FOOD ADDITIVE SAFETY

Food additives that improve or modify characteristics of food such as color, appearance, taste and odor are chemicals added to foods to provide various benefits such as extending shelf life, preventing certain health risks, reducing food losses and preserving nutritional value (Taylor & Baumert, 2014; Şen, Aksoy, & Yılmaz, 2017). There are numerous food additives. Food additives are classified as acidifiers, anti-caking agents, antimicrobial agents, browning inhibitors, antioxidants, emulsifying agents, nutrient supplements, complexing agents, stabilizers, spices, oleoresins and extracts, flavorings, enzymes, synthetic colorants, natural colorants, sweeteners, and non-nutritive sweeteners.

Sweeteners and extracts comprise a large portion of food additives (Taylor & Baumert, 2014).

Because food additives obtained naturally or synthetically interact with biological systems in the human body and while providing benefits on one hand can potentially create risks on the other, they have been included in research topics of scientists, particularly due to their frequent use. Research has shown that some food additives are genotoxic and carcinogenic, while others play a role in the development of hyperactivity, allergies, neurodegenerative diseases, obesity, diabetes, and reproductive and gastrointestinal disorders, and their use has been restricted (Şen, Aksoy, & Yılmaz, 2017). Since food additives are intentionally added to foods, their safety is generally evaluated through nutritional experiments in laboratory animals. Chemicals that do not pose a risk under normal exposure conditions and/or have a long history of safe use are permitted to be used as food additives (Taylor & Baumert, 2014). There are numerous reports showing the inclusion of illegal food additives in food products or in some cases their improper listing on labels and other malpractices by food manufacturers. At the beginning of the 19th century, deaths were reported from consuming candies and puddings colored with arsenic derivatives and cheese products painted with red lead and vermillion (HgS). Similarly, milk was colored yellow to conceal that cream had been removed and it was diluted with water, and because this practice was widespread, it caused people to suspect uncolored milk of being adulterated (Verhagen, 1997). These reports awakened the public and created awareness about food product composition, increasing demand for stricter inspections, guidelines and regulations concerning food additives (Msagati, 2018). The United States (US) first imposed pre-approval requirements for food additives in the 1950s, and in 1958 the Food Additives Amendment came into force, establishing the necessity of evaluating food additives for safety in the US (Richardson, et al., 2013; Meulen, 2014). Food additives are regulated in the US under the Federal Food, Drug, and Cosmetic Act by the US Food and Drug Administration (FDA)

(Richardson, et al., 2013; Newell-McGloughlin & Burke, 2014; Wang & Sun, 2015). In the US, food additives are legally classified as (1) generally recognized as safe (GRAS) substances, (2) flavorings and extracts, (3) direct additives, and (4) color additives (Richardson, et al., 2013; Taylor & Baumert, 2014).

Many food additives were in common use long before comprehensive food laws such as the 1958 Food, Drug, and Cosmetic (FD&C) Act in the US were passed. These substances are evaluated as GRAS based on their safe use history. More than 600 chemical substances are found on the FDA's GRAS list. Although GRAS substances are thought to have a safe use history, this does not actually mean that significant toxicological data exist for all these substances. New concerns about GRAS substances can occasionally emerge, such as concerns related to sodium chloride arising from the importance of sodium levels in diet and hypertension. The FDA removes these agents or their uses from the GRAS list when there is evidence that they pose a hazard to consumers (Richardson, et al., 2013; Taylor & Baumert, 2014). For example, nordihydroguaiaretic acid (NDGA) is a potent antioxidant and was accepted as a GRAS food additive until animal studies proved it caused kidney toxicity (Betz, Garland, & Page, 2002). On the other hand, a new agent is recommended to be added to the GRAS list through an expert panel based on peer-reviewed scientific literature published on the evaluation of the substance's safety based on the substance's properties, composition, safe use history and toxicological characteristics, or documents demonstrating its safe use (Richardson, et al., 2013; Taylor & Baumert, 2014). The objective of the European Union (EU) food additives legislation is to protect public health in the harmonized EU internal food market. A general framework regulation establishing a common authorization procedure for food additives, food enzymes and food flavorings, Regulation 1331/2008, was adopted in December 2008 and replaced the 1988 Food Additives Regulation.

