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Sensitisation data (human)

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Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
other: Any kind of reliability rating is not considered to be applicable, since human studies/reports are not conducted/reported according to standardised guidelines
Rationale for reliability incl. deficiencies:
other: Reliability rating according to Klimisch is not applicable for sensitisation studies in humans.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Provocation of sulfite sensitive asthma
Author:
Goldfarb, G. & Simon, R.
Year:
1984
Bibliographic source:
J. Allergy Clin. Immunol. 73, 135
Reference Type:
publication
Title:
Adverse reactions caused by metabisulfites, with particular emphasis on contact allergy - a study of 396 patients and review of literature
Author:
Polańska, A. et al.
Year:
2011
Bibliographic source:
Central European Journal of Immunology 36(4): 293 - 297.
Reference Type:
publication
Title:
The spectrum of metabisulphite induced asthmatic reactions; their diagnosis and management
Author:
Baker, G. J. & Allen, D. H.
Year:
1982
Bibliographic source:
Aust. N.Z.J. Med. 12: 213.
Reference Type:
publication
Title:
Oral challenges to detect aspirin and sulfite sensitivity in asthma
Author:
Simon, R.A.
Year:
1994
Bibliographic source:
Allergy Immunol. 26: 216-218.
Reference Type:
publication
Title:
Metabisulfite (MBS) skin testing in 2000 allergy clinic patients
Author:
Wells, J.H.
Year:
1988
Bibliographic source:
J. Allergy Clin. Immunol. 81: 220.
Reference Type:
publication
Title:
Bronchospastic responses to aerosolized metabisulfite in asthmatic subjects: Potential mechanism and cinical implications
Author:
Schwartz, H.J. & Chester, E.H.
Year:
1984
Bibliographic source:
J. Allergy Clin. Immunol. 74: 511-513.
Reference Type:
publication
Title:
Asthma induced by sulfites
Author:
Allen, D.H.
Year:
1985
Bibliographic source:
Food Technol. Australia 37: 506-507.
Reference Type:
publication
Title:
Inhaled metabisulfite sensitivity
Author:
Koepke, J.W. et al.
Year:
1985
Bibliographic source:
Ann. Allergy 54: 213-215.
Reference Type:
publication
Title:
The relationship of inhaled sulfur dioxide reactivity to ingested metabisulfite sensitivity in patients with asthma
Author:
Delohery, J.; et al.
Year:
1984
Bibliographic source:
Am. Rev. Respir. Dis. 130, 1027-1032
Reference Type:
publication
Title:
Oral challenges to detect aspirin and sulfite sensitivity in asthma
Author:
Stevenson, D. D.
Year:
1988
Bibliographic source:
New Engl. Reg. Allerg. Proc. 9, 135-142

Materials and methods

Type of sensitisation studied:
respiratory
skin
Study type:
study with volunteers
Principles of method if other than guideline:
STUDY 1 (Goldfarb & Simon, 1984):
This study was designed to determine by what routes (oral, subcutanoues, and inhalation) and in what doses sulfites pose a risk to sulfite sensitive asthmatics.

STUDY 2 (Polańska et al., 2011):
In this study results of patch tests with sodium metabisulfite performed in 396 patients was presented. All patients were patch tested with European standard set of contact allergens broadened by 1% sodium metabisulfite (pet.). Patch tests' protocol fulfilled recommendations and guidelines of the Allergy Section of the Polish Society Of Dermatology. The readings were performed according to the rules of the International Group Contact Dermatitis Research Group (ICDRG). Detailed clinical history on a possible occupational and nonoccupational contact with the allergen were taken.

STUDY 3 (Baker & Allen, 1982):
In this study oral challenges with metabisulfite were performed. Ten patients were tested. Challenges studies were either performed with capsules of metabisulfite or metabisulfite in acid solution in patients with no response to the capsules.

STUDY 4 (Simon, 1994): the purpose of this study was to find out the prevalence of patients sensitive to both sulfites and aspirin in subjects who were documented to be sensitive to one or the other.

STUDY 5 (Wells, 1988): in this study potassium metabisulfite was tested in 2000 patients. They were tested by prick and intradermal tests as well as by oral challenges.

STUDY 6 (Schwartz & Chester, 1984): in this study the response in eight asthmatic patients to aerolized metabisulfite was examined. Oral and aerosol challenges were carried out. Air samples were examined for the presence of sulfur dioxide, sulfites, and sulfates. Also, a skin prick test was conducted.

