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`
`~- JOURNAL OF THE AMERICAN COLLEGE OF
`
`NUTRITICON
`
`.... '
`
`''.
`'
`·::A·,i·
`--------------~--
`
`Page 1 of 6
`
`SENJU EXHIBIT 2319
`LUPIN v. SENJU
`IPR2015-01105
`
`

`
`Journal of the American College of Nutrition
`
`Volume 14, Number 3, June 1995
`
`EDITORIALS
`Validating Dietary Guidelines
`S. Kumanyika . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Diagnosing Food Allergy
`R. N. Hamburger. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`REVIEW ARTICLES
`Liver and Biliary Tract Changes and Injury Associated with Total Parenteral Nutrition: Pathogenesis and
`Prevention
`E. R. Briones and F. L !her . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Sulfite Sensitivity: Significance in Human Health
`M. R. Lester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`ORIGINAL PAPERS
`Diet DiVersity and Subsequent Cause-Specific Mortality in the NHANES I Epidemiologic Follow-up
`Study
`.
`• A. k. Kant, A. Schatzkin, and R. G. Ziegler. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Meat Allergy: I-Spqcific lgE to BSA and OSA in Atopic, Beef Sensitive Children
`A. Fiocchi, P. Restani, E. Riva, R. Qualizza, P. Bruni, A. R. Restelli, and C. L Galli. . . . . . . . . . . . . .
`
`Meat Allergy 11-Effects of Food Processing and Enzymatic Digestion on the Allergenicity of Bovine and
`Ovine Meats
`A. Fiocchi, P. Restani, E. Riva, A. R. Restelli, G. Biasucci, C. L Galli, and M. Giovannini . . . . . . . . .
`
`Soluble Fiber Enhances the Hypocholesterolemic Effect of the Step I Diet in Childhood
`C. L Williams, M. Bollella, A. Spark, and D. Puder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Effect of N-3 Polyunsaturated Fatty Acid Supplemented Diet on Neutrophil-Mediated Ileal Permeability
`and Neutrophil Function in the Rat
`A. Chawla, P. I. Karl, and S. E. Fisher . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Immune Status of Children with Phenylketonuria
`S. S. Gropper, H-C. C. Chaung, L E. Bernstein, C. Trahms, S. Rarback, and S. J. Weese.... . . . . . . .
`
`Food Selection in Anorectics and Bulimics: Food Items, Nutrient Content and Nutrient Density
`G. van der Ster Wallin, C. Norring, M. A-C. Lennemiis, and S. Holmgren . . . . . . . . . . . . . . . . . . . . .
`
`Bone Composition and Histological Analysis of Young and Aged Rats Fed Diets of Varied Calcium
`Bioavailability
`C. A. Peterson, J. A. C. Eurell, K. W. Kelley, and J. W. Erdman, Jr. . . . . . . . . . . . . . . . . . . . . . . . . .
`
`215
`
`217
`
`219
`
`229
`
`233
`
`239
`
`245
`
`251
`
`258
`
`264
`
`271
`
`278
`
`Daily Energy Metabolism in Patients with Type 1 Diabetes Mellitus
`A. V. Greco, P. A. Tataranni, G. Mingrone, A. De Gaetano, A. Manto, P. Cotroneo, and G. Ghirlanda .
`
`286 · ,t.....--/
`
`Changes in Tissue Calcium and Phosphorus Content and Plasma Concentrations of Parathyroid Hormone
`and Calcitonin after Long-Term Magnesium Deficiency in Rats
`E. Planells, J. Llopis, F. Perlin, and P. Aranda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`292
`
`(continued)
`
`Journal of the Ame,ican College of Nutrition (ISSN 0731-5724) is published bimonthly by the
`American College of Nutrition, c/o Hospital for Joint Diseases, 301 E. 17th St., New York, NY
`10003. POSTMASTER: Send address changes to Journal of the American College of Nutrition,
`P.O. Box 3000, Denville, NJ 07834. Postage paid at New York, NY and at additional mailing
`offices. Subscription price; $40 annually for members (allocated from dues), $75 for nonmember
`individuals, and $150 for institutions. Add $40 for postage if outside the US. Indexed in Index
`Medicus, Excerpta Medica, Science Citation Index, Current Contents/Life Sciences, SciSearch,
`Research Alert, Chemical Abstracts, BIOSIS Data Base, and CABS. Copyright 1995 by the
`American College of Nutrition, Inc. Printed in the USA.
