Review ACDS’ Allergen of the Year 2000-2015

Allergen Focus

Review ACDS’ Allergen of the Year 2000-2015

November 2014

Allergic contact dermatitis (ACD) is a widespread skin condition affecting more than 14 million Americans each year.¹ The economic burden of this disease is high in terms of school absences, work time loss, and medical expenditures, an estimated economic cost of $3 billion per year.^1,2

However, a thorough medical history and epicutaneous patch testing can lead to identification of the responsible allergen and the potential to institute an avoidance regimen. With appropriate avoidance, patients can have resolution of their dermatitis and prevent further episodes, which would significantly improve patient quality of life and decrease healthcare costs.¹ Non-compliance may result in recurrent or chronic dermatitis or progression to systemic disease.^3,4

Contact dermatitis is a classification for a group of conditions whose common thread is they are all states of reactivity to external stimuli. The 2 main disorders in this group are irritant contact dermatitis (ICD) and ACD. ICD, the most common form, occurs when an individual is exposed to a substance that causes irritation and damage to the keratinocytes. It can be an acute reaction to a concentrated household cleaning agent or a chronic reaction to a soap, for example, to which there has been a significant duration of exposure. In contrast, ACD results from a delayed-type hypersensitivity reaction to an allergen-containing substance. Common sites for contact dermatitis include the hands, face and scalp; however, any body region that comes into contact with the irritant or allergen-containing substance may develop an inflammatory reaction. ACD may also occur secondarily to the symptomatic treatment of another underlying dermatitis or dermatosis. Examples include atopic patients who develop an allergy to topical corticosteroids or wound care patients who develop an allergy to bacitracin.

There are a significant number of contact allergens documented to cause relevant ACD; however, some are more deserving than others in receiving the American Contact Dermatitis Society (ACDS) Allergen of the Year “award.” The purpose of the award is to draw attention to the agents causing the most significant clinical effects, those that are underrecognized and those that have become obsolete or for which exposure patterns have changed. While the original intent was academic in nature, the awards have played a key role in generating public awareness.

In this article, we review the notable ACDS Allergen of the Year Awardees from the inaugural awardee in 2000 to the up-and-coming 2015 allergen, discuss their significance in causing ACD and when possible, draw attention to a clinical pearl highlighted in 2014.

Formaldehyde (2015)

Formaldehyde is an inexpensive biocidal preservative used in a wide range of products, such as tissue specimen and cadaveric preservation solutions, nail polish, Brazilian blowout treatments and wrinkle-free fabrics (Figure 1). Its historical importance stems from its effectiveness in preventing contamination of personal hygiene products (PHPs).⁵ Morse et al⁶ reported 6 cases of septicemia resulting from Klebsiella pneumoniae contamination of a nurses’ hand cream due to a lack of appropriate germicidal preservatives. Of notable importance, formaldehyde was used to inactivate poliovirus in the development of Salk’s 1952 polio vaccine.⁷

Formaldehyde-releasing preservatives (FRPs) are among the leading contact allergens and are found in many PHPs, medications and household cleansers.⁵ Sources of FRPs include shampoos, body washes and hand soaps, lotions and creams, baby wipes, mascara, disinfectants, fabric softeners, topical wart remedies, adhesives and tissue specimen preservation solutions.^8-11 According to the FDA Voluntary Cosmetic Registration Program database, about 20% of PHPs and cosmetics contain a FRP, with imidazolidinyl urea as the most common.¹² Of interest, FRPs were developed to avoid formaldehyde-induced contact allergies assuming that the formaldehyde release level would not be sufficient from the releaser to cause a skin reaction.^13,14 However, many FRPs have also been demonstrated to be contact allergens, some related to the release of formaldehyde, while others by their own chemical properties.^13,15

In the latest reported North American Contact Dermatitis Group (NACDG) frequency data, formaldehyde ranked seventh, with 5.8% positive reactions noted in the 4,308 patients referred for testing.¹⁶ This high rank as well as formaldehyde’s ubiquity and important role as a top allergen have been noted for the last 75 years.¹⁷ In 2015, formaldehyde will receive the ACDS Allergen of the Year Award. Notably, it is also 1 of only 5 chemicals that have been listed by the Consumer Product Safety Commission as “strong sensitizers” since 1961.¹⁸

It is important for people to be aware of sources of formaldehyde exposure and understand that many products containing formaldehyde or FRPs may not indicate this on their labels. A study by Rastogi¹⁹ reported that 33% of 67 moisturizers evaluated did not have proper labeling in regards to their formaldehyde/FRP content. In 2014, Friis et al²⁰ reported a case of contact dermatitis after a patient applied an alcohol swab to the skin. The swab was labeled as having 82% ethanol and water as the only ingredients. However, high performance liquid chromatography analysis showed that the alcohol swab contained formaldehyde as an undisclosed ingredient.

