Adverse reactions
`to sulfites
`
`William H. Yang,"’ MD, FRCPC
`Emerson C.R. Purchase,* MD, FRCPC
`
`Sulfites are widely used as preservatives in the food
`and pharmaceutical industries. In the United States
`more than 250 cases of sulfite-related adverse
`reactions, including anaphylactic shock, asthmatic
`attacks, urticaria and angioedema, nausea, abdomi-
`nal pain and diarrhea, seizures and death, have
`been reported, including 6 deaths allegedly associ-
`ated with restaurant food containing sulfites. In
`Canada 10 sulfite-related adverse reactions have
`been documented, and 1 death suspected to be
`sulfite-related has occurred. The exact mechanism
`
`of sulfite-induced reactions is unknown. Practising
`physicians should be aware of the clinical manifes-
`tations of sulfite-related adverse reactions as well as
`which foods and pharmaceuticals contain sulfites.
`Cases should be reported to health officials and
`proper advice given to the victims to prevent
`further exposure to sulfites. The food industry,
`including beer and wine manufacturers, and the
`pharmaceutical industry should consider using al-
`ternative preservatives. In the interim, they should
`list any sulfites in their products.
`
`On utilise beaucoup les sulfites comme agents de
`conservation dans les
`industries alimentaire et
`pharmaceutique. Aux Etats-Unis on a rapporté plus
`de 250 cas d’effets nuisibles des sulfites, y compris
`choc anaphylactique, asthme, urticaire et oedéme
`géant, nausée, douleurs abdominales et diarrhée,
`convulsions et méme décés; 6 décés seraient reliés 5
`la consommation de sulfite dans un restaurant. Au
`Canada on dénombre 10 cas, dont 1 mortel, ou l’on
`soupconne le r6le d’un sulfite. La pathogénése de
`ces accidents est inconnue. Le praticien doit étre au
`courant de leurs manifestations cliniques et savoir
`quels sont les aliments et les médicaments conte-
`nant des sulfites. On devrait rapporter aux autori-
`tés de santé des cas d’effets nuisibles des sulfites et,
`afin d’éviter l’exposition additionnelle, donner aux
`victimes des conseils adéquats. L’industrie alimen-
`taire, y compris brasseries et établissements oenoco-
`les, et l’industrie pharmaceutique devraient recou-
`
`Immunology,
`From the Section of Allergy and Clinical
`Department of Medicine, Ottawa Civic Hospital and Ottawa
`General Hospital, University of Ottawa
`
`‘Clinical assistant professor, Department of Medicine, Uni-
`versity of Ottawa
`
`Reprint requests to: Dr. William H. Yang, 1081 Carling Ave.,
`Ste. 800, Ottawa, Ont. KIY 4G2
`
`i
`
`la on
`rir 5 d’autres agents de conservation. D’ici
`devrait signaler
`la présence de sulfites sur
`les
`étiquettes.
`
`S ulfites are widely used in food processing to
`
`sanitize fermentation equipment and food
`containers,
`to reduce or prevent microbial
`spoilage of foods, to selectively inhibit undesirable
`microorganisms in fermentation industries and to
`prevent oxidative discolouration and nonenzyme
`browning during preparation, distribution and
`storage of food.” Apparently the earliest known
`use was in the treatment of wines with sulfur
`dioxide in Roman times.‘
`
`Six sulfiting agents have been listed by the
`United States Food and Drug Administration
`(FDA) as generally recognized as safe (GRAS) for
`use in food since 1959:“ sulfur dioxide (S0,),
`sodium sulfite (Na2SO,), sodium and potassium
`bisulfite (NaHSO3 and KHSO3), and sodium and
`potassium metabisulfite (Na2S2O5 and KZSZO5). The
`FDA allows the addition of sulfites to non-thia-
`mine—containing foods and drinks without disclo-
`sure or other restrictions.” Rats maintained on
`diets providing adequate thiamine suffered no ill
`effects attributable to consumption of sulfites, up
`to 300 mg/kg per day.‘ Thiamine—deficient rats,
`however, showed toxic effects at doses as low as 50
`mg/kg per day. Furthermore, although federal and
`state regulations prohibit the use of preservatives
`in ground beef, the addition of sulfites and other
`preservatives to ground beef to preserve the red
`colour has been common practice in the state of
`New York.”
