Food additives are more specifically defined by the Codex Alimentarius as “any substance not normally consumed as a food in itself and not normally used as a characteristic ingredient of food whether or not it has nutritive value, the intentional addition of which to food for a technological purpose in the manufacture, processing, preparation, treatment, packaging, transport, or storage of such food results, or may be reasonably expected to result in it or its by-products becoming directly or indirectly a component of such foods.”
A. Wesley Burks MD, in Middleton's Allergy: Principles and Practice, 2020
Prevalence of Reactions to Additives
Many food and drug additives have been reported to cause adverse reactions ranging from lethargy to severe asthma and anaphylaxis. Many of the food and drug additives listed inBoxes 80.1 and80.2 have been reported to cause adverse reactions. However, many of these adverse reactions have not been verified by appropriate diagnostic challenge procedures. Several food and drug additives have been extensively studied, including synthetic colorants, sulfites, monosodium glutamate (MSG), aspartame, and benzoates. The prevalence of food allergies and food additive-induced sensitivities has been assessed in several large studies. In a Dutch study that started with a survey of 1483 Dutch adults and proceeded through clinical challenge trials, only three individuals were identified with food additive sensitivities,2 amounting to 0.2% of the population. In a large Danish study of food additive-induced sensitivities that started with a survey of 4274 Danish school children, an intolerance to food additives confirmed by double-blind challenge occurred in 2% of the children selected from the survey on basis of atopic history but only 0.13% of the entire surveyed population.3 Young et al.4 evaluated the prevalence of sensitivities to food additives among a British population using a combination of a survey questionnaire given to 18,582 individuals and a series of mixed additive challenges conducted at home with self-reporting of symptoms. The researchers estimated the prevalence of adverse reactions to food additives as 0.01% to 0.23%.4 A study of the prevalence of adverse reactions to foods was conducted in Berlin, Germany, in which a questionnaire was answered by 4093 persons, and those with self-reported food reactions were followed up by telephone and clinical investigation including double-blind, placebo-controlled food challenges. The prevalence of adverse reactions to food additives (a mixture of various colors, preservatives, antioxidants, and flavor enhancers) was estimated at 0.18%.5 Although this estimate is somewhat higher than in the earlier Dutch and Danish studies, the German study included more food additives and higher doses.
The assessment of the prevalence of adverse reactions to food additives is difficult because the reactions are often linked to chronic disorders such as asthma, chronic urticaria, and atopic dermatitis. Because the disorders are chronic, placebo reactions can occur. In a study of 54 Koreans (ages 1-44 years) with a variety of allergic diseases (asthma, rhinitis, atopic dermatitis, chronic urticaria) challenged with a mixture of seven common additives versus placebo, five (9.3%) responded to the food additives, two (3.7%) reacted to both placebo and the additives, and three (5.5%) reacted to the placebo.6 The authors concluded that there were no statistically significant differences between placebo and food additives. Similarly, in a study of 100 patients with chronic urticaria including 43 patients who reported possible history of reactions to food and drug additives, only two patients had a positive urticarial response on single-blind challenge, and neither of those patients were reactive on double-blind, placebo-controlled challenge.7
Definitions of food additives (direct food additives, ingredients added to foods for a specific purpose) vary among government agencies and organizations and include the following:
US Food and Drug Administration (FDA): The term ‘food additive’ means “any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation (21 CFR 179 is the primary regulation that covers irradiation in the production, processing, and handling of food and describes radiation and radiation sources, which include gamma ray, e-beam, and X-ray, as well as the general provisions for food irradiation also list other radiation processes, including radio frequency radiation, ultraviolet, and pulsed light intended for any such use), if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case as a substance used in food prior to 1 January 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use, except that such term does not include (1) a pesticide chemical in or on a raw agricultural commodity or processed food or (2) a pesticide chemical or (3) a color additive or (4) any substance used in accordance with a sanction or approval granted prior to the enactment of this paragraph pursuant to this Act, the Poultry Products Inspection Act (21 U.S.C. 451 and the following) or the Meat Inspection Act of 4 March 1907 (34 Stat 1260) as amended and extended (21 U.S.C. 71 and the following); (5) a new animal drug; or (6) an ingredient described in paragraph (ff) in, or intended for use in, a dietary supplement (US FFDCA §201 (s)).”
