A few selected Medline citations:
1: Am Fam Physician 1990 Nov;42(5):1347-50
Hahnemann University School of Medicine, Philadelphia, Pennsylvania.
Tartrazine (FD & C Yellow No. 5) is an approved azo dye present in many drugs
and food products. During the 1970s, many cases of tartrazine sensitivity were
reported. This led to new regulations that required the listing of azo dyes on
package inserts of drugs and on packages of food products. Tartrazine
sensitivity is most frequently manifested by urticaria and asthma. Although azo
dyes have been implicated in accentuating hyperkinetic syndromes, tartrazine is
not considered an offender. Vasculitis, purpura and contact dermatitis
infrequently occur as manifestations of tartrazine sensitivity.
Cross-sensitivity in aspirin-sensitive and NSAID-sensitive patients may also
occur. The mechanism of sensitivity is obscure and has been called
pseudoallergic. Management consists mainly of avoidance of drugs and food
products that contain tartrazine.
PMID: 2239641, UI: 91051158
2: Postgrad Med 1989 May 1;85(6):265-6
Persistent urticaria caused by a common coloring agent.
Medical College of Wisconsin, Milwaukee.
As this case illustrates, foods or drugs may be ignored as possible causes of
urticaria when they are not commonly accepted offenders or when they previously
have been consumed with no adverse effect. In some instances, an additive or dye
in a food or drug may be responsible for the reaction. In addition, a change of
brands or dosage form of a drug may provoke urticaria or other reactions in
PMID: 2710728, UI: 89220700
3: Allergy 1998 Aug;53(8):816-7
A strange case of "tuna allergy".
Ambulatorio di Allergologia, Ospedale Caduti Bollatesi, Bollate (MI), Italy.
PMID: 9722237, UI: 98387692
4: Rev Alerg Mex 1996 Nov-Dec;43(6):152-6
[Prevalence of chronic urticaria following the ingestion of food additives in a
third tier hospital].
[Article in Spanish]
Jimenez-Aranda GS, Flores-Sandoval G, Gomez-Vera J, Orea-Solano M
Servicio de alergia e inmunologia clinica del Hospital Regional Lic. Adolfo
Lopez Mateos, ISSSTE. Mexico.
We studied 40 patients with the clinical diagnostic of chronic urticaria from
January to June, 1995 and excluded 4 patients who did not fulfilled the entry
criteria. 29 women and 7 men with age from 4 to 62 years old. We performed a
basic clinics history and the oral challenge tests (PRO) included Tartrazine
(Ta), Sodium Metabisulfite (MS), Potasium Metabisulfite (MP) and Sodium
Bisulfite (BS) in consecutive days with increasing doses unless an adverse
reactions appear. Other tests included Skin Prick tests for food (PC), complete
blood counts, coprology and immunology tests (IgE, IgA, IgM, IgG, C3, C4, Cel LE
and ANA) and paranasal sinus X Ray. 63.8% (23/36) had positive PRO. 47.2%
(17/36) positives to Ta,, 36.1% (13/36) to MS, 33.3% (12/36) to BS and 30.5%
(11/36) to MP. 72.2% (26/36) had positive PC to one or more foods, 65.3% (17/26)
besides had positive PRO. 41.1% (7/17) of the patients who had positive PRO and
positive PC to foods had sinusitis. One patient (0.23%) had palpebral angioedema
with PRO. The prevalence was 3.1%. Ta was the additive that cause more
reactivity. It is possible to find reactivity to one or more additives in a
patient with chronic urticaria.
PMID: 9053127, UI: 97185519
5: Lakartidningen 1995 Jan 25;92(4):296-8
[Hypersensitivity to azo coloring agents. Tartrazine in food may cause rash and
[Article in Swedish]
Statens livsmedelsverk, Uppsala.
PMID: 7845103, UI: 95147574
6: Ann Allergy 1993 Oct;71(4):379-84
Adverse reactions to food additives.
