Contents
A. Case study
B. More information
C. Editors' comments
D. References
E. CPD questions (South Africa, Australia)

 

 


A. Case study
A 7-year-old boy was referred to a dietitian to determine the cause of recurring episodes of generalized urticaria, as the ailment was thought to be food-related. The clinical history revealed that he had experienced episodes of slight urticaria infrequently (about twice per year) since early childhood. In the previous 6 months, the severity of the episodes of urticaria had become greater. Most of the more severe reactions occurred during friends' birthday parties or on vacation.

THOUGHT PROCESS:
What can cause urticaria? There are many causes (see also the March Educational Newsletter's case study):

  • Hypersensitivity to a drug: The mother was questioned about her son's use of pharmaceuticals, including over-the-counter medications, vitamins, "naturopathic" supplements and other herbal remedies. The mother related an episode from when her son was 4 years old. He experienced a severe reaction after taking cough syrup. The doctor suspected a drug allergy, and the medication was never prescribed after that.

    •
  • Hypersensitivity to a food or food additive: Because the child developed reactions mostly while at parties, some substance found in typical party food could be a cause. The mother said that she kept "party food" (such as sweets, chips and soft drinks) for treats and special occasions, so that her son did not have them often. He might therefore eat more of these types of foods at parties than he is used to.

    •
  • Because he experienced the symptoms in a different environment than he is used to, environmental allergens (e.g., house dust mite, fungi, pollen, trees, pets or a chemical present in a toy or used in a hobby) needed to be considered. But no correlation could be found.

    •
  • Physical stimuli, contact sensitivity, hypersensitivity to insect stings or bites, collagen vascular disease, chronic idiopathic/auto-immune urticaria and infectious diseases were excluded as possible causes.

    Sensitivity to additives was suspected, as it can be present in both cough syrup and "party foods". Cough syrups often contain a coloring agent to make them more appealing to children. Tartrazine is often used.

    How does one test for a sensitivity to additives?

  • There are no skin prick tests or serum-specific IgE tests for additives, as reactions to them are not thought to be IgE-mediated.

    •
  • Blood CAST (Cellular Allergen Stimulation Tests) tests can be done for certain additives, although they do not have a high level of sensitivity compared to serum-specific IgE tests.

    •
  • An elimination diet can be done, but was not practical in this case, because it was already known that the child reacted to foods that contain additives.
  • Double-blind placebo-controlled challenges can be done. A doctor colleague of the dietitian was asked to assist in performing the challenges. The child reacted to a dose of 10mg of tartrazine. The diagnosis was made.


    •  
    TIP for Allergy Advisor users:
    More details on tartrazine can be accessed in Allergy Advisor. To assist in the management of a tartrazine sensitive patient such as the above, Allergy Advisor contains a diet sheet for a tartrazine-free diet. The diet sheet lists the foods that are allowed and those that could contain and therefore should be avoided. The diet sheet can be modified by the health professional, if required, to make the diet sheet more individual. In addition, an information sheet on tartrazine sensitivity can be printed from Allergy Advisor for patients to take home with them. Together with the diet sheet, this sheet helps the patient understand the condition better and helps ensuring that the patient will stay symptom-free in the long-term.


    B. More information:
    Tartrazine is a water-soluble synthetic dye that is commercially available in the form of a sodium salt. Tartrazine is also available as the water-insoluble Aluminium Lake. Tartrazine is a monoazo dye, derived from coal tar. Azo dyes are a large category of colorings used in food and cosmetics and include Quinoline Yellow, Yellow 2G, Sunset Yellow FCF, Carmoisine, Amaranth, Ponceau, Erythrosine, Red 2G, Patent Blue V, Indigo Carmine, Brilliant Blue FCF, Green S, Black PN, Brown FK, Chocolate Brown, Pigment Rubine, Acid Yellow, Azodisalicylate, Chicago Sky Blue, Congo Red, Direct Black 38, Direct Blue 6, Direct Blue 15, Direct Brown 95, Fast Yellow, Lithol Red, Methyl Orange, Methyl Red, Methyl Yellow, Naphthalene Fast Orange 2G, Neoprontosil, New Coccine, Orange II, Phenylazo-2-naphthol, Ponceau 3R, Ponceau SX, Red 2G, Red 10B, Salicylazosulphapyridine, Sunset Yellow, and Trypan Blue.

    Tartrazine is used to give foods a lemon-yellow color, particularly those foods with lemon and lime flavours. It is generally used in combination with other colors, such as blue (to yield various shades of green). It appears reddish at alkaline pH.1 Tartrazine is stable to heat and light and has an ADI (Adequate Daily Intake) of 7.5 mg/kg body weight.