European Economic Community (EEC): A food additive is “any substance not normally consumed as a food in itself and not normally used as a characteristic ingredient of food whether or not it has nutritive value, the intentional addition of which to food for a technological purpose in the manufacture, processing, preparation, treatment, packaging, transport, or storage of food results or may be reasonably expected to result, in it or its by-products becoming directly or indirectly a component of such foods.” 89/107/EEC.
World Health Organization (WHO): Food additive means “any substance not normally consumed as a food by itself and not normally used as a typical ingredient of the food whether or not it has nutritive value, the intentional addition of which to food for a technological (including organoleptic) purpose in the manufacture, processing, preparation, treatment, packing, packaging, transport, or holding of such food results or may be reasonably expected to result (directly or indirectly), in it or its by-products becoming a component of or otherwise affecting the characteristics of such foods.” The term does not include contaminants or substances added to food for maintaining or improving nutritional qualities. Codex Alimentarius, second edition (revised 1995), volume 1A (General Requirements), p. 11.
Fred F. Ferri MD, FACP, in Ferri's Clinical Advisor 2022, 2022
Etiology & Risk Factors
Many different drug additives (Boxes E1 andE2) are reported to cause adverse reactions. For example, when used in a corticosteroid solution, commonly used cellulose derivatives (carboxymethylcellulose) have been reported to cause anaphylactic shock in susceptible individuals.7
Common Categories of Food Additives
From Burks AW et al:Middleton’s allergy: principles and practice, ed 9, Philadelphia, 2021, Elsevier.
Emulsifying agents such as gums (arabic and tragacanth) have caused urticaria when administered in antihistamines and corticosteroid tablets.7
Individuals have developed anaphylaxis to gelatin in vaccines. In some of these individuals, prick skin tests to the vaccine have been positive, and specific IgE antibodies to gelatin were found in the patient’s serum.8
Sulfites used as antioxidants in drugs are well recognized as causing asthma and other adverse reactions.9
Ethylenediamine is associated primarily with contact dermatitis, and sensitization occurs through cutaneous exposure.9 Ethylenediamine is also a component of aminophylline and has produced urticaria, exfoliative dermatitis, and anaphylaxis in sensitized individuals.7 Likewise, thermosal, a preservative, often acts as a contact sensitizer, but it has caused anaphylaxis and other adverse reactions.7
Seven sources of ingested allergens (eggs, peanut, milk, nuts, soy, fish, wheat) are generally considered to account for more than 90% of food-induced allergy.10
Ingested food proteins can evoke a variety of symptoms, with certain sources often linked with specific allergic manifestations. For example, peanuts, fish, and crustaceans are often associated with anaphylaxis, eggs and milk are associated with atopic dermatitis, and wheat allergens may be associated with exercise-induced anaphylaxis. Food allergens tend to be stable when exposed to heat and acid, and more resistant to proteases than nonfood allergens, thereby facilitating their entry through the gut mucosa.10
The U.S. Food and Drug Administration (FDA) recognizes more than 3000 substances allowed for addition to foods in the United States. Similarly, pharmaceutical products contain an enormous number of additives (Box E1) or “inactive ingredients,” many of which can be found in theU.S. Pharmacopeia. Approximately 773 chemical agents are approved for use in drug products by the FDA.11
Additives in pharmaceuticals also serve numerous functions. Drug additives commonly serve as agents of coloring, flavoring, emulsification, thickening, binding, and preservation (Box E2). Unlike in foods, the inert ingredients in pharmaceutical products often comprise the majority of the product. This isbecause active pharmaceutical ingredients are frequently present as a small fraction of the total mass of the product.11
Food allergens can also be animal derived, seed derived, or fruit and vegetable derived.
Food additives are natural or synthetic chemicals added to food to preserve flavor, enhance its texture or appearance, or for other technological functions. Food additives are among the safest chemicals in food due to their low toxicity, rigorous safety testing, and control of use by the law. The permission to use specific food additives is recommended by the Codex Alimentarius Commission and approved by national legislation. The use of food additives is subject to strict controls, underpinned by scientific studies to demonstrate their safety to human health. Their use brings many benefits including increased safety, and greater choice of food products.
This general article on food additives provides an overview of the issues associated with food additives and their safety. Several food additives that may be considered as controversial are examined.
