Adverser

Adverse Reactions to Food AdditivesRonald A. Simon, MDAddressDivision of Allergy, Asthma, and Immunology, Scripps Clinic,10666 N. T orrey Pines Road, La Jolla, CA 92037, USA.E-mail: rsimon@Current Allergy and Asthma Reports 2003, 3:62–66Current Science Inc. ISSN 1529-7322Copyright © 2003 by Current Science Inc.IntroductionThe list of additives used by the food industry is extensive and includes thousands of antioxidants, flavorings and col-oring substances, preservatives, sweeteners, thickeners, and many others; however, only a small number of additives have been implicated in immunoglobulin E (IgE)-medi-ated or other (immunologic or nonimmunologic) adverse reactions (Table 1). Many adverse reactions attributed to additives were anecdotal or characterized by poorly con-trolled challenge procedures [1].Tartrazine and other dyes, benzoates, and parabens may occasionally aggravate chronic urticaria. Sulfites, although not implicated in chronic urticaria, have occa-sionally been reported to provoke anaphylaxis. Monso-dium glutamate (MSG) has been reported to provoke angioedema in a single case report. Aspartame, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) have been shown to cause isolated cases of chronic idiopathic urticaria. Nitrates and nitrites have not been associated with urticaria/angioedema or anaphylaxis. Sev-eral case reports have described anaphylaxis with erythri-tol, annatto, and carmine.Although there are rare cases of asthma provoked by benzoate, MSG and tartrazine (or other azo and nonazo dyes) have also been reported but not confirmed in rigor-ous double-blind, placebo controlled challenges. Sulfites, however, have clearly been shown to produce serious, even life-threatening, asthmatic reactions by several pro-posed mechanisms. Approximately 3% to 5% of asth-matic patients are sulfite-sensitive, most of whom react by inhaling sulfur dioxide generated when sulfites are placed in solution. When the Food and Drug Administration banned adding sulfites to fresh foods in 1986, the fre-quency, and, therefore, importance, of this problem was greatly diminished. Spearmint flavoring also has been shown to trigger asthma.Although many additives have been reported to pro-voke urticaria/angioedema or asthma [2,3], the prevalence of reactions to any food additives in such patients is unknown—not because of an inadequate number of stud-ies, but rather the lack of properly and vigorously con-trolled studies. In part, this relates to problems inherent in challenging patients who have asthma or chronic urticaria/ angioedema [4]. Many early reports suffered from “false-positive” reactions resulting from previous suspension of medications (for asthma or urticaria/angioedema) and use of single-blind protocols in which placebo was given initially and reappearance of disease activity associated with subsequent additive challenge was misinterpreted as a positive response. The most efficient means to control for the inherent variability in activity of chronic conditions that may wax and wane with time, as well as other poten-tial confounders, is by maintaining routine medications and utilizing double-blind, placebo-controlled challenge protocols [5,6].With the exception of the additives discussed later, the potential for negative reaction (urticaria/angioedema, asthma, anaphylaxis) to these commonly consumed addi-tives has not been described and is exceptionally rare if the potential exists at all. Recent studies [7] performed under properly controlled conditions imply that sensitivity to food additives (MSG, nitrates, benzoates, parabens, sulfites, BHA, BHT, tartrazine [FD&C yellow #5], sunset yellow [FD&C yellow #6]) in patients with chronic urti-caria/angioedema is very uncommon. Several case reports have described the potential for anaphylaxis with sulfite, erythritol, annatto, and carmine [8–10,11•]. In individuals with asthma, the potential for provocation of broncho-spasm has been observed in a subgroup with sensitivity to sulfites; rare cases of asthma provoked by benzoate, MSG, and tartrazine have also been reported but not confirmed in rigorous double-blind, placebo-controlled challenges, as discussed later.There are thousands of additives used by the food industry for a variety of purposes