`
`Page 2 of 6
`
`

`
`Review Article
`
`Sulfite Sensitivity: Significance in Human Health
`
`Mitchell R. Lester, MD
`
`Department of Pediatrics, Children's Hospital, Boston, Massachusetts
`
`Key words: sulfite, food additive, sulfite sensitivity, sulfite reactions
`
`Endogenous sulfite is generated as a consequence of the body's normal processing of sulfur-containing
`amino acids. Sulfites occur as a consequence of fermentation and also occur naturally in a number of foods and
`beverages. As food additives, sulfiting agents were first used in 1664 and approved in the United States as long
`ago as the 1800s. With such long experience with their use, it is easy to understand why these substances have
`been regarded as safe. They are currently used for a variety of preservative properties, including controlling
`microbial growth, preventing browning and spoilage, and bleaching some foods.
`It is estimated that up to 500,000 ( <.05% of the population) sulfite-sensitive individuals live in the United
`States. Sulfite sensitivity occurs most often in asthmatic adults--predominantly women; it is uncommonly
`reported in preschool children. Adverse reactions to sulfites in nonasthmatics are extremely rare. Asthmatics who
`are steroi~:dependent or · who have a higher degree of airway hyperreactivity may be at greater risk of
`experiencing a reaction to sulfite-containing foods.
`Eyen wi~hin this limited population, sulfite sensitivity reactions vary widely, ranging from no reaction to
`se;ere. Th~ majority of reactions are mild. These manifestations may include dermatologic, respiratory, or
`gastrointestinal signs aqqlymptoms. Severe nonspecific signs and symptoms occur less commonly. Broncho(cid:173)
`constriction is the m?st common sensitivity response in asthmatics.
`The precise mechanisms of the sensitivity responses have not been completely elucidated. Inhalation of
`sulfur dioxide (S02) generated in the stomach following ingestion of sulfite-containing foods or beverages, a
`deficiency in a mitochondrial enzyme, and an 1gB-mediated immune response have all been implicated.
`The FDA requires labeling of foods containing 10 ppm or more of sulfites. Most sulfite-sensitive individuals
`will, react to ingested sulfite in quantities ranging from 20 mg to 50 mg. Avoidance should be advised in known
`sensitive or high-risk individuals. Sulfiting agents are thought to pose no risk to the majority of the population.
`
`Key teaching points: _
`
`• A small percentage of individuals, primarily adult asthmatics, experience mild, moderate, or severe dermatological, respiratory, or
`gastrointestinal reactions to sulfites.
`• Sulfite-sensitive individuals may react to ingested sulfites found in food or beverages, or inhaled S02 from pharmaceutical agents
`or polluted air.
`• Ingested sulfites may provoke reactions in sensitive individuals in quantities ranging from 20 to 50 mg.
`• Explanations posited for sulfite reactions include sensitivity to inhaled S02 generated in the stomach following ingestion of
`sulfite-containing foods or beverages; inefficient production of the mitochondrial enzyme sulfite oxidase, which promotes
`oxidation of sulfite to s~lfate; and 1gB-mediated mechanisms.
`
`INTRODUCTION
`
`Sulfiting agents have been used for many years by many
`people and for many purposes. The ancient Greeks used S02 to
`fumigate their homes, and the Romans and Egyptians used it to
`cleanse wine receptables [1 ]. As food additives, sulfiting agents
`
`were first used in 1664 and approved in the United States as
`long ago as the 1800s. With such long experience with their
`use, it is easy to understand why these substances have been
`regarded as safe. They are currently used for a variety of
`preservative properties, including controlling microbial growth,
`preventing browning and spoilage, bleaching some foods, such
`
`Reprints not available from author.