`
`Sulfites are used in restaurant foods to keep
`salad-bar vegetables and fruits looking fresh and
`to prevent browning in avocado dips. They are also
`used in seafood, potatoes, beer, wine, fruit drinks,
`baked goods and dried fruits and in the processing
`of some food ingredients,
`including beet sugar,
`corn sweeteners, food starches and gelatin.3'3-1°!“ In
`addition, many pharmaceuticals contain sulfites as
`antioxidants: they include bronchodilators, such as
`Alupent, Bronkosol, Isuprel, Micronefrin and Va-
`ponefrin;
`injectable Adrenalin;
`local anesthetics,
`such as Novocain and Xylocaine;
`injectable cor-
`ticosteroids,
`including Celestone, Decadron and
`Hydrocortone;
`injectable
`antibiotics,
`including
`Amikin, Garamycin and Nebcin;
`injectable an-
`tiarrhythmics, including Pronestyl; injectable lido-
`caine; analgesics,
`such as Demerol; antishock
`agents, including Aramine, Intropin and Levophed;
`CAN MED ASSOC], VOL. 133, NOVEMBER 1, 1985
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`ophthalmic drops, including dexamethasone, Pred
`Mild, Pred Forte, prednisolone and sulfacetamide;
`and solutions for total parenteral nutrition and
`dialysis.“*1"
`In Canada manufacturers are required to dis-
`close the presence of sulfiting agents in all manu-
`factured foods and beverages except wine and beer.
`The maximum concentration of sulfiting agents
`allowed in various foods and drinks is shown in
`Table I.
`
`The average person consumes 2 to 3 mg of
`sulfites per day. Wine and beer drinkers consume
`up to 10 mg/d. Restaurant foods may have the
`highest quantity, and those who eat in restaurants
`may ingest up to 150 mg/d.
`
`Clinical manifestations
`
`A level of sulfur dioxide as low as 1 part per
`million (ppm) may provoke airway obstruction in
`subjects with asthma." However, it is reported that
`0.1 to 0.6 ppm of sulfur dioxide may be generated
`during nebulization of bronchodilator solutions
`(e.g., Alupent, Bronkosol, Isuprel and Micronef-
`rin).13 In 1976 Prenner and Stevens” reported the
`first case of anaphylaxis following ingestion of
`sodium metabisulfite in a restaurant salad. Skin
`
`testing and passive transfer testing gave positive
`results, which suggested an IgE-mediated reaction.
`Subsequently it was reported that sulfur dioxide in
`orange drinks could induce asthma attacks.” In
`1977 Stevenson and Simon“ reported on four
`subjects with asthma who were sensitive to meta-
`bisulfites. Using single-blind provocative chal-
`lenge testing with oral gelatin capsules containing
`lactose alone (placebo) or potassium metabisulfite
`in graduated doses of 1, 5, 10, 25 and 50 mg, they
`showed a significant decline in forced expiratory
`volume in 1'second (FEV,) and forced vital capacity
`(FVC) in the subjects. The drop in FEV1 and FVC
`was promptly relieved by an aerosol bronchodila-
`tor. Prick skin testing with potassium metabisul-
`fite gave negative results. There was no peripheral
`basophil histamine release after the addition of
`metabisulfite at concentrations ranging from 10*‘
`M to 10“° M. While these investigators could not
`find evidence of an IgE-mediated reaction,
`they
`postulated that activation of cholinergic reflexes
`could account for the clinical signs and symptoms
`in their four patients.
