Unmasking the toxic culprit(s) in pet-food recalls
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BACKGROUND: On March 16, 2007, Menu Foods Inc., a Canadian manufacturer of wet pet food, issued a recall because of concerns about adverse effects of some of their products on kidney functions of cats and dogs.
The recall was unprecedented in scope, eventually involving an estimated 1,000 products manufactured by Menu Foods and other large pet-food companies.The food was manufactured by Menu Foods between Dec. 3, 2006, and March 6, 2007. On Feb. 22 and 28, 2007, Menu learned of the illness of two cats that ate some of their food. About the same date, it received a separate consumer complaint about the death of a cat that consumed the food.
On March 6 and 7, a company that Menu Foods retained to perform routine palatability tests informed the company of the death of one cat and the euthanasia of two of 20 other cats in a routine palatability study.
On March 9, four more cats assigned to the first palatability panel were euthanized because of severe illness. Two cats assigned to a different palatability panel also were euthanized.
About the same time, food-related acute to subacute renal failure was diagnosed in dogs and cats in veterinary clinics across the country. Menu Foods contacted the Food and Drug Administration (FDA) on March 15, 2007, and issued a voluntary pet-food recall the next day.
Aminopterin, an antagonist of folic acid at one time used to treat cancer, was initially thought to be the toxin in the recalled pet food. However, this finding was not confirmed by the FDA. Therefore, testing for other food-related contaminants continued. Menu Foods identified seven different ingredients, including wheat gluten, common to all incidents. Tests did not reveal any contaminants in the ingredients. However, melamine was eventually detected in the wheat gluten. The FDA confirmed this finding.
Later it was learned that melamine originating in China was added to wheat gluten. Contaminated wheat gluten subsequently was identified in rice protein concentrate. Then, the FDA learned that samples of the contaminated wheat gluten and rice protein were mislabeled. Both products actually were wheat flour contaminated with melamine and melamine-related products.
Melamine is an industrial chemical of no known nutritional value to dogs or cats. In mice and rats, it causes urolithiasis. Chronic irritation of the urothelium by uroliths induces urothelial hyperplasia and subsequent urinary bladder neoplasia in these rodents.
Melamine has been reported to cause diuresis in rats and dogs, crystalluria in mice, rats and dogs and fatal uremia characterized primarily by crystalluria in sheep.
Apparently melamine has been marketed as a fertilizer because of its high nitrogen content. In context of pet foods, because protein concentration in ingredients of food is measured by analysis of total nitrogen content, it has been alleged that melamine was intentionally added to increase the apparent protein content.
Melamine has a relatively high safety margin, and it is unlikely that melamine itself directly caused renal failure in these cats.
The FDA later announced that, in addition to melamine, cyanuric acid (also originating in China and containing a relatively high level of non-protein nitrogen) was added to pet foods.
Cyanuric acid is structurally related to melamine. It is sometimes used as a stabilizer in outdoor swimming pools and hot tubs to minimize the decomposition of hypochlorous acid by light. Unfortunately, a paucity of data is available about the toxicity of cyanuric acid in mammals. Sodium cyanurate fed subchronically to mice and rats caused uroliths, indicating poor solubility.
The evidence suggests that a combination of chemicals (melamine, cyan-uric acid, possibly others) formed insoluble crystals in the kidneys of these unfortunate pets, with subsequent physical damage to the renal tubules. Cornell University's Animal Health Diagnostic Center identified melamine in:
1) pet food
2) urine from cats that ate the contaminated food
3) in the kidney of one cat participating in Menu Food's palatability studies.
The University of Guelph's Laboratory Services Division induced a crystal-line complex of melamine-cyanuric acid in vitro by adding melamine and cyanuric acid to cat urine. Further analysis of the crystals revealed that they were composed of approximately 70 percent cyanuric acid and 30 percent melamine and were extremely insoluble.
Two other melamine-related substances (ammelide and ammeline) were identified. Whether these metabolites also are nephrotoxic is being evaluated. Additional in vivo studies revealed that melamine alone and cyanuric acid alone were not acutely nephrotoxic. However, as demonstrated by investigators at the University of California-Davis, the combination of these two industrial chemicals was extremely nephrotoxic, especially to cats.
The March 2007 pet food-associated renal failure epidemic in North America is similar to a March 2004 epidemic of pet food–associated renal failure that occurred in Asia, in which an estimated 6,000 dogs and fewer cats developed nephrotoxic renal failure after ingesting a certain brand of pet food.
Compare this data to that from Banfield, The Pet Hospital, which suggest that an estimated 39,000 dogs and cats developed renal failure in the 2007 North-American food-borne epidemic.
Minnesota Urolith Center input
The Asian epidemic (2004) and the North American (2007) epidemic corre-spond in many respects to the sudden recognition by our staff of uroliths received beginning in October 2002.
These uroliths and crystals were similar (if not identical) in appearance to the crystals and uroliths later described by several investigators (Figures 2 to 8).
The infrared spectrum of the uroliths did not match any of the known minerals in our database. We consulted with several laboratories in the United States; none was familiar with the substance in question.
Therefore, we sent samples to colleagues in Germany for analysis. They were evaluated via infrared spectro-scopy and solid-state NMR spectro-scopy; the analysis revealed uric acid monohydrate. This mineral type had been recently (2005) reported in humans. Since 2002, we have received uroliths containing the minerals of interest (uric acid monohydrate) retrieved from 520 dogs and cats living in Asia (Figure 1).
During the period from 2006 to Aug. 11 this year, we have received 16 uroliths from the United States containing uric acid monohydrate (12 dogs and 4 cats: Figure 1).
Staff at the Characterization Facility, University of Minnesota, compared our previously unknown samples to references for uric acid monohydrate obtained from the Cambridge Crystallographic Data Center (< http://www.ccdc.cam.ac.uk/>), utilizing X-ray microdiffraction and electron dispersive spectroscopy.