in the foods we eat. However, only a small number have been implicated in causing adverse reactions in humans. Although there are reported cases of individuals who have reactions to single additives, most of the medical literature involves patients with asthma or chronic idiopathic urticaria/angioedema whose condi-tions are exacerbated after ingestion of food additives. Many of these reports are characterized by poorly con-trolled challenge procedures. Recent studies performed under properly controlled conditions imply that sensitivity to food additives in patients with chronic urticaria/ angioedema is very uncommon.Adverse Reactions to Food Additives • Simon63Food Dye and Coloring ActFood Dye and Coloring Act (FD&C)–approved dyes, such as tartrazine, are coal tar derivatives. Use of FD&C–approved dyes is ubiquitous in foods and beverages. Tartra-zine has been the additive reported most frequently in pro-voking asthmatic reaction. However, critical review of the medical literature supports the contention that sensitivity to tartrazine in asthmatic patients is, at best, extremely unusual. Well-designed, double-blind, placebo-controlled studies in adults [12] and in children [13] with chronic, often steroid-dependent, asthma found no tartrazine-sen-sitive subjects among approximately 50 in each report. A 40% to 50% incidence of tartrazine sensitivity in aspirin-sensitive asthmatics was described by several investigators [14–17]; however, more recent reports utilizing double-blind, placebo-controlled challenge protocols in aspirin-sensitive asthmatics have found no adverse reactions in 165 aspirin-sensitive asthmatics who were challenged with a dose of 50 mg tartrazine [18••]. These data imply that the notion that tartrazine “cross-reacts” with cyclo-oxygen-ase–inhibiting drugs and that tartrazine should be avoided in aspirin-sensitive asthmatics should be abandoned. ParabensParabens are aliphatic esters of parahydroxybenzoic acid and include methyl-, ethyl-, propyl-, and butyl- parabens.Sodium benzoate is a closely related substance and may cross-react with other parabens. There has been only one subject reported in the medical literature to be benzoate sensitive, in a double-blind, placebo-controlled study of additive-provoked asthma [19]; this patient was not aspi-rin-sensitive and did not experience amelioration of asthma symptoms while on a benzoate-free diet.BHA and BHTBHA and BHT are antioxidants commonly used in break-fast cereals and other grain products to maintain crispness and prevent rancidity. There is one well-documented report of chronic urticaria, confirmed by double-blind, placebo-controlled challenges, exacerbated by these agents [20]. Sensitive subjects also exhibited improvement in urti-caria after elimination of BHA and BHT from the diet. Nitrates and NitritesNitrates and nitrites are widely used as preservatives in pro-cessed meats (eg, frankfurters, salami). These agents have not been associated with hypersensitivity reactions, but can provoke vascular headache; their metabolic products (nitrosamines) are known carcinogens. Monosodium GlutamateMSG is a nonessential dicarboxylic amino acid that forms approximately 20% of our normal dietary protein. MSG is added to food as a flavor enhancer, particularly in Asian food, and has been commonly reported to produce many symptoms [21] including headache, myalgia, backache, neck pain, nausea, diaphoresis, tingling, flushing, and chest heaviness (MSG symptom complex, otherwise known as “Chinese Restaurant Syndrome”). Urticaria was attributed to MSG in one report [22], but the potential for exacerbation of chronic urticaria with MSG has not been demonstrated in carefully performed, placebo-controlled challenges [7]. One case has been reported of angioedema with onset 16 hours after ingestion of 250 mg MSG, con-firmed by single-blind, placebo-controlled challenge [23]. MSG has also been associated with provocation of asthma in several reports [24,25]; however, this association has not been supported in more recent studies characterized by double-blind, placebo-controlled MSG challenges in high-risk asthmatic subjects (aspirin-sensitive or history posi-tive), in which no reactors were found [26••,27]. AspartameAspartame (NutraSweet; Chicago, IL), a