Guidelines for Health Care Professionals

Melamine contamination of food products made in China

Updated: 28 October 2008

 

• The issue
• Melamine and melamine analogues (cyanuric acid, ammelide and ammeline)
• Toxicology of melamine
• Role of melamine in the formation of renal stones
• Clinical description
• Key diagnostic criteria for melamine-associated illness
• Testing for melamine in urine
• Clinical treatment
• Screening of asymptomatic, potentially exposed children
• Additional information of interest

 

The issue

There is an outbreak of disease characterized by renal stones and renal failure in very young children in China, associated with consumption of milk formula contaminated with melamine. As of October 15, 2008, more than 49,000 children have been hospitalized, with at least 150 cases of renal failure and 3 confirmed deaths. Melamine contamination has also been found in other Chinese milk products and products that have a dairy component, including candies and a coffee drink.

Infant formula manufactured in China is not approved for sale in Canada. Health Canada has confirmed with the four major manufacturers of infant formula sold in Canada that they do not use any milk ingredients that come from China. However, some products containing milk-derived ingredients from China that were sold in Canada were found to contain melamine and were recalled by the Canadian Food Inspection Agency.

There is no evidence to date of illness in young children in Canada associated with milk products contaminated with melamine. The Public Health Agency of Canada is working with paediatricians and paediatric institutions to monitor for potential cases.

Melamine and melamine analogues (cyanuric acid, ammelide and ammeline)

Melamine and its derivatives are industrial compounds made from cyanic acid that are used to form resins for various purposes. They are very rich in nitrogen, hence their use to increase the apparent amount of protein in liquid and solid foodstuffs, particularly dairy and wheat products.

Melamine contamination was linked to a series of pet dog and cat deaths in the US and Canada in 2007, due to consumption of adulterated pet food.

Toxicology of melamine

Melamine is not metabolized and is rapidly eliminated in the urine. No human data are available 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 generally not shown any renal toxicity or the formation of renal stones, although crystals may be found in the urine whose composition can be of value in making an etiological diagnosis.

The FDA/USDA performed a risk analysis of melamine in 2007 and concluded the following: “Based on currently available data and information, the results of the safety/risk assessment indicate that the consumption of pork, chicken, domestic fish, and eggs from animals inadvertently fed animal feed contaminated with melamine and its analogues is very unlikely to pose a human health risk”.

Thus, while the data are limited, there are no known long term health effects of low levels of melamine consumption at this time. However, research studies have shown that bladder stones resulting from chronic exposure to melamine increase the risk of bladder cancer in male rats.

Role of melamine in the formation of renal stones

Animal data have not shown that melamine alone causes renal failure or the formation of renal stones. 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. Additional animal studies have confirmed the interacting role of these two compounds in nephrolithiasis. In the current outbreak of disease in China, the presence of cyanuric acid has not yet been confirmed.

Clinical description

Paediatric:

The clinical presentation of the disease(s) will be the same for renal stones and renal failure in the very young, including:

• Vague irritability
• Unexplained crying in infants, especially when urinating, possible vomiting
• Failure to thrive
• Macroscopic or microscopic haematuria
• Polydipsia, polyuria, episodes of dehydration
• Stones discharged while passing urine
• High blood pressure, edema, painful when knocked on kidney area
• Acute obstructive renal failure: oliguria or anuria

Additional symptoms and signs may be unexplained fever arising from secondary urinary tract infections / bacteraemia.

Adult:

Adult illness associated with melamine contamination has not been reported from China or other countries. However, one would predict signs and symptoms of nephrolithiasis:

• Pain in the back and side or lower abdomen
• Macroscopic or microscopic haematuria
• Nausea and vomiting
• Polyuria, dysuria

Key diagnostic criteria for melamine-associated illness:

1. Epidemiologic exposure (i.e. consumption of contaminated product)
2. Having one or more of the above clinical manifestations
3. Laboratory test results: routine urine tests with macroscopic or microscopic haematuria; blood biochemistry; liver and kidney function tests; urine calcium/creatinine ratio (usually normal); urinary red blood cell morphology shows normal morphology of red blood cells (not glomerular haematuria)
4. Imaging examination: preferably ultrasound B exam of urinary system

Melamine can be detected in urine and directly from tissue by liquid chromatography " tandem mass spectroscopy. Rapid testing procedures have not been validated. Fourier-transform infra-red microscopic analysis of crystals and ELISA tests have been described.

Testing for melamine in urine:

There are a variety of tests available to detect melamine in urine and directly from tissue. Most are based on mass spectrometry and are highly sensitive. These tests would not be generally available in clinical or public health laboratories. The Public Health Agency of Canada advises the following with regard to testing of clinical samples:

At this time, testing for melamine should be restricted to symptomatic individuals who may be epidemiologically linked (i.e. through consumption) to contaminated milk from China. Candies, chocolates, instant coffee and other products and other sources of melamine would not produce these clinical syndromes based on preliminary data on melamine content in these products. A high level of melamine consumption is the link to symptomatic disease. Samples that should be tested in symptomatic individuals include urine, renal tract stones or sand, and finally kidney tissue.

The Canadian Food Inspection Agency (CFIA) and most toxicology labs have the capability to perform this type of testing, but few currently have established analyses in place. The National Microbiology Laboratory (NML) does not perform this type of testing.

Samples should be referred out if this testing capacity is not available at the provincial level. The CFIA recommends that, in general, samples be tested by laboratories accredited through the Standards Council of Canada (SCC). Information on SCC accredited laboratories can be obtained at: http://palcan.scc.ca/SpecsSearch/TLSearchForm.do

The NML will provide assistance in locating possible sources of testing if difficulties in locating a suitable laboratory are encountered.

Clinical treatment:

1. Immediately stop using melamine-contaminated food products.
2. Medical treatment: use infusion and urine alkalinization to dispel the stones. Correct the water, electrolyte and acid-base imbalance. Closely monitor routine urine tests, blood biochemistry, renal functions, ultrasound findings (with particular attention to the renal pelvis, ureter expansion, and the change of the stones in shape and location). If the stones are loose and sand-like, they are very likely to be passed out with urine.
3. Treatment of complicated acute renal failure: priority should be given to the treatment of life-threatening complications such as hyperkalemia. If possible, blood dialysis and peritoneal dialysis can be used early. Surgical measures can be taken to remove the obstruction if necessary.
   

Screening of asymptomatic, potentially exposed children

The current information from China is quite limited, therefore it is not possible to quantify the risk of illness for a given exposure. It appears that a fraction of Chinese children who were fed contaminated milk formula developed renal stones, after several months of consumption.

For young children newly arrived from China, whether as adopted children or as immigrants: if the child is asymptomatic, but a history of consumption of contaminated milk is suspected, it would be prudent for the physician to order a plasma creatinine and a renal ultrasound.

Additional information of interest

Surveillance:

In an effort to identify any potential clinical cases of melamine intoxication in Canada, staff at the Public Health Agency of Canada have made a number of enquiries within the medical community and are considering what further efforts for syndromic surveillance may be appropriate.

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 is undertaking a survey of Canadian paediatricians to ask whether they have seen potentially related cases. Surveillance activities in other countries are being examined and will help guide further efforts in Canada.

On-line risk assessment reference:

WHO - Melamine and Cyanuric acid: Toxicity, Preliminary Risk Assessment and Guidance on Levels in Food (25 September 2008) http://www.who.int/foodsafety/fs_management/Melamine.pdf