3 de junio de 2009

Following a request from the European Commission to the European Food Safety Authority (EFSA), the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to provide a scientific opinion on the safety of Se-methyl-L-selenocysteine (Se-methylselenocysteine) added for nutritional purposes as a source of selenium in food supplements and on the bioavailability of selenium from this source.

The present opinion deals only with the safety of Se-methylselenocysteine as a source of selenium and the bioavailability of selenium from this source. The safety of selenium itself, in terms of amounts that may be consumed, is outside the remit of this Panel.

Se-methylselenocysteine is a naturally occurring monomethylated selenoamino acid in which selenium replaces the sulphur of the S-methylcysteine molecule. Se-methylselenocysteine is found in plants of the Allium and the Brassica families and also in yeast. As much as 80% of the total selenium found in vegetables such as broccoli, radish, Brussels sprouts, cabbage, garlic, onion, leek, ramps, and milk vetch (Astragalus spp, Fabaceae) is present as Se-methylselenocysteine.

Se-methylselenocysteine is readily absorbed from the gastrointestinal tract and has been shown to be bioavailable in studies in animals. It is converted via the action of ß-lyase, found in many tissues, to methylselenol and then to hydrogen selenide, which is also the key metabolite derived from the inorganic forms of selenium, selenite or selenate. Hydrogen selenide is then used for the production of specific selenoproteins such as glutathione peroxidase. Excess hydrogen selenide is sequentially methylated to mono-, di-, and trimethylated metabolites that are ultimately excreted in human urine and/or breath, or converted into selenosugars and excreted. It is also oxidised to selenium dioxide, a pathway associated with toxicity.

Four-week toxicity studies with Se-methylselenocysteine in rats and dogs, together with shorter-term studies in mice, indicate that the toxicity is comparable to or possibly higher than that of other selenium compounds. No specific studies are available on the genotoxicity, carcinogenicity or developmental and reproductive toxicity of Se-methylselenocysteine. While positive results have been reported for a number of selenium compounds in in vitro genotoxicity assays, results from genotoxicity studies in vivo in rodents are mainly negative.

Intakes of selenium in the range of 3200-6990 µg/day by humans are associated with chronic selenosis, with no selenosis being observed for the intake range of 240-1510 µg/day (mean 750 µg/day). The Scientific Committee on Food (SCF) has previously given an opinion on the Tolerable Upper Intake Level (UL) of selenium, defining proportionately lower intake levels for children, based on body weight differences compared to adults. On the basis of the findings in humans, the SCF noted that an intake of about 850 μg/day could be taken as a No-Observed-Adverse-Effect-Level (NOAEL) for clinical selenosis. Using an uncertainty factor of 3 to allow for the remaining uncertainties of the studies, the SCF derived a UL for selenium of 300 μg/day.

The use level of Se-methylselenocysteine in food supplements proposed by the petitioners, of 200 μg selenium/day, will be below the UL of 300 µg selenium/day in adults and that of 250 µg selenium/day for children aged 15-17, established by the SCF in 2000. The Panel notes however that the proposed use level is equal to the UL for children between 11 and 14 years old, and is above the ULs of 60, 90, and 130 µg selenium/day for children in the age ranges of 1-3, 4-6 and 7-10 years respectively as defined by the SCF. The Panel also notes that when dietary intake is taken into consideration in addition to supplementation with Se-methylselenocysteine at the proposed use level of 200 μg selenium/day, the ULs of 250 µg selenium/day as defined by the SCF for children between 15 and 17 years old and the UL of 300 µg selenium/day for adults will be exceeded at the high percentile intake level.

However, the Panel considers that given the absence of human studies on Se-methylselenocysteine, the relatively sparse database on the bioavailability of selenium from this source, and the limited data on its safety compared with other selenium compounds used in food supplements, the ULs for selenium defined by the SCF for adults and children cannot be used for judging its safety. The Panel has therefore used the 28-day toxicity studies carried out with Se-methylselenocysteine in the dog and the rat for the purpose of risk assessment.

The Panel concludes that an additional uncertainty factor of 5 should be applied to the lowest-observed-adverse-effect-levels (LOAELs) determined in these studies in dogs and rats, which also allows for additional deficiencies in the database. The Panel considers that the margins of safety derived, of 4 to 12 at the supplementation dose of 200 μg/day in humans (equivalent to approximately 3.3 μg/day for a 60 kg person) proposed by the petitioners, is inadequate, and concludes that there is concern regarding the safety of this source of supplemental selenium at the proposed use level.

The Panel considers that given the sparsity of the experimental database on this substance, the concerns expressed by the SCF in 1999 about the way in which the body handles organic selenium compared with inorganic forms, are still applicable to Se-methylselenocysteine.