`
`Journal of the American College of Nutrition, Vol. 14, No. 3, 229-232 (1995)
`Published by the American College of Nutrition
`
`229
`
`Page 3 of 6
`
`

`
`Sulfite Sensitivity
`
`as maraschino cherries, and modifying the texture of some
`types of dough (2].
`However, during the past decade, questions have arisen
`concerning the safety of these substances as food additives,
`particularly with respect to potential aoverse effects reported
`among at-risk individuals (3].
`Moreover, some studies have failed to clarify the issue of
`risk. This article, therefore, will examine basic information
`about these chemicals, identifying where they exist in the
`environment; evaluating the risk these chemicals pose for the
`general public, based on a review of the literature; and explor(cid:173)
`ing the possibility of adverse effects in those persons most at
`risk, asthmatic patients.
`
`SULFITE SENSITIVITY: PREVALENCE
`AND EXPOSURE
`
`Given the ubiquity of sulfites in our environment, it is
`important to examine the manifestations of sulfite sensitivity
`and to attempt to identify who is at risk for such reactions and
`who is not at risk. Determining the prevalence of sulfite sen(cid:173)
`sitivity has been problematic.
`While approximately 10% of the population is asthmatic,
`based on experimental evidence, only 2% to 5% of asthmatics
`are estimated to I?e sulfite-sensitive (approximately 500,000
`individuals). Not all sulfite-sensitive individuals are asthmatic,
`but asthmatics represent most of the significant sensitivity
`reactions to ingested sulfites. The subgroup of greatest concern,
`therefore, is the sulfite-sensitive asthmatic population, and
`most of these individuals are aware of the need to avoid
`sulfite-containing substances.
`According to Bush and colleagues, "in spite of a great deal
`of attention in the popular media and anecdotal reports, adverse
`reactions to sulfites in nonasthmatics are extremely rare" (1 ]. It
`is the asthmatic patient who appears at greatest risk of experi(cid:173)
`encing sulfite sensitivity reactions. Asthmatics who are steroid(cid:173)
`dependent or who have a higher degree of airway hyperreac(cid:173)
`tivity may be at greater risk of experiencing a reaction to
`sulfited foods. However, it should be noted that numerous
`studies have also noted a great variability of reactions even in
`these high-risk populations, ranging from no reaction to mild,
`moderate, or severe reactions. In all of the studies reported in
`the literature, the investigators call for more research to identify
`the precise mechanisms of the sensitivity responses and to
`account for the variability among sensitive patients.
`The average age of the individual who experiences sulfite(cid:173)
`sensitivity asthma is 40 years; sensitivity occurs predominantly
`in women (4,5]. It is uncommonly reported in preschool chil(cid:173)
`dren, perhaps because their diets include fewer foods with high
`sulfite content and they do not drink beer or wine.
`The amount of sulfite required to produce a response also
`varies. For example, 1 to 5 mg ingested potassium metabisulfite
`provoked a reaction in a sulfite-sensitive person [6]. According
`
`to Simon, most sulfite-sensitive. individuals will react to in(cid:173)
`gested metabisulfite in quantities ~anging from 20 to 50 mg (5].
`In addition to the problem of iden~ifying the precise prevalence
`of sulfite sensitivity, it is also difficult to measure sulfites in
`foods and beverages accurately. According to Bush et al, the
`amount of sulfite added to foods doe~ ~ot reflect the residual
`levels after processing, storage, and preparation [1].
`Estimates of the average daily sulfite consumption in the
`United States range from 7 to 19 mg of sulfur dioxide equiv(cid:173)
`alents (SDE). However, the actual consumption may vary
`widely based on individual patterns of ingestion. For example,
`one report estimated that an average restaurant meal can con(cid:173)
`tain 25 to 100 mg of sulfites [5]. Another study reported the per
`capita intake of sulfite in the 99th percentile of the population
`to be 163 mg of SDE [4]. As a working framework, the average
`consumption is <20 mg of SDE per day. The Food and Drug
`Administration (FDA) requires that foods containing ~10 ppm
`include sulfite in the ingredient label and has also banned the
`use of sulfiting agents on fresh fruits and vegetables. Levels
`<10 ppm cannot be measured and foods that contain <10 ppm
`are not regarded as posing any risk even to the most highly
`sensitive individuals [5].
