Melamine is a urea- and formaldehyde-based synthetic polymer used in a wide range of products: kitchen utensils and dishes, Formica, laminate flooring, whiteboards, wood-based kitchen cabinets and assemble-it-yourself furniture, fire retardants (including flame-retardant fabric), cleaning compounds (e.g., Magic Eraser), disinfectants, latex-based coatings (e.g., paint), and fertilizer. It is considered highly stable, has good heat resistance (but will melt under high heat, such as in a microwave), and is difficult to recycle.

Melamine is not widely studied in animals but is considered only minimally toxic. LD50 for oral exposure in rats is 3248 mg/kg and in mice is 3296 mg/kg. LD50 for skin exposure in rabbits is >1000 mg/kg. The lowest published lethal dose for intraperitoneal exposure in rats is 3200 mg/kg (source).

According to OSHA, potential symptoms of melamine exposure include

Irritation of eyes, skin, and mucous membranes; dermatitis; in animals: chronic inflammation of kidneys (female rats); ulceration of urinary bladder epithelium (mice), urolithiasis (rats and mice); bladder cancer (male rats).

. . .

The main constituents of the stones in the urinary bladders of rats given melamine in the diet were reported to be unchanged melamine and uric acid in a 1:1 molar ratio.

Dimelamine phosphate was reported to be a urinary product of melamine in dogs and rats, which showed a diuretic response to melamine.

According to VIN, cats would need to eat huge amounts of recalled food (on the order of 4 kg per day) before we’d see mortality rates approaching the LD50 for rats (assuming you can accurately extrapolate LD50 data for rats to other species).

Melamine is a metabolite of the insecticide cyromazine, which is used in livestock and poultry without restriction in the United States. Cyromazine breaks down into melamine. A report from the European Agency for the Evaluation of Medicinal Products notes that pharmakokinetic studies show that dealkylation of cyromazine leads to the presence of melamine in the urine of animals that have ingested cyromazine. Could cyromazine residues in beef and poultry tissue be the source of the melamine in pet food?

So, melamine might well prove not to be the toxin causing acute renal failure dogs and cats, but it could be useful as a marker for determining whether a given pet with renal failure has ingested the recalled food.

Research articles
Cremonezzi DC, Diaz MP, Valentich MA, Eynard AR, Neoplastic and preneoplastic lesions induced by melamine in rat urothelium are modulated by dietary polyunsaturated fatty acids, Food Chem Toxicol. 2004 Dec;42(12):1999–2007.

Results show that dietary PUFA [polyunsaturated fatty acids] modulate differentially both normal and pre-neoplastic urothelial proliferation induced by melamine. FO [fish oil], rich in n-3 fatty acids, showed a strong protective effect.

Neerman MF, Chen HT, Parrish AR, Simanek EE, Reduction of drug toxicity using dendrimers based on melamine, Mol Pharm. 2004 Sep–Oct;1(5):390–393. [Melamine-based dendrimers found to reduce the hepatotoxicity of cancer drugs such as methotrexate (which is almost identical to aminopterin).]

Ogasawara H, Imaida K, Ishiwata H, Toyoda K, Kawanishi T, Uneyama C, Hayashi S, Takahashi M, Hayashi Y, Urinary bladder carcinogenesis induced by melamine in F344 male rats: correlation between carcinogenicity and urolith formation, Carcinogenesis. 1995 Nov;16(11):2773–2777. [This study found that among rats fed diets containing 3 percent melamine, 90 percent developed urinary carcinomas. Note that the diets recently tested by the FDA contained far smaller amounts of melamine: 0.01–0.2 percent. Also:]

[M]elamine-induced proliferative lesions of the urinary tract of rats were directly due to the irritative stimulation of calculi, and not molecular interactions between melamine itself or its metabolites with the bladder epithelium.

Okumura M, Hasegawa R, Shirai T, Ito M, Yamada S, Fukushima S, Relationship between calculus formation and carcinogenesis in the urinary bladder of rats administered the non-genotoxic agents thymine or melamine, Carcinogenesis. 1992 Jun;13(6):1043–1045.

Heck HD, Tyl RW, The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment, Regul Toxicol Pharmacol. 1985 Sep;5(3):294–313.

[Melamine] induced bladder tumors in rats in chronic feeding studies. However, it is likely that these tumors were secondary to the development of calculi. . . . [Melamine is] apparently nongenotoxic, and [it does] not appear to be metabolized. Increased cell replication in the urothelium of the bladder caused by chronic physical injury was probably a major factor in the mechanism of induction of bladder tumors by bladder stones.

Melnick RL, Boorman GA, Haseman JK, Montali RJ, Huff J, Urolithiasis and bladder carcinogenicity of melamine in rodents, Toxicol Appl Pharmacol. 1984 Feb;72(2):292–303. [This multi-variable study examined the effects of melamine on mice and rats fed a melamine-laced diet (in concentrations ranging from 750 to 18,000 ppm) for either 13 or 103 weeks “to determine its toxicologic profile, including carcinogenic potential.” Most of the study’s findings relate to urinary bladded stones (generally increased among groups fed melamine, and more so among males than females) and carcinomas (increased incidence among male rats fed higher amounts of melamine; not found among male or female mice), although among female rats, “chronic inflammation of the kidney was observed at an increased incidence (relative to controls) in both the low (4500 ppm) and high (9000 ppm) dose groups.”]

Mast RW, Jeffcoat AR, Sadler BM, Kraska RC, Friedman MA, Metabolism, disposition and excretion of [14C]melamine in male Fischer 344 rats, Food Chem Toxicol. 1983 Dec;21(6):807–810. [This study found that in (male) rats melamine is not metabolized, “distrubtes in body water,” concentrates in the kidneys and urinary bladder at slightly higher levels than elsewhere in the body, and is cleared by the kidneys at a rate of 2.5 ml/min.]

National Toxicology Program, NTP Carcinogenesis Bioassay of Melamine (CAS No. 108-78-1) in F344/N Rats and B6C3F1 Mice (Feed Study), Natl Toxicol Program Tech Rep Ser. 1983 Mar;245:1–171. [Full report here.]

Questions

  • Given the wide variety of materials that contain melamine (including many dog bowls and cat bowls, as well as disinfectants used in the food manufacturing inustry), is it possible that exposure is commonplace? Could the finding in pet food and cats that ate recalled food be incidental?
  • Some veterinarians have been skeptical of the finding that aminopterin was repsonsible for the deaths and illness from the recalled food because of the lack of hepatic symptoms. Is it possible that the presence of melamine had a protectant effect on the liver and thus reduced the number of hepatic symptoms seen?
  • How long before we know whether the melamine in the recalled food is causing urinary bladder cancer among pets that ate it?
  • Why have the FDA and other labs not been able to confirm the New York State lab’s finding of aminopterin (excepting a Canadian lab that reports finding aminopterin in amounts too low to cause damage)?
  • Why is the FDA no longer focusing on aminopterin? Given the lack of evidence that melamine is nephrotoxic in cats and dogs, is the FDA looking for yet more contaminants?

Melamine resources
Wikipedia
MSDS
OSHA Chemical Sampling Information
National Toxicology Program report
PAN Pesticides Database
“What the FDA Isn’t Telling Us about Melamine”