Esta - solfiti

Testo originale: http://www.efsa.eu.int/science/nda/nda_opinions/catindex_en.html XX. ADVERSE REACTIONS TO SULPHITES
SUMMARY
Sulphites, or sulphiting agents, are defined as sulphur dioxide (SO2) and several inorganic sulphite
salts that may liberate SO2 under appropriate conditions. They can occur naturally in foods as a
consequence of fermentation, but they are also added to foods as preservatives. The prevalence
of sulphite sensitivity in the general population is unknown, but it appears to be rare among non-
asthmatics. Most reactions to sulphites are characterised by severe bronchospasm, which can
occur within minutes after ingestion of sulphite-containing foods.
The smallest concentration of sulphites able to provoke a reaction in sensitive individuals has not
been determined. Use of sulphating agents in fruits and vegetables intended to be consumed raw
appears to be responsible for several cases of sulphite-induced bronchospasm.
This led to the prohibition of sulphite use in raw fruits and vegetables by the United States Food
and Drug Administration, which also requires labelling of foods containing sulphating agents in
concentrations of 10 ppm (10 mg/kg) or more. Though the threshold for sensitivity reactions may
be even lower, the regulation is based on the fact that the assay used to detect the level of
sulphites in foods is not sensitive enough to detect amounts less than 10 mg/kg.

1. BACKGROUND
Although adverse reactions to ingested sulphites were first reported in 1976 (Prenner and
Stevens, 1976), it was not until after 1980 that reports on sulphite sensitivity became sufficiently
common to attract the attention of the scientific community, consumer groups and regulatory
agencies (Gunnison and Jacobsen, 1987). Despite the increased amount of data that has
accumulated on sulphites as the interest of the medical community on the issue has grown in
recent years, several questions regarding prevalence, pathogenesis and best protection of
sulphite-sensitive patients remain to be settled.
1.1 Chemistry and possible sources of exposure to sulphites
Sulphites, or sulphiting agents, are defined as sulphur dioxide and several inorganic sulphite salts
that may liberate SO2 under appropriate conditions. These include sodium and potassium
metabisulphites (Na2S2O5, K2S2O5), sodium and potassium bisulphites (NaHSO3, KHSO3) and sodium
and potassium sulphites (Na2SO3, Na2SO3) (Simon, 1998). The structural formula of the sulphite ion
is given in Figure 1.

Figure 1. Structural formula of the sulphite ion
Sulphites are a well-recognised part of the human natural and artificial environment.
Considerable quantities of them are generated in the body by normal catabolic processing of
sulphur-containing compounds, notably the amino acids cysteine and methionine (Cooper, 1983;
Gunnison and Jacobsen, 1987). In foods, sulphites can occur naturally as a consequence of
fermentation (e.g. during the fermentation of wine) (Taylor et al., 1986), but they are also added
to foods and used as preservatives, a practice that has been implemented for centuries (Bush et al.,
1986a). Sulphites can also be found in medications, including those used for the treatment of
allergic reactions (Nicklas, 1989). Finally, individuals are daily exposed to SO2 as part of the air
pollution mix.

1.2 Sulphites in foods
As previously indicated, sulphites can occur naturally in foods as a consequence of fermentation,
but they are also added to foods as preservatives. Though sulphites were already used in antiquity
by Egyptians to cleanse their wine vessels, their first recorded use as food preservatives occurred
in 1664, when cider was stored in flasks of SO2 to retard spoilage. In the United States, SO2 has
been widely used since the late 1800 and the sulphite salts since
1920; they were first used in the manufacture of wine and beer and their use expanded to several
other products (Bush et al., 1986a).
Sulphites provide a number of useful attributes when applied to foods: they inhibit enzymatic
browning (especially in fresh fruits and vegetables, shrimps and raw potatoes), as well as
nonenzymatic browning (especially in dried foods and dehydrated vegetables) (Taylor et al., 1997;
Simon, 1998). They also have antimicrobial activity (as in wine and beer), doughconditioning
properties (as in frozen pies and pizza crusts) and bleaching effects (as in maraschino cherries) and
they are used as processing aids in beet sugar (Bush et al., 1986a; Simon, 1998). The E numbers
that correspond to various sulphating agents used as food additives are given in Table 27.