`The manifestations of sulfite sensitivity are diverse. In the
`majority of instances, the reactions are mild. These manifesta(cid:173)
`tions· may include dermatologic symptoms such as urticaria,
`angioedema, hives and P,ruritus, flushing, tingling, and swell(cid:173)
`ing; respiratory symptoms including dyspnea, wheezing, and
`bronchoconstriction; and gastrointestinal symptoms such as
`nausea and stomach cramps. However, less common but more
`severe nonspecific signs and symptoms, such as hypotension,
`cyanosis, diaphoresis, shock, and loss of consciousness have
`been reported. Bronchoconstrictidn is a common feature of the
`sensitivity responses in asthmatics, particularly in steroid-de-
`pendent asthmatics.
`•
`
`SOURCES OF SULFITES
`
`..._
`
`The principal substances that will be discussed are so2 and
`five sulfite salts (Table 1 ). In addition to their use as additives,
`these substances occur naturally, in varying quantities, as a
`consequence of fermentation, and are, therefore, found in foods
`and beverages such as wine and beer (Table 2).
`Sulfite salts and S02 are water-soluble. Sulfite is a strong
`nucleophilic. anion that is capable of reacting with a variety of
`
`Table 1. Sulfate Salts
`
`Name
`
`Chemical formula
`
`Potassium metabisulfite
`Sodium metabisulfite
`Potassium bisulfite
`Sodium bisulfite
`Sodium sulfite
`
`KzSz03
`Na2S20 3
`KHS03
`NaHS03
`Na2S03
`
`230
`
`VOL. 14, NO.3
`
`Page 4 of 6
`
`

`
`Table 2. Estimated Total S02 Level as Consumed for Some
`Sulfited Food
`
`High Sulfite Level
`(>100 ppm)
`Dried fruit (excluding dark
`raisins and prunes)
`Lemon juice (non-frozen)
`Lime juice (non-frozen)
`Wine
`Molasses
`Sauerkraut juice
`
`Low Sulfite Level
`(10-49.9 ppm)
`Pectin
`Shrimp (fresh)
`Com syrup
`Sauerkraut
`Pickled peppers
`Pickled cocktail onions
`Pickles/relishes
`Com starch
`Hominy
`Frozen potatoes
`Mapl~ syrup:" ·
`Imported jams and jellies
`Fresh mushrooms
`
`Moderate Sulfite Level
`(50-99.9 ppm)
`Dried potatoes
`Grape juice (white, white
`sparkling, pink sparkling,
`red sparkling)
`Wine vinegar
`Gravies, sauces
`Fruit topping
`Maraschino cherries
`
`Undetectable Sulfite Level
`(:;;to ppm)
`Malt vinegar
`Dried cod
`Canned potatoes
`Beer
`Dry soup mixes
`Soft drinks
`Instant tea
`Pizza dough (frozen)
`Pie dough
`Sugar- {esp. beet sugar)
`Gelatin
`Coconut
`Fresh fruit salad
`Domestic jams and jellies
`Crackers
`Cookies
`Grapes
`High fructose com syrup
`
`immunologic components that may potentially lead to toxicity
`[4]. It is important to remember, however, that endogenous
`sulfite is also generated as a consequence of the body's normal
`processing of sulfur-containing amino acids. Cysteine and me-:(cid:173)
`thionine are the amino acids that produce sulfite in the body. In
`normal individuals, endogenous sulfite is maintained at a very
`low, steady-state level. A mitochondrial enzyme, sulfite oxi(cid:173)
`dase, is believed responsible for maintaining this level, and for
`promoting the oxidation of sulfite to sulfate, which is excreted
`in urine [1,2,4]. Because the generation of sulfite from dietary
`cysteine or methionine involves a series of physiologic pro(cid:173)
`cesses, manifestations of endogenous sulfite sensitivity may
`occur more slowly than manifestations that may be associated
`with the direct ingestion of exogenous sulfite [4]. Many inves(cid:173)
`tigators have suggested that a defect in this enzymatic oxidative
`process may account for sulfite sensitivity in some individuals
`in whom ingested and absorbed sulfites increase demand on
`sulfite oxidase and overwhelm its capacity to metabolize sulfite
`to sulfate. In addition, ingested sulfites are converted to S02 by
`the acidic gastric environment. Thus, so2 may be inhaled after
`burping and cause bronchoconstriction in people with airway
`hyperreactivity.