dipeptide of aspar-tic acid in phenylalanine, is a low-calorie artificial sweet-ener 180 times sweeter than sucrose [28]. Aspartame has been reported to cause granulomatous panniculitis [29]. Two cases of aspartame-induced urticaria, confirmed byTable 1.Additives most commonly associated with adverse reactionsFD&C dyesAzo dyesTartrazine (FD&C yellow No. 5)Ponceau (FD&C red No. 4)Sunset yellow (FD&C yellow No. 6)Amaranth (FD&C red No. 5)Nonazo dyesBrilliant blue (FD&C blue No. 1)Erythrosine (FD&C red No. 3)Indigotin (FD&C blue No. 2)Parabens/benzoatesParahydroxybenzoic acidMethylparabenEthylparabenButylparabenSodium benzoateHydroxybenzoic acidButylated hydroxyanisole (BHA)Butylated hydroxytoluene (BHT)NitratesNitritesMonosodium glutamate (MSG)SulfitesSulfur dioxideSodium sulfite, potassium sulfite, bisulfite, metabisulfiteFD&C—Food Dye and Coloring Act.64Food Allergyplacebo-controlled, double-blind challenge have been reported [30] , and additional cases by the same author have also been described [31]; however, other investigators have encountered difficulty recruiting subjects with adverse reactions to aspartame and have found that such subjects do not have reproducible reactions [32,33]. Reports of aspartame-provoked headaches have been variable, with both positive and negative findings, depending on study design [34,35].SulfitesSulfites have been widely used for centuries to freshen and prevent oxidative discoloration (browning) of foods. Sulfites are also used as sanitizers and to inhibit the growth of nondesirable micro-organisms in the fermentation indus-try. Sulfiting agents include sulfur dioxide and sodium potassium sulfite, bisulfite, and metabisulfite. Foods con-taining sulfites are listed in Table 2. Currently, the highest levels of sulfites are found in dried fruits (such as apricots), potatoes, wine, and some seafood items [36]. Sulfiting agents have clearly been shown, in double-blind, controlled studies to be the cause of serious and potentially life-threat-ening asthmatic reactions [37–39]. Although the number of sulfite-sensitive asthmatics remains unknown, reports indi-cate that as many as 5% of the asthmatic population may experience adverse reaction ranging from mild wheezing to severe bronchospasm following ingestion of sulfite-contain-ing foods or beverages [38,40,41]. Although the mechanism of sulfite sensitivity is not fully understood, the overwhelm-ing majority of sensitive asthmatics react via inhalation of sulfur dioxide generated from sulfite solutions in an acidic environment. In two reports (three patients), sulfite-sensi-tive asthmatics with positive skin tests to sulfite, compatible with IgE-mediated pathogenesis, were described [42,43]. Some asthmatics with severe reactions to sulfites may have low levels of the enzyme sulfite oxidase, which is necessary to oxidize sulfite into inactive sulfate [44]. These asthmatics,and skin test–positive asthmatics, may respond to low amounts of sulfite ingested in capsule form; others react only to challenge with sulfite-containing solutions (generat-ing sulfur dioxide). There are isolated case reports of nonas-thmatic reactions to sulfites, including urticaria [45,46]; however, rigorously controlled double-blind, placebo-con-trolled challenges have either not been performed or have not provoked adverse reaction in these individuals. Two cases of anaphylaxis related to sulfite ingestion with positive skin tests have been reported [8,43]. Three reports assessed sulfite sensitivity in subjects with idiopathic anaphylaxis: in one, one subject among 130 challenged was found to be sulfite sensitive [47]; in another, one subject experienced a systemic reaction following a sulfite skin test [48]; a third found no sulfite sensitivity among subjects studied [ 49]. Other AdditivesAnaphylaxis has been attributed to naturally occurring food dyes, including annatto and carmine [10,11], and to erythritol (ERT; 1,2,3,4-butanetetrol), a sweetener [9]. Annatto is a common natural yellow food coloring used to color many foods including cereal, cheese, ice cream, mar-garine, oils, and beverages. Annatto dye extract is produced from the pericarp of the fruit of the annatto tree, Bixa orel-lana. Carmine is a natural red food dye derived from the dried bodies