    A comment by FACTS's food scientist, Maritza van Dyk:
    Tartrazine is approved and certified by the Food and Drug Administration (FDA) as FD&C Yellow no. 5 and is also known as E 102. It is listed as a color that may be used in a wide range of foodstuffs, subject to specific quantitative limits. The use of tartrazine is, however, prohibited in some countries such as Austria and Norway.

    Synthetic colors such as tartrazine are used more frequently in the food industry because they are less expensive than natural colorants, uniform, and extremely potent (i.e., less can be used to gain the same effect); and remain stable in high processing temperatures, acids, carbon dioxide, storage and light.

    Where is tartrazine used?
    Tartrazine is widely used for coloring drinks, foods, drugs and cosmetics, for identification purposes and to produce an attractive appearance. The content of tartrazine in one tablet may vary from 0.02 to 2.5mg, while 250ml of soft drink may contain from 0.8 to 8.0mg tartrazine.1,2 High concentrations are used in, for example, snack foods such as sweets to create bright colors to make them more acceptable to children.

    Foods: The foods in which tartrazine is typically used include baked goods, cereals, soft drinks (particularly orange and lime drinks), canned foods; ice cream and other frozen desserts; other desserts, sweets and confectionery; pickles, sauces and seasonings.1

    Drugs: The dye is added to drugs in both solid and liquid preparations, including commonly prescribed drugs as well as non-prescription drugs. Examples of these are nutritional supplements, antihistamines, antibiotics, analgesics, antidepressants, oral contraceptives, sedatives, hypnotics and corticosteroids.1,3

    Azo dyes are also widely used in the textile, printing and paper manufacturing industries,4 as well as in laboratories as either biological stains or pH indicators.5

    Labelling issues:
    According to the Codex Alimentarius Commission standards, additives used as ingredients to perform specific functions in pre-packaged foods must be declared on the label by the appropriate category name, e.g., colorant, followed by the approved name or serial number. No foodstuff containing tartrazine may be sold unless the word "tartrazine" appears in the list of ingredients.

    However, if tartrazine occurs in a food within a food (e.g., in jam within a packaged cake), it does not have to appear on the list of ingredients,6 unless it contributes to more than 2% of the product's weight.

    Adverse reactions to tartrazine:
    Some experts suggest that additives (including tartrazine) do not cause ANY adverse reactions. Studies that do report adverse reactions to tartrazine are noted below. Some of the suggested effects of tartrazine are controversial. This is mainly because of the limited number of studies done and the variation in the methodology used.

    Overwhelming evidence suggests that tartrazine does not induce an IgE-mediated response, although allergic mechanisms have been suspected. The exact mechanism of reaction has not been established thus far. Adverse reactions to tartrazine are considered to be due to an intolerance or sensitivity. The amount of tartrazine required to produce sensitivity in susceptible persons varies from 0.85ug to 25mg. It is estimated that the average daily consumption of dyes is 15mg, about 85% of which is tartrazine.1

    The most common manifestation of tartrazine sensitivity is urticaria and, to a lesser extent, angioedema. Evidence also suggests that chronic urticaria may be caused by tartrazine.1

    a. Skin manifestations:

  • Acute and/or chronic urticaria7,8,9,10,11,12,13

  • Angioedema7,8,9,10,13
    One published case report suggests that food-additive intolerance should always be considered in patients who experience repeated episodes of urticaria/angiodema after the ingestion of commercial food products, even if these are considered free of additives.10

  • Atopic dermatitis14,15

  • Contact dermatitis1

  • Various types of purpura1,16,17,18,19,20

  • Recurrent fixed drug eruption (a distinctive eruption characterized by recurrences of one or more circumscribed lesions in the same site, or sites, when the causative "drug", in this case tartrazine, is given)6
    •

    b. Systemic reactions:

  • Eosinophilia7,8,9,21

  • Anaphylactic-like reactions1,22,23,24

  • Headache, migraine25

  • Inhibition of platelet aggregation26
    •

  • Hyperactivity:
    Tartrazine has been implicated in hyperactivity (also referred to as hyperkinesis or overactivity), concentration difficulties and learning difficulties in children.25 Whether this is true is controversial and is yet to be proven. There have been many conflicting results in studies. This can be partly explained by methodological variations in trial design such as the use of placebos, the number of double-blind challenges, and challenge doses.27