Table 27. E numbers corresponding to sulphiting agents
E number Sulphiting agent
E 220 sulphur dioxide
E 221 sodium sulphite
E 222 sodium hydrogen sulphite
E 223 sodium metabisulphite
E 224 potassium metabisulphite
E 226 calcium sulphite
E 227 calcium hydrogen sulphite
E 228 potassium hydrogen sulphite
The levels of sulphites contained in foods range from under 10 mg/kg (e.g. frozen doughs, corn
syrup, jellies) to 60 mg/kg (e.g. fresh shrimp, pickles, fresh mushrooms) to 100 mg/kg (e.g. dried
potatoes, wine vinegar). The highest levels of sulphites (up to 1000 mg/kg) can be found in dried
fruit, wine, fruit juices (e.g. lemon, lime, grape) and certain freshly prepared sauces available from
retailers (Simon, 1998). In Table 28, Lester (1995) presents a list of certain foods by level of their
total content in sulphites (naturally-occurring plus added).
The SCF (1994) identified a no observed effect level (NOEL) of 70 mg/kg body weight/day of
sulphur dioxide equivalents (SDE) for gastric irritation in animals. Based on this and on a safety
factor of 100, the Committee estimated an Acceptable Daily Intake (ADI) of 0-0.7 mg SO2/kg body
weight that would ensure that gastric reactions will not occur in man. It explicitly stated, however,
that “a numerical ADI would not prevent the occurrence of
sulphite-induced asthma” and that it considered that “EC labelling regulations should ensure that
the presence of added sulphites in foods and non-alcoholic beverages is always indicated in the list
of ingredients”. It also expressed its concern that no such labelling was required for alcoholic
beverages and recommended that “the presence of added sulphite should be declared on labels of
alcoholic beverages.”
Directive 95/2/EC3 on food additives other than colours and sweeteners states maximum levels of
sulphites expressed as SO2 in mg/kg or mg/L and relates this to the total quantity available from all
sources for several foods and beverages. It is also stated that an SO2 content of not more than 10
mg/kg or 10 mg/L is not considered to be present.

Table 28. Estimated total SO2 levels in foods which have been treated with sulphites

1.2.1 Methods of measurement of sulphites in foods
Several methods for measuring sulphite residue levels in foods are available (Fazio and Warner,
1990; Su and Taylor, 1995). Levels of sulphating agents in foods are usually expressed as SO2
equivalents. Variations of the Ripper method (Ripper, 1892) are used to detect free SO2. The
Monier-Williams method (Monier-Williams, 1927) measures total SO2, which includes the same
substances detected by the Ripper method plus some combined forms of sulphites. Neither
method is entirely satisfactory since non-sulphite substances may interfere in the analyses, some
combined forms may not be measured under the assay conditions and others, which do not pose a
risk, may be detected (Bush et al., 1986a).
3 European Parliament and Council Directive 95/2/EEC on food additives other than colours and sweeteners.
Official Journal of the European Union L 061, 18.03.1995, p. 1-40.
The United States Food and Drug Administration (FDA) regulation, which requires food
manufacturers and processors to disclose the presence of sulphiting agents in concentrations of
10 parts per million (i.e. 10 mg/kg) or more, is based on the fact that the assay used to detect the
level of sulphites in food is not sensitive enough to detect amounts less than 10 mg/kg in all foods,
but the threshold for eliciting reactions in sulphite sensitive individuals may be even lower.

1.2.2 Estimation of average daily exposure to sulphites from foods
Assessment of consumer exposure to sulphites in foods is inadequate. This is partially due to the
shortcomings of the methods of measurement. Storage and preparation of food also affects the
final amount of consumed sulphites.
Though the actual consumption may vary widely, based on individual dietary practices, average
daily sulphite consumption in the United States has been estimated to be 19 mg of SDE (297 μmol
of sulphite), with the 99th percentile of the population consuming daily 163 mg of SDE (~2.5mmol
of sulphite) (FDA, 1985). In France, researchers have estimated an average daily intake of 20 mg
SO2, reaching 31.5 mg/day among consumers of cider, beer and wine (Mareschi et al., 1992). As a
working framework, the average daily consumption is less than 20 mg of SDE (Lester, 1995).
It should be noted that sulphites are frequently used in restaurant foods as preservatives. A report
has estimated that an average restaurant meal may contain 25 to 100 mg of sulphites (Simon,
1989).

2. FREQUENCY
The prevalence of sensitivity to sulphating agents in the general population is unknown (Bush et
al., 1986b). Estimates of the percentage of asthmatics characterised as sensitive to oral sulphite
challenge range from less than 4% up to 66% (Table 29).
The probable reasons for the wide disparity are the difference in the physical form of the orally
administered sulphating agent (i.e. solution vs encapsulated, the former generating more positive
reactions than the latter, due to inhalation of volatilised SO2), the differences in the selection
criteria of the sample populations submitted to oral challenges and the nonuniformity in the upper
limit of challenge dose as well as in the minimum decrement in pulmonary function accepted as
evidence of sulphite-induced bronchoconstriction. In addition, adequate placebo challenges have
not been carried out in some studies (Gunnison and Jacobsen, 1987).
The SCF stated that the percentages of sulphite sensitivity reported in the literature (1-4% among
all asthmatics and 5-10% among steroid-dependent asthmatics) are probably overestimates based
on patients referred to allergy clinics (SCF, 1994). The FDA estimates that one out of a hundred
people are sulphite sensitive, and that 5% of those who have asthma are also at risk of suffering an
adverse reaction to the substance (FDA, 1996).
The average age of the individual who experiences asthma after exposure to sulphites is 40 years,
and sensitivity is reportedly higher among women (Gunnison and Jacobsen, 1987, Simon, 1989). It
is uncommonly reported in preschool children, perhaps because their diets include fewer foods
with high sulphite content and do not include wine (Lester, 1995).

