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Home , Potassium benzoate, Sodium ascorbate, Sorbic acid, Sulfite

Review Antioxidants versus Food Additives and Food

Rafael Franco 1,2,* , Gemma Navarro 2,3,* and Eva Martínez-Pinilla 4,5,6

1 Chemistry School, University of Barcelona, 08028 Barcelona, Spain 2 Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, 28031 Madrid, Spain 3 Department of Biochemistry and Physiology, Faculty of Pharmacy, University of Barcelona, 02028 Barcelona, Spain 4 Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain; [email protected] 5 Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33003 Oviedo, Spain 6 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain * Correspondence: [email protected] or [email protected] (R.F.); [email protected] (G.N.); Tel.: +34-934-021-208 (R.F.)  Received: 14 October 2019; Accepted: 5 November 2019; Published: 11 November 2019 

Abstract: Natural and processed foods are fragile and can become unpalatable and/or rotten. The processed food industry uses preservatives to enable distribution, even to different continents, and to extend the useful life of their products. Preservatives impede oxidation, a mandatory step in rotting, either by aerobic or anaerobic mechanisms. From a functional point of view, these compounds are antioxidants, and, therefore, a kind of contradiction exists when a is considered “bad” for human health while also thinking that antioxidants provide benefits. The basis of antioxidant action, the doses required for preservation, and the overall antioxidant action are revisited in this work. Finally, the bad and the good of food additives/preservatives are presented, taking into account the main mediator of antioxidant beneficial actions, namely the innate mechanisms of detoxification. Foods that strengthen such innate mechanisms are also presented.

Keywords: human safety; food rotting; food decay; food contamination; reaction; taste; sulfites

1. Introduction Approved food additives, denoted in Europe by an “E” followed by, at least, three numbers, are divided into different categories. Two of them are considered in this paper: “antioxidants” and “preservatives.” in the past mainly relied on cold temperatures (achieved using snow), chloride (), sugar (bioavailable sugars at a high concentration, as in honey or jam), spices (cumin or cinnamon) or vegetable oils, none of which cause the concern of users [1,2]. From the very beginning of the sale of processed foods in shops/markets, there has been controversy regarding whether food additives are harmful, i.e., whether they are detrimental for human health. The debate is on stage, and the message is, fortunately, that additives are needed and for good reasons, some of which are not of general knowledge. Additives in the amounts ingested by humans are safe or GRAS (generally recognized as safe) in the standard nomenclature [3]. This paper does not consider other additives such as pesticides that cannot be considered safe and that lack specific regulation on final-product labeling.

Antioxidants 2019, 8, 542; doi:10.3390/antiox8110542 www.mdpi.com/journal/antioxidants Antioxidants 2019, 8, 542 2 of 13