`Sulfites were subsequently reported to produce
`a wide spectrum of severe adverse reactions, in-
`cluding
`anaphylaxis,1“1
`urticaria
`and
`angio-
`edema,“ asthma,“»2‘-25 abdominal pain and diar-
`rhea,“ seizures“ and death.5'7'27
`
`Incidence
`
`The exact incidence of sulfite sensitivity is not
`known. It has been estimated that 5% to 11% of
`people with asthma may be sensitive to metabisul-
`fites;73‘ thus, approximately 450000 to 990000 of
`the 9 million people with asthma in North Ameri-
`
`866
`
`CAN MED ASSOC _l, VOL. 133, NOVEMBER 1, 1985
`
`ca may be sulfite-sensitive.’ It has recently been
`documented that 30% of the reported cases of
`sulfite sensitivity have been in people with no
`known history of asthma? The exact incidence of
`sulfite sensitivity in the nonasthmatic atopic popu-
`lation and in the general population remains
`virtually unknown; further studies are required to
`explore this.
`The FDA has received more than 250 reports
`of suspected sulfite-related reactions; as of Febru-
`ary 1984 the FDA had received 6 reports of deaths
`allegedly associated with restaurant food contain-
`ing sulfites.” In Canada 10 sulfite-related adverse
`reactions have been reported, and 1 death suspect-
`ed to be sulfite-related has occurred (unpublished
`data, 1985).
`
`Mechanism
`
`n
`
`The exact mechanism of sulfite-induced reac-
`tions remains unknown.” An IgE-mediated mech-
`anism is suggested by the immediate onset of the
`reaction (e.g., anaphylaxis, bronchospasm, urticaria
`and angioedema, and rhinoconjunctivitis) and by
`positive results of scratch and intradermal skin
`testing with sodium bisulfite, 10 mg/mL, and
`passive transfer
`testing.” We reported on four
`patients” (one with anaphylaxis and three with
`asthma) who were found to be sensitive to potassi-
`um metabisulfite in single-blind provocative chal-
`lenge testing according to the protocol of Steven-
`son and Simon.“ Three of
`the four also had
`positive results of skin tests with potassium meta-
`
`Table I-—-Maximum concentration of sulfites allowed in
`various
`foods and drinks in Canada (B.L. Huston:
`personal communication, 1984)
`
`Food or drink
`
`Concentration, parts
`per million tppiri'i*
`
`Fresh or prepared foods and dips in
`salad bars
`Dried fruits and vegetables
`Apple or rhubarb jam, fancy, refiner’s
`or table molasses, fig or pineapple
`marmalade with pectin, frozen sliced
`apples, fruit juices, gelatin, jelly with
`pectin, mincemeat, pickles and
`relishes, tomato paste, tomato puree
`Unstandardized foods'l'
`Beverages
`Frozen mushrooms
`Cider, honey, wine
`Glucose. glucose syrup
`Glucose solids, dried glucose syrup
`Dextrose anhydrous, dextrose
`monohydrate
`Ale, beer, light beer, malt liquor, porter.
`stout
`
`Unlimiteo
`2500
`
`20
`
`15
`
`*1 ppm " 1 mg/kg or 1 mg/L.
`thiamine or
`’FExcept
`those recognized to be a source of
`unstandardized preparations of meat or meat bv~proclucts
`fish, or poultry or poultry by-products.
`iln free state: 350 ppm in combined state as sulfur Cll0XlLl6-'5
`
`Page 2 of 4
`
`

`
`bisulfite, 1 mg/mL (one prick and two intrader-
`mal). Passive transfer testing gave positive results
`in both patients in whom it was carried out.’
`Interestingly, when the serum from these two
`patients was heated to 56°C for 1 hour, passive
`transfer was not demonstrable, which suggested
`that an IgE-mediated mechanism was involved.
`Another possible mechanism is stimulation of
`an orobronchial reflex — possibly due to inhala-
`tion of
`sulfur dioxide during swallowing or
`mouthwashing.”
`More recently Jacobsen and colleagues” dis-
`covered that in sulfite-sensitive subjects with asth-
`ma, sulfite oxidase activity in fibroblasts may be
`reduced.
`Interestingly, cyanocobalamin (vitamin
`B12), 1000 to 5000 ug taken orally, may fully or
`partially block the asthmatic response on challenge
`with metabisulfites.
