research on Cancer (IARC) has concluded that there is sufficient evidence in experimental animals for the carcinogenicity of melamine under conditions in which it produces bladder stones. There is inadequate evidence for carcinogenicity in humans.
Role of melamine in the formation of kidney stones
Animal data have shown that melamine alone can lead to formation of kidney stones after high dose exposure. Evidence from an earlier outbreak of acute renal failure in cats and dogs associated with contaminated pet food suggests that a combination of melamine and cyanuric acid does cause renal toxicity. Both of these compounds were found in the pet food together with other triazine compounds. Subsequent experimental studies in animals have shown that when they are fed a mixture of melamine and cyanuric acid this causes the formation of crystals in the tubules of the kidneys, eventually blocking them and causing renal damage and renal failure. The source of the cyanuric acid in the pet food was unknown but it may have been present as a contaminant of the melamine that had been illegally added to wheat gluten used in formulating the petfood. In the current event in China, the presence of cyanuric acid has not yet been confirmed.
Health-based Guidance Values
Following the pet food incident in 2007 described above, several authorities have preformed preliminary risk assessments. The US FDA has published an interim safety/risk assessment on melamine and structural analogues and has established for melamine a tolerable daily intake (TDI) of 0.63 mg per kg of body weight per day.
The European Food Safety Authority (EFSA) has published a provisional statement and recommended to apply a TDI of 0.5 mg per kg of body weight per day as tolerable intake value for melamine.
Triggered by the event of melamine contamination in Chinese dairy products and dairy containing products (including infant formula) the United States Food and Drug Administration (US FDA), Health Canada and the European Food Safety Authority (EFSA), carried out new Risk Assessment/Statement on melamine in food. A new interim safety and risk assessment of melamine and melamine-related compounds in food, including infant formula, has been issued by the US FDA on 3 October 2008 (and updated 28 November). The TDI recommended for food and food ingredients other than infant formula is of 0.063 mg per kg of body weight per day.
An updated statement by EFSA on the risk for public health due to the presence of melamine in infant milk and other milk products in China has been issued on 24 September 2008. In this statement the TDI of 0.5 mg per kg of body weight is still applied.
Health Canada announced a risk assessment for melamine in foods containing milk and milk-derived ingredients where a toxicological reference dose for melamine of 0.35 mg per kilogram body weight per day is established.