2. Preservatives Versus Antioxidants First of all, it is worth noting that there is no a clear border for a given drug being a preservative or antioxidant. The term preservative is more user-friendly and more direct, as any substance that prevents food rotting is immediately considered a preservative. A prototypical preservative is the enzyme lysozyme. On the one hand, it is found in egg whites but also in tears to avoid eye bacterial infection. On the other hand, it acts as bactericide because it cleaves the carbohydrates of wall(s). Another example is sorbic acid, or sorbates, which is efficacious because there are few microorganisms that can use it as a source of energy, thus preventing the starting of cell growth; accordingly, these compounds are kind of bacteriostatic [4,5]. The definition of an antioxidant is not so straightforward, as one can use a rigorous chemistry path, i.e., any substance that is a reductant and reacts with an oxidant, or a more lax definition such as one that may be found in the Britannica Encyclopedia: “Antioxidant: any of various chemical compounds added to certain foods, natural and synthetic rubbers, gasolines, and other substances to retard autoxidation, the process by which these substances combine with oxygen in the air at room temperature. Retarding autoxidation delays the appearance of such undesirable qualities as rancidity in foods, loss of elasticity in rubbers, and formation of gums in gasolines. Antioxidants most commonly used are such organic compounds as aromatic amines, phenols, and aminophenols.” In the former, the term is relative, as one given substance may be both oxidant or antioxidant depending on which is the “other” reacting molecule. This does not mean as any substance participating in a reduction–oxidation (REDOX) reaction has the so-called standard reduction potential (ε0), which can be calculated (see for [6–8] for pioneering studies on technical methods for ε0 calculation and [9] as a recent article on this subject). Nevertheless, as much as possible, we avoid to use ε and other markedly technical chemical terms in this paper. To summarize, in the food industry field preservatives are used to avoid rotting while antioxidants are used to prevent the chemical (oxidization) reactions leading to unpleasant taste and/or smell. From a strict chemistry view, in the list of preservatives and antioxidants displayed in Table1, there are pure antioxidants, pure preservatives, and compounds with mixed properties. Ascorbic acid () is a pure antioxidant, whereas sorbic acid (or sorbate salts) and (or benzoate salts) are pure preservatives. However, it is not completely clear why propyl gallate is considered an antioxidant or sodium sulfite is considered a preservative. Sulfites and bisulfites may be considered in vivo antioxidants: sulfites are oxidized to , and bisulfites, also in the preservative list, are oxidized to bisulfates [10]. In other words, their mode of action in food preservation is that of antioxidants. It is true that sulfites may be involved in other actions, one of them being the prevention of undesired enzymatic reactions in foods/beverages [10–12]. At this point, it is interesting to discuss toxicity data. In this sense, we argue that dosage must be considered and that not all antioxidants are innocuous, but food additives at the doses used can be considered safe. Surely, this data-based opinion can be extended to food preservatives. AntioxidantsAntioxidants 20192019,, 88,, xAntioxidantsx FORFOR PEERPEER 2019REVIEWREVIEW, 8, x FOR PEER REVIEW 33 ofof 1414 3 of 14 Antioxidants 2019, 8, xAntioxidants FOR PEER REVIEW2019, 8, x FOR PEER REVIEW 3 of 14 3 of 14 Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 3 of 14 3 of 14 AntioxidantsAntioxidants 20192019,, 88,, xxAntioxidants FORFOR PEERPEER 2019REVIEWREVIEW,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 33 ofof 1414 3 of 14 Antioxidants 2019, 8, 542 3 of 13 TableTable 1.1. FoodFood preservativespreservativesTable 1. Food andand antioxidants.preservativesantioxidants. and antioxidants. Table 1. Food preservativesTable 1. Food and antioxidants.preservatives and antioxidants. Table 1. Food preservativesTable 1. Food and antioxidants.preservatives and antioxidants. TableTable 1.1. FoodFood preservativespreservativesAntioxidantsAntioxidantsTable 1. Food andand antioxidants.preservativesantioxidants.Antioxidants and antioxidants. Table 1. Food preservativesAntioxidants and antioxidants.Antioxidants Antioxidants Antioxidants AscAsc Asc Antioxidants Antioxidants Ascorbi orbiAsc E3AntioxidantsPropyl E3 Propyl E300 orbiAscE300 orbiAsc E3 Propyl E3 Propyl E300 orbiAscAscc E300 orbiAscc E310 Propylgallate E310 gallatePropyl E300 orbic E300 orbic 10E3 gallatePropyl E310 gallatePropyl E300 orbiacidorbic E300 acidorbic E310E3 gallatePropylPropyl E310 Propylgallate E300 AscorbicE300E300 acid acidc E300 acidc 10 E310gallate 10 Propyl gallate gallate acidcc acidc 1010 gallategallate 10 gallate acid acid acidacid Sodiacid SodiSodi Sodi Sodium Sodium Sodium Sodium E3 Erythorb E3 Erythorb E301 SodiSodiascoumE301 Sodiascoum E3 Erythorb E3 Erythorb E301 ascoumE301 ascoum E315 Erythorbic acid E315 Erythorbic acid E301 ascorbatumumE301 ascorbatum 15E3 Erythorbic acid E315 Erythorbic acid E301 ascorbatE301 ascorbat E315E3 ErythorbErythorbic acid E315 Erythorbic acid E301 SodiumE301E301 ascorbateascorbatascoe E301 ascorbate 15 E315ic acid 15 Erythorbic ic acid acid rbate rbate 1515 icic acidacid 15 icic acidacid rbatrbate rbate e Calce CalcCalcee Calce Calcium Calcium Sodium Sodium Calcium Calcium E3 Sodium E3 Sodium E302 CalcCalcascoiumE302 Calcascoium E3 erythorbSodium E3 erythorbSodium E302 ascoiumE302 ascoium E316 erythorbSodium E316 erythorbSodium E302 ascoiumrbatiumE302 ascorbatiumium 16E3 erythorbSodiumSodiumate E316 erythorbSodiumate E302 ascorbatE302 ascorbat E316E3 erythorbate E316 erythorbate E302 CalciumE302E302 ascorbateascorbatascoe E302 ascorbate 16 E316erythorberythorbate Sodium16 erythorbateerythorbate rbate rbate 1616 ate 16 ate rbatrbate rbate ateate ate Fatt Fatt Fatte Fatte Fattey Fatty Fatty Fatty Tertiary- Tertiary- FattacidFatty acidFatty Tertiary- Tertiary- acidy acidy Tertiary-butyl Tertiary-butyl acidesteyy acidestey E3 Tertiary-butyl E3 Tertiary-butyl E304 esteacidE304 acideste E3 Tertiary-hydroquiTertiary-butyl E3 hydroquiTertiary-butyl FattyE304 acid esters ofacidrsesteacid ofE304 rsacideste of E319 hydroquibutyl E319Tertiary-butyl hydroquibutyl E304 E304 rseste ofE304 rseste of 19E3 E319hydroquibutylbutylnone E319 hydroquibutylnone E304ascorbic acid rsascoesteeste