Figure 1. Formaldehyde is an inexpensive biocidal preservative used in a wide range of products, such as tissue specimen and cadaveric preservation solutions, nail polish, Brazilian blowout treatments and wrinkle-free fabrics.

Benzophenone (2014)

Benzophenones are a group of aromatic ketones that can absorb UVA and UVB rays. They were initially used as preservatives to prevent photodegradation and extend the shelf life of items such as paints and varnishes.²¹ In the 1950s, however, benzophenones were added to sunscreens as chemical UV absorbers.²²

Today, benzophenones can be found in sunscreens, perfumes, soaps, nail polish, hair sprays and dyes, body washes, body moisturizers, shampoos, paints, pesticides, textiles, inks, adhesives and plastic lens filters used in color photography.^23,24 Nail acrylates containing benzophenones have been reported to cause eyelid ACD from transfer of the chemicals from the fingers to the eyelids.²⁵ The 4 benzophenone derivatives commonly used in skin products are oxybenzone, sulisobenzone, dioxybenzone and mexenone. Oxybenzone is used most frequently in sunscreens, and is also the number 1 photoallergen in sunscreens.²⁶ A photoallergic contact dermatitis results from a cell-mediated immune reaction to a photoactivated antigen. In the recent NACDG data, benzophenone-3 yielded a 0.9% positive reaction rate in the referred population, with 47% of these being of definite or probable clinical relevance.¹⁶

In 2014, Liao et al²⁷ studied the benzophenone content of 231 PHPs, such as toothpastes, hair products, body washes, hand soaps, skin lotions, facial creams and makeup. More than 80% of these products were shown to have oxybenzone, underscoring its high utilization in the cosmetic industry. Because benzophenones are frequently incorporated into PHPs for their photoprotective properties, they were chosen as the ACDS Allergen of the Year for 2014.

Methylisothiazolinone (2013)

In the 1940s, the Chicago-based company Chemtoy revolutionized the toy industry by selling bubble solutions, and in the 1960s, bubbles became a sign of peace during the ‘hippie movement’.²⁸ As bubbles became more and more popular, companies found ways to preserve bubble solutions. Methylisothiazolinones (MIs) are biocidal preservatives added to bubble solutions, bubble baths, soaps and cosmetic products (Figure 2). The biocidal activity comes from their ability to interact with microorganisms and oxidize accessible cellular thiols.²⁹ The chemical structure (2-methyl-4-isothiazolin-3-one) makes them highly compatible with surfactants and emulsifiers. In addition, MIs can maintain their biocidal activity over a wide pH range, making them favorable for use as preservatives in surfactants.³⁰

Since the 1980s, these preservatives have been noted to be a source of ACD. Castanedo-Tardan et al³¹ reported that twice as many US cosmetic products contained MIs in 2010 than in 2007, and in 2013, Urwin et al³² showed that there has been an increase in the prevalence of MIs or methylchloroisothiazolinones (MCI) to a level of 4.9% of those who are patch tested. Of special note, it has been reported that the MCI/MI mix can miss approximately 40% of MI allergies and testing with MI (0.2% aqueous) may be necessary to improve detection rates.^31,32 The recent increase in prevalence of contact dermatitis to MIs in soaps, cleansing products and cosmetics made this class of substances the Allergen of the Year for 2013. Unfortunately, MI allergy can be easily missed.

In 2014, Vandevenne et al³³ reported a case in which a middle-aged man developed severe and recurrent generalized dermatitis; his lesions were shown to be linked to MI-containing leather products that had been applied to his leather sofa, underscoring the role of household cleaning agents in causing significant disease.

Figure 2. Methylisothiazolinones are biocidal preservatives added to bubble solutions, bubble baths, soaps and cosmetic products.

