This issue was sponsored by Abbott Laboratories S.A (PTY) LTD All Abbott products are lactose and gluten free Tel: +27 (0)11 8582054

 

Contents A. Case study B. More information C. Editors' comments D. References E. CPD questions

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INDEX

A. Case study
[The following case presentation was modified and adapted from Asero R. Perennial rhinitis induced by benzoate intolerance. J Allergy Clin Immunol. 2001 Jan;107(1):197]

A 45-year-old woman was referred to a hospital’s allergy clinic after a 7-year history of unresolved perennial rhinitis. She experienced watery rhinorrhoea, itching of the nasal mucosa, and frequent uncontrollable sneezing fits. She said there were periods of slight improvement, but she could not associate these with anything in particular. Previous treatment had included antihistamines as well as local corticosteroids, both of which had had little or no effect.

QUESTIONS AT THIS POINT:
a. Did she have a history of allergy or asthma?
b. As it was spring at the time of the referral, could the change of season, with the increased pollen count, have aggravated symptoms?
c. Did she or a family member smoke?
d. Could any of a range of common environmental allergens or aero-allergens (dog, cat, grasses, cockroach, house dust mites, moulds, pollens) be a causative factor?
e. Was there an underlying sinus infection or inflammation?
f. Were there any structural abnormalities or polyps?

DISCUSSION:
a. On questioning, she revealed no prior symptoms of atopy or asthma and appeared generally well.
b. Previous episodes had occurred at different times of year and did not consistently coincide with seasonal changes.
c. She and her husband did not smoke.
d. Their home was not carpeted, although there were a few rugs on the wooden floors. They had had a dog for the last 9 years, who slept in an outside kennel. In order to rule out potential IgE-mediated reactions, skin prick tests were done and serum IgE levels were tested for the most common inhalant/airborne allergens (seasonal and perennial). Common food allergens were also checked to cover all possibilities. The results of skin prick tests with commercial extracts and the tests of serum IgE levels were all negative, ruling out IgE-mediated mechanisms.
e and f. Plain radiographs as well as a coronal CT scan all produced normal findings. Blood counts did not show any abnormalities. Several ear, nose and throat investigations found only a few inflammatory changes and excluded both structural deformities and polyps.

WHAT CAN BE DONE AT THIS POINT?
Investigate the possibility of a non-immune-mediated mechanism. The symptoms of non-allergic rhinitis are similar to those seen in persistent allergic rhinitis, with two exceptions: eye symptoms are less frequent, and nasal blockage is more prominent. The patient demonstrated severe nasal blockage and no eye involvement, so possible non-immune mechanisms were suspected.

The following tests can be carried out to assist in reaching a conclusion:
a. Patch test
b. CAST test
c. Elimination-challenge test

DISCUSSION:
a. The patch test was negative
b. CAST test: it was felt that the results would not be as conclusive and helpful as the outcome of an elimination-challenge test.
c. In view of the possible association between additive intolerance and respiratory symptoms such as asthma, an elimination diet that was free of food additives was started as a last resort.

On the fifth day, nasal symptoms totally disappeared. Although the improvement was dramatic, it may have been coincidental. As diet had not been assessed previously, the absence of any additive or almost any food could have been responsible for the improvement. The actual amounts of various additives in her diet was unknown making it difficult to identify higher than expected intakes of a particular additive. Environmental changes at the time of implementation or even psychological factors could have played a role.

It was decided to continue an additive-free diet for a month and then to challenge the patient with various common additives.

During the next 3 weeks, she remained symptom-free, but before returning to the clinic she decided to experiment at home and went back to her previous unrestricted diet. After 3 days, nasal symptoms recurred and worsened progressively until she returned to the clinic.

The relapse during her unplanned open challenge at home warranted returning her to an additive-free diet and implementing a double-blind placebo-controlled additive challenge under controlled hospital conditions once her symptoms had disappeared.

The additive-free diet was resumed, and after 4-5 days symptoms gradually disappeared. After 3 weeks without symptoms, the patient underwent double-blind, placebo-controlled oral challenges with various common food additives. The additives and placebos were given in identical opaque capsules. Each additive was increased in incremental doses until acceptable daily intake (ADI) levels were reached or she developed clinical manifestations. The additives tested included sodium metabisulphite, sodium benzoate, sodium glutamate, sodium nitrite, sulphur dioxide, tartrazine and sorbic acid. The patient continued the additive-free diet throughout the study period. She was randomly challenged with single additives and multiple placebos at intervals of a week. Both the active substances and the placebos were masked in orange juice, which was free of additives. Oranges also do not contain natural benzoates. The patient was monitored at the allergy clinic for at least 2 hours after each challenge.