EU Commission Regulation 234/2011 details the procedural arrangements necessary for updating existing lists of substances approved for use in food in the EU.

Legal use of agents to be used as food additives becomes possible only through evaluation of information needed for risk assessment including information about legal use, safety information, technical information related to safety, biological and toxicological data, information about proposed uses, normal and maximum use levels and estimates of dietary exposure (Barlow, 2013). Risk assessment of food additives has been conducted by the European Food Safety Authority (EFSA), an EU agency since 2003 (Barlow, 2013). There are specialized agencies and specific regulations for monitoring food additives in the EU. The Directorate-General for Health and Consumer Affairs (DG SANCO) is responsible for regulating food additives in the EU and essentially for approving food additives. The EU Food Scientific Committee (SCF) is fundamentally responsible for evaluating the safety of food additives. If a new food additive passes the evaluation, the commission initiates the process of regulation changes for its addition to appropriate directives and permission for its use in food content. Food additives that have undergone evaluation regarding their use and have had usage limits established are added to the list of food additives permitted for use in the EU. Due to the hybrid system developed by the Union, substances suitable for use must also comply with the national legislation of the country in which they will be used (Wang & Sun, 2015).

In product labeling, the general name of the food additive and/or the E number provided by regulations and based on a specific classification must be indicated (Barlow, 2013).

To establish international standards, risk assessment in food additives is conducted through three joint committees of the Food and Agriculture Organization (FAO) and World Health Organization (WHO) (FAO/WHO Joint Committee on Food Additives (JECFA), FAO/WHO Joint Meetings on Pesticide Residues (JMPR), and Joint FAO/WHO Meetings on Microbiological Risk Assessment (JEMRA)) by recommending maximum limits for pesticide residues, microorganisms and other food safety matters (Richardson, et al., 2013; Meulen, 2014). The Codex Alimentarius code, established and compiled by the Codex Alimentarius Commission (CAC) brought together by FAO and WHO in 1963, contains more than 200 standards, nearly 50 food hygiene and technology implementation rules, approximately 65 guidelines, over 1000 food additive and contaminant evaluations, and more than 3200 maximum residue limits for pesticides and veterinary drugs (Richardson, et al., 2013; Meulen, 2014; Zepeda, 2014). The Codex General Standard for Food Additives (CODEX STAN 192-1995) sets out the conditions under which food additives permitted in all foods may be used. According to this standard, a food additive refers to any substance not normally consumed as food and not typically used as its component, whether or not it has nutritional value, intentionally added to or reasonably expected to result from (directly or indirectly) for a technological purpose in the production, refining, preparation, application, packaging, transport or storage (including organoleptics) of foods, or any substance in byproducts of such foods that becomes contained in or affects the characteristics of such foods (Richardson, et al., 2013; Meulen, 2014). JECFA has accepted the determination of acceptable daily intake (ADI), which describes the amount that a chemical can be consumed daily throughout an entire lifetime without a significant risk through food (Richardson, et al., 2013; Taylor & Baumert, 2014; Koza, 2016; Teitelbaum, 2018). The FDA, EFSA, and JECFA have made toxicological evaluation of food additives mandatory, and while they require animal experiments designed according to Organization for Economic Cooperation and Development (OECD) and EU guidelines in toxicological studies, information obtained from human studies is also accepted (Penningroth S., 2010; Barlow, 2013).

These toxicological studies include toxicokinetic, acute toxicity, subchronic toxicity, reproductive and developmental toxicity, chronic toxicity, carcinogenicity, and genotoxicity studies (Barlow, 2013).