Acrylates (2012)

During the first half of the 19th century, the Swedish chemist Jons Jakob Berzelius was experimenting with the thermal decomposition of vegetable oils when he accidentally discovered a new substance, which he named “acrolein.”³⁴ Later, the chemist Josef Redtenbacher demonstrated that acrolein is formed by the dehydration of glycerol, and that acrolein could be oxidized to acrylic acid.³⁵ Over a half a century later, the chemist Otto Rohm described acrylic acid as having properties of both rigid plastic and flexible glass. Later, Rohm partnered with businessman Otto Haas, and the 2 began manufacturing Plexiglas, a transparent safety glass composed of polymethylmethacrylate (PMMA). Plexiglas was used in cockpit windows of WW II aircrafts, watch glasses and instrument covers.³⁶

Acrylic acid entered the field of dentistry as dental fillers, and the realm of cosmetics as a nail enhancing substance. At the end of the 1970s, the FDA reported cases of allergic reactions and loss of nail plate as a result of acrylics.³⁶ Investigations into the toxicity of acrylics showed that the monomeric methyl methacrylate (MMA) was responsible for these findings.

Today, PMMA can be found in exterior automobile lights, paint and hard contact lenses. Allergies to acrylics are most commonly seen in individuals who work with artificial nails, dental cements and composite dental resins. This is thought to be due to MMA exposure. Kwok et al³⁷ showed that in 257 cases of ACD in beauticians, identified between 1996 and 2011, acrylates were the most common cause.

The numerous possible exposures to acrylates in both the occupational (eg, dentists, painters, printers, beauticians) and non-occupational settings have designated this class of substances as the Allergen of the Year for 2012.

A noteworthy point, patch test preparations of acrylates may evaporate during storage, which may lead to markedly reduced patch test concentrations and false negative results. Mose et al³⁸ investigated the stability of various acrylates after storage in 3 different chambers and at 2 different temperatures. They showed how the patch test concentrations of MMA, 2-hydroxyethyl methacrylate (2-HEMA), and 2-hydroxypropyl acrylate (2-HPA) decreased after storage in 2 of the chambers, the IQ chamber and IQ Ultimate. However, MMA and 2-HPA maintained their concentrations when kept refrigerated in the Van der Blend transport container.

In 2014 Fremlin et al³⁹ reported a case of ACD to UV-cured acrylates in a windscreen repair worker. The worker presented with dryness, vesicles and desquamation of the fingers. He initially used vinyl gloves, and patch testing was positive for 2-HEMA. Nitrile gloves have been noted to confer better protection and a longer “breakthrough time” than vinyl or latex gloves in acrylate sensitized individuals; and, once switching to nitrile gloves, the patient had marked improvement.

Dimethyl Fumarate (2011)

Dimethyl fumarate (DMF) is a fumaric acid ester that has been used for many years in the treatment of psoriasis and as a preservative, stored in desiccant sachets for the transport of furniture and shoes.^40,41 DMF has been shown to inhibit bread mold and to have antibacterial activity against Escherichia coli.^42,43 Therefore, it is used in various products, such as in shoes and sofas to prevent mold formation during transport by sea.

In 2008, there was a large increase in the number of cases of ACD caused by DMF in shoes.⁴¹ This shoe dermatitis classically presents as a bilateral vesicular and edematous eruption accompanied by pruritus or pain. Most patients report the purchase of a new pair of shoes and the development of symptoms hours after wearing the shoes. However, some cases of DMF dermatitis have been more difficult to decipher given the presentation of posterior lower extremity and back dermatitis. These were eventually linked to exposure to leather sofas and armchairs imported from China.⁴⁴ DMF used in sachets placed inside sofas can cause pruritic eruptions in areas of skin-to-sofa contact.

In 2009, the European Commission banned the importation of consumer products containing greater than the maximum allowable amount of DMF due to the increasing incidence of allergic reactions to furniture and shoes.⁴⁵ DMF was chosen as the Allergen of the Year for 2011 to highlight that it was still used in overseas products.