ofE304 rsascoeste of E319E3 hydroquinone hydroquinoneE319 hydroquinone (TBHQ) E304E304 ascors ofE304 rsasco of 19 hydroquihydroqui(TBHQ)none 19 hydroqui(TBHQ)none rsascorsrbic ofof rsascorbic of 1919 (TBHQ)none 19 (TBHQ)none ascorbic ascorbic (TBHQ)nonenone (TBHQ)none ascorbicascoacid ascoacidrbic (TBHQ) (TBHQ) acidrbic acidrbic (TBHQ)(TBHQ) (TBHQ) acidrbicrbic acidrbic Butylate Butylate acidToc acidToc Butylate Butylate acidTocacid acidToc Butylated Butylated Tocoph ophToc E3 Butylated E3 Butylated E306 ophTocE306 ophToc E3 ButylateButylatehydroxyd ButylatedE3 hydroxyanisoleButylatehydroxyd E306E306 Tocopherols TocopherolTocE306 erolTocoph E320 E320hydroxyd E320 hydroxyd E306 erolophE306 eroloph 20E3 hydroxyanisole dd E320 (BHA)hydroxyanisoled E306 erolophophs E306 erolophs E320E3 hydroxyanisole E320 hydroxyanisole E306E306 erols E306 erols 20 hydroxyhydroxyanisole(BHA) 20 hydroxyanisole(BHA) erolerols erols 2020 (BHA)anisole 20 anisole(BHA) Alps Alps Butylateanisole(BHA)anisole Butylateanisole(BHA) Alpss Alps Butylate(BHA) Butylate(BHA) Alpha- Alpha- Butylate(BHA)(BHA)d Butylate(BHA)d Alpha- Alpha- E3 Butylated E3 Butylated E307 tocoAlpha-AlpE307 tocoAlpha- E3 hydroxytButylateButylated ButylatedE3 hydroxytoluenehydroxytButylated E307 Alpha-tocopherolE307 tocoha-E307 tocoha- E321 E321hydroxytd E321 hydroxytd E307 tocopherha-ha-E307 phertocoha- 21E3 hydroxytoluene dd E321 (BHT)hydroxytoluened E307 phertocoE307 phertoco E321E3 hydroxytoluene E321 hydroxytoluene E307E307 phertocotocool E307 phertocotocool 21 hydroxythydroxytoluene(BHT) 21 hydroxyt(BHT)oluene pherol pherol 2121 (BHT)oluene 21 (BHT)oluene pherpherol pherol (BHT)olueneoluene oluene(BHT) ol ol (BHT) (BHT) olol ol (BHT)(BHT) (BHT) Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 14 4 of 14 Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 4 of 14 4 of 14 Ga Ga Antioxidants 2019, 8,Antioxidants x FOR PEER 2019 REVIEW, 8, x FOR PEER REVIEW 4 of 14 4 of 14 Antioxidants 2019, 8, 542 mmGa mmGa Extracts Extracts 4 of 13 Antioxidants 2019, 8, Antioxidantsx FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 4 of 14 4 of 14 mma- mma- E3 Extractsof E3 Extractsof E308 GaE308 Ga Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEWtoco, 8a-, x FOR PEER REVIEWtocotocoa- E392 rosemarof E392 rosemarof 4 of 14 4 of 14 E308 mmGaE308 mmGa Extracts Extracts tocopher phertoco 92Table rosemar 1. Conty . 92 rosemary Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW,mm a-8, x FOR PEER REVIEWmma- E3 Extracts of E3 Extractsof 4 of 14 4 of 14 E308 pherGaolE308 pherGaol y y tocoa- tocoa- 92E3 rosemarof 92E3 rosemarof E308 Deltmmol E308 Deltmmol AntioxidantsExtracts Extracts phertocoGa phertocoGa 92 rosemary 92 rosemary Delta- Delta- E3 of4- E3 of4- E308 phermmol E308 phermmol E5 Extractsy E5 Extractsy E309 tocoa-E309 tocotocoa- 92 Hexylresrosemar4- 92 Hexylresrosemar4- Delta-ol Deltola- E5E386 of E5E386 of E308 Gamma-tocopherolE309E308 tocopherE309E308 phertoco E392Hexylresorcinol y ExtractsHexylres oforcinol rosemaryy tocoDelta- Delttocoa- 8692 rosemar4- 8692 rosemar4- pherol pherol E5 orcinol E5 orcinol E309 tocophera-E309 tocophera- Hexylres4-y Hexylres4-y Deltol Deltol Preservatives86E5 Preservatives86E5 E309 phertocool E309 phertocool PreservativesHexylresorcinol PreservativesHexylresorcinol a- 4- 86 Delt Delta- PreservativesE586 Potassiu PreservativesPotassiu4- E309 tocopherSorol pherSorol HexylresPotassiuorcinol E5 Potassiuorcinol E309 Delta-tocopherol Sora-E309 tocoSora- E286 E5864-m 4-HexylresorcinolE2 Hexylresm4- E200 bicolE200 bicol PreservativesE2 Potassiu m PreservativesE586E2 E200 pherSorbicE309E200 phertocoSorbic E5 orcinol 28 Hexylreshydrogeorcinol E309 toco E228 Hexylreshydrogem PreservativesE228 hydrogem E200 acidbicol E200 acidbicol Preservatives86Preservatives Potassiu 86 Potassiu pherSor Sorpher 28 hydrogenorcinol sulfite 28 nhydrogeorcinol sulfite acid acid PreservativesE2 Potassium E2 Potassium E200 SorbicolE200 bicSorol n sulfite Preservativesn sulfite 28E2 hydrogem 28E2 hydrogem E200E200 Sorbic acid acidbicE200 acidbic E228Potassiu PotassiumPreservatives hydrogenPotassiu sulfite Sor Pota Preservatives28 nhydroge sulfite 28 nhydroge sulfite Pota PotaacidSor E2 m E200 acidbic Potassiu E2 Potassium PotassiuE200 PotassiuSorbic 28 hydrogen sulfite n sulfite Sor E2 a E228 hydrogea E202 acidm E202 acidm E2 Nisinm a E2 Nisinm a E202E200 ssiubicm E200E202 ssiubicm 34 nNisin sulfite 34 nNisin sulfite Pota Pota E23428 hydrogea E22834 hydroge E202 sorbm E202 sorbacidm Nisin Nisina Potaacidssiu ssiuPota 34 34 n sulfite sorbate sorbate E2 n sulfite E2 E202 PotassiumE202 sorbatessiumE202 ssium E234 Nisina NisinNisina a Potaate Potaate 34E2 34E2 E202 sorbm E202 sorbm Nisina Nisina ssiu 34 34 Pota Potasorbatessiu E2 sorbate a E2 a E202 m E202 ssium Nisin Nisin ssiuate ate 34 E234 sorbBen sorbBen E2 a a E202 m E202 m E2 NatamycNisin E2 NatamycNisin E210 BenzoicateE210 zoicBenate 34 34 sorb sorb E235 E235 Natamycinin E210 zoicacidE210 acidzoic E210 Benzoic acid Benate Benate 35 E235in 35 Natamycin in acid acid E2 Natamyc E2 Natamyc E210 zoicBenE210 zoicBen 35E2 Natamycin 35E2 Natamycin E210 SodiacidzoicE210 acidSodizoic Ben Ben 35 Hexametin 35 Hexametin Sodiacidum Sodiacidum E2 Natamyc E2 Natamyc E210 zoicE210 zoicBen E2 Hexamethylene E2 Hexamethylene E211 BenbenumE211 benum 35 in E235 Natamycin E211 Sodium benzoateSodiacidE210 Sodiacidzoic E239 E239Natamyctetraminhylene Hexamethylene E239 tetramintetraminhylene tetramine E211E210 zoatzoicbenE211 zoatben Hexamet 35 Hexametin Sodium Sodiumacid 3935 tetraminine 39 tetramine zoatacide zoate E2 Hexamethylene E2 Hexamethylene E211 benumE211 benum e e Sodie Sodie 39E2 tetraminhylene 39E2 tetraminhylene E211 PotazoatbenE211 zoatPotaben HexametDimethy HexametDimethy um um 39 tetramine 39 tetramine PotaSodizoatssiue SodiPotazoatssiue E2 Dimethyhylenel E2 Dimethyhylenell E212 PotassiumE212E211 benzoatebenE211E212 ben E242Hexamete DimethylHexamet dicarbonatee ssiuumme ssiuumme E24239 dicarbontetraminl E23942 dicarbontetraminl E212 PotazoatE212 Potazoat E2 Dimethyhylene E2 Dimethyhylene E211 benm E211 benm 42 dicarbonatee 42 dicarbonatee Potassiue ssiuPotae E239 Dimethytetraminl E239 Dimethytetraminl E212 zoatbenE212 zoatben ate ate ssium ssium 42E2 dicarbonel 42E2 dicarbonel E212 Potae E212 Potae Dimethy Dimethy ssiubenm benm E242 dicarbonatel 42 dicarbonate E212 Pota Potassiu Dimethy E2 Dimethyl benm E212 ben 42 dicarbonate ate ssiu ssium E2 l E242 dicarbonl E212 benE212 ate m benm 42 dicarbon 42 dicarbonate ben ben ate ate Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 5 of 14 5 of 14

Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW,zoat 8, x FOR PEER REVIEWzoat 5 of 14 5 of 14 e e zoat zoat Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEWCalc, 8e, x FOR PEER REVIEWCalce 5 of 14 5 of 14 ium ium Ethyl Ethyl Calc E2 E2 E213 zoatbenE213 Calczoatben lauroyl lauroyl ium ium 43 Ethyl 43 Ethyl AntioxidantsAntioxidants 20192019, 8,, 8x,Antioxidants FOR 542 PEER REVIEW2019zoat, 8e, x FOR PEER REVIEWzoate E2 arginate E2 arginate 5 of5 of14 13 5 of 14 E213 benE213 ben lauroyl lauroyl Calce e 43 43 Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEWzoat, 8, x FOR PEER REVIEWCalczoatzoat arginate arginate 5 of 14 5 of 14 iumEth iumEth Ethyl Ethyl e ee E2Table 1. Cont. E2 E213 zoatbenyl E213 zoatbenyl lauroyl lauroyl Eth Eth 43 43 Calczoatpe- zoatCalcpe- arginate arginate yl Preservatives hydriume hydriumyle E2 PotassiuEthyl E2 PotassiuEthyl E214 CalcE214 Calc E2 E2 E213 benoxyp- E213 oxybenp- 49 mlauroyl 49 mlauroyl nitrite iumEth iumEth 43 Ethyl 43 Ethyl hydrzoatben hydrbenzoat E2 Potassiuarginate E2E2 Potassiuarginate E213 CalciumE213E214 benzoatebenyl E214E213 benyl E243 lauroyl Ethyl lauroyllauroyl arginate zoatoxye oxyzoate 4349 m nitrite 4943 m nitrite zoatbenp- benzoatp- arginate arginate hydrEthe Ethe E2 Potassiu E214 zoate hydrzoate E2 Potassiu Sodioxyyl E214 Sodiyl 49 m nitrite Ethe oxyEthe 49 m nitrite benump- ump- Sodiyl Sodibenyl Ethyl hydrzoatethy ethyhydr E2 Potassiu E2 Potassiu E214 E214 ump- E214 zoatump- E249 Potassium nitrite p-hydroxybenzoateoxyl ep - loxy p- 49 m nitrite 49 m nitrite hydrethy ethyhydre E2 PotassiuSodium E2 PotassiuSodium E214E215 SodihydrbenE215E214 hydrben oxyl p- Sodiloxy p- 4950 mnitrite nitrite 5049 mnitrite nitrite zoatoxyum oxyzoat E2 Sodium E2 Sodium E215 hydrbenE215 hydrbenum ethybene bene 50 nitrite 50 nitrite zoatoxy ethyoxyzoat Sodizoatl p- zoatSodil p- Sodium ethyl bene bene E2 Sodium E2 Sodium E215 E215 hydrume E215 hydrum E250 p-hydroxybenzoateSodizoat zoatSodi 50 nitrite ethyoxyMet Metethy 50 nitrite ume oxyume benlhyl p- hyll p- ethyMet Metethyben E2 Sodium E2 Sodium E215 hydrzoatp- E215 hydrp- lhyl p- zoathyll p- 50 nitrite 50 nitrite hydroxye hydroxy E2 Sodium E2 Sodium E215E218 hydrp-E218E215 hydrpe- Metbenoxy oxyben 5051 nitritenitrate 5150 nitratenitrite Methyl hydroxy hydrMetoxy E2 Sodium E2 Sodium E218 E218 zoatbenhylE218 benzoat E251 Sodium nitrate p-hydroxybenzoateoxyben oxybenhyl 51 nitrate 51 nitrate zoatpe- zoate zoatben benzoatp- hydrMete Mete E2 Sodium E218 zoate hydrzoate E2 Sodium SodioxyhylE218 Sodihyl 51 nitrate Mete oxyMete 51 nitrate benump- ump- Antioxidants 2019,, 8,, xxAntioxidants FORFOR PEERPEER 2019REVIEWREVIEWSodi,hyl 8, x FOR PEER REVIEWSodibenhyl 6 of 14 6 of 14 Antioxidants 2019hydrzoat,met 8, x FOR PEER REVIEWhydrmet E2 Sodium E2 Sodium 6 of 14 SodiumE218 methyl ump- E218 zoatump- E2 Potassiu E2 Potassiu E219 E219 oxyhyle E219 hyloxy 51 E252nitrate Potassium51 nitrate nitrate p-hydroxybenzoatehydrmetben hydrmetbene E252 mSodium nitrate E252 mSodium nitrate E218 Sodibenp-E218 benbenp- E2 Potassiu E2 Potassiu E219 zoatoxyhylE219 Sodizoathyloxy 51 nitrate 51 nitrate hydrzoatum hydrzoatzoat 52 m nitrate 52 m nitrate benpe- benumpe- metoxye oxyee hydrSulpzoat hydrSulpzoatmet E2 Potassiu E219 SodiSulphyl SulpSodi E2 Potassiu oxyhure E219 oxyhylhure E252 mPropioni nitrate E2 Propioni E220 ump- E220 hurum 52E2 mPropioni nitrate E220 Sulphur dioxideSodidioxE220 Sodidioxp- 80 E280 c acid 80 Propionic c acid acid hydrmet dioxmet 80 c acid umideide hydrumide E2 Potassiu E2 Potassiu E219 oxyhyl E219 oxyidehyl Sodimet Sodimet 52 m nitrate 52 m nitrate Sodip- Sodip- E2 PotassiuSodium E2 PotassiuSodium E219 hylumE219 hylum E2 Sodium E2 Sodium E221 SodiumE221 sulfite hydrumE221 hydrum 52E2 E281mpropiona nitrate SodiumE252 mpropiona propionate nitrate E221 sulfip- E221 sulfip- 81 propiona 81 propiona sulfioxy sulfioxy 81 te 81 te hydr hydrte te te tete te oxy Sodioxy Sodi Sodi um um um hydr hydr Calcium Calcium hydr hydr E2 Calcium E2 Calcium E222 ogeE222 oge E2 propiona E2 propiona E222 ogeE222 oge 82 propiona 82 propiona n 82 82 te n n tete te sulfi sulfi sulfi te tete te Sodi Sodi Sodi um Potassiu um um Potassiu Potassiu met met E2 m E2 m E223 metE223 met E2 m E2 m E223 E223 abis 83 propiona abis abis 83 propiona 83 propiona ulfit te ulfit ulfit tete te e e e Pota Pota Pota ssiu ssiu ssiu m m m m E2 Boric E2 Boric E224 metE224 met E2 Boric E2 Boric E224 metE224 met 84 acid 84 acid abis 84 acid 84 acid abis abis ulfit ulfit ulfit e e e Calc Calc Calc Calc Sodium Sodium ium ium E2 Sodium E2 Sodium E226 iumE226 ium E2 tetrabora E2 tetrabora E226 sulfiE226 sulfi 85 tetrabora 85 tetrabora sulfi sulfi 85 te; borax 85 te; borax te te te; borax te; borax te te Calc Calc Lysozym Lysozym Calc Calc E1 Lysozym E1 Lysozym ium ium E1 e (N- E1 e (N- E227 iumE227 ium 10 e (N- 10 e (N- Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons E227 hydrE227 hydr 10 acetylmu 10 acetylmu Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons hydr hydr 5 acetylmu 5 acetylmu oge 5 5 ramide oge oge ramide ramide Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 6 of 14 6 of 14 Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEW, 8, x FOR PEER REVIEW 6 of 14 6 of 14 ben ben Antioxidants 2019, 8, xAntioxidants FOR PEER 2019REVIEWzoat,ben 8, x FOR PEER REVIEWzoatben 6 of 14 6 of 14 zoate zoate Antioxidants 2019, 8, xAntioxidants FOR PEER REVIEW2019Sulpben, 8e, x FOR PEER REVIEWSulpbene 6 of 14 6 of 14 Sulpzoathur Sulpzoathur E2 Propioni E2 Propioni E220 E220 E220 dioxbenhure hurbene E280 Propionic acid E2 Propioni E220 dioxE220 diox 80 c acid 80 c acid dioxSulpzoatide Sulpdioxzoatide 80 c acid 80 c acid idee Sodihur Sodihuridee E2 Propioni E2 Propioni E220 E220 Sodium Sodium SodiSulpdioxum dioxSodiSulpum E280 c acid 80E2 c acid E221 E221 propionaSodium propionaSodium sulfihurumide sulfiideumhur E281 Propioni E281 Propioni E221E220 sulfiE221E220 81 propionate propiona sulfidioxSodite Sodisulfidiox 8180 c acidte 8180 c acidte te te Sodiumte Sodiumte ideumte umidete E2 E2 Antioxidants 2019, 8E221, 542 SodiE221 Sodi propiona propiona 6 of 13 Sodisulfium sulfiSodi 81 81 um um Sodiumte Sodiumte hydrumte hydrumte E2 Calcium E2 Calcium E221 E221 E2 propiona E2 propiona E222 hydrsulfiSodiogeE222 Sodihydrsulfioge 81 propionaCalcium 81 propionaCalcium E222 oge E282Table propiona 1. Contte . E2 te E222 ogeumten E222 ogeumte 82 propionate 82 propiona n n 82 te 82 te Sodihydrsulfin hydrn Calciumte Calciumte sulfi sulfiSodi E2Preservatives E2 E222 sulfiogeumte E222 sulfioge propiona propiona te umte 82 82 hydrSoditen Sodihydrten Calciumte Calciumte Sodium hydrogen E2 E2 E222 E222 SodisulfiogeumE222 sulfiSodiogeum E282propionaPotassiu CalciumpropionaPotassiu propionate sulfite 82 82 metumten metumten E2 Potassiutem E2 Potassiumte E223 E223 sulfiSodiabismet Sodisulfiabismet E283 propionam E283 propionam E223 E223 abisulfitumte ulfitabisumte 83 propionaPotassiute 83 propionaPotassiute Sodiulfitmete ulfitSodimete E2 tem E2 mte E223 SodiumE223 metabisulfite E223 E283 Potassium propionate Potaabisume Potaabisume 83 propionaPotassiu 83 propionaPotassiu Potaulfitmetssiu Potaulfitssiumet E2 mte E2 tem E223 E223 abisssiume ssiuabisme 83 propiona 83 propiona E2 Boric E2 Boric E224 Potaulfitmetm E224 Potaulfitmetm te te Potassium E284 Boricacid E284 Boricacid E224 E224 abisssiumete E224 ssiuabismete E284 Boric acid metabisulfite 84 acid 84 acid Potaabisulfitm abism ulfit ulfitPota E2 Boric E2 Boric E224 ulfitssiumete E224 ulfitmet e ssiue 84 acid 84 acid Calcabisme Calcabisme E2 SodiumBoric E2 SodiumBoric E224 CalculfitmetiumE224 Calculfitiummet E2 E2 E226 CalciumE226 sulfite E226 84 E285tetraboraSodiumacid Sodium 84 tetraborate;tetraboraSodiumacid borax sulfiabisiume sulfiiumabise E285 E285 E226 E226 tetraborate; borax tetrabora sulfiCalculfitte Calcsulfiulfit 85 te; borax 85 te; borax te te te;Sodium borax te;Sodium borax Calciumtee Calciumtee E2 Lysozym E2 Lysozym E226 E226 E1 tetrabora E1Lysozymetetrabora Calcium hydrogenCalcsulfiium sulfiCalcium 85 Lysozyme (N- 85 Lysozyme (N- E227 E227 E110 te;Sodium borax NE110 te;Sodium borax Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons E227 E227 hydriumte iumiumte E210E1105 acetylmue (N- ( E2-acetylmuramidee (N- Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons E227E226sulfite hydrE227E226 hydr 105 tetraboraacetylmu 10 acetylmutetrabora Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons hydrsulfiCalcoge Calchydrsulfi 855 Lysozymacetylmuramide glycanhydrolase)855 Lysozymacetylmu oge oge E15 te;ramide borax E15 te;ramide borax iumogete iumogete a Nomenclature of Liu andramidee (N Hansen,- 1990 [13ramide].e (N- E227 E227 10 10 Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons Calchydr hydrCalc Lysozymacetylmu acetylmuLysozym E15 E15 iumoge ogeium ramidee (N- ramidee (N- E227 E227 10 10 Enzyme de 14 kilodaltonsEnzyme de 14 kilodaltons hydr hydr acetylmu acetylmu 5 5 oge oge ramide ramide Antioxidants 2019, 8, 542 7 of 13