    • Some studies show that parents' reports of their child's adverse behavioral changes after ingestion of tartrazine could not be validated objectively when double-blind challenges were done. This does not exclude the possibility that there are children who experience behavioral changes upon the ingestion of additives such as tartrazine. However, it does show that parents' beliefs in the behavioral effects of tartrazine are often groundless and unreliable. This is in contrast to the situation of children with atopic disease, where tartrazine may act as a trigger for asthma and eczema. Improved control of the disease (including the exclusion of tartrazine) is often accompanied by a significant improvement in behavior and concentration.28

    Parents should be informed of the range of factors that are known to influence behavior, as well as the limited amount of evidence that exists for the role of food additives and foods in causing behavior disturbances. Many health professionals do not believe that azo dyes cause hyperkinesis. Many families are unaware that clinical and educational psychologists, family therapy and other facilities can assist in treating behavioral problems in children.1,27

    As suggested above, conditions such as uncontrolled eczema and perennial hayfever should also be considered as causes of "hyperactivity" in children. Itching from eczema and severe nasal obstruction from hay fever may lead to sleep deprivation or disturbed sleep, causing fatigue or paradoxically, hyperactivity (restless movement subconsciously aimed at generating the stimulus for staying awake) the next day. In the case of these underlying conditions, which can indirectly cause hyperactivity, a sensitivity to additives may be falsely blamed.

    C. Respiratory reactions:
    Asthma has been linked to tartrazine sensitivity in many studies7,8,9,13,29, but not all studies confirm this30. More recent and well designed studies are fairly conclusive in showing that tartrazine may present a significant problem for asthmatics.1 Routine tartrazine exclusion will not benefit most asthmatics, only those very few individuals with proven sensitivity.31

    Aspirin-sensitivity:

    Aspirin intolerance can induce cutaneous and/or respiratory reactions.32 It has been suggested that aspirin-sensitive individuals are more prone to be sensitive to tartrazine as well, and that tartrazine will exacerbate asthma in aspirin-sensitive individuals. Various studies report the frequency of adverse reactions to tartrazine among aspirin-intolerant patients with asthma to vary widely, ranging from 0 to 44%.2 Settipane33 reported that 15% of aspirin-sensitive asthmatics reacted to tartrazine doses of 0.22 to 0.44mg, whereas Samter reported an 8% incidence of tartrazine sensitivity in aspirin-intolerant patients. Another study found that approximately 2.4% of aspirin-allergic individuals cross-react to tartrazine.2,9 Rosenhall found that 8% of 1868 patients with rhinitis or asthma reacted to a challenge of tartrazine, although the loose criteria for positive challenges has been commented on.

    However, some studies have found negative results. Weber34 found that a 16% tartrazine reaction rate in 44 patients with perennial asthma could not be replicated with a double-blind challenge. None of the patients reacted. One article (with a review of studies on this subject) came to the conclusion that asthmatics or patients with urticaria, whether aspirin-sensitive or -insensitive, have no reason to avoid tartrazine, unless it is specifically demonstrated that tartrazine provokes an adverse reaction during controlled ingestion challenges.30 The difference between the various studies in the literature may be due to the variation in interpretation of the reactions and in the methodologies used.1

    In aspirin-intolerant individuals, various drugs, most of which are prostaglandin inhibitors, have been found to also cross-react with aspirin. These include (in decreasing order of frequency) indomethacin (100%), ibuprofen, mefenamic acid, phenylbutazone, sodium benzoate and acetaminophen (5%).33 It is not clear whether the cross-reactivity between these drugs and aspirin is similar to that between tartrazine and aspirin.

    Relationship with other azo dyes:
    Few adverse reactions have been reported to other azo dyes (see list above). It is not clear whether the attention given to tartrazine is because it is a more commonly used than other azo dyes, or because the others cause fewer reactions in proportion to their use. Tartrazine is, however, structurally unique as it contains a sulfanil group in addition to its pyrazolone structure, but the clinical significance is not known.1

    Other cross-reactions of tartrazine:
    Azo dyes can cross-react with permanent hair dyes containing p-phenylenediamine.

      compiled by Karen du Plessis B.Sc. Diet.
    karen@allergyadvisor.com
    Food & Allergy Consulting & Testing Services (FACTS)
    PO Box 565
    Milnerton 7435
    South Africa


    C. Comments by our editor

    Dr. Harris Steinman M.B.Ch.B.
     Even though there is no conclusive evidence that tartrazine causes hyperactivity in children, there are many parents and even health professionals that believe this. There are so many holes in the methodology used in the various studies done that one cannot rule out that tartrazine can cause hyperactivity or not. And this is the case with many other types of adverse reactions. It is important to consider all aspects of a patient's history before ruling out a diagnosis - no matter if it has not been confirmed by literature.