Table 29. Prevalence of sulphite sensitivity among asthmatics
3. CLINICAL FEATURES
3.1 Symptoms
Most reactions to sulphites are characterised by bronchospasm, occasionally severe, which can
occur within minutes after ingestion of sulphite-containing foods. In restaurants, the sudden
choking sensation may incorrectly be attributed to aspiration of food (Nicklas, 1989). Bradycardia,
flushing and prominent gastrointestinal symptoms (Sheppard et al., 1980; Schwartz, 1983), as well
as urticaria, angio-edema, hypotension (Prenner and Stevens, 1976; Habenicht et al., 1983;
Schwartz, 1983) and shock (Lester, 1995) have also been observed.

3.2 Diagnosis
A careful history, though important in detecting sulphite sensitivity, is not sufficient to make the
diagnosis and skin testing (prick puncture or intradermal technique) can identify only a small
fraction of patients. Therefore, various challenge protocols have been developed. For sensitivity to
ingested sulphites, the substances used for the challenges are usually containedin opaque
capsules. False negative results may occur if the sensitivity has to do with inhaled sulphites. On the
other hand, as a high proportion of asthmatics (unlike non-asthmatics) are sensitive to inhaled
sulphur dioxide, challenges with acid solutions may produce false positive results if the dosage is
high (Simon, 1998). The standard practice has been to use challenges for asthmatics below 100
mg/mL of sulphites. As for subjects with a history suggesting sulphite-induced urticaria or
anaphylaxis, capsule challenges up to a maximum dose of 200 mg are used (Simon, 1996).

4. PATHOGENESIS
The pathogenesis of adverse reactions to sulphites has not been clearly documented. Three
possible mechanisms have been invoked: an IgE-mediated reaction, a sulphite-induced cholinergic
response and low levels of the enzyme sulphite oxidase (Bush et al., 1986a; Nicklas, 1989; Lester,
1995).
There have been reports of positive skin tests to sulphites, in vitro mediator release or passive
sensitivity transfer (Prenner and Stevens, 1976; Twarog and Leung, 1982; Wolf and Nicklas, 1985;
Yang et al., 1986; Simon and Wassserman, 1986; Boxer et al., 1988), all of them suggesting that
some reactions to sulphites may in part be IgE-mediated. A specific antibody, however, has never
been identified (Lester, 1995) and the majority of studies have not been able to demonstrate and
IgE-mediated mechanism (Gunnison and Jacobsen, 1987; Nicklas, 1989). It appears that IgE-
mediated mechanisms, if they do exist, are very rare in sulphite sensitive individuals or are limited
to a subset of patients (Bush et al., 1986a; Sainte-Laudy et al., 1994).
The bronchoconstrictive effect of inhaled SO2, mediated by parasympathetic nerve endings in the
bronchi, has been studied with respect to environmental pollutants. Whether gastroesophageal
reflux of SO2 causes bronchospasm in sulphite sensitive patients is not clear. It has been
hypothesised that it is also possible to mechanically distend the stomach, produce a cholinergic
response and stimulate release of gastrin and other active mediators in sulphite sensitive patients
(Nicklas, 1989).
Low levels of the mitochondrial enzyme sulphite oxidase have been demonstrated in some
sulphite sensitive patients (Jacobsen et al., 1984; Stevenson and Simon, 1984). Absorbed sulphites
are added to those produced endogenously and increase the demand placed on the enzyme
sulphite oxidase. It is possible that when this demand is not met, sulphite sensitive patients exhibit
symptoms.
Finally, it has also been hypothesised that a number of food additives, including sulphites, induce
intolerance because of their aspirin-like properties (Williams et al., 1989) and an association
between respiratory reactions to aspirin and those to sulphites has been reported (Sabbah et al.,
1987; Hassoun et al., 1994).

