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An Update On Benzoates

An Update On Benzoates

Allergic contact dermatitis (ACD) is an important disease that notably affects 14.5 million Americans each year.1 The economic impact of this disease is high in terms of both patient morbidity and loss of income, school, and work, not to mention significant expenditures for visits to health care providers and for medicaments. A correct diagnosis of ACD will improve, prevent, or “cure” the dermatitis and decrease overall costs to the health care system.1 Once patch testing is performed and a culprit has been identified, education becomes the critical intervention to ensure adherence to an avoidance regimen.

With allergen avoidance, remission of the dermatitis ensues. If patients are unable to comply with the avoidance regimen, they become at risk for recurrent or sustained dermatitis or progression to a systematized presentation.2,3 The 2 main types of contact dermatitis are irritant and allergic, with irritant contact dermatitis (ICD) being the most common. ICD may occur in anyone who is exposed to an irritating substance with significant duration or in significant concentrations such as chronic or frequent water exposure, abrasive cleansers, detergents, and soaps. It is important to note that ICD can at times precede or be a concomitant diagnosis with ACD.4,5 ACD is a delayed type-IV hypersensitivity reaction that can occur due to a large number of chemicals from poison ivy to fragrances in shampoos. The evaluation of ACD fits well with theranostic theory, as the epicutaneous patch test diagnostic evaluation dictates the avoidance management in each individual patient.

Although ACD is not “curable,” many individuals will achieve complete remission with assiduous avoidance. This article highlights ACD and explores top relevant allergens, regional-based dermatitis presentations, topic-based dermatitis presentations, and clinical tips and pearls for diagnosis and treatment, with a focus on benzoates.


Flowers of Benjamin: A Brief History
“This acid was known to the ancient chemists under the name of Flowers of Benjamin, or of Benzoin, and was procured, by sublimation, from the gum or resin called Benzoin.”
 - Antoine Lavoisier, Elements of Chemistry, 17896

Alchemist Michel de Nostradame, more popularly known as prophesier Nostradamus, first described benzoic acid in 1556.7,8 To produce benzoic acid, Nostradame dry-distilled gum benzoin, the balsam resin from trees of the genus Styrax.9 (“Gum” is a misnomer, as resin is not a water-soluble polysaccharide.9) Gum benzoin was popularly used at that time in fragrances, especially incense.10 Other benzoates were discovered and used as fragrances and flavorings. Sources from the 18th and 19th century describe benzoates used as fragrances and flavorings. For example, in the Handbook of Soap Manufacture, benzyl benzoate is noted for its use as a “fixateur,” a perfume that possessed the property to help soap “retain other and more delicate odours.”11 It was also said to be used to produce counterfeit arrack, a rum-like alcoholic beverage from the East Indies.12,13 (The author the Cookery Book directs 2 scruples of benzoic acid to be dissolved in 1 quart of rum to make “mock arrack.”12)
At the turn of the 20th century, a combination of events brought benzoates to the forefront of food preservation. Harvey Washington Wiley, head of the bureau of chemistry in the Department of Agriculture (now the FDA), led a movement for food safety and quality, which included the regulation of food additives.14 Around the same time, means of mass synthetic production of benzoates were discovered.15 Sodium benzoate, the most water soluble of the readily mass-produced benzoates, became one of the first preservatives approved by the FDA for use in certain foods and cosmetics.14,16,17

Benzoates as Preservatives
The term “benzoates” refers to the aromatic compound benzoic acid and its salts, esters, and alcohols.18,19 (Table 1). The primary mechanism of action for benzoates is believed to be a function of their acid dissociation quotient (pKa). Benzoates function best in acidic conditions because, as weak acids, they are undissociated at lower pHs.17,20

In their undissociated state, they are lipophilic, and capable of crossing the cell membrane of microbes.15,20 These microbes depend on a transmembrane gradient for energy.15,20 They maintain neutral conditions within their cytoplasmic membrane, and use the gradient for energy or amino acid transport. 5,20 However, they dissociate once inside the controlled neutral environment of the cell, leading to both a decrease in intracellular pH and the gradient required for the cells to make energy. Not only is less energy made, more energy is required in an effort to restore the pH to neutral within the cell. With the decrease in energy, the cells have decreased ability to transport necessary amino acids into the cell, hurting their ability to maintain function.

Because the acidic conditions in which benzoates are functional also prohibit the growth of many bacteria, the primary function of benzoates as preservatives is the inhibition of yeast and mold.20

Modern Day Utilization
Benzoates are primarily used today as preservatives, especially in consumable and personal hygiene products. (Table 2). In personal hygiene products, they have been increasingly used in lieu of formaldehyde-releasing preservatives.21 Interest in benzoates as food preservatives also remains high, and as recently as May 2013, legislation in the United States led to the allowance of sodium benzoate and benzoic acid as meat and poultry additives.22 This occurred following a request from Kraft Foods Group Inc to re-evaluate these preservatives, which had previously been prohibited due to concerns that they may be used to cover up poor-quality meat.23 Conversely, precedence has also been set by companies seeking to remove benzoates. In the early 1900s, the H. J. Heinz Company ran an advertising campaign for ketchup that was free of benzoates, calling them “unhealthful and injurious.”21,24 More recently, in 2008, British concern about benzoates in consumables reacting with ascorbic acid to form the carcinogen benzene led to the removal of benzoates from one of the most popular spiced colas in that country, diet Coca-Cola (Coca-Cola Company, Great Britain).25