of females of the tropical American insect Cocus cacti, used in foodstuffs such as candy, ice cream, cookies, pastries, syrups, liqueurs, vinegar, cheese, butter, delicatessen meats, jam, and caviar. Erythritol is a four-car-bon sugar alcohol prepared from glucose by fermentation that is used as a sweetener, and may occur naturally in foods such as wine, beer, soy, cheese, mushroom, grape, and watermelon.The flavors spearmint (Mentha spicata), peppermint (Mentha piperita), and menthol (Mentha labiateae), used in chewing gum and toothpaste, have been confirmed by challenges in two cases to have triggered asthma [50,51].Table 2.Sulfite-containing foodsHigh content Moderate content Low content (<10 ppm)*Dried fruit (excluding dark raisins Dried potatoes Corn starch Instant teaand prunes)Wine vinegar Hominy Pizza dough (frozen) Lemon juice (nonfrozen)Gravies, sauces Frozen potatoes Pie doughLime juice (nonfrozen)Fruit topping Maple syrup Sugar (especially beet sugar) Wine Maraschino cherries Imported jams and jellies GelatinMolasses Pectin Fresh mushrooms CoconutSauerkraut juice Shrimp (fresh)Malt vinegar Fresh fruit saladGrape juice (white, white sparkling, Pickled peppers Dried cod Domestic jams and jellies pink sparkling, red sparkling)Pickled cocktail onions Canned potatoes CrackersPickles/relish Beer CookiesDry soup mix GrapesSoft drinks High fructose corn syrup*Foods with low sulfite content have not been implicated in inducing reactions in sulfite-sensitive individuals.ppm—parts per million.Adverse Reactions to Food Additives • Simon65Although hyperactivity in children has been suspected to be due to “additives” [52] , well-controlled studies have failed to support this hypothesis [53].ConclusionsCarefully designed, well-controlled studies have failed to confirm food additives as a cause for chronic idiopathic urticaria/angioedema. Tartrazine and other dyes, ben-zoates, and parabens may occasionally aggravate but have not been reported as the cause of chronic urticaria. Para-bens have been shown to provoke (rarely) anaphylaxis when given parenterally. Sulfites, although not implicated in chronic urticaria, have occasionally been reported to provoke anaphylaxis. MSG has been reported to provoke angioedema in a single case report. Aspartame, BHA, and BHT have been shown to be the cause of isolated cases of chronic idiopathic urticaria. Nitrates and nitrites have not been associated with urticaria/angioedema or anaphylaxis.Studies have also failed to confirm tartrazine (or other azo and nonazo dye)-provoked asthmatic reactions. Sulfites, however, have clearly been shown to produce serious, even life-threatening, asthmatic reactions by several proposed mechanisms. Approximately 3% to 5% of asthmatic patients are sulfite sensitive, most of whom react by inhaling sulfur dioxide generated when sulfites are placed in solution. When the FDA banned adding sulfites to fresh foods in 1986, the frequency, and, therefore, importance of this problem was greatly diminished. Benzoates and parabens have not been conclusively shown to be a significant problem for asthmat-ics, even those who are aspirin sensitive. MSG may occasion-ally produce asthmatic reactions but does not present a problem to most asthmatics. BHA and BHT have not been shown to produce asthmatic problems. Recently, spearmint flavoring has been shown to trigger asthma in two cases. References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:•Of importance••Of major importance1.Simon RA: Adverse reactions to food and drug additives.Immunol Allergy Clin North Am 1996, 16:137.2.Ortolani C, Pastorello E, Fontana A, et al.: Chemicals anddrugs as triggers of food-associated disorder. Ann Allergy1988, 60:358–366.3.Genton C, Frei PC, Pecond A: Value of oral provocation teststo aspirin and food additives in the routine investigation of asthma and chronic urticaria. J Allergy Clin Immunol 1985,76:40–45.4.Pearson D, Shaw S: The Life Extension Companion. New York:Warner Books; 1984.5.Bock SA, Sampson HA, Atkins F, et al.: Double blind, placebo-controlled food challenge (DBPCFC) as an office procedure:a manual. J Allergy Clin Immunol 1988, 82:986–997.6.Sampson HA: Food allergy. Part 2: Diagnosis and manage-ment. 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