In 1959, the German chemist Schweckendiek discovered the anti-psoriatic properties of fumaric acid, and in 1994, fumaric acid esters were offered as an oral treatment for plaque psoriasis in both Germany and Holland.^46,47 Although effective in 50% to 70% of cases, its use was limited due to nephrotoxicity and lymphocytopenia.⁴⁷ Studies then investigated a topical role for fumaric acid esters, and efforts were abandoned due to the pruritic erythematous reactions caused by topical DMF.⁴⁸ Of note, a study reported pharmacy technicians developing pruritic maculopapular eruptions on the arms and face after filling oral prescriptions of fumaric acid esters.⁴⁹

In 2014, it was reported that DMF may also cause contact urticaria. Stingeni et al⁵⁰ reported a case of a patient with DMF-induced immediate contact urticaria to a pair of jeans. The association was eventually confirmed via a positive immediate occluded patch test (reading at 20 minutes, rather than delayed) and a positive prick test with DMF.

Neomycin (2010)

Neomycin is an aminoglycoside antibiotic that is commonly used in triple antibiotic ointments to prevent or treat bacterial skin infections. In 1949, Selman Waksman, PhD, isolated neomycin from the actinobacteria Streptomyces fradiae, which was found to have suppressive activity on other bacterial species (aka antibiotic properties).⁵¹ Dr. Waksman later received the Nobel Prize in 1951 for the discovery of streptomycin, which was revolutionary in the treatment of tuberculosis.⁵² Notably, neomycin is effective against gram-negative bacteria, but has partial activity against gram-positive bacteria.⁵³ Aminoglycoside mechanism of action is to block the prokaryotic 30s ribosomal subunit, and thus disrupt protein synthesis. Poor absorption from the gastrointestinal tract and nephrotoxicity have specifically limited the use of neomycin to mainly topical preparations for skin and mucous membrane infections, burns and wounds.^54,55

Neomycin also is found in medicated ophthalmic and antibiotic drops, deodorants, soaps and root canal fillings.⁵⁵ The high utility of neomycin in many over-the-counter products, along with its high allergen frequency (second only to nickel), led to its designation as the ACDS Allergen of the Year for 2010. In the recent NACDG allergen frequency data, neomycin tested positive in 8.7% of patients referred for patch testing, with 30% of positive tests being of definite, probable or possible clinical relevance.¹⁶

Patients with neomycin sensitivity may have a cross-reaction with other related aminoglycoside antibiotics, such as gentamicin, tobramycin, kanamycin and streptomycin.^9,56 Landeck et al⁵⁷ conducted a 10-year retrospective study of patients in Europe who were referred for periorbital dermatitis due to suspected contact allergy to ophthalmic medications. Patch testing results were positive in 8.1%, 5.9% and 4.9% of patients for gentamicin, neomycin and kanamycin, respectively. Because kanamycin is exclusively used in topical ophthalmic preparations, some patients may indirectly be sensitized to neomycin.

Polysensitization is when a patient has a positive patch test reaction to 3 or more unrelated allergens. In 2014, Fraser et al⁵⁸ reported neomycin as one of several allergens with demonstrable clinical relevance in polysensitized patients, highlighting the point that secondary contact dermatitis can occur to medicaments used to treat long-standing dermatoses and dermatitis.

Mixed Dialkylthiourea (2009)

Thioureas are organosulfur compounds used in synthetic rubber synthesis to speed up the cross-linking of chloroprene to neoprene (polychloroprene) in a process called vulcanization.⁵⁹ Neoprene is one of the most common synthetic rubbers used in car parts, diving and sports gear and orthopedic medical devices. Thioureas are also used as a fixative agent in photography and photocopying. Sources of ACD to thiourea derivatives include swimming goggles, various medical devices such as knee braces and positive airway pressure masks, rubber gloves, paint removers and keyboard wrist supports.^60-65 Powell et al⁶⁶ illustrated a case in which a soccer player developed ACD to the padding of his shin guards, which contained neoprene. Because mixed dialkylthioureas may be encountered on a daily basis from a number of sources, they were chosen as the 2009 ACDS Allergen of the Year.

Thiourea allergy may be missed by only screening for mixed dialkylthiourea; therefore, it is recommended that patch testing with a component of the patient’s neoprene product be considered.