About an hour after the administration of 50 mg sodium benzoate, the patient reported itching of the nasal mucosa that worsened during the next hour, and sneezing and rhinorrhoea manifested. The rhinitis lasted for about 36 hrs. No other substance induced nasal symptoms. To confirm this finding, she was re-challenged 2 weeks later with sodium benzoate and 3 placebos in a double-blind and randomised fashion. Again, she responded to the active substance only; the rhinitis lasted about 36 hours.

CONCLUSION:
Sodium benzoate intolerance was diagnosed. The patient’s prior unrestricted diet frequently included soft cheeses, carbonated drinks, and processed and pickled foods, all of which usually contain sodium benzoate.

The challenge with sodium benzoate exactly reproduced the clinical symptoms that had been present over the past 7 years. As in most cases of food additive intolerance, the pathogenic mechanisms remained elusive. The observation that perennial rhinitis may be caused by the frequent (probably daily) ingestion of small doses of a non-tolerated substance suggests that some patients with chronic rhinitis might actually be intolerant of a particular food additive.

TIP for Allergy Advisor users: Information on benzoates can be found in the main search area of the program. Click on "Items, Substances & Allergens" and enter "Benzoates" in the search field. The information includes foods in which benzoates are present, background information, its function as an additive in food, adverse reactions that have been recorded to this substance, as well as the references to this information. In addition the program also offers a diet sheet for benzoate sensitivity as well as a patient information sheet to inform the patient about his/her condition.

B. More information:
Food intolerance is an adverse reaction to a food which does not involve the immune system. It is caused by toxic, pharmacological, metabolic or idiosyncratic reactions to the food or to chemical substances in the food.

Food additives, from a chemical and functional perspective, are a heterogeneous group of substances including preservatives, antioxidants, dyes, emulsifiers, stabilisers and sweeteners. Their consumption has led to much public concern and debate, particularly as possible causes of a number of illnesses. There is a great discrepancy, however, between the subjective perception of hypersensitivity to food additives and the results of objective diagnostic tests and research.^1,2,3,4,5

Hypersensitivity to preservatives, including benzoates, is usually due to a non-immune-mediated response (intolerance).

A. WHAT ARE BENZOATES AND WHERE ARE THEY FOUND?
Benzoates were first described in 1680 and have been used as food and beverage preservatives since the early 1900’s.

Benzoates are among the world’s most commonly used additives in food manufacturing. For the purpose of this review, “benzoates” will refer to the 2 most common forms, namely benzoic acid and sodium benzoate, which will be discussed in detail. Benzoic acid and sodium benzoate are widely used as antimycotic agents and antibacterial preservatives in various foods and beverages, as well as in some pharmaceuticals (such as antihistamine medication).⁶

Benzoic acid is a white crystalline solid with an acidic pH. It is an organic compound with a carboxyl group bound directly to a benzene ring. It demonstrates limited solubility in water and is moderately soluble in oils, stable and odourless. It can be synthesised from a variety of organic compounds, including benzyl alcohol, benzaldehyde, toluene and phthalic acid. Commercially manufactured/synthetic benzoic acid is obtained mainly by the oxidation of toluene.^6,7

The salts of benzoic acid are produced by the reaction between the acid and an appropriate hydroxide. Commercially, sodium benzoate is the most commonly used of the three benzoic acid salts. Occasionally, potassium benzoate is used where lower sodium content is required. In contrast to its acidic precursor, sodium benzoate is a white crystalline powder with an alkaline pH and is water-soluble as well as soluble in alcohol, ether, chloroform and fixed oils, making it the preferred form for use in food products.⁶

Benzoate Metabolism
When ingested orally, benzoic acid and sodium benzoate are rapidly absorbed from the digestive tract. On reaching the liver they combine with the amino acid glycine and are excreted in the urine. As long as liver function is healthy and adequate glycine is available, both chemicals are completely eliminated from the body (75-100% of the dose is excreted within 6 hours and the remaining portion within 2-3 days).^6,8,9

For a dermally applied benzoic acid dose, excretion varies depending on the amount applied and the site of application, due to differing scales of penetration. The forehead demonstrates the greatest facility for penetration, followed by the abdomen, then the thigh, chest, arm, and the back, which allows the least penetration.^6,8

Benzoic acid and sodium benzoate molecules

a. Benzoates in manufactured products
Benzoates are used mainly as preservatives to inhibit the growth and other actions of yeasts and moulds. Both benzoic acid and sodium benzoate are used to prevent spoilage by microorganisms in a wide variety of processed foods, beverages, and pharmaceuticals, thereby extending their shelf life. They are not as effective against bacteria as other preservatives, and their antimicrobial activity appears to be most effective when they are at acidic pH.^6,9

They are often synergistically used in combination with other preservatives, such as sorbates, and are also used in conjunction with sulphur dioxide for the purpose of inhibiting enzymatic action and browning. Their use in yeast-raised flour products is not allowed, as they inactivate the yeast.

