Focus on T.R.U.E. Test Allergens #21, 13 and 18: Formaldehyde and Formaldehyde-Releasing Preservatives


A llergic Contact Dermatitis is an important disease with a high impact both in terms of patient morbidity and economics. The contact dermatitides include irritant contact dermatitis, contact urticaria and allergic contact dermatitis. Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses. Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this would be latex hypersensitivity. While this is beyond the scope of this section, we acknowledge this form of hypersensitivity due to the severity of the potential reactions and direct the reader to key sources.1,2 Allergic contact dermatitis, on the other hand, is a delayed type IV hypersensitivity reaction. The primary focus of this section is to highlight the educational component of allergic contact dermatitis. Clinical Illustration We present a case of a medical student who presented with erythematous eczematoid plaques on her trunk and legs and fine vesiculation of her scalp, 3 weeks after starting anatomy class. Of note, she routinely washed her face and arms after leaving the anatomy lab, but remained in her scrubs for the rest of the day. History of Formaldehyde and the Formaldehyde-Releasing Preservatives The desire to improve one’s appearance with topical applications dates back to the Egyptian Queen, Cleopatra, who was fond of using creams and make-up for skin beautification.3 What once was fit for a queen has become a $30 billion a year cosmetic industry.4 With the cosmetic boom came the concern of microorganisms in cosmetic creams introduced during manufacture or transferred to the product through use.5 A variety of reports of cosmetic contamination from Klebsiella pneumoniae have been reported. In addition, this bacterium has been linked to septicemia after contact with a contaminated hand cream dispenser.6,7 Consequently, considerable attention has been given to topical pharmaceutical preparations with effective methods of antimicrobial preservation. Preservatives are biocidal chemicals added to cosmetics, topical medicaments and foods to protect against spoilage, bacterial and fungal contamination, and biological degradation.7 The ideal preservative should be stable, antimicrobial, nontoxic, non-irritating and active over a broad range of pH values. In 1938, the FDA passed the Food, Drug and Cosmetic Act requiring the cosmetic industry to prove product safety before marketing to consumers.8 Prior to that, products such as Lash-Lure (by the Los Angeles-based company) containing paraphenylenediamine had caused blindness, and a whitening foundation containing lead oxide had caused muscle paralysis.9 Soon thereafter, formaldehyde preservation of cosmetics was being streamlined for its many advantages. It was cheap and effective in eliminating a wide range of microorganisms and aggressively destroying degradation enzymes, thus slowing product decomposition. Formaldehyde remains a commonly used preservative in cosmetics today with an average concentration between 0.02% and 0.3%.10 How It Was Discovered A formaldehyde-based white brittle material, polyformaldehyde was discovered during the incomplete combustion of carbon in 1859 by the Russian chemist, Alexander Mikhailovich Butlerov. This leader in isomer chemistry (and synthesizer of the first artificial sugar) has had a crater on the moon named after him to commemorate his work.11,12 Ten years after the polymer discovery, the German chemist, August Wilhem von Hofman, found that by passing methanol and air over a heated platinum spiral, he could create pure formaldehyde (a technique is still used today).13 In 1892, the year of Hofman’s death, Friedrich August Kekule von Stradonitz, the scientist who introduced the concept of chemical bonds, isolated pure formaldehyde by the catalytic oxidation of methanol. First Commercial Uses One of the first mass commercial uses of formaldehyde was in medical embalming (a practice known to be utilized during the Civil War).14 Interestingly, formaldehyde use evolved with medical advancement. In 1883, Robert Koch made a landmark discovery with a weighty economic impact to the food industry. He found that the bacterium, Vibrio cholerae, the cause of cholera, could be transmitted via food and water. This discovery initiated the demand for government regulation of food industry sanitation and the necessitation of antimicrobial food additives.8 In 1900, San Franciscan Chinese