Nickel (2008)

Nickel is a natural element and transition metal that makes up 3% of the earth’s composition.⁶⁷ The word nickel is derived from the German word kupfernickel, which means devil’s copper. In 1751, it was added to the periodic table with the chemical symbol Ni, and in the mid-19th century, it became a component of the 5-cent coin. During WW II, nickel was removed from coins for use in vehicle armor plating. The nickel was substituted with an alloy of copper, silver and manganese until 1945.⁶⁸ Today, this 5-cent piece is made with an inner copper core and an outer layer consisting of 75% copper and 25% copper-nickel alloy.⁶⁹

Nickel is used in metal alloys, and sources of exposure include: zippers, safety pins, doorknobs, keys, scissors, eyelash curlers, belt buckles, metal eyeglass frames, razors, thimbles, coins, construction tools, appliances, household utensils, alkaline batteries, paper clips, multivitamins, jewelry, mobile phones and nickel-plated objects.^68,70-72 Much of nickel is used in nickel-steel alloys (eg, stainless steel); however, nickel is so firmly bound in stainless steel that it usually does not cause contact dermatitis.¹⁰ However, organic acids, especially at cooking temperatures, may release nickel from stainless steel cookware.⁷³ Nickel-sensitive patients should be aware of the potentially enhanced nickel release associated with cooking acidic foods.

Keep in mind, nickel is currently the most prevalent allergen with a prevalence rate of about 17% in those who are patch tested worldwide.^74,75The alarming rise in the prevalence of ACD to nickel led to its designation as the 2008 ACDS Allergen of the Year. Nickel may cause localized, id (at areas that may not have direct contact with nickel) and systemic contact dermatitis.⁶⁸ Localized dermatitis typically occurs on the earlobes, neck, wrists and periumbilical areas due to jewelry or metal snaps of jeans and belt buckles. Clinically, the dermatitis presents as pruritic papules or papulovesicles, but lichenification can occur with chronic dermatitis.

There have been increasing numbers of reports of ACD to nickel-containing electronics, such as cell phones, laptops and iPhones. In 2014, iPads were found to release a significant amount of nickel and have been associated with a systematized nickel reaction.⁷⁶ It is important for sensitive individuals to be aware of various electronic exposures and to use nickel-free cases to reduce skin-to-device contact.

Fragrance (2007)

Fragrances have had great cultural importance since the ancient Chinese and Egyptian civilizations.⁷⁷ Dating back to around 3000 bc, the ancient Egyptians burned the incense Kyphi to sanctify their homes. During the European Renaissance era (1450-1600), the French believed that the black plague spread through poisoned air, and thus the citizens of Paris carried perfumes and flowers so that the fragrances could ward off the plague. In 1921, Gabrielle “Coco” Chanel released Chanel No. 5, which started a new era of designer perfumes.

Fragrances consist of both natural and synthetic materials. Natural fragrances are derived from distilled botanical compounds, yet the difficulty in acquiring consistently high volumes of natural products has led to the development of synthetic fragrances. Nearly 90% of fragrances are synthetic compounds, which estimates to more than 5,000 different compounds.⁷⁷

Fragrances are found in many products, such as colognes, cosmetics, medications, foods, PHPs and cleaning products. Fragrance allergy occurs more often in women, which may be due to the fact that 30 to 50 substances are used to create the unique fragrance mix found in perfumes.⁷⁷ In addition, fragrances are responsible for 30% to 45% of ACD to cosmetics.

In the latest published NACDG allergen frequency data, fragrance mix I was the third ranking allergen, with 8.3% positive reactions in those patch tested, with 90% of these positive results being of definite, probable or possible relevance.¹⁶ Particularly, Myroxylon pereirae had a 7.2% positive reaction rate (with 86% having definite, probable or possible relevance) and fragrance mix II had a 4.7% positive reaction rate (with 94% having definite, probable or possible relevance).¹⁶ Common areas of fragrance allergy include the face, neck, axilla, hands and behind the ears. Fragrances in toothpastes and mouthwashes, chewing gum and mentholated cigarettes may cause oral and perioral dermatitis. Given the complex mix of fragrances in perfumes, colognes and other scented products, fragrance was designated as the ACDS Allergen of the Year for 2007.