As a side note, kola nuts, which come from the conifer tree Cola acuminate, are used as a source of flavor and caffeine in cola beverages.26-28 This is especially of interest because conifers are known to naturally contain similar or related allergens to balsam of Peru, such as colophonium, balsam of Tolu, wood tar, turpentine, styrax, or propolis.18

Outside of the food and beverage industry, sodium benzoate is frequently used as an excipient in medications such as liquid medications (cough syrups, antibiotic syrups) coated pills, vitamins, and heparin.29,30 It may be an additive in local anesthesia.31 In dentistry, it may be used to treat dental plaque, and as preservatives in toothpastes and mouthwashes.17,32 Sodium benzoate is used as a treatment for acute hyperammonemia in patients with urea cycle enzymopathies.17, 33-35 By facilitating conjugation in the acylation of amino acids, it increases the rate of elimination of nitrogen.17,33
Benzoic acid (which, unlike the other benzoates, occurs in nature) also may be used as the active ingredient itself as a topical antifungal treatment.17,36 Benzoic acids also function as intermediates in dibenzoate plasticizers and diethylene and dipropylene glycol.17 Benzyl benzoate is used as a topical treatment option for scabies.37 Beyond medicine, sodium benzoate may be used as a corrosion inhibitor in engine additives and antifreeze solutions, and as a stabilizer to photographic baths.17,38 Benzoate alcohols are sometimes used as solvents in topical applications, such as sunscreens19 (Table 3).

Health Implications
Benzoates may lead to type I (anaphylactic) and type IV (delayed-type) hypersensitivity responses.17 Benzoic acid and sodium benzoate are also known to rarely cause “pseudoallergy,” or nonimmunological contact response, especially in atopic patients.17 The National Institutes of Health lists potential toxicities of benzoates as cough, rash, urticarial, eye redness, nausea, vomiting, and abdominal pain.33,39 Cases have been reported of perioral rash caused specifically by consumables such as spiced cola and canned food.21 Benzoates have also been implicated in orofacial granulomatosis, as well as attention deficit behaviors in children.40,41 Penicillin is known to compete for renal secretion with the conjugates of sodium benzoate.33 Probenecid may inhibit renal transport of benzoates.33

Benzoate Sensitization
As a common component of personal hygiene products, it may produce dermatitis on the face, especially the mouth due to its extensive use in dental products. It is also at risk of causing systemic dermatitis because of its extensive use in foods.29

While there are few scholarly articles regarding benzoate sensitization, a retrospective analysis of 79,046 patients in Germany, Switzerland, and Austria showed that sensitization to sodium benzoate had increased in the studied population by more than 10% between 1996 and 2009.42
Therefore, it is an important consideration for many patients, especially as a potential cross-reactant and component of balsam of Peru, one of the top 5 most common causes of contact dermatitis.18

Patch Testing
Patch testing is often necessary to identify the relevant allergen(s) responsible for the patients’ ACD. Screening patch test trays are available to isolate the most common chemicals and offer the provider clues for potential sources. The American Contact Dermatitis Society (ACDS) and North American Standard Series include allergens from several different categories. Supplemental trays directed at specific populations or allergies, such as hairdressing, dental materials, and fragrance/flavors, are also available for purchase.43 Sodium benzoate and benzoic acid are included in bakery series, antimicrobial series, and sodium benzoate is also found in the cosmetic grouping.44,45 Balsam of Peru, which may contain levels of benzoic acid and sodium benzoate high enough to elicit a reaction,46 is included in the ACDS Standard 80 Core Allergen series and the Thin-Layer Rapid Use Epicutaneous (T.R.U.E.) Test (SmartPractice, AZ).47

Those who react to balsam of Peru may require subcomponent testing to confirm whether the person is sensitized to sodium benzoate and benzoic acid, or other balsam of Peru constituents.

Pearls of Treatment: Every Dose Counts in Avoidance
A person may be exposed, and subsequently sensitized to a particular allergen for days to years before actually developing ACD. Exposures can be additive, eventually causing one’s immune system to become trained to identify a chemical, at which time a cutaneous response would be elicited upon exposure.4 Conversely, repeated avoidance over time increases the threshold of exposure to elicit a response (decreasing reactivity), leading to remission. Avoidance creativity, however, may be necessary by utilizing alternatives and being aware of indirect exposures. In some patients with ACD (for which extended patch testing is not available), Pre-Emptive Avoidance Strategies (P.E.A.S.) which target removal of the 10 most common ACD allergens (including balsam of Peru and benzoates) may be beneficial.48

There are programs available to aid allergen avoidance. The Contact Allergen Management Program (CAMP), a service offered through ACDS, and SkinSAFE (formerly the Contact Allergen Replacement Database), developed in association with the Mayo Clinic, can assist with identifying allergen-free products.49,50 Both programs allow the provider to personalize “shopping lists” of products void of specific dermatitis-inducing chemicals, as well as any cross-reactors.

Dr McGowan is a resident at Loma Linda University Medical Center in Loma Linda, CA.
Dr Jacob, Section Editor of Allergen Focus, is a board-certified dermatologist and professor at Loma Linda University in Loma Linda, CA. She is founder and chief executive officer of the Dermatitis Academy public outreach education campaign.

Disclosure: Dr McGowan reports no relevant financial relationships.

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