immigrants suffered from an outbreak of the bubonic plague. The city board of health quarantined Chinatown and dusted the district with a mixture of lime and formaldehyde to control the spread of disease.15 In 1912, Dr. Harvey Wiley, Head of the Department of Chemistry in Washington D.C. (Predecessor to the Food and Drug Administration), founded the “poison squad”. This squadron of volunteers ate food to test the safety of added preservatives (for example, borax, benzoic acid, sulfuric acid and formaldehyde). The poison squad was so popular with the public that minstrel shows sang about it: “Next week he’ll give them mothballs, a la Newburgh or else plain; O, they may get over it, but they’ll never look the same.”8 After 5 years of experiments, vomiting and stomach pain, Dr. Wiley publicly resolved that preservatives in food and medications should “only be used when absolutely necessary,” despite big business fighting him “tooth and nail”.8 In the 1950s, formaldehyde again made its mark in the medical news. Jonas Salk’s team created a polio vaccine. This was made possible through the use of formaldehyde to kill the poliovirus.15 Success with Plastics Although the medical and food industries had mixed experiences with formaldehyde, the plastics industry thrived because of it. Prior to innovation of formaldehyde-derived plastics, the celluloid plastics had been highly flammable and not suitable for mass marketing.16 At the turn of the century, the International Galalith Gesellschaft Hoff and Company compounded formaldehyde and fat-free milk curd to formulate a new synthetic plastic (casein-formaldehyde), which became a main constituent of buttons.16,17 The biggest landmark in formaldehyde-based plastics came in 1910. Leo H. Baekeland condensed phenol and formaldehyde to make the first non-flammable synthetic plastic, Bakelite, which had high utility as an electronics insulator.10,18 Bakelite sales skyrocketed, as it was marketed in toys, jewelry and cameras. The Bakelite Museum in England even boasts a Bakelite coffin!19 Its amber color contributed to its popularity in jewelry, but limited its potential when transparency was needed.10 During the Bakelite heyday, circa 1912, scientists, Daniel J. O’Conor and Herbert Faber, added formaldehyde to a urea polymer to develop a novel insulation substitute for mica, aka formica.18 The 1920s and ’30s, saw the explosive age of the urea formaldehyde resins whose colorless properties allowed new lines of plastic products in bright colors, i.e the trendy plastic versions of marble dishes, bandalasta.11,21 Today, urea-formaldehyde resins and melamine-formaldehyde laminates dominate the commercial market. What began as a reach for a new plastic alternative and preservative has become a $500 billion industry, representing 5% of the United States’ gross national product.11 Formaldehyde is used to make plywood, asphalt shingles, car gears and bearings. Specifically, p-tert-Butylphenol formaldehyde resin is used in bonded leather, construction materials and waterproof glues. In addition, fertilizers and photographic developers are also known to contain formaldehyde.11 A Powerful Allergen The rates of sensitization to formaldehyde have risen to 9.2%.22,23 Formaldehyde is second only to fragrances as the most common sources of cosmetic-associated contact dermatitis.24 To decrease sensitization and lower the concentration of formaldehyde, the formaldehyde-releasing-preservatives (FRPs) are often used in place of frank formaldehyde, for example quaternium-15 (see Table 1).7,22,25 Herbert and Rietschel explain that if the concentration of formaldehyde that is released by FRPs is below the threshold of reactivity for virtually all formaldehyde-sensitive patients (somewhere between 30 and 250 ppm), there would not be an allergy to the FRP.25 Many cases of contact dermatitis to formaldehyde/FRPs present as eyelid dermatitis associated with the use of cosmetics (mascara, blush and foundation), shampoos, medical creams or nail hardeners, to name a few. Other important sources of exposure include permanent press clothing, cleaning agents, baby wipes, disinfectants, paper and even cigarette smoke.22 As is often the case in contact dermatitis, the distribution of the dermatitis can provide insight into the exposure. For example, patients sensitized to formaldehyde from adorned permanent-press clothing tend to present with a chronic dermatitis around their body folds, where the clothes rub against the