The toxicity of compounds in Table1 is fairly low. An example retrieved from the Toxnet platform in October, 2019 [14] showed that 4.9 g/kg is the 50% per oral lethal dose (LD50) of in rodents. As seen on fcsimage [15], also in October, 2019, the LD50 value for the allegedly dangerous ethylene glycol is 4.4 g/kg in rats and 100 mL of pure compound in humans. Overall, these data indicate that the additives in Table1 should be considered generally safe at the doses found in final food products. Exceptions may occur in the case of poor control quality or in cases of acute exposure such as that reported for dioxide (see below). We have experience in preservatives safety; a pre-graduate student in her last academic year fainted after ingesting a tiny amount of a sodium azide-diluted solution, which is used to prevent bacterial growth in biomolecule-containing preparations. After investigating our first hypothesis regarding possible poisoning, we found out that toxicity of sodium azide for mammals is low and that this compound has been reported as a potential antihypertensive drug [16,17]. In summary, the amount taken in a meal is too low to consider that food preservatives/antioxidant additives are dangerous in the short or long run. Similarly, there is a consensus regarding the health benefits of moderate consumption despite that the fact that wine contains sulfites. What is more toxic in wine, sulfites or alcohol? In moderate amounts, both are safe; however, putting aside the potential addictive effect of , excess wine consumption may lead to cirrhosis due to ethanol, but no serious detrimental effect has been attributed to sulfites [18,19]. Long-term scientific experience with sulfite-containing wine has shown that prejudices regarding wine come from ethanol and may come from pesticides in grapes but not from approved wine additives.