STUDY 7 (Allen, 1985): in this study four different tests were conducted in order to investigate the effect of sulfites. Sulfites were tested by oral and inhalation challenge as well as by naso-gastic intubation. Some of the subjects were asthmatics.

STUDY 8 (Koepke et al., 1985): in this study sensitivity to an inhaled sulfite-containing solution was evaluated in 13 asthmatics and ten nonasthmatic controls. Three of the 13 asthma patients were known to be sensitive to ingested sulfite and ten were not sensitive.

STUDY 9 (Delohery, J.; et al., 1984):
In order to test the hypothesis that asthma provoked by ingestion of acidified solutions of metabisulfite is due to inhalation of sulfur dioxide during swallowing, 3 groups of 10 subjects were studied (asthmatics, reactors and non-reactors to ingested metabisulfite and non-asthmatic controls). Patients were challenged, on separate days, with metabisulfite in solution and SO2 gas.

STUDY 10 (Stevenson, D. D., 1988):
In this study, standard procedures for challenges in the Scribbs Clinic and Reseach Foundation are reported between 1979 and 1987. In addition to the standard challenges with aspirin/NSAID, ASA, sulfite sensitivity was assessed with metabisulfite solutions.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: STUDY 1: powder & solution; STUDY 2 - 5: no data; STUDY 6: solutions (inhalation challenge) & no data (oral & dermal challenge); STUDY 7, 8 & 9: solution; study 10: solution/capsules
Details on test material:
STUDY 1:
- Name of test material (as cited in study report): sulfites
- Physical state: powder in gelatin capsules and solution

STUDY 2:
- Name of test material (as cited in study report): 1% sodium metabisulfite (pet.)

STUDY 3:
- Name of test material (as cited in study report): metabisulfite

STUDY 4:
- Name of test material (as cited in study report): sulfites

STUDY 5:
- Name of test material (as cited in study report): potassium metabisulfite
- Molecular formula: K2S2O5

STUDY 6:
- Name of test material (as cited in study report): potassium metabisulfite

STUDY 7:
- Name of test material (as cited in study report): sulfites

STUDY 8:
- Name of test material (as cited in study report): sodium metabisulfite

STUDY 9:
- Name of test material (as cited in study report): sodium metabisulfite

STUDY 10:
- Name of test material (as cited in study report): potassium metabisulfite

Method

Type of population:
general
Ethical approval:
other: STUDY 1 - 7 & 10: no data; STUDY 8 & 9: confirmed and informed consent free of coercion received
Subjects:
STUDY 1:
- Number of subjects exposed: 6 sulfite sensitive asthmatics (SSA)

STUDY 2:
- Number of subjects exposed: 396 patients (treated and diagnosed in the Department of Dermatology, Poznan University of Medical Sciences in Poznań)

STUDY 3:
- Number of subjects exposed: 10 patients

STUDY 4:
- Number of subjects exposed: 70 patients with documented aspirin sensitivity and 33 subjects documented sulfite-sensitive asthmatics.

STUDY 5:
- Number of subjects exposed: 2000 consecutive patients
- Age: 18 years of age and older

STUDY 6:
- Number of subjects exposed: 8 asthmatic patients
- Sex: 2 males / 6 females
- Age: adult

STUDY 7:
- Study A:
Number of subjects exposed: 3 groups of 10 subjects (group 1: asthmatic subjects who reacted to ingested sulfite; group II: asthmatic non-reactors to sulfite; group III: non-asthmatic control subjects)
- Study B:
Number of subjects exposed: 5 sulfite-sensitive subjects
- Study C:
Number of subjects exposed: 15 asthmatic subjects
- Study D:
Number of subjects exposed: 5 subjects

STUDY 8:
- Number of subjects exposed: 13 asthmatics (3 asthmatics were sensitive and 10 asthmatics were not sensitive to sulfite ingestion)
- Sex: 4 males / 9 females (1 male and 2 females were were sensitive and 3 males and 7 females asthmatics were not sensitive to sulfite ingestion)
- Age: 13 to 59 years of age (mean age: 39.8 years)
- Onset of asthma: 2 to 41 years of age
- none of the studied subjects were smokers.