Benzoates, specifically benzoic acid, can be used for flavouring, but since they provide a distinctive flavour to foodstuffs, the concentration at which they can be used is limited.

Sodium benzoate may be used as a preservative in margarine, codfish, bottled soft drinks, maraschino cherries, mincemeat, fruit juices, pickles, fruit jelly preserves and jams. In addition, it may be added to the ice used for cooling fish, and may be an ingredient in eye creams, vanishing creams, and toothpastes.^6,9

Benzoic acid may be used in carbonated and non-carbonated beverages, ice-cream, ices, candies, baked goods, pie and pastry fillings, icings, chewing gum and tobacco. It may also be used in pickles and margarine. In such processed foods, benzoic acid is used up to a level of 0.1%.^6,9

b. Benzoates in natural sources
Benzoates (particularly benzoic acid) occur naturally in foods at varying levels. They may be present in the form of free acid, simple salt, esters and amides.⁹

Benzoates are also substances that are natural to the body’s metabolism, and para-aminobenzoic acid (PABA) is produced by the intestinal flora. PABA plays a role in the breakdown and use of proteins and in the formation of red blood cells. It stimulates folic acid production and helps maintain healthy skin and hair.⁷

Single foods which are considered to contain high levels of benzoic acid include^6,7,8:
• Most berries, especially strawberries, raspberries and cranberries
• Apples, prunes, apricots, greengage plums
• Ceylon tea
• Spices such as cinnamon, nutmeg, clove and anise
• Cherry bark (used in natural cherry flavour beverages and ice creams)
• Cassia bark (used as a natural flavouring of cola, and as a spice flavouring in ice cream, baked goods, and beverages)
• Cocoa
• Mushrooms
• Honey
• Yoghurt

Combinations of natural benzoate-containing foods may also contribute to a higher than expected level of natural benzoates, e.g., in raspberry yoghurt.

There is unfortunately no definitive list of the natural benzoate levels in various products. A study was carried out in South Africa (2002) to attempt to identify such levels, and these are listed in the table below. According to the WHO Concise Chemical Assessment document No. 26, concentrations of naturally occurring benzoic acid in several foods do not exceed average values of 40 mg/kg food (see table below). Most of the values found in the South African research, however, fell far below these WHO values. The South African study also found that benzoates do not occur naturally in milk; and that the benzoates in yoghurt are in fact formed during the period of incubation with the culture.^7,10

Levels of natural benzoic acid in foods:

*Vaccinium species = cranberry, blueberry, lingonberry, loganberry, bilberry

This research highlights many unresolved issues regarding naturally occurring benzoates:
• More research is needed to compile a more definitive list.
• Values may be “country-specific,” and particularly in fruits and vegetables may be influenced by growing conditions and seasons.
• In fermented and cultured foods, there is uncertainty whether all culture strains or only a specific species is responsible for producing benzoic acid.

c. Benzoates in cosmetic and pharmaceutical products
In managing individuals with benzoate hypersensitivities, information regarding potential benzoate sources other than food is essential. Benzoates are used commercially in pharmaceutical preparations and cosmetics and have been used as ringworm treatments and antifungal agents. Benzoic acid is used in a wide variety of cosmetics as a pH adjuster and a preservative. Sodium benzoate is also used in various cosmetic products as a preservative. Another product which may occur in cosmetic formulations as a fragrance component, preservative, solvent and viscosity-decreasing agent is benzyl alcohol, which is metabolised in the body to benzoic acid.⁸

Intravenous sodium benzoate therapy (with sodium phenyl acetate) has been shown to be beneficial for patients with an inborn error of the urea cycle and acute hyperammonaemia. The drugs provide alternative pathways to ureagenesis for waste nitrogen disposal and help maintain nitrogen homeostasis.^11,12

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INDEX

This issue was sponsored by Abbott Laboratories S.A (PTY) LTD All Abbott products are lactose and gluten free Tel: 011-8582054