Department of Dermatology, University Hospital Zurich, Switzerland.
Food additives can induce a wide range of adverse reactions in sensitive
individuals. A prevalence of 0.03% to 0.23% is estimated. The complexity of the
different pathophysiologic mechanisms possibly involved in the allergic
(immunologic) or in the intolerant (nonimmunologic) reactions to food additives
continues to create great difficulties in the understanding of such conditions.
From the clinical point of view it is useful to make a distinction between an
intolerance reaction and intolerance provocation. The pathogenic mechanisms of
adverse reactions to the azo dye tartrazine and to sulfite preservatives are
discussed briefly. Due to the lack of reliable skin or in vitro tests, the
diagnosis of an intolerance to food additives is still based on
placebo-controlled oral provocation tests. Two typical cases of a "restaurant
syndrome" due to sulfite allergy or sensitivity are described, as well as a case
of disulfite-induced urticaria-vasculitis and a case of anaphylactoid purpura
associated with tartrazine and benzoates.
PMID: 8214803, UI: 94028178
7: Arch Dis Child 1992 Jun;67(6):709-11
Tartrazine in atopic eczema.
Devlin J, David TJ
Department of Child Health, University of Manchester.
Multiple double blind placebo controlled challenges with tartrazine 50 mg (three
challenges) and glucose placebo (three challenges) were performed in 12 children
with atopic eczema aged 1 to 6 years. The children were selected on the basis of
severity (regular clinic attenders) and a parental history that tartrazine
provoked worsening of the eczema. In only one patient did the three tartrazine
challenge periods correspond with the highest symptom scores or the highest
physician observer scores, and the probability of this occurring by chance in
one or more patients out of 12 was 0.46. In this sample we were unable to
confirm intolerance to tartrazine in 11 out of 12 patients.
Controlled clinical trial
Randomized controlled trial
PMID: 1626990, UI: 92328573
8: Pediatr Med Chir 1992 Jan-Feb;14(1):39-42
[Unusual reactions to food additives].
[Article in Italian]
Novembre E, Dini L, Bernardini R, Resti M, Vierucci A
Servizio di Allergologia, Clinica Pediatrica 3, Firenze, Italia.
The most important symptoms caused by food additives are urticaria and
angioedema, but rhinitis, asthma and gastrointestinal disturbances are also
reported. Only seldom food additives have been shown to induce symptoms in other
organs such central nervous system or joints and with a sparse objective
evidence. In this study, we report two cases of unusual reactions to food
additives (tartrazine and benzoates) involving mainly the central nervous system
(headache, migraine, overactivity, concentration and learning difficulties,
depression) and joints (arthralgias), confirmed with diet and double blind
challenge. The possible pathogenetic mechanisms are also discussed.
Controlled clinical trial
PMID: 1579515, UI: 92253437
9: J Nerv Ment Dis 1991 Feb;179(2):108-9
Desipramine-induced urticaria: a clinical problem.
Bajwa WK, Asnis GM
Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical
Center, Bronx, New York.
PMID: 1824949, UI: 91116345
10: Yonsei Med J 1989 Dec;30(4):339-45
Oral provocation tests with aspirin and food additives in asthmatic patients.
Hong SP, Park HS, Lee MK, Hong CS
Aspirin and food additives are known to induce bronchoconstriction, angioedema
or urticaria in susceptible patients. To evaluate the incidence of
hypersensitivity to aspirin and food additives, 36 subjects with bronchial
asthma, 33 of whom were non-allergic asthmatics and 3 were allergic asthmatics
who had a history of aspirin sensitivity, were challenged orally with six
compounds: acetylsalicylic acid (ASA), sodium bisulfite, tartrazine, sodium
benzoate, 4-hydroxy benzoic acid, and monosodium L-glutamate. Significant
bronchoconstrictions were found in 15 (41.7%) of the 36 subjects tested. Eight
of the 15 subjects showed positive asthmatic responses to the aspirin, two
showed asthmatic responses to the food additives, and five responded to both
aspirin and the food additives. It is suggested that ASA and food additives
could be causes of clinically significant bronchoconstriction in moderately
severe non-allergic asthmatic patients.