`As noted, sulfites occur- naturally in the body and are also
`added to foods as preservatives. Sulfur dioxide is found in
`
`~
`
`Sulfite Sensitivity
`
`ambient air, particularly in areas with high levels of pollution.
`While the adverse health effects of inhaling polluted air are
`well documented, inhalation of atmospheric so2 poses little
`risk of sulfite sensitivity in the normal individual. However, in
`the sulfite-sensitive person-particularly one with hyperreac(cid:173)
`tive airways--such inhalation can provoke a serious broncho·
`spastic response. The degree of reactivity is dependent upon
`exercise rate, concentration, and the cooling or drying factor of
`the airways.
`Finally, sulfites are added to some parenteral and aerosol(cid:173)
`ized pharmaceutical agents,. notably antibiotics and antioxi(cid:173)
`dants. They are no longer used in bronchodilators. In sensitive
`individuals, worsening of FEY 1 (forced expiratory volume [in
`one second]) and other pulmonary function parameters has
`been noted.
`
`MECHANISMS OF SULFITE
`SENSITIVITY
`
`Understanding the possible pathogenic mechanisms may
`help explain the variability among sulfite-sensitive patients.
`Three major theories have been advanced to explain the ad(cid:173)
`verse effects associated with sulfites in the asthmatic popula(cid:173)
`tion. The most widely held theory is that reactions occur as a
`result of inhalation of so2 generated in the stomach following
`ingestion of sulfite-containing foods or beverages. Simon noted
`that when sulfites are placed in solution, so2 is produced, and
`this production is enhanced in a higher temperature and lower
`pH. The warm, acidic environment of the mouth and stomach
`are prime conditions for the production of Sb2 (Fig. 1) [5]. It
`is well known that asthmatics, particularly steroid-dependent
`asthmatics, have hyperreactive airways and will be more sen(cid:173)
`sitive to this circumstance than other individuals.
`Anibarro and colleagues, as well as Belchi-Hemandez et al,
`have examined the cholinergic pathway in triggering broncho(cid:173)
`spasm in asthmatics [7 ,8]. · Gunnison and Jacobsen summarize
`the data concerning stimulation of the parasympathetic nervous
`system suggested to be operative in the sulfite-sensitive indi(cid:173)
`vidual [4]. Studies showing the full or partial blockade of
`sulfite-induced bronchoconstriction with atropine support the
`
`Air
`
`S02 sulfur dioxide
`N
`H2S03
`sulfurous acid
`tJ, pKa=1.81
`HS03
`bisulfite ion
`~
`tJ, pKa = 6.91
`so3=
`sulfite ion
`~
`t J,
`sulfite oxidase
`.... so4=
`sulfate ion
`Fig. 1. Chemical reactions of sulfites in solution [1 ].
`
`sulfite salts
`
`bisulfite or
`metabisulfite salts
`
`JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
`
`231
`
`- _;;,' : ~
`
`Page 5 of 6
`
`

`
`Sulfite Sensitivity
`
`validity of this theory. These investigators note, however, that
`such mechanisms are present in both asthmatic and nonasth(cid:173)
`matic patients, and suggest that another mechanism may also be
`at work.
`One possible explanation may be that sulfite-sensitive indi(cid:173)
`viduals have a defect in the mitochondrial enzyme, sulfite
`oxidase. This enzyme helps maintain the body's steady-state
`level of endogenous sulfite generated by cysteine and methio(cid:173)
`nine. Sulfite oxidase promotes the oxidation of sulfite to sul(cid:173)
`fate, which is then excreted in urine [1,2,4]. If the body is
`unable to appropriately manage endogenous sulfite generated
`from these specific amino acids, this may account for an
`exaggerated response when that individual is confronted with
`exogenous sulfites found in food, beverages, or pharmaceutical
`agents, or is exposed to air pollution (Fig. 1 ).