STUDY 9:
- Number of subjects exposed: 3 x 10 subjects, divided in
Group 1: 10 subjects; asthmatic individuals sensitive to ingested metabisulfite
Group 2: 10 subjects; asthmatic individuals not sensitive to ingested metabisulfite
Group 3: 10 control subjects; nonasthmatics not sensitive to ingested metabisulfite (hospital employees, who volunteered for the study)
- Sex: 2 males; 8 females
- Age: 14-69
The members of each group were sex and age-matched to within the decade with members of the other 2 groups, except for one subject.

STUDY 10:
- Number of subjects exposed: ~276 subject, asthmatics and aspirin (ASA) sensitive asthmatics
- Sex: no data
- Age: no data
Clinical history:
STUDY 1 - 3 & 7: no data
STUDY 4: patients were known to be either sensitive to aspirin or sulfites
STUDY 5: six patients had histories suggestive of sulfite sensitivity.
STUDY 6: patients had given a clinical history that they had suffered attacks of asthma, gastrointestinal distress, and in some instances hypotension during restaurant meals.
STUDY 8: based on previous testing the following was known about the subjects: the sulfite-sensitive asthma patients had a decrease in FEV1 of more than 20% following doses between 1 to 25 mg of metabisulfite. The non-sulfite-sensitive asthmatics did not demonstrate a change in pulmonary functions after receiving doses of 1, 5, 10, 25, 50, and 200 mg of metabisulfite at 30 minutes intervals. None of the studied subjects were smokers.
STUDY 9: 15 asthmatic patients (previously undergone food additive challenge testing). The other 5 were known asthmatics (3 with histories suggesting history sensitivity to metabisulfite, who had not undergone previous challenge testing).
STUDY 10: asthmatics and aspirin (ASA) sensitive asthmatics
Controls:
STUDY 1: placebo
STUDY 2 - 6: no data
STUDY 7: study A: non-asthmatic control subjects; citric acid solution alone was used as control during oral challenges
STUDY 8: ten subjects (5 males / 5 females; age: 22 to 55 years old; mean age: 33.9 years) without a history of reactive airways disease and with normal pulmonary function tests were used as controls.
STUDY 9: Group 3: 10 control subjects; nonasthmatics not sensitive to ingested metabisulfite (hospital employees, who volunteered for the study)
STUDY 1:
STUDY 10: placebo challenge one full day with spirometry recorded each hour between 8 AM and 5 PM.
Route of administration:
other: STUDY 1, 3 - 7 & 10: oral; STUDY 1: subcutaneous; STUDY 1, 6 - 8: inhalation; STUDY 2, 5 & 6: dermal; STUDY 5: intradermal; STUDY 7: naso-gastric; STUDY 9: inhalation & oral
Details on study design:
STUDY 1 (Goldfarb & Simon, 1984):
Double blind, placebo controlled graded challenges were performed on the sulfite sensitive asthmatics (SSA). Routes of sulfite administration included oral (powder in gelatin capsules and solution) subcutaneous and inhalation.

STUDY 2 (Polańska et al., 2011):
TYPE OF TEST(S) USED: patch test (epicutaneous test)
All of the patients were patch tested with European standard set of contact allergens broadened by 1% sodium metabisulfite (pet.). Patch tests' protocol fulfilled recommendations and guidelines of the Allergy Section of the Polish Society Of Dermatology. The readings were performed according to the rules of the International Group Contact Dermatitis Research Group (ICDRG). In order to evaluate the clinical significance of allergy in patients with positive test results with sodium metabisulfite, detailed clinical history on a possible occupational and non-occupational contact with the allergen were taken. Particular attention in these patients was paid to the occurrence of adverse reactions during minor surgery with local anaesthetic.

STUDY 3 (Baker & Allen, 1982):
Oral challenge studies were performed, while patients were on additive-free exclusion diets.
Challenge studies were either performed with capsules of metabisulfite and metabisulfite in acid solution in patients with no response to the capsule. The practice is to challenge with capsules containing increasing doses of metabisulfite (10 mg to 300 mg) at 0.5 hourly intervals. If no reaction to 300 mg then the patient is given 25 mg of metabisulfite in 50 mL of 0.5% citric acid.