`
`Conclusions
`
`Practising physicians should be aware of the
`clinical manifestations of sulfite-related adverse
`reactions. Single-blind provocative challenge test-
`ing with oral potassium metabisulfite carried out
`under close supervision by experienced specialists
`is necessary to confirm the diagno5is.“'“'29 Physi-
`cians are urged to report documented sulfite-relat-
`ed adverse reactions to the Food Additives and
`Contaminants Section, Chemical Evaluation Divi-
`sion, Bureau of Chemical Safety, Health Protection
`Branch, Department of National Health and Wel-
`fare, Tunney’s Pasture, Ottawa, Ont. KIA 0L2.
`The ultimate question is, Should sulfites be
`banned? In the United States the National Restau-
`rant Association (NRA) has advised its members,
`who operate 100000 food service outlets, to stop
`using sulfites;"“-1‘ in June 1984 the NRA reported
`that only 4% of its members had continued to use
`sulfites.” The FDA has asked retail food establish-
`ments, including grocery stores and restaurants, to
`inform consumers by signs or notes that sulfiting
`agents have been used. In addition, the FDA has
`advised food processing companies, interstate con-
`veyers and caterers that consumers must be noti-
`fied if sulfites are used on foods that are eaten
`raw."
`safe
`that sulfites are not
`is now clear
`It
`preservatives.“ Consideration should be given to
`using alternatives to sulfiting agents. Agents such
`as 1% to 2% citric acid can prevent browning of
`vegetables such as cauliflower, radishes and pota-
`toes for up to 2 hours at room temperature. For
`long-term protection, 1% citric acid and 0.5% to 1%
`ascorbic acid can extend shelf life up to 7 days.
`One of the advantages of ascorbic acid is that it is
`a nutrient and thus would be favourably viewed by
`the consumer.’ For economic reasons, citric acid
`and erythorbic acid could be used.‘''7 In the interim,
`for consumer protection the food industry, includ-
`ing wine and beer manufacturers, and the pharma-
`ceutical industry should voluntarily list any sul-
`fites in their products.
`
`We are grateful to Dr. Bev Huston, head, Additives and
`Contaminants Section, Chemical Evaluation Division,
`Bureau of Chemical Safety, Health Protection Branch,
`Department of National Health and Welfare, for provid-
`ing the information in Table 1. Our special thanks to
`Drs. Ian Hart, Michel Drouin, Robert Rivington, David
`Copeland and André Peloquin, for their constructive
`criticism and for referring patients, and our office staff,
`for their technical assistance.
`This study was supported by the Dr. Roy Horo-
`vitch Memorial Fund, Department of Medicine, Ottawa
`Civic Hospital.
`
`References
`
`1. Joslyn MA, Braverman JBS: The chemistry and technology
`of the pre-treatment and preservation of fruit and vegetable
`products with sulfur dioxide and sulfites. Adv Food Res
`1954; 5: 97-147
`. Chichester DF, Tanner FW Jr: Sulfur dioxides and sulfites.
`In Furia TE (ed): Handbook of Food Additives, 2nd ed, CRC
`Pr, Cleveland, Ohio, 1972: 142
`. IFT Scientific Status Summary: Sulfites as Food Additives,
`Institute of Food Technologists, Chicago, 1975
`. A scientific status summary by the Institute of Food
`Technologists’ Expert Panel on Food Safety and Nutrition
`and the Committee on Public Information: Sulfites as food
`additives. Nutr Rev 1976; 34: 58-62
`. Hecht A, Willis J: Sulfites: preservatives that can go wrong.
`FDA Consum 1983; Sept: 11
`. Andres C: Sulfites still
`receiving major attention: new
`sulfite alternatives introduced. Food Process 1984; Mar: 34
`. Nolan AL: The sulfite controversy. Food Eng 1983; Oct: 84-
`85, 89-90
`. Code of Federal Regulations, title 21: Food and Drugs (pt
`10-199), Office of the Federal Register, General Services
`Administration, Government Printing Office, Washington,
`1976
`. Karasz AB, Maxstadt JJ, Reher J et al: Preservatives and
`artificial sweeteners — rapid screening procedure for the
`determination of preservatives in ground beef: sulfites,
`benzoates, sorbates, and ascorbates. J Assoc Off Anal Chem
`1976; 59: 766-769
`. Lecos C: Food preservatives: a fresh report. FDA Consum
`1984; Apr: 23-25
`. Levine AS, Labuza TP, Morley JE: Food technology. N Engl
`J Med 1985; 312: 628-634
`. Twarog F], Leung DYM: Anaphylaxis to a component of
`isoetharine (sodium bisulfite). JAMA 1982; 248: 2030-2031
`. Koepke JW, Selner JC, Dunhill AL: Presence of sulfur
`dioxide in commonly used bronchodilator
`solutions. J
`Allergy Clin Imm unol 1983; 72: 504-508
`. Simon RA: Adverse reactions to drug additives. J Allergy
`Clin lmmunol 1984; 74: 623-630
`. Huang AS, Fraser WM: Are sulfite additives really safe? [C].