Food additives such as colorants, sweeteners and flavorings are generally misused in street foods, and street vendors do not pay much attention to the labels and instructions that should be followed in the use of food additives. This frequently results in excessive use and consequently exposure to concentrations at or exceeding maximum levels. Another risky situation is the use of a food additive for purposes other than its intended use. For example, as a result of using a flavor enhancer such as monosodium glutamate to provide salty taste instead of the intended flavor, the substance must serve a different function, making excessive monosodium glutamate use possible (Wirakartakusumah, Purnomo, & Dewanti-Hariyadi, 2014). Cases of acute toxicity caused by food additives generally include excessive adverse reactions resulting from overconsumption of the additive, misuse of the additive by the manufacturer or consumer, and abnormal sensitivity in some consumers to specific food additives (Taylor & Baumert, 2014; Msagati, 2018). Food additives are responsible for less than 1 percent of cancer development (Penningroth S., 2010). The frequency of food additive-related asthma exacerbations confirmed by double-blind, placebo-controlled studies is below 5 percent (Bush & Montalbano, 2014). FD&C dyes, sulfites, parabens, annatto, carmine, saffron and mannitol have been reported to cause acute urticaria, chronic urticaria, anaphylaxis and adverse effects can be observed in skin tests (Bosso & Robertson, 2014). Consumer demand for products with ingredient lists free of food additives is driving product development in this category in Europe. The term 'clean label' is used to describe this trend. To this end, certain components claiming to replace colorant additives are being incorporated into products. Rosemary, grape seed, chestnut and olive leaf extracts as antioxidants have undergone safety evaluation as food additives, been approved and permitted. Beet and grape skin extracts have been approved and permitted as coloring food substances, and there is an increasing trend in the use of spinach, pumpkin, nettle and Spirulina extracts for this purpose. The EU is examining these uses and issuing guidance (Saltmarsh & Insall, 2013).

Briefly addressing some food additives:

Sorbitol (E420) and Hexitols: These are alternative sweeteners frequently used in confectionery and chewing gums because they do not cause tooth decay. These sugar alcohols are not absorbed as easily as sugar, but once absorbed and entering the bloodstream they have calories as high as sugar. Due to slow absorption, these sweeteners can cause osmotic diarrhea if consumed in excess. In cases, patients were generally observed to consume more than 20 g of these sweeteners. Infants are more sensitive to this osmotic diarrheal effect than adults. Dietary diarrhea associated with these polyol food additives is a good example of poisoning resulting from excessive consumption of a food additive (Taylor & Baumert, 2014).

Color Additives (E100-E199):

Some synthetic color additives have been banned since 1958 due to concerns about possible chronic toxicity (Taylor & Baumert, 2014). FD&C Red #2 (E123), FD&C Red #40 (E129), FD&C Red 3 (E127), Quinoline Yellow (E104), Sunset Yellow FCF (E110), Orange Yellow S (E110), Ponso 4R (E124), Purple Wine Color (E123), Indigo Carmine (E132), Brilliant Blue (E133); along with causing nausea, vomiting, allergies, asthma, skin redness, skin itching, urticaria, and hyperactivity reactions, they have been prohibited in countries such as Austria, Australia, Japan, Belgium, France, Norway, Sweden, Switzerland, Finland, Germany, Canada and the US due to causing DNA damage, various types of cancer and tumors, and changes in the reproductive system in animal studies, while their use is permitted within certain limits in England (Taylor & Baumert, 2014; Pandey & Upadhyay, 2016). Tartrazine (FD&C Yellow #5, E102); consumption of this approved synthetic food colorant, which has been widely used in foods and pharmaceuticals for many years, has been observed to cause adverse reactions (asthma and chronic urticaria) in a group of consumers in sensitive subpopulations (Verhagen, 1997; Taylor & Baumert, 2014). It has been banned in Norway and Austria due to the possibility of causing hyperactivity, asthma, skin itching and migraine pain (Verhagen, 1997; Pandey & Upadhyay, 2016). On the other hand, its asthmatic effect has not been proven in double-blind, placebo-controlled studies (Verhagen, 1997; Bush & Montalbano, 2014).

Sulfites (E220-E229):

Sulfites (sodium and potassium metabisulfate (E223 and E224), sodium and potassium bisulfite (E222 and E222), sodium sulfite and sulfur dioxide (E221 and E220)) that prevent browning of food and control microorganism activity and damage are used in the food industry as antioxidants, reducing agents, bleaching agents, pH controllers and stabilizers (Güneş, 2014; Taylor & Baumert, 2014). The daily intake of sulfite (E220-E229) has been determined as an average of 43 mg/g for individuals with daily consumption of 60 kg, and the acceptable daily intake is 0-0.7 mg/kg expressed as sulfur dioxide (E220) (Güneş, 2014). Sulfites (E220-E229) have the potential to trigger asthma even when taken within safe limits in sensitive individuals, who constitute a very small portion of the population. The estimated prevalence of sulfite sensitivity in adult asthmatics is 3-10 percent, with higher prevalence in those with moderate-to-severe persistent asthma (Bush & Montalbano, 2014; Taylor & Baumert, 2014). The intestinal microbiota plays an important role in the metabolism of xenobiotics including food additives (Cirlini, Bruni, & Dall'Asta, 2015). Sulfites (E220-E229) inhibit the growth of four beneficial intestinal bacteria species due to their bacteriostatic and bactericidal effects at concentrations considered safe for food, altering intestinal protection and oral microbiome. For this reason, it is believed that sulfites may affect patients with dysbiotic microbiota (Irwin, Fisher, Graham, Malek, & Robidoux, 2017).