STUDY 4 (Simon, 1994):
Antihistamine, cromolyn/nedocromil and beta agonists should be withheld for at least twelve hours before the start of the first challenge.
Patients should then undergo a full day of placebo challenges (single-blind) with spirometry recorded each hour between 8 a.m. and 5 p.pm. If the FEV1 value varies by 10% or less during this period of time, then one can proceed with the other challenges. If the FEV1 value varies by more than 10%, a more active treatment for asthma should be instituted (using corticosteroids).
The dosages for a three-day placebo-controlled single-blind aspirin challenge were as follows (challenges at 8 a.m., 11 a.m., and 2 p.m.): day 1: placebo (every time); day 2: 3 aspirin doses or 30 mg, 60 mg aspirin, and 100 mg aspirin; day 3: 150 mg aspirin, 325 mg aspirin, and 650 mg aspirin.
The dosages for sulfite challenge were as follows (challenge with sulfite in capsules; 30 minute intervals): 1, 5, 10, 25, 50, 100, and 200 mg
A positive reaction is defined as a 20% fall in the FEV1 value from baseline.

STUDY 5 (Wells, 1988):
2000 patients who were to be skin tested for any reason were also tested with potassium metabisulfite (1 mg/mL). The first 1000 patients received both prick and intradermal tests, thereafter only intradermal tests were applied.
Oral challenges with the test substance were also carried out (not clear, if testing was conducted with all patients).

STUDY 6 (Schwartz & Chester, 1984):
- aerosol challenges: for challenge, solutions containing 0.05 mg/mL, 0.5 mg/mL, and 5.0 mg/mL were made. The challenge involved the patient inhaling 2 mL of a solution of potassium metabisulfite via a De Vilbiss nebulizer and Pulmo-Aide over a 5- to 10-minute period. The diluent was 0.9% sterile saline. The patient rested 30 minutes before test initiation. Baseline pulse, blood pressure, spirometry, and body plethysmographic studies were obtained. A 0.9% saline diluent challenge was then delivered, and the patient was studied at 15 and 30 minutes afterward and at appropriate intervals throughout the study. Test procedures were reproduced on a separate study day during which time air samples were collected to determine whether or not sulfur dioxide and/or sulfates were produced during nebulization of metabisulfite solutions. Air samples were analysed for the presence of sulfur dioxide, sulfites, and sulfates both when 0.5 mg/mL of potassium metabisulfite was nebulized and when 5 mg/mL was nebulized. Air samples were analysed by chromatography for sulfates and sulfites and by ion chromatography for sulfur dioxide.
A positive response is defined as having a 50% or higher change in measurements of specific airway resistance.

- oral challenges: patients underwent oral metabisulfite challenge (5, 10, 25, and 50 mg). Doses were given by mouth every 30 minutes until a positive result was obtained. Aerosol challenges were carried out a minimum of 4 weeks after the oral challenges had been conducted. A positive response is defined as having a 50% or higher change in measurements of specific airway resistance.

- skin prick testing was conducted.

STUDY 7 (Allen, 1985):
Study A: three groups of 10 subjects were studied: group I were asthmatic subjects who reacted to ingested sulfite; group II were asthmatic non-reactors to sulfite; and group III were non-asthmatic control subjects. Subjects were challenged with 50 mg of sulfite in citric acid solution and, on a separate day with sulfur dioxide gas via a steady-state system at increasing concentrations: 0.5, 1.5, 3, and 5 mg/L. Peak expiratory flow rates were then measured.

Study B: five sulfite sensitive subjects were challenged with the sulfite solution by mouthwash (3 seconds) and by nasogastric tube. Asthma was provoked in all five subjects by the mouthwash but not by the gastric challenge.

Study C: subjects were challenged by mouthwash with incremental doses of sulfite up to 100 mg in 30 mL of citric acid solution. Bronchoconstriction was assessed by calculating the concentration of sulfite in mg per 30 mL of citric acid solution required to produce a 20% fall in forced expired volume in one second.

Study D: release of sulfur dioxide gas in the stomach after ingestion of sulfite (25 - 50 mg) administered in capsules was studied in the subjects by sampling stomach gases via a nasogastric tube.