`N Engl J Med 1984; 311: 542
`. Schwartz HJ, Sher TH: Bisulfite sensitivity manifesting as
`allergy to local dental anesthesia. J Allergy Clin lmmunol
`1985; 75: 525-527
`. Boushey HA: Bronchial hyperreactivity to sulfur dioxide:
`physiologic and political implications. 1 Allergy Clin Im-
`munol 1982; 69: 335-338
`. Koepke JW, Selner JC, Dunhill AL: SO; derived from
`bronchodilator solutions [abstr]. J Allergy Clin lmmunol
`1983; 71: 147
`. Prenner BM, Stevens JJ: Anaphylaxis after ingestion of
`sodium bisulfite. Ann Allergy 1976; 37: 180-182
`. Freedman B]: Asthma induced by sulfur dioxide, benzoate
`and tartrazine contained in orange drinks. Clin Allergy
`1977; 7: 407-415
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`
`867
`
`continued on page 880
`
`Page 3 of 4
`
`

`
`to his practice and to his exercise routine over the
`next 6 weeks. Sequelae 15 months later included
`occasional slight loss of balance and low weight.
`
`V Discussion
`
`Torteni noted the absence of a pathognomonic
`syndrome and the presence of misconceptions that
`hinder the diagnosis of leptospirosis in humans‘
`Gutman and coworkers‘ emphasized this problem
`in their account of a patient with leptospirosis that
`was signalled by an ocular disorder. Avery’ and
`Hart and colleagues‘ described the behavioural and
`soclal sconseflllences of .mlsSed !agnoses'
`a.nd
`Cheng specified leptospiral arteritis as a major
`cause of cerebrovascular di5ea5e-
`The use of rapid, accurate methods for detect-
`ing leptospires in blood and urine along with the
`IHA test for early antibodies can facilitate diagno-
`sis. However, the immune response to leptospiral
`infection is highly variable, and, therefore, serolog-
`ic testing alone should not be depelnded upon to
`. establish the diagnosis. Culture of b cod and urine
`samples with commercially available albumin-
`polysorbate-80 medium is now practical and
`should always be done in patients at
`risk of
`leptospirosis. Treatment with doxycycline is indi-
`cated because of its specificity, its ability to pene-
`trate into the cerebrospinal fluid and the anterior
`chamber of the eye, and its long half-life (16 hours)
`in the body.‘
`The potential for exposure of Canadians to
`leptospiral infection increases with the amount of
`time spent with livestock. The risk of this debili-
`tating disease, with its serious sequelae, merits
`much concern: public health authorities should
`obtain survey data, veterinarians should caution
`clients and coworkers and try to control
`the
`sources of infection, and the medical profession
`should recognize leptospirosis as a zoonosis indig-
`enous to Canada.
