7. Safety aspects of peptides

The term food allergy refers to an immune response directed toward food and affects approximately 8% of children and 1–2% of adults, and its frequency is increasing [35]. Most allergens reacting with IgE antibodies are proteins found in peanuts, soybeans, tree nuts, milk, egg, fish, crustaceans, and wheat [53, 70].

European Food Safety Authority (EFSA) encourages the use of in silico tools for initial prediction of potential allergens from food proteins [8]. Although the toxicity and the allergenicity of food products must be assessed also in vitro and in vivo, the in silico tools can be also used to predict the toxicity of peptides [29]. The available bioinformatics-based allergen prediction tools consist of two groups. The first group is based on searches for sequence similarities following the Codex alimentarius guidelines produced by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO), which states that a "protein is potentially allergenic if it either has an identity of over six contiguous amino acids or a minimum of 35% sequence similarity when compared to known allergens" [13]. The second group utilizes databases aiming to identify conserved, allergenicity-related linear motifs [13]. AlgPred (http://www.imtech.res.in/raghava/algpred/) integrates different approaches by means to predict the allergenicity of proteins [62].

After ingestion of food, proteins are naturally hydrolyzed in the gastrointestinal digestion. The digestion often produces peptides with low MW and free amino acids, which are transported across the intestine wall [57]. Highly hydrolyzed proteins and peptides with low MW are not generally toxic and are known to be less allergenic than the native proteins and are widely used in the formulation of hypoallergenic infant foods [32]. However, toxic peptides have been identified from plant as well as animal origin, and they can result in acute, physiological effects, and death. Toxic peptides are usually rich in residues like Asn, Cysm His, and Pro, whereas nontoxic peptides contain dominantly residues Ala, Arg, Gln, Ile, Leu, Lys, Met, Phe, Thr, and Val. [53].

Altogether, the in silico assessment of toxicity is not enough, and in vivo studies in animal models should be carried out before human consumption. The in vivo assessment of the toxicity of food products must be carried out following the guidelines proposed by international authorities. Large quantities of scientific evidence and tests need to be carried out on vertebrate models and cell lines, or unicellular microbial species [47]. Multiple peptide toxicity studies have been carried out in animal models to date [12, 57].