skin. 22 Patients sensitized to formaldehyde in clothing textiles have been found to become secondarily sensitized to quaternium-15, presenting with a diffuse nummular dermatitis or erythroderma.24 Systematized dermatitis is seen with both formaldehyde and the FRPs. Inhalation (smoking) and ingestion of formaldehyde containing foods are important systemic sensitization sources (see Table 2).27-30 For example, diet soda and yogurt containing aspartame (Nutrasweet), release formaldehyde in their natural biological degradation. One of aspartame’s metabolites, aspartic acid methyl ester, is converted to methanol in the body, which is oxidized to formaldehyde in all organs, including the liver and eyes.22 Patients with a contact dermatitis to formaldehyde have been seen to improve once aspartame is avoided22 Notably, the case that Hill and Belsito reported had a 6-month history of eyelid dermatitis that subsided after 1 week of avoiding diet soda.22 Formaldehyde-Releasing Preservatives The formaldehyde releasers are reversible polymers of formaldehyde.31 Formaldehyde is formed in different amounts based on the pH, temperature, and amount of water.31,32 The antibacterial effects are independent of the amount of formaldehyde released.29 An allergic reaction can be seen specifically to the FRP, formaldehyde or both.31 Quaternium-15, a colorless, odorless, biocidal FRP is highly water-soluble, stable, and active over a broad range of pH. It has broad antimicrobial activity, particularly Pseudomonas aeruginosa, yeasts, and molds.22 As the most common sensitizer among the formaldehyde-releasers, it is included on the T.R.U.E. test and has many alternative names (see Table 3).23 Occupational sources Occupation is one of the biggest risk factors for quaternium-15 exposure. Occupations such as hair dressing, painting, printing, textile dyeing, paper processing and working with disinfectants all have greater risks of developing allergies to quaternium-15, according to Haz-Map, an organization that evaluates occupational risks for exposures to hazardous chemicals. Formaldehyde is both an irritant and a contact allergen. Contact urticaria and anaphylaxis to formalin have been described in a patient after a root canal and in a hemodialysis patient, respectively (see list of systemic formaldehyde effects in Table 4).28,33 Garment industry workers, hemodialysis nurses, embalmers, pathologists, and dermatologists are at great occupational risk for occupational-based formaldehyde allergy. Due to the notoriety it has received as a potential carcinogen, irritant, and sensitizer, formaldehyde use in cosmetics has significantly decreased. Notably, formaldehyde is prohibited in cosmetics in Sweden and Japan.22 Testing for Allergy to Formaldehyde and FRPs Patch testing for formaldehyde, quaternium-15, and p-tert-Butylphenol formaldehyde resin allergy can be accomplished with the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) test (sites 18, 21, and 13, respectively). The T.R.U.E. test is the commercially available, globally used, allergen screening system. While it is widely used, the discrepancy in allergen prevalence and uncertain relevance has led to scrutiny of its utility. The T.R.U.E test contains 23 allergens and one negative control. At best, the T.R.U.E test is a minimum screening tool because it tests only 23 of the more than 3,700 possible allergens that can cause allergic contact dermatitis. Krob et al. recently demonstrated that nickel, thimerosal, cobalt, fragrance and balsam of Peru are the most prevalent allergens detected by the T.R.U.E. test, yet a significant number of relevant allergens, not present on the T.R.U.E. test, are potentially missed by this screening tool used alone.34 Value of this Patient Case Our patient underscores the importance of appropriate patch testing and education. Once we identified the allergy to formaldehyde and quaternium-15, we provided patient education materials regarding the common and not-so-common locations of these chemicals and cross-reactors. We also gave the patient information on avoidance and safe alternatives (see Table 5). Fortunately, with technical advances, this student completed the anatomy section via electronic learning tools. By avoiding formaldehyde, including anatomy lab, FRP in her shampoo and cosmetics, and aspartame in her diet, this patient dramatically improved. As with all contact dermatitides, the mainstay of treatment for allergic contact dermatitis is avoidance.