.....Studies of melamine have been conducted in rodents.1, 2 Only one oral long-term dog study has been reported. Apart from crystalluria (excretion of crystals in the urine) in that study, no toxic effects were observed in dogs fed 1200 mg/kg/day for one year.1, 3 No oral studies with cat or human subjects have been reported.
Brief histopathological reports from affected pets indicate that acute/subchronic kidney failure is the mechanism of toxicity. It is still unclear whether there is a direct relationship between the kidney failure and crystallization in the kidneys subsequent to purported melamine consumption, although crystals were found in the kidneys and urinary bladder (crystals are much smaller than stones and their presence does not necessarily result in tissue/organ pathology or dys).
High (4500 ppm or 263 mg/kg bw/day) and continuous (2 years) dietary exposure to melamine in controlled studies is associated with an increase in the production of bladder stones and an increased incidence of urinary bladder tumors in male rats.2, 4 The two incidences are highly associated with each other.5
The NOAEL for stone formation of melamine toxicity is 63 mg/kg bw/day in a 13-week rat study.2 This value is the lowest NOAEL noted in the published literature and is used with human exposure assessments below to provide an estimate of human safety/ risk.
Margins of Safety and Levels of Concern for Melamine Compounds
The point of departure (POD) is the NOAEL of 63 mg/kg/day from the rodent subchronic bioassay. This POD was then divided by two 10-fold safety/uncertainty factors (SF/UF) to account for inter- and intra-species sensitivity, for a total SF/UF of 100. The resulting Tolerable Daily Intake (TDI) is 0.63 mg/kg bw/day. The TDI is defined as the estimated maximum amount of an agent to which individuals in a population may be exposed daily over their lifetimes without an appreciable health risk with respect to the endpoint from which the NOAEL is calculated. 6
In considering all of the exposure estimates presented above, including the 90th percentile estimates from Scenario 1 (Table 3), all are well below the TDI of 0.63 mg/kg/day or 630 μg/kg bw/day and have large Margins of Safety (MOS). The MOS is defined as the TDI divided by the estimate of exposure. For Scenario 2, the MOS would be approximately double that for Scenario 1. Indeed the highest exposure estimate for the worst case scenario (Scenario 3) of 2.5 μg/kg bw/day is 252 times lower than the TDI.
Table 3: Margins of Safety (MOS) for Scenario 1 Food Type 90th percentile intake (μg/kg bw/day) MOS
Catfish 0.34 μg/kg-bw/d 1853
Chicken (breast, leg, drum, thigh, wing) 0.21 μg/kg-bw/d 3000
Eggs 0.16 μg/kg-bw/d 3938
Pork (chops, steaks, cutlets, ham, roasts) 0.17 μg/kg-bw/d 3706
Combined Catfish, Chicken, Eggs and Pork 0.24 μg/kg-bw/d 2625
When considering what concentrations of MCs might be of concern in food, it is important to take into account the amount of a given food product that is eaten by an individual per day. Table 4 shows the "Level of Concern" (LOC) calculated for pork, poultry, eggs and catfish. The LOC takes into account the consumption of each product (based on CSFII data) and the TDI of melamine. These LOCs represent levels of MCs in the products below which there is no appreciable risk. The following table contains LOCs for animal-derived foods. Each value is derived on the basis of a consumption amount and the TDI according to the following formula where the body weight used to derive these values is 60 kg:
LOC = TDI (0.63 mg/kg/day) x 60 kg/ 90th percentile consumption level
Table 4: Levels of Concern (LOC) for Total MCs
* Food consumption levels used for the food types from Table 1 used to derive LOCs.
In light of the calculation that the highest estimate of exposure (i.e., 2.5 μg/ kg bw/day for a 60 kg individual) is more than two orders of magnitude lower than the TDI (0.63 mg.kg.day), which are based on reasonable assumptions and a 100-fold safety factor, the consumption of pork, poultry, eggs and domestic fish is very unlikely to pose a human health risk.