Monosodium Glutamate (E621):

It began with the report of Chinese Restaurant Syndrome (CRS) described by Dr. Robert Kwok in 1968 as "numbness in the back of the neck, numbness radiating to both arms and back, general weakness and palpitations" from his experience in a Chinese restaurant (Woessner, 2014). Monosodium glutamate (E621), a flavor enhancer, is found as an additive in various ready-made and packaged foods. The effect of monosodium glutamate (E621) on the digestive system begins by increasing saliva secretion and makes people think the food has excessive flavor characteristics, stirring up the desire to eat more and faster. It is thought that this flavor-enhancing additive may lead to obesity. While there are views that monosodium glutamate (E621) does not cause obesity, it has not yet been fully proven to be harmless (Koza, 2016; Dal, et al., 2017). Monosodium glutamate (E621) causes chest pain, headache, facial redness, shortness of breath, edema, sweating, disturbances in learning and memory mechanisms, harmful effects on the baby's nervous system, retina and kidneys due to excessive use during pregnancy and in advanced age it is claimed to cause neurodegenerative diseases such as infertility, growth disorders, Alzheimer's, Parkinson's and epilepsy (Koza, 2016). On the other hand, current scientific literature lacks clear evidence documenting that monosodium glutamate (E621) can be a cause of serious acute or chronic medical problems in the general population (Woessner, 2014).

Nitrites and Nitrates (E240-E259):

Nitrite and nitrate salts (E240-E259) are used as food additives in meat, fish and cheese products due to their antimicrobial effects (Öztürkcan & Acar, 2017). Nitrite, which combines with myoglobin that gives meat its color to form nitrosomyoglobin, creating permanent color formation, contributing to oxidative stability by preventing lipid oxidation and thereby preventing taste deterioration, shows an inhibitory effect against pathogens such as Clostridium botulinum that produce botulinum toxin. Nitrite and its metabolites, when consumed in food in the body, depending on their quantity and chemical structure, following their reduction by bacteria in oral flora can cause methemoglobin formation, a drop in systemic arterial blood pressure by causing vasodilation of vascular smooth muscle, circulation disorders and acute or chronic poisoning manifested by shock, as well as cancers of the stomach, liver, central nervous system, esophagus, kidney, intestine and lymphoid system (Verhagen, 1997; Öztürkcan & Acar, 2017). Due to these effects, the use of nitrite and nitrate (E240-E259) as food additives has been completely banned in some countries, with WHO determining maximum daily intake values as 0-5 mg/kg and 0-0.5 mg/kg respectively (Öztürkcan & Acar, 2017).

Non-Nutritive Sweetener Cyclamate (E952):

It has been banned in the US because it has weak carcinogenic activity in laboratory animals (Taylor & Baumert, 2014).

High Fructose Corn Syrup:

High fructose corn syrup, which has become an alternative to sucrose and other sweeteners due to its ease of use and cost-effectiveness and is used as a flavor enhancer, was obtained by chemical and enzymatic hydrolysis of corn starch and entered the food and beverage industry in the late 1960s (Turasan, 2014). Consumption of high amounts of fructose has been reported to have negative effects on metabolism, and consequently may lead to health problems including obesity and diabetes, fatty liver disease, insulin resistance, hypertriglyceridemia, hyperuricemia, rapid aging, diabetes complications, increased uric acid, chronic diarrhea, irritable bowel syndrome and urticaria (Turasan, 2014; Pandey & Upadhyay, 2016).