Eight chemical substances are used in the fragrance mix I for screening for fragrance contact allergy, namely: isoeugenol, eugenol, cinnamic aldehyde, cinnamic alcohol, hydroxycitronellal, geraniol, a-amyl cinnamic aldehyde and oak moss absolute.⁷⁸ In 2005, fragrance mix II was added as an additional screening tool, consisting of citronellol, hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral), hexyl cinnamal, citral, coumarin, and farnesol.⁷⁹ Lyral has been the top fragrance mix II allergen and is frequently found in household and personal care products. Its lipophilic structure allows it to readily penetrate the skin.⁸⁰ Notably, in 2014, the fragrance limonene, which is frequently used in hand cleansers and cleaning products, was shown to be an important source of ACD.⁸¹

Para-phenylenediamine (2006)

Para-phenylenediamine (PPD) is an easily oxidized substance that gained popularity in the early 20th century as a permanent dye. Hair could be washed without stripping the hair of the dye’s color. The PPD hair dyes are packaged in 2 containers: the PPD dye and the developer (also called oxidizer). PPD itself is colorless and needs to be oxidized to color. In fact, it becomes the allergenic hapten when partially oxidized into an intermediate state in the epidermis or dermis.⁸² PPD may cause ACD in sensitive individuals, such as hairdressers and cosmetologists, printers, textile dyers and photography developers, who come into contact with the partially oxidized intermediate state.⁸³ Reactivity to PPD has also been noted in persons who frequently dye their hair as well as their close contacts, such as spouses and children.⁸⁴ In 2006, PPD was designated the ACDS Allergen of the Year. In the most recent NACDG frequency data, PPD ranked ninth, with 5.5% of patients patched tested exhibiting a positive reaction, with 54% of these positive results being of definite, probable or possible clinical relevance.¹⁶

Of special note, in 1961, PPD was listed as a “strong sensitizer” by the Consumer Product Safety Commission; only 1 of 5 allergens labeled as such.^85,86 While PPD is allowed in hair dyes, the FDA prohibits its use on the skin; nevertheless, black henna tattoo artists may use PPD to promote rapid drying and lasting color in their temporary tattoos (Figure 3).⁸⁷ To address the paucity of data on the incidence of ACD secondary to black henna temporary tattoo use, the FDA launched a website (MedWatch, www.fda.gov/Safety/MedWatch/) and hotline (800-332-1088) in 2001 to warn consumers of the dangers of temporary tattoo use. These efforts were fueled by reports of severe bullous eruptions from temporary tattoo use.⁸⁸

Reactions to PPD are variable and can range from mild dermatitis to severe blistering of the scalp, eyelids and ears. There have been accounts of urticaria and, rarely, anaphylaxis from PPD exposure.⁸⁹ In addition, ingestion of PPD has been associated with angioedema, rhabdomyolysis, direct renal tubule damage, methemoglobinemia, myocarditis and right bundle branch block.⁹⁰ In 2014, cutaneous pseudolymphoma has also been linked to PPD dye use,⁹¹ underscoring the continued recognition of this allergen’s role in clinical disease.

Figure 3. Black henna tattoo artists may use para-phenylenediamine to promote rapid drying and lasting color in their temporary tattoos.

Corticosteroids (2005)

Corticosteroids are among the most frequently used topical therapies due to their anti-inflammatory properties. The introduction of topical corticosteroids into medical practice dates back to 1950 when Tom Spies, MD, and Robert Stone, MD, used topical hydrocortisone to successfully treat a case of chronic hand dermatitis.^92,93 Later, as the demand for hydrocortisone went up, the Syntex Company discovered a less expensive method to synthesize hydrocortisone by using sarsasapogenin derived from Mexican yams.⁹⁴

Contact allergy to hydrocortisone was first noted in 1959. However, routine screening for corticosteroid contact sensitization did not begin until the 1990s.⁹⁵ In the recent NACDG report of frequency data, corticosteroids accounted for 4% of the positive patch test reactions, with tixocortol accounting for 50% of the reactions.¹⁶

Throughout the decades, topical corticosteroids became one of the most important drugs in the treatment of various types of dermatitis. Nevertheless, some individuals may develop ACD to 1 or more of the classes of topical corticosteroids; this may present as a dermatitis that is unresponsive to or exacerbated by application of topical corticosteroids. In 2011, Baeck et al⁹⁶discussed a new 3-group classification system for corticosteroids according to allergenic groups. This is a simplification of the A, B, C, D1 and D2 classification system. Group 1 (A, D2; eg, hydrocortisone, prednisone, triamcinolone) is characterized by non-methylated and, most often, non-halogenated molecules. Group 2 (B; eg, desonide, fluocinonide) is characterized by halogenated molecules and a C16/C17 cis ketal or diol structure. Group 3 (C, D1; eg, betamethasone, clobetasol propionate, mometasone furoate) is characterized by halogenated molecules with C16-methyl substitution. While some patients may react to multiple steroids, the majority of patients are specifically sensitive to a certain group characterized by the presence or absence of methylation and/or halogenation.