    For more information on this subject and other allergy and intolerance related topics, visit:
    http://www.allallergy.net
    http://www.allergyadvisor.com
    http://users.bigpond.net.au/allergydietitian

    To join a professional food allergy discussion list where this subject can be discussed further, go to http://groups.yahoo.com/group/AllergyDietitian or
    Subscribe: AllergyDietitian-subscribe@yahoogroups.com
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    We invite you to send us interesting case studies. We pay US$100 for each case study we use in our newsletter.

    To subscribe or unsubscribe, send an e-mail to tammy@allergyadvisor.comand put "subscribe Educational" or "unsubscribe Educational " as the subject.

    D. References
    1. Dipalma JR. Tartrazine sensitivity. Am Fam Physician 1990;42(5):1347-1350.
    2. Virchow C, Szczeklik A, Bianco S, et al. Intolerance to tartrazine in aspirin-induced asthma: results of a multicenter study. Respiration 1988;53:20-23.
    3. Bhatia MS. Allergy to tartrazine in alprazolam. Indian J Med Sci 1996;50(8):285-286.
    4. Chung KT, Stevens SE Jr, Cerniglia CE. The reduction of azo dyes by the intestinal microflora. Crit Rev Microbiol. 1992;18(3):175-90.
    5. Chung KT. The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes. Mutat Res. 1983 Apr;114(3):269-81.
    6. Orchard DC, Varigos GA. Fixed drug eruption to tartrazine. Australas J Dermatol 1997;38(4):212-214.
    7. Settipane GA, Chafee FH, Postman M, et al. Significance of tartrazine sensitivity in chronic urticaria of unknown aetiology. J Allergy Clin Immunol 1976;57:541-546.
    8. Stenius BSM, Lemola M. Hypersensitivity to acetylsalicylic acid (ASA) and tartrazine in patients with asthma. Clin Allergy 1976;6:119-128.
    9. Morales MC, Basomba A, Pelaez A, et al. Challenge tests with tartrazine in patients with asthma associated with intolerance to analgesics (ASA-triad): a comparative study with placebo. Clin Allergy 1985;15:55-59.
    10. Asero R. A strange case of "tuna allergy". Allergy 1998;53:816-817.
    11. Jimenez-Aranda GS, Flores-Sandoval G, et al. Prevalence of chronic urticaria following the ingestion of food additives in a third tier hospital. Rev Alerg Mex 1996;43(6):152-156.
    12. Montano Garcia ML, Orea M. Frequency of urticaria and angioedema induced by food additives. Rev Alerg Mex 1989;36(1):15-8.
    13. Collins-Williams C. Clinical spectrum of adverse reactions to tartrazine. J Asthma. 1985;22(3):139-43.
    14. Worm M, Vieth W, Ehlers I, Sterry W, Zuberbier T. Increased leukotriene production by food additives in patients with atopic dermatitis and proven food intolerance. Clin Exp Allergy 2001;31(2):265-73.
    15. Van Bever HP, Docx M, Stevens WJ. Food and food additives in severe atopic dermatitis. Allergy 1989;44(8):588-594.
    16. Criep LH. Allergic vascular purpura. J Allergy 1971;48:7-12.
    17. Michaelson G, Pettersson L, Juhlin L. Purpura caused by food and drug additives. Arch Dermatol 1974;109:49-52.
    18. Wüthrich B. Adverse reactions to food additives. Ann Allergy 1993;71(4):379-84.
    19. Kubba R, Champion RH. Anaphylactoid purpura caused by tartrazine and benzoates. Br J Derm 1975;Suppl2:61-2.
    20. Kalinke DU, Wüthrich B. Purpura pigmentosa progressiva in type III cryoglobulinemia and tartrazine intolerance. A follow-up over 20 years. Hautarzt 1999;50(1):47-51.
    21. Bell RT, Fishman S. Eosinophilia from food dye added to enteral feeding. N Engl J Med 1990;322:1822.
    22. Trautlein JJ, Mann WJ. Anaphylactic shock caused by yellow dye in an enema (case report). Ann Allergy 1978;41:28-29.
    23. Pohl R, Balon R, Berchou R, Yeragani VK. Allergy to tartrazine in antidepressants. Am J Psychiatry 1987;144:237-238.
    24. Desmond RE, Trautlein JJ. Tartrazine (FD&C yellow #5) anaphylaxis: a case report. Ann Allergy 1981;46:81-2.
    25. Novembre E, Dini L, Bernardini R, Resti M, Vierucci A. Unusual reactions to food additives. Pediatria Medica e Chirurgica 1992;14(1):39-42.
    26. Gallagher JS, Splansky GL, Bernstein IL. Inhibition of platelet aggregation by tartrazine and a pyrazolone analogue in normal and allergic individuals. Clin Allergy 1980;10:683-90.
    27. Pollock I, Warner JO. Effect of artificial food colours on childhood behaviour. Arch Dis Child 1990;65:74-77.
    28. David TJ. Reactions to dietary tartrazine. Arch Dis Child 1987;62(2):119-122.
    29. Chafee FH, Settipane GA. Asthma caused by FD&C approved dyes. J Allergy 1967;40:65-72.
    30. Stevenson DD, Simon RA, Lumry WR, Mathison DA. Adverse reactions to tartrazine. J Allergy Clin Immunol 1986;78(1 Pt 2):182-191.
    31. Ardern KD, Ram FS. Tartrazine exclusion for allergic asthma. Cochrane Database Syst Rev. 2001;(4):CD000460.
    32. Moneret-Vautrin DA, Wayoff M, Bonne C. [Mechanisms of aspirin intolerance] Ann Otolaryngol Chir Cervicofac. 1985;102(5):357-63.
    33. Settipane GA. Aspirin and allergic diseases: a review. Am J Med. 1983 Jun 14;74(6A):102-9.
    34. Weber RW, Hoffman M, Raine DA, Nelson HS. Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes and preservatives in a population of perennial asthmatics. J Allergy Clin Immunol 1979;64:32-37.