PMID: 2626838, UI: 90177345
11: Clin Exp Allergy 1989 May;19(3):267-72
A double-blind assessment of additive intolerance in children using a 12 day
challenge period at home.
Wilson N, Scott A
Department of Paediatrics, Royal Postgraduate Medical School, Hammersmith
Alleged food-additive intolerance (respiratory, dermatological, behavioural or
abdominal) was assessed in 19 children using daily challenge drinks of either,
base product alone, base product plus sunset yellow/tartrazine, or base product
plus sodium metabisulphite/sodium benzoate. The same type of drink was given for
12 days, double-blind and in random order. During the trial the children were
maintained on an additive-free diet under supervision. Diary cards were used to
record symptoms and medication usage. If there was an apparent association
between symptoms and drink ingredient the trial was repeated, again
double-blind. Additive intolerance was confirmed by a consistent deterioration
of symptoms in only three children. In one, urticaria was induced by the
colourings, in another extremely abnormal behaviour was induced by the
preservatives and a third child was only free of asthma and abdominal pain on
placebo. This form of individual trial, using 12 daily drinks, overcomes some of
the objections to a single challenge study. Despite this, intolerance to the
additives was only confirmed in 3/19 children in whom it had been believed to
Randomized controlled trial
PMID: 2736427, UI: 89287844
12: Rev Alerg Mex 1989 May-Jun;36(3):107-9
[Adverse reactions induced by food additives: sulfites].
[Article in Spanish]
Montano Garcia ML
Many chemicals are used to preserve, color and flavor foods and drugs. There
have been numerous reports of adverse reactions, including urticaria,
angioneurotic edema, asthma an anaphylaxis following the ingestion of food
additives such as tartrazine, monosodium glutamate and benzoic acid. Recently
the food and drug additives reaching medical awareness as a cause of sensitivity
are the sulfiting agents. Sulfites are widely used in the food and beverage
industry as preservatives and antioxidants. They are also used by the
pharmaceutical industry. This work describes the common uses of sulfiting
agents, the mechanisms of sulfite sensitivity, the diagnosis, prevention and
treatment of adverse reactions to sulfites.
PMID: 2672278, UI: 89368647
13: Ann Allergy 1989 Jan;62(1):21-5
Additives contained in drug formulations most frequently prescribed in
Kolly M, Pecoud A, Frei PC
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois,
The presence of substances known to induce pseudoallergic reactions was
investigated by means of a questionnaire to the manufacturers of 1,467
frequently administered formulations. Benzoates were found in 15% of the
formulations, sorbates in 5.5%, sulfites in 3.8%, and benzalkonium in 3.0%. The
occurrence of the seven artificial colours studied was as follows: indigotin
7.8, erythrosine 7.4, sunset yellow 6.6, tartrazine 4.9, quinoline yellow 2.8%,
ponceau (new coccine) 2.6, and amaranth 1.7%. A significant risk of exposure to
preservatives and dyes likely to induce asthma, urticaria, or other
pseudoallergic reactions exists for all individuals taking commercial drug
PMID: 2912321, UI: 89103989
14: Rev Alerg Mex 1989 Jan-Feb;36(1):15-8
[Frequency of urticaria and angioedema induced by food additives].