`Finally, involvement of the immune system has also been
`suggested by a report of a patient who developed urticaria from
`sulfites and exhibited an immediate skin reaction. This and
`other studies implicate an 1gB-mediated mechanism. However,
`no IgE antibodies to sulfite have been shown directly.
`The multitude of potential mechanisms responsible for the
`diverse signs and symptoms associated with sulfite exposure,
`coupled with the variability of response even among sulfite(cid:173)
`sensitive individuals, tnake it extremely difficult to diagnose a
`priori the person who might experience some type of sensitivity
`effect. Traditional diagnostic protocols are not advised for a
`variety of reasons. The at-risk population is small, and even in
`this at-risk population, skin tests and other easily administered
`procedures to demonstrate specific antisulfite IgE are unreli(cid:173)
`able. Well-controlled challenge testing is potentially dangerous
`for the practicing physician. It should be performed only in
`specialized centers or in a research setting. In the face of these
`obstacles, one must rely on the weight of information gleaned
`from the patient's history and the scientific literature.
`
`CONCLUSION
`
`Reactions to sulfites rarely occur in children and are more
`commonly seen in adults; this may reflect greater exposure to
`S02 or SOrequivalents in the daily diet. It is believed that only
`
`a very small percentage of individuals are at risk of experienc(cid:173)
`ing adverse effects, and the vast majority of at-risk patients are
`adult asthmatics. Sensitivity reactions are exceedingly rare in
`nonasthmatics, but may be seen in up to 5% of patients with
`asthma, most of whom are steroid-dependent [1-7]. Thus, in
`this high-risk group, one might !dvise ca~tion and/or avoidance
`with respect to sulfited foods, beverages, and pharmaceutical
`agents (Table 2). However, among the general population, such
`caution need not be exercised.
`
`ACKNOWLEDGMENT
`
`This work was supported by a grant from Welch's.
`
`REFERENCES
`
`1. Bush RK, Taylor SL, Busse W: A critical evaluation of clinical trials
`in reactions to sulfites. J Allergy Clin Immunol 78:191-201, 1986.
`2. Taylor SL, Bush RK, Selner JC, Nordlee JA, Wiener MB, Holden
`K, Koepke JW, Busse WW: Sensitivity to sulfited foods ·among
`sulfite-sensitive subjects with asthma. J Allergy Clin lmmunol 81:
`1159-1167, 1988.
`3. Wuthrich B: Adverse reactions to food additives. Ann Allergy
`71:379-384, 1993.
`4. Gunnison AF, Jacobsen DW: Sulfite hypersensitivity: a critical
`review. CRC Crit Rev Toxicol185-214, 1987.
`5. Simon RA: Sulfite challenge for the diagnosis of sensitivity. Allergy
`Proc 10:357-362, 1989.
`6. Stevenson DD, Simon RA: Sensitivity to ingested metabisulfites in
`asthmatic subjects. J Allergy Clin Immunol 68:26-32, 1981.
`7. Anibarro B, Caballero T, Garcia-Arj MC, Diaz-Pena JM, Ojeda JA:
`Asthma with sulfite intolerance in ~hlldren: a blocking study with
`cyanocobalamin. J Allergy Clin lmmunol 90:103:-109, 1992.
`8. Belchi-Hemandez J, Florido-Lepez JF, Estrada-Rodriq~ez JL, Mar(cid:173)
`tinez-Alzamora F, Lopez-Serrano C, Ojeda-O.sas JA: Sulfite(cid:173)
`induced urticaria. Ann Allergy 71:23~232, 1993.
`9. Life Sciences Research Office: "The randomization of the GRAS
`studies of sulfiting agents." Report by the Federation of American
`Societies for Experimental Biology, January 1985.
`
`Received July 1994; revision accepted December 1994.
`
`232
`
`VOL. 14, NO. 3
`
`Page 6 of 6