`
`References
`
`. Torten M: Leptospirosis. ln Steele JH (ed): CRC Handbook
`Series in Zoonosis, vol 1, CRC Pr, Boca Raton, Fla, 1979:
`363-421
`
`. Gutman I, Walsh J B, Knapp AB: Cotton-wool spots as a sign
`in leptospirosis. Ophthalmologica 1983; 187: 133-136
`
`. Avery TL: Leptospirosis and mental illness [C]. NZ Med J
`1983; 96: 701
`
`. Hart RJC, Gallagher I, Waitkins S: An outbreak of lepto-
`spirosis in cattle and men. Br Med J 1984; 288: 1983-1984
`
`. Cheng M-K: A review of cerebrovascular‘ surgery in the
`People's Republic of China. Stroke 1982; 13: 249-255
`
`. McClain JBL, Ballou WR, Harrison SM et al: Doxycycline
`therapy for leptospirosis. Ann Intern Med 1984; 100: 696-698
`
`Addison, pernicious
`continued from page 857
`
`Disease of the Supra—renal Capsules, Samuel Highley,
`London, 1855
`. Garrison F: An Introduction to the History of Medicine, 4th
`ed, Saunders, Philadelphia, 1929: 422-423
`. White IR, MacDonald DM: Thomas Addison, MD. First
`dermatologist at Guy's Hospital. 1 Am Acad Dermatol 1982;
`6: 426_430
`. Long ER: A History of Pathology, Dover, New York, 1965:
`93
`. Upstairs, downstairs at Guy's: Addison, Bright, and Hodg-
`kirk HOSP PMCI1977: 12(5): 119-131
`fif5:;"7!’8‘f";‘9';
`-
`:§4D"5'~’359: 3”‘ ed: CC
`. Hale-White W: Thomas Addison, M.D. Guy's Hosp Rep
`1929;76:253_279
`. Medvei VC: A History of Endocrinology, MTP Pr, Hing-
`ham, Montana, 1982: 225-244
`. Addison T: On the Constitutional and Local Effects of
`Dim‘? 0‘ '1"? 5"P’“°""1 CaP5"1°5r Samuel Hi8h19Yr
`1855‘ 4
`
`lbid: 8
`'
`. Hilton J: Discussion of Dr. Addison's paper on anaemia.
`'
`'
`Med Gazette 1849; 43: 562-563
`. Addison T: On the Constitutional and Local Effects of
`Disease of the Supra-renal Capsules, Samuel Highley,
`London, 1855: 3
`. Wilks 6: Daldy (eds): Prefatory remarks on disease of the
`supra-renal capsules.
`In A Collection of the Published
`Writings of the Late Thomas Addison, M.D., New Syden-
`ham Society, London, 1868
`. Bishop PMF: Dr. Addison and his work. Guy's Hosp Rep
`1955;104:275—294
`.Wilks S, Bettany G: A Biographical History of Guy's
`Hospital, Ward, Lock Bowden, London, 1892: 223-234
`
`Adverse reactions
`continued from page 867
`
`. Stevenson DD, Simon RA: Sensitivity to ingested metabi-
`sulfites in asthmatic subjects. J Allergy Clin lmmunol 1981;
`68: 26-32
`
`. Schwartz H]: Sensitivity to ingested metabisulfite: varia-
`tions in clinical presentation. J Allergy Clin lmmunol 1983;
`71: 487-439
`. Habenicht HA, Preuss L, Lovell RC: Sensitivity to ingested
`metabisulfites: cause of bronchiospasm and urticaria. lm-
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`.Schwartz H], Chester EH: Bronchospastic responses to
`aerosolized metabisulfite in asthmatic subjects: potential
`mechanisms and clinical implications. J Allergy Clin Im-
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`. Stevenson DD, Simon RA: Sulfites and asthma [E].
`469-472
`. A growing concern over sulfites. Chem Week 1983; Nov: 16
`. Sulfite update. FDA Drug Bull 1984; 14 (3): 2.4
`. Twarog F] : Metabisulfite sensitivity in asthma. Allergy
`Proc 1983; 4: 100-103
`. Yang WH, Purchase ECR, Rivington RN: Positive Praus—
`nitz—Kiistner reaction in metabisulfite sensitive subjects
`[abstr]. J Allergy Clin lmm unol 1985; 75: 373
`. Delohery J, Castle W, Simmul R et al: Metabisulfite and
`SO; reactivity in asthmatics [abstr]. J Allergy Clin Immunol
`1984; 73: 136
`. Jacobsen DW, Simon RA, Singh M: Sulfite oxidase defi-
`ciency and cobalamin protection in sulfite-sensitive asth-
`matics (SSA) [abstr]. lbid: 135
`
`lbid:
`
`CAN MED ASSOC J, VOL. 133, NOVEMBER 1, 1985
`
`For prescribing information see page 923 —>
`
`Page 4 of 4