3. Precautions with Preservatives and Antioxidant Food Additives One of the main issues surrounding food additives is the lack of information about their contents in a given product. Therefore, the safety of food additives has been assumed in a semi-blind basis, i.e., knowing the chemical structure but lacking the concentration in the final product and/or in the final meal/beverage [3]. As a first example, we may consider that sulfites lead to the degradation of vitamin B1 (thiamine), which is an adverse effect; obviously, this can be conveniently addressed if enough vitamin B1 is taken in the diet or as a dietary supplement (see [20]). Sulfite, and metabisulfite additives have been quantified in the food of a Korean population for which the “acceptable daily intake” (ADI) was assessed. The authors of that study concluded that “The overall exposure to antioxidants and color fixatives in foods did not exceed the ADI. We estimated exposure to be within safe levels for all population groups” [21]. For its part, can be dangerous depending on the dose, and there is a situation that illustrates the precautions needed for some additives and/or in some circumstances. It is known that the compound irritates the respiratory tract, and it is, thus doubtful that it may cause harm unless inhaled. However, a closer look has indicated that it may cause serious problems to certain individuals, such as those suffering from asthma. To our knowledge, the first reported case of such a reaction was due to dried fruits treated with the gas and distributed in a tightly sealed package. The sulfur dioxide coming out from the bag, when opened, was enough to produce acute episodes in an asthma patient; authors reported: “coughing, shortness of breath, expiratory wheezes and rhonchi” [22]. The allergenic effect of sulfur dioxide can be likely ruled out, but we cannot rule out the irritant properties that could not affect healthy subjects but could affect patients with respiratory diseases. In spite of this, it must be highlighted that, being a gas, the side effects of sulfur dioxide can be minimized if the food is aerated (or heated in open pans) before consumption ([22] and face-to-face comment by Paul F. Wehrle). Another example of precaution advice is related to sodium metabisulfite (labeled as E223; Table1), or other additives in shrimps, prawns or similar animals (even if directly frozen). The “head” of prawns quickly becomes dark (browning) due to polyphenol oxidase-induced melanosis [23,24], and producers know that consumers prefer that these crustaceans keep the red color. Though sucking fresh crustaceans is pleasant to many and safe, if the product has been hypothetically treated with unknown quantities of additives, such as sodium metabisulfite, a similar action could be neither tasty Antioxidants 2019, 8, 542 8 of 13 nor completely safe (if the dose is high or a high number of pieces are consumed). An advice in cases in which plenty of prawns are going to be cooked and consumed is to remove the “head,” which retains more chemicals than the rest of the body. A possible alternative is the use of resorcinol derivatives that may have equal benefits in crustaceans but cause less concern than bisulfites [25]. In the last two years in Spanish shops, we have noticed a change in the way fresh tuna fish is sold. Years ago, tuna fish was red when fresh and became brown (oxidized, starting by the surface) with time. By looking at the color after cutting a steak, one may figure out how fresh it is. Additionally, the shops got rid of fresh tuna fish quickly, i.e., the same day. Nowadays, tuna is stored in a plastic wrap and keeps its reddish color for days. It seems that this product has been treated with an antioxidant that, at present, is not labeled. The quantity of additives to keep the red color may be quite high, and, again, no quality control may be performed (or, if performed, may not be in compliance with good laboratory practices). In parallel, we have noticed that the label of the packs of “fresh” fish products is not entirely clear. Apart from altering the taste of the real food, procedures that are not well controlled do not guarantee safety even if a generally safe additive is used (we mean that the concentration is surely quite high and the additive is going to be ingested in full with the food). In our own experience with sausages that have not been cooked but have been cured using additives, it seems that producer (small producer usually) uses an excess of the additive in some cases. This situation, which may be due to lack of appropriate quality control, can be detected when the taste buds notice roughness and/or dryness upon sausage biting. Not long ago, a well-known and successful Spanish brand of dairy products publicized the benefits of its new yogurts by stating that they were 100% natural and free from “artificial” additives. However, this advertising campaign caused a great debate in the public opinion, since it was discovered that their products contained E960 (steviol glycosides) whose extraction from Stevia rebaudiana is performed in a laboratory using solvents and exchange resins that, in other countries, do not allow for labeling as a “natural ingredient” [26]. Moreover, the specific product, a yogurt, also contained E162 (beetroot red), a colorant of natural origin but denoted in the label as a betanin pigment, for which no adequate toxicity studies were available. The brand was forced to rectify the labeling days later, but they claimed that their additives were natural while those of other brands were not [27]. This is one of the many examples of considering a natural product better than a non-natural one. In summary, despite the fact that the general population prefers “natural” compounds/additives, in food and in other fields, natural versus non-natural is not a convenient approach to distinguish between friend and foe. Proper discussion and convenient examples are provided in the book by Collman [28], whose subtitle is “Surprising facts about food, health and environment;” the author shows that not all products made by nature are safe, nor are man-made products unsafe. Additionally, one must be aware when noticing something looking bizarre via taste or smell senses, or when a lot of processed food is being consumed in a unique intake: the “dose” matters.