[Article in Spanish]
Montano Garcia ML, Orea M
Certain food additives are known to induce urticaria and angioneurotic edema in
susceptible patients. Thirty-three patients with chronic urticaria and
angioneurotic edema whose case history suggested a possible link between
exacerbations of the symptoms and ingestion of food additives or with acute
exacerbations of the disease without any known triggering event were challenged
orally in a double-blind study with increasing doses of the following additives:
sodium benzoate, sodium metabisulfite and tartrazine and lactose as placebo. Ten
of the 33 patients (30.3%) were intolerant to at least one compound. Among 132
oral provocation tests 11 (8.3%) were positive (appearance of acute
urticaria/angioneurotic edema): 5 (15.1%) to sodium benzoate, 4 (12.1%) to
tartrazine an 2 (6%) to sodium metabisulfite. There was no reaction to placebo
and no serious reaction was observed. Under the conditions used, oral
provocation tests proved to be feasible, safe and useful in the routine
investigation of chronic urticaria and angioneurotic edema.
Controlled clinical trial
PMID: 2749124, UI: 89317205
15: G Ital Dermatol Venereol 1988 Apr;123(4):177-80
[Pseudo-crossreactivity between aspirin and tartrazine].
[Article in Italian]
Valsecchi R, Tribbia G, Rossi A, Perego GB, Cainelli T
PMID: 3182007, UI: 89032439
16: Allergol Immunopathol (Madr) 1988 Jan-Feb;16(1):43-7
Acetyl salicylic acid induced-urticaria and/or angioedema in atopic children.
Botey J, Navarro C, Aulesa C, Marin A, Eseverri JL
Servicio de Alergia e Inmunologia Clinica, Hospital Infantil de La Vall
D'Hebron, Universidad Autonoma de Barcelona, Spain.
From the report of Hirschberg, only 3 years after aspirin synthesis, there have
been numerous works dedicated to showing the different types of adverse
reactions found following aspirin administration. However, there are few
publications on the process of urticaria and/or acute angioedema induced by ASA
and few reported cases were found in children. Thus, we present 6 atopic
children with urticaria and/or angioedema related with ASA. A carefully detailed
history, oral provocation with ASA, oral provocation with other NSAI and HBDT
with ASA were done to all of them. The oral provocation with ASA was positive in
5 of the 6 cases. The provocations with the rest of the NSAI and tartrazine and
sodium benzoate were negative in all of the patients. The HBDT was positive in 5
of the cases. In conclusion, we insist that aspirin intolerance is not
infrequent in infancy and it is not rare to see urticaria and or angioedema, in
spite of the fact that asthmatics, atopics or non atopics, usually present as
bronchospasm. We also believe that the HBDT can be a method of diagnosis used in
PMID: 3381713, UI: 88250048
17: N Engl Reg Allergy Proc 1987 Jan-Feb;8(1):39-46
The restaurant syndromes.
The Restaurant syndromes can be caused by five major factors: food allergens,
sulfites, monosodium glutamate (MSG), tartrazine, and scombroidosis (and other
seafood poisoning). A history of atopy and ingestion of known food allergens
such as peanuts, egg, fish, and walnuts, together with positive results of skin
tests or RAST to these foods, will favor a diagnosis of food allergy. Allergic
reactions to peanuts have produced fatalities in minutes through an IgE mediated
reaction. An extremely rapid onset (minutes) of symptoms consisting of flushing,
bronchospasm and hypotension is consistent with a sulfite reaction. Burning,
pressure, and tightness or numbness in the face, neck, and upper chest following
ingestion of Chinese food favors a diagnosis of adverse reaction to MSG. Also,
development of late onset bronchospasm (up to 14 hours) may be related to MSG
reactions. Bronchospasm and urticaria in a patient with a history of aspirin
intolerance suggests tartrazine sensitivity. If everyone ingesting a fish meal
develops flushing, urticaria, pruritus, gastrointestinal complaints, or
bronchospasm, this implies scombroidosis, ciguatera, or other seafood poisoning.
Finally, severe headache or hypertension can result from ingestion of naturally
occurring amines, such as tyramine (cheese, red wine) and phenylethylamine
(chocolate). A double-blind oral challenge test may be the only way of
confirming the diagnosis for most of the etiological factors of the Restaurant
syndromes. The treatment of choice for acute reaction is epinephrine followed by
antihistamine. Proper labeling and avoidance of these ingredients in sensitive
individuals are the best preventive measures.