Unconventional Theories and Unproven Methods in Allergy
A. Wesley Burks MD, in Middleton's Allergy: Principles and Practice, 2020
Food Additive Sensitivity
Attention deficit–hyperactivity disorder (ADHD) in children and some adults, previously calledhyperactivity, hyperkinesis, and minimal brain dysfunction, is considered to be a psychiatric condition characterized by excessive activity, inattention that is inappropriate to the stage of development, increased level of impulsivity, difficulty in discipline, and poor school/work performance. It is not an uncommon problem of childhood and is increasingly recognized in adolescents and adults as well. The natural history is unpredictable, with some children losing all symptoms during puberty and others continuing to exhibit some or all manifestations into adulthood. The cause is unknown, but the disorder is thought to encompass some combination of constitutional, genetic, environmental, and psychosocial factors.
Feingold first suggested in 1973 that ADHD can be caused by sensitivity to aspirin and other salicylates.28 Accordingly, elimination of dietary salicylates as treatment for this and other psychiatric conditions was the recommendation, and initial reports claimed improvement in up to 50% of children with ADHD. Because other investigators had reported that asthma attacks in patients with aspirin-sensitive asthma could be triggered by ingestion of the yellow food coloring dye tartrazine,29 it was recommended thatall food dyes and other additives, regardless of their chemical structure, toxicity, or pharmacologic properties, be eliminated. Thus the “Feingold diet” evolved as a salicylate-free, additive-free diet. Most plants contain some salicylate, making it unlikely that any plant food is truly salicylate-free. Small amounts of salicylates are found in certain animal products and even in drinking water. In fact, a true salicylate-free diet would be limited to plain meat, egg, and distilled water only.30 In practice, adherents of the Feingold diet focus on eliminating food additives, particularly dyes and preservatives, so the role of natural salicylates in foods—the issue on which the diet was based—eventually lost importance to the proponents.
Scientific evidence for direct effects on the central nervous system caused by toxicity, idiosyncrasy, or allergic hypersensitivity to food additives is lacking. Acute asthma attacks precipitated by the ingestion of aspirin and other nonsteroidal antiinflammatory drugs are discussed inChapter 78. Several published controlled clinical trials have used different protocols that have produced conflicting results. A consensus conference by the Office of Medical Applications for Research of the National Institutes of Health concluded that only a few children might benefit from improvement in behavior from a defined diet.31 Thus the hypothesis that naturally occurring food salicylates and artificial food additives cause ADHD is unproved. An additive-free diet cannot be recommended as definitive therapy for children with this condition. No evidence is available at this time to confirm that any food additive affects behavior in children through an immunologic or allergic mechanism.
Food additives are substances that are not normally consumed as food itself but are added to food intentionally for one or more technological purposes. Food additives are classified into many functional classes, for example, acidity regulators, antioxidants, colors, emulsifiers, preservatives, stabilizers, sweeteners, and thickeners. Approval of substances for use as food additives, identity and purity criteria of approved additives, maximum use level of the approved additives at the different commodities in which they may be used, and food items in which their use is not acceptable are regulated by international or national authorities.
Food additives are used to prevent spoiling or to enhance flavor; they include such substances as preservatives, artificial colors, artificial flavorings, and acidifiers. Although the government has banned many synthetic food additives, it should not be assumed that all the additives currently used in the U.S. food supply are safe. Many synthetic food additives that are being linked to such diseases as depression, asthma or other allergy, hyperactivity or learning disabilities in children, and migraine headaches remain in use.29–32
The U.S. Food and Drug Administration has approved the use of more than 2800 different food additives. It is estimated that the per-capita daily consumption of these food additives is approximately 13 to 15 g. This amount is astounding and leads to many questions. Which food additives are safe? Which should be avoided? An extremist might argue that no food additive is safe. However, many food additives fulfill important functions in the modern food supply. Many compounds approved as additives are natural in origin and possess health-promoting properties, whereas others are synthetic compounds with known cancer-causing effects. Obviously, the most sensible approach is to focus on whole, natural foods and avoid foods that are highly processed.
An illustration of the problem with food additives is one of the most widely used synthetic food colors: Food, Drug, and Cosmetic Act yellow dye no. 5, or tartrazine. Tartrazine is added to almost every packaged food as well as to many drugs, including some antihistamines, antibiotics, steroids, and sedatives. In the United States, the average daily per-capita consumption of certified dyes is 15 mg, of which 85% is tartrazine; among children, consumption is usually much higher.