4. Antioxidants: Beneficial or Detrimental for Human Health This section deals with the interesting debate that de facto exists between the defendants of the goodness of antioxidants and the persons worried by antioxidants as food additives. From a strict point of view, there are no good and bad antioxidants; actually, it is not convenient to raise a debate in terms of good and bad substances. Often, we use water as an example of something that is neither good nor bad. It is needed for life on Earth, but one must use it correctly; pure water usage has the same deadly consequences as using sea water. Water must be consumed with the right concentration of water itself and with the right composition and concentration of salts. Another example of the “danger” of water was reported in Legends website ([29], as quoted in [28]) in which the statement “Accidental inhalation can kill you” together with other complementary information led 43 out of 50 recipients to be convinced that the substance (water) should be banned. Analogously, the interest of the academic researchers and/or entrepreneurs in placing the focus in the health benefits of any antioxidant makes little sense. On the one hand, “antioxidant” is a relative term that depends on the reaction with a reductant. If we go to an extreme, some of the most potent antioxidants, even in vivo, Antioxidants 2019, 8, 542 9 of 13

are those containing sulfhydryl (—SH) groups. Accordingly, one could assume that SH2 (hydrogen sulfide), which is an antioxidant, may provide benefits. However, SH2 is one of the most toxic gases, more toxic than a more well-known chemical: hydrogen cyanide (liquid but with very poisonous vapors; its boiling point is <30◦). On the other hand, any antioxidant action measured in vitro or very indirectly in vivo may not have physiological relevance, either by lack of appropriate reductant or by a kinetic issue, e.g. slow reaction. The described variety of methods for testing antioxidant power (see [30] for details) faces the wall that antioxidant power is a constant in standard conditions (reduction potential; ε0) and, unfortunately, none (it may be some exceptions) of the methods now used take this fact into account. In addition, usually REDOX reactions take place mole by mole (eventually with 1:2 or 2:1 stoichiometry); therefore, no antioxidant could prevent the number of oxidants that are produced in a human body. It should be noted that a good proposal to determine overall REDOX status has not been yet considered in a routine basis. This method consists of measuring the ratio of oxidized versus reduced coenzyme Q, i.e., of ubiquinone versus ubiquinol, in plasma [31,32]. Surely, such an in vivo measured ratio will be more appropriate than measuring the total level of the “antioxidant;” in addition, an increased oxidized versus reduced status would indicate whether the compound is really behaving as in vivo antioxidant or not. Once more, the belief that natural substances—food additives in the context of this paper—are “better” than synthetic molecules has not been substantiated by scientific data [28]. Natural polyphenols may be beneficial or detrimental, i.e., they may be good or bad [33,34]. The reasons for this are basically those provided in the previous paragraph, but a further detail is as follows: there is no risk at the concentrations present in food. In other words, to assume that all polyphenols have health benefits because they act as antioxidants in vitro is not a solid reason to sell them as supplements with health benefits [34,35]. Taken together, this debate leads to the conclusion that the antioxidants that are used as food additives do not pose any risk to the health at the concentrations approved/suggested. All of the antioxidant food additives, whose nomenclature in Europe is E plus a number (EXXX), have been carefully studied to conclude that, at the right, doses they are GRAS. We would like to further highlight a theme whose relevance has not yet been generally accepted. We refer to the need to boost the innate mechanisms of defense in mammals. This consists of fueling, for instance, the mechanism that keeps Fe2+ in hemoglobin; if the ion is oxidized to Fe3+, the resulting molecule, methemoglobin, is unable to bind (and transport) oxygen. The Fe3+/Fe2+ reduction mechanism operating in the erythrocyte does not rely in antioxidant supplements. It is well known and consists of cycles of oxidized/reduced glutathione (a cysteine-SH-containing tripeptide) that needs reduced nicotinamide adenine dinucleotide phosphate (NADPH), produced from the reducing power in and glucose-6-phosphate dehydrogenase. Hemolytic anemia is a well-known inherited disease due to the reduced expression/activity of glucose-6-phosphate dehydrogenase [36,37]. We argued in a previous paper that substances from foods, from additives or from supplements, that fuel those innate mechanisms are real antioxidants [35]. Obviously, not all in vitro antioxidants are able to afford direct actions on innate detoxification mechanisms. There is an additional aspect to consider that is whether the opposite to an antioxidant, i.e., an oxidant or a pro-oxidant, may be of benefit. The answer is “yes.” Some foods, the most known being fava beans, contain pro-oxidants that serve to keep the antioxidants functional and keep their mechanisms ready for operating in the erythrocyte. Vicine and convicine are the key compounds that lead to hemolysis in the absence of the enzyme [38]. By the same token, additives that are considered “less good” may provide significant benefits if they contribute to keeping the innate antioxidant/detoxification mechanisms alive and ready, i.e., with all the components at adequate levels of expression. Regarding sulfite-containing food additives, it has been shown that these substances “are relatively harmless because animals have efficient detoxication systems that oxidize sulfite to ” [11,12,39]. It is therefore tempting to speculate that sulfites in wine and in other foods serve to keep the human body ready to cope with some of the environmental factors impacting human life. An introduction to these so-called hormetic mechanisms and references to first reports on hormesis Antioxidants 2019, 8, x FOR PEER REVIEW 11 of 14