PMID: 3302666, UI: 87286811
18: Clin Allergy 1986 Nov;16(6):527-33
Cell-mediated immune responses to artificial food additives in chronic
Warrington RJ, Sauder PJ, McPhillips S
In some cases of chronic urticaria it is suspected that food additives such as
tartrazine and sodium benzoate or salicylates may play a role in the
pathogenesis of the condition. Since, at times, chronic urticaria may appear
histologically similar to a mild cell-mediated immune response, the release of
the T cell-derived lymphokine leucocyte inhibitory factor (LIF), in response to
incubation with these additives and with acetylsalicylic acid (ASA), was
measured in vitro using cells from normal controls, from patients with chronic
urticaria with or without clinically associated additive sensitivity and from
patients with asthma with or without associated ASA sensitivity. It was found
that significant production of LIF occurred in response to tartrazine and sodium
benzoate in those individuals with chronic additive induced urticaria. In
addition, tartrazine caused LIF release from mononuclear cells of ASA-sensitive
asthmatics. These results may indicate a possible role for additive-induced
cell-mediated immune responses in the pathogenesis of some cases of chronic
urticaria and suggest a potential diagnostic test for this condition.
PMID: 3539408, UI: 87078821
19: N Engl Reg Allergy Proc 1986 Nov-Dec;7(6):533-42
Adverse reactions to food additives.
There are thousands of agents that are intentionally added to the food that we
consume. These include preservatives, stabilizers, conditioners, thickeners,
colorings, flavorings, sweeteners, antioxidants, etc. etc. Yet only a
surprisingly small number have been associated with hypersensitivity reactions.
Amongst all the additives, FD&C dyes have been most frequently associated with
adverse reactions. Tartrazine is the most notorious of them all; however,
critical review of the medical literature and current Scripps Clinic studies
would indicate that tartrazine has been confirmed to be at best only
occasionally associated with flares of urticaria or asthma. There is no
convincing evidence in the literature of reactivity to the other azo or nonazo
dyes. This can also be said of BHA/BHT, nitrites/nitrates and sorbates. Parabens
have been shown to elicit IgE mediated hypersensitivity reactions when used as
pharmaceutical preservatives; however, as with the other additives noted above,
ingested parabens have only occasionally been associated with adverse reactions.
MSG, the cause of the 'Chinese restaurant syndrome' has only been linked to
asthma in one report. Sulfiting agents used primarily as food fresheners and to
control microbial growth in fermented beverages have been established as the
cause of any where from mild to severe and even fatal reactions in at least 5%
of the asthmatic population. Other reactions reported to follow sulfite
ingestion include anaphylaxis, gastro intestinal complaints and dermatological
eruptions. The prevalence of these non asthmatic reactions is unknown. The
mechanism of sulfite sensitive asthma is also unknown but most likely involves
hyperreactivity to inhale SO2 in the great majority of cases; however, there are
reports of IgE mediated reactions and other sulfite sensitive asthmatics have
been found with low levels of sulfite oxidase; necessary to oxidize endogenous
sulfite to sulfate.
PMID: 3302664, UI: 87286804
20: Ann Allergy 1986 Aug;57(2):133-4
Sensitivity to non-acetylated salicylates in a patient with asthma, nasal
polyps, and rheumatoid arthritis.
Chudwin DS, Strub M, Golden HE, Frey C, Richmond GW, Luskin AT
A woman experienced exacerbations of bronchial asthma after taking aspirin and
other non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis.
On oral challenges, she developed an urticarial reaction after tartrazine;
urticarial and bronchospastic reactions after salicylsalicylic acid; and
urticarial and bronchospastic reactions after choline magnesium trisalicylate.
Non-acetylated salicylates have been recommended for use in aspirin- and/or
tartrazine-sensitive patients. The results of sensitivity studies of our patient
indicates that such patients may also be sensitive to non-acetylated
PMID: 3740556, UI: 86293830