Although the overall rate of allergic reactions to tartrazine is quite low in the general population, allergic reactions to tartrazine are extremely common (20%–50%) in individuals sensitive to aspirin as well as other allergic individuals. Like aspirin, tartrazine is a known inducer of asthma, hives, and other allergic conditions, particularly in children. In addition, tartrazine, as well as benzoate and aspirin, increases the production of a compound that raises the number of mast cells in the body. Mast cells are involved in producing histamine and other allergic compounds. A person with more mast cells in the body is typically more prone to allergies. For example, an examination of patients with hives shows that more than 95% have a higher-than-normal number of mast cells.
In studies using provocation tests to determine sensitivity to tartrazine and other food additives in patients with hives, results have ranged from 5% to 46%. Diets eliminating tartrazine as well as other food additives in sensitive individuals have, in many cases, been shown to be of great benefit in patients with hives and other allergic conditions, such as asthma and eczema.
Food additives are strictly limited; only additives explicitly authorized may be used in food. Monitoring foodstuffs for additives is an area of increasing concern and importance. Due to its excellent figures of merit, HPLC–MS is often a method of choice. Food additives are groups of substances commonly classified according to their application and not to their chemical structure. Some of these are small molecules (like benzoic acid used for conservation), some are macromolecules (like the ‘infamous’ guar gum, causing concern a few years ago), some are synthetic products, while others are natural extracts. For these reasons, it is difficult to generalize the ‘proper’ analytic method to be used for their characterization. Some methods are compound-specific (and do not estimate total amount of a given class of compounds); some characterize groups of substances. Often, both identification and quantification are required. Generic procedures for the simultaneous extraction of various classes of food additives and residues in various matrices are in use.
JECFA and JMPR serve as independent, international scientific advisory bodies that perform toxicological evaluation and risk assessments on chemicals and provide advice to FAO, WHO, and the member countries of both organizations, as well as to the CAC. The CAC was created in 1963 by FAO and WHO to develop food standards, guidelines, and related texts such as codes of practice under the Joint FAO/WHO Food Standards program. The main purposes of this program are protecting the health of consumers, ensuring fair trade practices in the food trade, and promoting coordination of all food standards work undertaken by international governmental and nongovernmental organizations.
All countries need to have access to reliable risk assessments of chemicals in food, but relatively few have the expertise and funds available to carry out separate risk assessments on large numbers of chemicals. JECFA and JMPR perform a vital role in providing a reliable source of independent expert advice, and some countries establish their national regulatory programs using information from these bodies. In the same way, based on JECFA evaluations on food additives, contaminants, and naturally occurring toxicants, the Codex Committee on Food Additives, the Codex Committee on Contaminants, and the Codex Committee on Residues of Veterinary Drugs in Food develop standards and guidelines, and the Codex Committee on Pesticide Residues provides advice, based on the evaluations of JMPR, on appropriate standards for pesticide residues in food, for adoption by the CAC.
An important aspect of the Codex Committees work results from the agreement, as a result of the Uruguay Round in which the WTO achieved the General Agreement on Tariffs and Trade, that scientific, risk-based standards adopted by the CAC should be applied under the terms of the Sanitary and Phytosanitary (SPS) agreement to address fair trade practices. Governments wishing to argue particular cases at WTO are likely, therefore, to turn increasingly to Codex, and through Codex to JECFA, JMPR, and other FAO/WHO scientific bodies, for advice on their own legislation. Within the WTO-SPS agreement, Codex standards are listed as the international benchmark.
Food additives are substances intentionally added to food to perform specific functions, such as preservatives, bleaching agents, antioxidants, sweeteners, coloring agents, and flavoring agents, among others. Food additives are one of the most studied classes of compounds regarding their toxicity. Food additives can be classified according to their sources, such as from substances that are isolated from edible plants or from living material, substances that naturally occur in foodstuffs but are obtained by chemical synthesis, and substances that are not found in nature. In Europe, every additive has an E-number, and each is classified according to its function in food. As with any other substance used for food production, the toxicity of the additives must be assessed by different toxicological tests. In addition, some substances have to be revised, and, in some cases, they have been removed from the authorized list of additives. The most interesting additives from a toxicological point of view are preservatives, antioxidants, sweeteners, coloring agents, flavoring agents, and flavor enhancers (Table 4).
Table 4. Food additives and toxicants formed during food processing, preparation, storage, packaging, and intake
Use in food
Benzoic acid; sodium benzoate (E 211)
Acidic foods such as salad dressings, carbonated drinks, jams, and fruit juices