155 on hormesis can be found elsewhere [34,35,41,42]. It is worth mentioning that genes, whose products 156 alter their expression level depending on environmental factors, are known as vitagenes [43]. Antioxidants 2019, 8, 542 10 of 13 157 5. Future Prospects on Health Concerns Due to Food Additives 158 Preservatives and antioxidant food additives are safe if used with caution and follow the can be found elsewhere [33,34,40,41]. It is worth mentioning that genes, whose products alter their 159 approved rules. It is, however, important to know whether these compounds can have direct benefits expression level depending on environmental factors, are known as vitagenes [42]. 160 on the human body and do not only preserve foods from oxidation or rotting. We think that the 1615. Futurepathways Prospects by which on Health sulfites Concerns are metabolized Due to Foodand eliminated Additives should be characterized while looking 162 into their possible benefits, i.e., whether the human body is readier to cope with external stress when 163 consumingPreservatives those and additives. antioxidant This food may additives include arethe safedetermination if used with of caution expression and followlevels of the “detoxifying” approved 164rules. enzymes It is, however, when a importantmammal eats to know food whetherwith or without these compounds additives. canIt is havepredicted direct that benefits hormesis on the and 165human hormetic body andmechanisms do not only related preserve to food foods and from food oxidation additives or rotting. will be We active think research that the fields pathways that bymay 166which provide sulfites valuable are metabolized answers andand eliminatedsound food-based should beinterventions. characterized while looking into their possible 167benefits, i.e.,Interestingly, whether the the human relationships body is between readier toglutathione cope with and external ascorbic stress acid when (vitamin consuming C) have those been 168additives. described This in may plants include for both the determinationcorrect metabolism of expression and stress levels tolerance of “detoxifying” [44]. Though enzymes we have when argued a 169mammal that vitamins eats food do with not or act without as antioxidants, additives. i.e., It is the predicted physiological that hormesis role of vitamins and hormetic is not mechanisms related to any 170related global to food antioxidant and food activity additives [45], will ascorbate be active synthesis research in fields liver thatmice may needs provide glutathione valuable [46]. answers In this andsense, 171sound it could food-based be hypothesized interventions. that vitamin C, in humans, is somehow related to glutathione-based innate 172 detoxInterestingly, mechanisms the relationshipsand, eventually, between to other glutathione not-yet-characterized and ascorbic antioxidant acid (vitamin machineries. C) have This been issue 173described is worth in being plants considered for both correct by scientists metabolism in the andantioxidant stress tolerance research field. [43]. Though we have argued 174that vitaminsWe would do not like act to as end antioxidants, this final section i.e., the with physiological a note of caution role of based vitamins in the is images not related in Figure to any 1. Is 175global more antioxidant beneficial activity to use [44 enough], ascorbate additives synthesis (in inte liverrms miceof type needs and glutathione concentration) [45]. Into thisprevent sense, all 176it could“senescence/decay” be hypothesized of that aliments vitamin or C, to in consume humans, f isood somehow that has related not expired to glutathione-based but that shows innatesigns of 177detox contamination mechanisms and,by living eventually, organisms to other that not-yet-characterized are contaminating it? antioxidant The identity machineries. of those contaminants, This issue 178is worthprobably being /fungi considered byin scientiststhe muffins in theof Figure antioxidant 1 is not research yet known, field. and, therefore, their effects on 179 human health are not known either.

180 Figure 1. Images of muffins with contaminants that arose way before the caducity date. Images 181 fromFigure muffins 1. inImages which of all muffins the chocolate with contaminan chips presentedts that this arose aspect way two-to-three before the caducity days after date package. Images 182 openingfrom and muffins more thanin which 45 days all the before chocolate the deadline chips pres writtenented in this the label.aspect Magnification two-to-three imagesdays after of apackage chip 183 in brownopening and and of a more chip inthan white 45 mudaysffi beforens (insets) the showdeadline signs written of biological in the label. contamination. Magnification The images product of a 184 comeschip from in ourbrown own and production of a chip ofin awhite supranational muffins (ins chainets) ofshow big signs supermarkets of biological and contamination. was bought in aThe 185 townproduct in Catalonia, comes Spain. from our Spanish own healthproduction authorities of a su werepranational informed, chain but of no big response, supermarkets on any and issue, was 186 has beenbought yet in given a town after in fourCatalonia, months. Spain. The Spanish label in theheal packageth authorities indicated were that, informed, apart frombut no unspecified response, on 187 “aromas,”any issue, the following has been additivesyet given wereafter present:four months. E160a(iii) The label (β-carotene), in the package E170 (calcium indicated carbonate) that, apart and from E516 () in white muffins; E412 (guar gum), E466 (sodium carboxymethyl cellulose), E481 (sodium stearoyl lactate) and E500 (sodium carbonates) in brown muffins; and E200 (sorbic acid), E202 (potassium sorbate), E450 (diphosphates) and E471 (mono- and diglycerides of fatty acids) in both types of muffins. Scale bar: approximately 10 mm. Antioxidants 2019, 8, 542 11 of 13

We would like to end this final section with a note of caution based in the images in Figure1. Is more beneficial to use enough additives (in terms of type and concentration) to prevent all “senescence/decay” of aliments or to consume food that has not expired but that shows signs of contamination by living organisms that are contaminating it? The identity of those contaminants, probably yeasts/fungi in the muffins of Figure1 is not yet known, and, therefore, their e ffects on human health are not known either.

Author Contributions: Conceptualization was agreed by R.F., G.N. and E.M.-P., who also scanned the literature, retrieved and extracted information from papers referenced in the review. R.F. compiled all the information and wrote the first version of the manuscript. G.N. and E.M.-P. critically read the manuscript, prepared a second version and the tables/figures in all versions of the paper. All authors edited the manuscript and revised the final submitted version. Funding: This research received no external funding. Acknowledgments: In Memoriam: Suso Pintor, a brilliant biochemist, stunning as a colleague and a good person. We acknowledge the inspiring work of Vince Gilligan and his team, especially for this quote: “I simply respect chemistry. Chemistry must be respected”—Walter White. We still consider that “Anything good or bad occurring in life has a common factor: Chemistry” [32]. Conflicts of Interest: The authors declare no conflict of interest.

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