5. POSSIBLE EFFECTS OF FOOD PROCESSING ON SENSITIVITY AND
DERIVED PRODUCTS
The amounts of sulphites initially used to treat foods do not reflect residue levels after processing.
Storage and preparation of food also affects the final amount of consumed sulphites. Mechanisms
of loss include volatilisation to SO2 in acidic conditions, leaching, autooxidation, as well as the
irreversible reactions with food constituents (Gunnison and Jacobsen, 1987).
Sulphites can react with food constituents, including sugars, proteins and lipids, to form combined
sulphites. Some of these reactions are reversible, while others are not. The former lead to
compounds that may serve as reservoirs for free sulphite, while the latter remove sulphites
permanently from the pool of available free SO2. Since free SO2 is the most likely cause of adverse
reactions to sulphiting agents, these chemical reactions have significant implications regarding
foods which may cause difficulty in sensitive patients (Bush et al., 1986a; Simon, 1998). The
likelihood of a particular food provoking a reaction depends upon the ratio of free to bound
sulphite. For example, lettuce has few components to which sulphites can react, therefore most of
the sulphite in lettuce remains in the free inorganic state and this explains why lettuce (salad bars)
seems to provoke sulphite sensitive reactions frequently (Martin et al., 1986; Simon, 1998). In
contrast, sulphites added to shrimp and potatoes tend to be bound and are not as likely to
produce reactions in sulphite sensitive subjects.

6. THRESHOLD DOSES
Toxicity studies in non-asthmatic individuals have been conducted primarily through oral
challenges and inhalation studies (Bush et al., 1986a). Small numbers of individuals have ingested
doses of up to 400 mg of SO2 equivalents per day, without adverse effect (Taylor et al., 1986).
However, doses of 4 to 6 g per day predictably caused nausea, vomiting, gastric irritation and
occasional gastrointestinal bleeding (Schwartz, 1984; Bush et al., 1986a). Prenner and Stevens
(1976) confirmed sulphite sensitivity in a patient after the ingestion of a total dose of 10 mg of
NaHSO3 solution. Case reports of positive oral challenges with encapsulated sulphites have been
made for doses of 10 mg (Schwartz, 1983) and 25 mg (Habenicht et al., 1983). Challenge studies in
larger number of non-asthmatics with a risk for adverse reactions to sulphites have failed to
identify a significant number of reactors (Meggs et al., 1985; Sonin and Patterson, 1985; Bush et
al., 1986a).
Among asthmatics, the amount of sulphite required to produce a response also varies and
quantities as low as 1 to 5 mg of ingested potassium metabisulphite have been reported to
provoke a reaction in sulphite sensitive asthmatics (Stevenson and Simon, 1981). Ingestion of
sulphited solutions is more likely to precipitate asthma than ingestion of encapsulated sulphites,
perhaps due to inhalation of volatilised SO2 (Bush et al., 1986b).
According to Simon (1989), most sulphite sensitive individuals will react to ingested
metabisulphite in quantities ranging from 20 to 50 mg (Simon, 1989; Lester, 1995). However,
threshold levels have not been systematically assessed and the smallest concentration of sulphites
able to provoke a reaction in a sensitive person is unknown.



7. CONCLUSION
The prevalence of sulphite sensitivity in the general population is unknown, but it appears to be
rare among non-asthmatics. Estimates of the percentage of asthmatics characterised as sensitive
to oral sulphite challenge range from less than 4% up to 66%. The SCF stated that the reported
prevalences of 1-4% among all asthmatics and 5-10% among steroid-dependent asthmatics are
probably overestimates based on patients referred to allergy clinics (SCF,
1994). Most reactions to sulphites are characterised by severe bronchospasm, which can occur
within minutes after ingestion of sulphite-containing foods. In restaurants, the sudden choking
sensation may incorrectly be attributed to aspiration of food. Assessment of consumer exposure
to sulphites in foods is inadequate, as the currently available measurement methods have several
shortcoming and the amounts of sulphites initially used to treat the foods do not reflect residue
levels after processing. The average daily sulphite consumption has been estimated to be
approximately 20 mg of sulphur dioxide equivalents. It should be noted, however, that sulphites
are frequently used in restaurant foods as preservatives and an average restaurant meal may
contain sulphites well in excess of 25 mg. Most sulphite sensitive individuals will react to ingested
metabisulphite in quantities ranging from 20 to 50 mg. Use of sulphating agents in fruits and
vegetables intended to be consumed raw appears to be responsible for several cases of sulphite-
induced bronchospasm. This led to the prohibition of sulphite use in raw fruits and vegetables by
the USA FDA, which also requires labelling of foods containing sulphiting agents in concentrations
of 10 mg/kg or more. Though the threshold for sensitivity reactions may be even lower, the
regulation is based on the fact that the assay used to detect the level of sulphites in foods is not
sensitive enough to detect amounts less than 10 mg/kg. However, threshold levels have not been
systematically assessed and the smallest concentration of sulphites able to provoke a reaction in a
sensitive person is unknown.

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