STUDY 8 (Koepke et al., 1985):
All subjects underwent inhalation challenges using a 0.3% metabisulfite solution (chosen since it is equivalent to that found in isoetharine and isoproterenol). A DeVilbiss #40 nebulizer was used with a DeVilbiss compressed air source. One-half millilitre of the metabisulfite solution, diluted with 2.0 mL of normal saline, was nebulized (final concentration of 0.6 mg/mL sodium metabisulfite). The amount of sulfur dioxide produced during the nebulization of the sulfite solution was measured, using a pulsed fluorescent monitor (result: peak value of 0.8 to 1.2 SO2). Flow volume curves were measured, using a Med Sciences 570 Wedge spirometer with a Hewlett-Packard x-y recorder. The best of three efforts was recorded at each measurement interval.
The patients were studied on two different days. The first day following measurement of baseline pulmonary function tests the subjects were challenged with inhaled sulfite. Each subject took 20 inhalations of the sulfite solution from FRC to TLC. Pulmonary function tests were measured at 3 and 15 minutes following the completion of the inhalation. At the conclusion of the test, 0.5 mL of isoetharine in 2 mL of saline was administered to the asthmatic patients and pulmonary function tests were repeated 3 minutes following the bronchodilator. The same protocol was followed on the second day using inhaled normal saline solution as a control instead of sulfite.

STUDY 9 (Delohery, J.; et al., 1984):
No sympathomimetic inhaler was used for 4 hours prior to challenge but all other medications were continued. One asthmatic in each group was using sodium cromoglycate (Cromolyn). The patients were challenged on separate days:
- Bronchoconstriction measurement (SO2 gas and metabisulfite solutions, single blind and placebo-controlled, baseline and progress peak expiratory flow rates (PEFR))
- Metabisulfite in citric acid challenge (30 ml 0.5 % citric acid control solution, 50 mg metabisulfite dissolved in 30 ml 0.5 % citric acid)
- Histamine sensitivity testing (doubling concentrations from 0.015 mg/ml to 8 mg/ml)
- SO2 gas inhalation studies (control gas of humidified air for 4 min, then on separate day, inhaled increasing concentrations (0.5, 1.5, and 5ppm) of SO2 gas for 4 min, or less (asthma symptoms)
Additional studies:
-Mouthwash and gastric challenges and measurements of headspace SO2 gas above metabisulfite solution, to clarify the mechanism and further identify the site of provocation of asthma by ingest metabisulfite solutions.

STUDY 10 (Stevenson, D. D., 1988):
Between 1979 and 1987, 276 patients (asthmatics and aspirin sensitive asthmatics) were admitted for challenges with aspirin and related substances in the cribs Clinic and Research Foundation. In addition to the standard challenges with aspirin/NSAID, ASA and related analgesics, nonsteroidal anti-inflammatory drugs, dyes, and preservatives, sulfite sensitivity was assessed.
Sulfite Challenges (screening): metabisulfite solutions of 0.5, 1, 5, 10, 25, 450 , 75, 100, and 200 mg (single-blind). FEV1: decline of 20% or > within 20 min after ingestion of solution/capsule.

Results and discussion

Results of examinations:
STUDY 1:
- all 6 sulfite sensitive asthmatics (SSA) reacted to the standard capsule challenge, at 10 - 50 mg sulfite, with >25% fall in FEV1. Sulfite solutions also produced equal reactions in all 6 SSA but with approximately 1/2 the capsule dose.
- no reactions to subcutaneous doses up to 10 mg.
- inhalation of sulfite solutions by nebulization provoked reactions at 1/10 - 1/100 the capsule dose.

STUDY 2:
Positive response in relation to sodium metabisulfite was observed in 26 patients (6.6%). The most frequently observed skin symptoms were hand dermatitis and generalized pruritus. Some patients, reported eruption of wheals and allergic conjunctivitis. Three patients (11.5%) of 26, associated the skin lesions with dental surgery performed with local anaesthesia, while 9 patients (34.6%) reported worsening of skin lesions after ingestion of wine, and 6 (23.1%) after consumption of fresh fruit. Another 6 patients (23.1%) complained about exacerbation of skin after bathing in the pool. None of the patients reported possible occupational exposure associated to sodium metabisulfite.

STUDY 3:
- 8 metabisulfite sensitive patients were identified
- sensitivity to other food additives or salicylic acid, in addition to metabisulfite was seen in 3 of 8 patients. Two patients were sensitive to benzoate or benzoic acid, one to the colouring agent Tartrazine and 3 to salicylic acid.
- 4 patients failed to react to large doses of metabisulfite contained in a capsules but who rapidly bronchoconstricted to an acid solution of metabisulfite.

