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Organosulfur compounds (OSCs) are secondary metabolites produced by different Allium species which present important biological activities such as antimicrobial, antioxidant, anti-inflammatory antidiabetic, anticarcinogenic, antispasmodic, etc. In recent years, their use has been promoted in the agri-food industry as a substitute for synthetic preservatives, increasing potential accumulative exposure to consumers. Before their application in the food industry, it is necessary to pass a safety assessment as specified by the European Food Safety Authority (EFSA). This work reviews the scientific literature on OSCs regarding their in vitro toxicity evaluation following PRISMA guidelines for systematic reviews. Four electronic research databases were searched (Web of Science, Scopus, Science Database and PubMed) and a total of 43 works were selected according to predeterminate inclusion and exclusion criteria. Different data items and the risk of bias for each study were included. Currently, there are very few in vitro studies focused on investigating the potential toxicity of OSCs. Most research studies aimed to evaluate the cytotoxicity of OSCs to elucidate their antiproliferative effects focusing on their therapeutic aspects using cancer cell lines as the main experimental model. The results showed that diallyl disulfide (DADS) is the compound most studied, followed by diallyl trisulfide (DATS), diallyl sulfide (DAS), Allicin and Ajoene. Only 4 studies have been performed specifically to explore the safety of OSCs for agri-food applications, and genotoxicity studies are limited. More toxicity studies of OSCs are necessary to ensure consumers safety and should mainly be focused on the evaluation of genotoxicity and long-term toxicity effects., Competing Interests: The authors declare no conflict of interest. The co-authors Dr. Alberto Baños and Dr. Enrique Guillamón affiliated to DMC Research Center declare that they have no conflict of interest.

Propyl-propanethiosulfinate (PTS) is a component of Allium essential oils. This organosulfur molecule can be used as a feed additive to decrease the appearance of bacterial resistances caused by the residues of antibiotics. In previous in vitro genotoxicity studies, contradictory results were reported for PTS. In this work, the in vivo genotoxicity of PTS in male and female rats was assessed for the first time, following OECD (Organisation for Economic Co-operation and Development) guidelines. After oral administration (doses: 5.5, 17.4, and 55.0 mg/kg PTS body weight), a combination of the micronucleus (MN) assay (OECD 474) in bone marrow and the standard and enzyme-modified comet assay (OECD 489) was performed. After necropsy, histopathological studies were also carried out. The results did not show the in vivo genotoxicity of PTS at any doses assayed, revealed by the absence of increased MN, and DNA strand breaks or oxidative DNA damage in the standard and enzyme-modified comet assays. The histopathological study revealed that only the highest dose tested (55.0 mg/kg) in the liver and all dose groups in the stomach presented minimal pathological lesions in the organs studied. Consequently, the present work confirms that PTS is not genotoxic at the doses assayed, and it is a promising natural alternative to synthetic preservatives and antibiotics in animal feed.

The application of stilbenes in the food industry is being considered because of their biological activities. Piceatannol, pterostilbene and ε-viniferin have awakened the industry's interest. However, before they can be commercialized, we must first guarantee their safety for consumers. The present work reviews the toxicological studies performed with these stilbenes. A wide variety of studies has demonstrated their cytotoxic effects in both cancer and non-cancerous cell lines. In contrast, although DNA damage was detected by some authors, in vitro genotoxic studies on the effects of piceatannol, pterostilbene, and ε-viniferin remain scarce. None of the three reviewed substances have been evaluated using the in vitro tests required by the European Food Safety Authority (EFSA) as the first step in genotoxicity testing. We did not find any study on the toxic effects of these stilbenes in vivo. Thus, more studies are needed to confirm their safe use before they can be authorized as additive in the food industry.

Genotoxic data of substances that could be used as food additives are required by the European Food Safety Authority. In this sense, the use of an extract from grapevine shoots containing a stilbene richness of 99% (ST-99), due to its antioxidant and antibacterial activities, has been proposed as an alternative to sulfur dioxide in wine. The aim of this work was to study, for the first time, the in vivo genotoxic effects produced in rats orally exposed to 90, 180, or 360 mg ST-99/kg body weight at 0, 24, and 45 h. The combination of micronucleus assay in bone marrow (OECD 474) and standard (OECD 489) and enzyme-modified comet assay was used to determine the genotoxicity on cells isolated from stomach, liver, and blood of exposed animals. The ST-99 revealed no in vivo genotoxicity. These results were corroborated by analytical studies that confirm the presence of stilbenes and their metabolites in plasma and tissues. Moreover, to complete these findings, a histopathological study was performed under light microscopy in liver and stomach showing only slight modifications in both organs at the highest concentration used. The present work confirms that this extract is not genotoxic presenting a good profile for its potential application as a preservative in the wine industry.