Saccharin (E954):

Saccharin (E954), one of the first non-nutritive sweeteners approved for food use, has been shown in laboratory animals to cause bladder, uterus, ovary, skin and blood vessel cancers, DNA damage and birth defects (Taylor & Baumert, 2014; Pandey & Upadhyay, 2016). It has been reported to disrupt blood clotting, blood sugar and digestive functions and may cause obesity, and its use has been banned in Germany, Spain, Portugal, Hungary, France, Malaysia, Zimbabwe, Israel, Fiji, Peru and Taiwan (Pandey & Upadhyay, 2016).

Aspartame (E951):

Although there is information that it can cause neurological damage particularly in children whose brain development is ongoing, crosses the placenta, can trigger Multiple Sclerosis and Non-Hodgkin Lymphoma and may cause obesity, only US Air Force pilots have been prohibited from consuming beverages containing aspartame (E951), a sweetener 200 times sweeter than sugar (Pandey & Upadhyay, 2016).

Olestra:

The food additive Olestra, a fat replacement agent, is poorly absorbed and not metabolized in the body. Thus, the excessive caloric gain from fat used in similar products does not occur with Olestra. However, consumption of Olestra has caused acute gastrointestinal complaints in some people, including anal leakage (Taylor & Baumert, 2014).

Niacin (E375):

Excessive consumption of niacin, a B vitamin that is considered beneficial when widely and properly used as a nutrient supplement food additive, can lead to acute conditions such as skin redness, particularly on the face and upper chest, pruritus, hives and burning or increased heat. The cases resulted from excessive enrichment of flour used in the preparation of rye rolls and corn flour (Taylor & Baumert, 2014).

Vitamin A:

Vitamin A, a nutrient supplement food additive whose benefits are well documented, can only lead to adverse reactions through excessive intake. Due to mistrust of commercial baby food, vitamin A poisoning occurred in twin babies fed for several weeks on a diet consisting largely of chicken liver, carrots, milk and vitamin supplements; after the twins developed vomiting and skin rash, symptoms resolved with a more normal diet. While estimated daily vitamin A and carotene intake for infants should be 1,500-4,500 IU per day, in this poisoning case it was 44,000 IU (Taylor & Baumert, 2014).

Phenolic Antioxidants:

Butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321) are phenolic antioxidants commonly added to foods containing solid or liquid fats at regulated concentrations. Despite concerns about animal toxicology, BHA (E320) and BHT (E321) generally have an ambiguous status on the GRAS list. Side effects in humans are best observed in the skin. The true frequency of adverse reactions to BHA (E320) and BHT (E321) remains uncertain (Weber, 2014).

Benzoates and Parabens (E210-E219):

They are widely used as antimycotic and antimicrobial chemical preservatives in food and beverages in most developed countries and do not have toxicity at approved concentrations. On the other hand, studies estimate the incidence of benzoate and paraben-related urticaria/angioedema at 2-3 percent. Some studies suggest that food additives, including benzoates, are effective in inducing atopic dermatitis in a small portion of patients. Benzoate exposure has rarely been reported as a cause of anaphylactic-type reactions, while paraben exposure has not been reported as a potential cause of anaphylaxis. Various types of adverse effects have been reported in children against benzoates and parabens, ranging from cutaneous vasculitis to rhinitis and hyperactivity. Additional studies are needed to verify these relationships (Pongonis & Fahrenholz, 2014).

Nanoparticles:

The use of nanoparticles as food additives aims to increase the intake of functional foods while also maintaining the protection of targeted delivery of functional foods. Nanoparticles such as nano-silver and zinc oxide have been applied as food additives or food supplements, but these applications have increased gastrointestinal absorption of the metals (Msagati, 2018). Food additives, which are indispensable for industrial production in the food sector, must be developed and used rationally for the sector's continuity. On the other hand, continuous exposure in our daily lives raises both public and academic concerns. These concerns should not be overlooked by the food industry but rather addressed by progressively resolving the questionmarks. As good manufacturing practices must be followed in production, national and international standards and limitations must be ensured. Particularly, health and toxicological limitations must be implemented with zero error and all questionmarks regarding public health must be resolved. It must always be kept in mind that food consumption is a basic necessity and cannot be separated from human health. It should not be forgotten that the consumption of healthy food is necessary for a long, healthy life.     Prof. Dr. Gül Özhan Istanbul University Faculty of Pharmacy Department of Pharmaceutical Toxicology           Pharmacist Dr. Yağmur Emre Arıcan           Dietitian Sevim Arıcan      

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