STUDY 4:
- patients with documented aspirin sensitivity challenged with sulfite did not meet the reaction criteria.
- sulfite-sensitive asthmatics have shown not to be aspirin-sensitive by challenge.

STUDY 5:
- potassium metabisulfite skin test was negative for the six patients with a history suggestive of sulfite sensitivity. When they were challenged orally with potassium metabisulfite, one positive result and one equivocal result were obtained.
- six patients had positive intradermal metabisulfite skin tests and no history of sulfite sensitivity. Two of these six received an unblinded oral metabisulfite challenge and both reacted.

STUDY 6:
- oral challenges: six of the eight oral challenges were positive at doses between 10 mg and 50 mg.
- aerosol challenges: two subjects were negative at all doses used, three subjects reacted at the 0.5 mg/mL dose, and three subjects reacted at the 5.0 mg/mL dose level. All patients who reacted to aerosol challenge demonstrated significant alterations in pulmonary functions 30 minutes after aerosol metabisulfite inhalation. These were most profoundly observed in measurements of specific airway resistance with changes from 51% to 199%. None of the patients reacted to inhalations of diluent only. No delayed or dual bronchospastic responses were observed.
- there did not appear to be a direct relationship between doses required for a positive oral challenge test and the dose at which the aerosol challenge was positive. It is clear that positivity to oral metabisulfite testing was usually but not always accompanied by a positive aerosol test.
- skin prick testing: all patients were tested negative.
- aerosol generated from the metabisulfite solution of 5 mg/mL concentration contained the following: 1.2 ppm sulfur dioxide, particulate sulfates, and no detectable sulfites. Sulfur dioxide, sulfates, and sulfites were not detected in air samples of 0.5 mg/mL metabisulfite solutions.

STUDY 7:
Study A:
- after ingestion of sulfite, the mean fall in peak expiratory flow rate was follows:
group I: 35 ± 14%
group II: 6 ± 6%
group III: 5 ± 3%
- after inhalation of sulfur dioxide, the mean concentration of sulfur dioxide which provoked a 20% fall in forced expired volume in one second was as follows:
group I: 1.19 ± 0.78 mg/L
group II: 2.25 ± 1.42 mg/L
group III: > 5 mg/L
means of group 1 and 2 were not statistically different (p = 0.075; type 2 error is recognised)

Study B:
- asthma was provoked in all five subjects by the mouthwash but not by the gastric challenge.

Study C: nine subjects reacted with a mean sulfite concentration of 37 ± 25 mg. All nine were re-challenged with sulfite mouthwash while holding the breath in order to prevent inhalation of sulfur dioxide; the mean sulfite concentration to produce a 20% fall in forced expired volume for all nine subjects was then greater than 100 mg per 30 mL.

Study D: sulfur dioxide concentrations found ranged from 4 to 50 mg/L and were related to the pH of the stomach contents.

STUDY 8:
- significant difference in reactivity to the sulfite inhalation as measured by the maximum decrease in FEV1 when asthmatics not sensitive to ingested sulfite were compared with the controls. Four of the ten asthmatics not sensitive to sulfite ingestion had a 20% or greater decrease in FEV1 post-sulfite inhalation. Two of the patients exhibited a maximum decrease at 3 minutes and two patients at 15 minutes following completion of the inhalation. None of the ten control subjects had a significant change in FEV1.
- the three patients sensitive to sulfite ingestion all demonstrated a greater than 20% fall in FEV1 from baseline after sulfite inhalation. The fall in FEV1 occurred within 3 minutes of completing the nebulization.
- no subject demonstrated a significant change in pulmonary function tests following the normal saline inhalation.
- all 13 asthma patients studied demonstrated a favourable bronchodilatory response following isoetharine with a return of FEV1 to near or above baseline.

STUDY 9:
- Metabisulfite solution ingestion challenges: airways obstruction in <2min, PEFR after ingestion: 35 ± 14% (Group 1); 6 ± 6% (Group 2).
- Sulfur Dioxide Challenges: mean Pc20.SO2: 1.19ppm ± 0.78 (Group 1); 2.25 ppm ± 1.42 (Group 2); control group had less than 20% fall in PEFR (inhalation 5 ppm)
- Mouthwash and nasogastric tube studies: nasogastric tube and mouthwash: no patient >20% fall in PEFR; brisk bronchoconstriction (mouthwash), similar in onset and severity to that provoked by swallowing the solution.