    E. CPD Questions (For South African dietitians only. Australian dietitians: where you have relevant learning goals, CPD hours related to this resource can be included in your APD log.)

    You can obtain 2 CPD points for reading this newsletter and answering the accompanying questions. This newsletter with questions has been accredited for dietitians.
    CPD reference number: DT03/3/074/13

    HOW TO EARN YOUR CPD POINTS
    1. Complete your personal details below.
    2. Read the newsletter and answer the questions.
    3. Indicate your answers to the questions by making a "X" in the appropriate block.
    4. You will earn 2 CPD points if you answer more than 75% of the questions correctly. If you score is between 60 and 75%, 1 CPD point will be allocated. A score of less than 60% will unfortunately not earn you any CPD points.
    5. Make a photocopy for your own records in case your answers do not reach us.
    6. Cut and paste the area indicated below into a e-mail message and e-mail it to karen@allergyadvisor.com to be received no later than 31 August 2003. Answer sheets received after this date will not be processed.

    PLEASE ANSWER ALL THE QUESTIONS
    (There is only one correct answer per question.)
    1. In which of the following would one not expect tartrazine to be present?
    (a.) Soft drinks
    (b.) Soda water
    (c.) Medications
    (d.) Textiles

    2. Which of the following are reasons why synthetic colorants are used more frequently in the food industry?
    (a.) They are less expensive than natural colorants.
    (b.) Less can be used to gain the same effect.
    (c.) They remain stable under high processing temperatures.
    (d.) All of the above.

    3. What is the main reason for the use of tartrazine in drinks, foods, drugs and cosmetics?
    (a.) Identification purposes and to create an attractive appearance
    (b.) To reduce the price of the product
    (c.) To increase the shelf life of the product

    4. Which of the following is true regarding the mechanism of reaction to tartrazine?
    (a.) It is IgE-mediated.
    (b.) It is an allergic mechanism.
    (c.) It is a toxic reaction.
    (d.) The exact mechanism of reaction has not been established thus far.

    5. What is the most common manifestation of tartrazine sensitivity?
    (a.) Urticaria
    (b.) Migraine
    (c.) Hyperactivity
    (d.) Inhibition of platelet aggregation

    6. True or false: Whether tartrazine causes hyperactivity is controversial and is yet to be proven.
    (a.) True
    (b.) False

    7. True or false: Routine tartrazine exclusion will benefit all asthmatic patients.
    (a.) True
    (b.) False

    8. True or false: Cross-reactivity with tartrazine should be considered in an aspirin-intolerant person.
    (a.) True
    (b.) False

    Cut and paste this section below into an e-mail message

    Tartrazine
    CPD Reference number: DT03/3/074/13

    HPCSA number: DT
    Surname as registered with the HPCSA:
    Initials:
    E-mail address:

    Please make an "X" in the appropriate block for each question

    1. a [ ] b [ ] c [ ] d [ ]   2. a [ ] b [ ] c [ ] d [ ]   3. a [ ] b [ ] c [ ]
    4. a [ ] b [ ] c [ ] d [ ]   5. a [ ] b [ ] c [ ] d [ ]   6. a [ ] b [ ]
    7. a [ ] b [ ]   8. a [ ] b [ ]    


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