STUDY 10:
The confirmatory challenge protocol shows only procedures (provoking dosages) for the challenges (single-blind challenge, placebos, solutions/capsules, double-blind dose).

Applicant's summary and conclusion

Conclusions:
STUDY 1:
According to the authors, these data show that sulfite sensitive asthmatics (SSA) have greater sensitivity to solutions of sulfite than previously recognized in capsule form. Also, they stated that the patients studied tolerated subcutaneous doses up to 10 times the amount in usual doses of epinephrine or local anaesthetics and that these 6 SSA were exquistitely sensitive to inhaled sulfites at levels that are fractions of those contained in usual doses of a number of commonly used bronchodilator aerosol solutions.

STUDY 2:
According to the authors, the results suggested the frequent occurrence of contact allergy in relation to metabisulfites, however, not in all cases its connection with the true expsoure can be shown. They mentioned that due to its ubiquitous nature, identification of sodium metabisulfites' source may cause difficulties.

STUDY 3:
The authors stated that they identified 8 metabisulfite sensitive patients by oral provocations studies of 10 patients.

STUDY 4: according to the authors, they have been unable to document cases of cross-sensitivity between aspirin and sulfites. They stated that despite clinical features of overlap, they were unable to document the cross reactivity between sulfite- and aspirin- sensitive subjects.

STUDY 5:
According to the authors, metabisulfite skin test reactivity occurs infrequently in an allergy clinic population, may indicate sulfite sensitivity, and is not necessarily associated with a positive history.

STUDY 6:
According to the authors, six of eight patients tested positive to oral metabisulfite challenge with doses from 10 mg to 50 mg and six of eight patients tested positive to aerosol metabisulfite challenge with doses of 0.5 mg/mL and 5.0 mg/mL. Furthermore, they stat that there did not appear to be a direct relationship between doses required for a positive oral challenge test and the dose at which the aerosol challenge was positive. They mentioned that it showed that positivity to oral metabisulfite testing was usually but not always accompanied by a positive aerosol test. Lastly, the authors indicated that aerosolizing solutions of metabisulfite at 5.0 mg/mL generated significant amounts of free sulfur dioxide.

STUDY 7:
According to the authors, absorption of sulfite from the gastro-intestinal tract is not part of the mechanism of sulfite-induced asthma.

STUDY 8:
According to the authors, all three sulfite-sensitive patients and four of the ten not sensitive to ingested sulfite developed bronchospasm following sulfite inhalation challenges. The control subjects showed no reaction to inhaled sulfite. The authors suggested that this study demonstrated that all asthmatics sensitive to ingested sulfite developed bronchoconstriction with inhaled sulfite. Furthermore, they mentioned that the sensitivity to inhaled sulfite was more common than sensitivity to ingested sulfite in asthmatic patients.

STUDY 9:
According to the authors, metabisulfite-sensitive asthmatics are not supersensitive to inhaled SO2 when compared to non-metabilsulfite sensitive subjects. Group 1 subjects (extremely sensitive to ingested metabisulfite) were similar in sensitivity to inhaled sulfur dioxide to the group 2 subjects (very insensitive to ingested metabisulfite). Sensitivity to ingested metabisulfite is unlikely to be due to supersensitivity to SO2 inhaled during the act of ingestion, as both groups of subjects have similar sensitivities to the gas. Heightened bronchial reactivity to SO2 gas in asthmatic subjects was confirmed and the concetration required to provoke bronchoconstriction is less than previously recognized (<1 ppm). Dose response relationship between increasing SO2 concentration and degree of bronchoconstriction has been confirmed. Concentrations of 5 ppm ma induce severe bronchoconstriction. SO2 sensitivity does not correlate with histamine reactivity (bronchoconstriction effects of SO2 and histamine are mediated by different receptors and/or pathways.

STUDY 10:
According to the authors, the issue of interpreting results of challenges with sulfite solutions has been a source of considerable discussion (cut off point for significant SO2 generation). However, sulfite sensitive patients can react to both solution and capsules of sulfite at higher dosages. If a patient reacts to solution of sulfite from 75 to 200 mg, they are not at very great risk for death from a reaction in the normal course of eating or drinking, whether or not the route of entry is inhalation of SO2. However, avoiding sulfites can prevent asthma attacks in such individuals.