While ACD to steroids is well reported, 2014 marked the first report of a bullous systemic contact dermatitis after a routine corticosteroid injection for chronic joint pain.⁹⁷

Cocamidopropyl Betaine (2004)

The earliest written accounts of soapmaking practice date back to ancient Babylon, around 2800 bc.⁹⁸Ancient Egyptian historical documentation in the “Ebers Papyrus” describes the combination of animal and plant fats with alkaline salts to create soap for use in bathing.⁹⁹ The first synthetic detergent was developed by the Germans during WWI to compensate for the shortage of fats;¹⁰⁰ these detergents worked better in cold water as well as water with high metal composition. In 1947, the first betaine-detergent was developed by the Goldschmidt Chemical Corporation;¹⁰⁰ however, its introduction into PHPs occurred in the 1950s when Johnson & Johnson developed the first cocamidopropyl betaine (CAPB) detergent shampoo using coconut oil. This shampoo gained popularity as the “no more tears” baby shampoo.¹⁰¹

CAPB is a zwitterion used as a surfactant in shampoos, cleansers and cosmetics.¹⁰² Cases of CAPB allergy emerged as early as 1983, and in 1997, it was suspected that the amidoamine and dimethylaminopropylamine impurities were the true culprits.^103,104Most cases of ACD have been reported in association with CAPB-based shampoos, liquid soaps, body wash gels, toothpastes, contact lens solutions, makeup removers and gynecologic hygiene products.^100,105-107 By 2003, the global consumption of detergents and soaps was greater than 27 million metric tons.¹⁰⁰With the increasing use of detergents, the ACDS designated CAPB as the 2004 Allergen of the Year. CAPB has recently been noted to be an important allergen in persons with atopic skin disease.¹⁰⁸

In 2014 Zhao et al¹⁰⁹ studied the frequency of contact sensitization to a European cosmetic series of allergens in a Beijing population, and found the top 3 leading allergens to be thimerosal, shellac and CAPB. Their results suggested that cosmetic-related contact allergens, like CAPB may be missed by only screening with the European standard series or the thin-layer rapid use epicutaneous patch test (SmartPractice Dermatology, Phoenix, AZ).

Bacitracin (2003)

Bacitracin is an antibiotic that is effective against gram-positive organisms by interfering with the dephosphorylation of C55-isoprenyl pyrophosphate, and therefore inhibiting the peptidoglycan cell wall synthesis.¹¹⁰ Bacitracin is often seen in combination with neomycin and polymyxin B sulfate for broader antimicrobial coverage of both gram-positive and gram-negative species.

The history of bacitracin dates back to 1943, when John Goorley, PhD, isolated a strain of Bacillus subtilis from tissue debrided from a fractured tibia of a 7 year old.¹¹¹ The bacteria secreted an antibiotic into its growth medium, which was named “bacitracin.” By 1948, bacitracin was successfully used to treat various surgical infections.¹¹² While it was successful in treating pneumonia, syphilis and amebiasis,¹¹³ it was discovered that the effectiveness of systemic bacitracin was directly proportional to its concentration. Unfortunately, as higher doses were administered, patients started to develop nephrotoxicity.¹¹⁴ Subsequently, bacitracin became limited to topical and ophthalmic use.

Today, bacitracin is available over-the-counter and is added to a variety of topical and ophthalmic medications, cosmetics and animal feed additives. Because of the high sensitization rates to neomycin, bacitracin became one of the most prescribed topical medications in the United States.¹¹³ In 1992, the US Department of Health and Human Services reported that bacitracin was the seventh most frequently prescribed medication for injury-related emergency department visits.¹¹⁵ The marked increase in use landed bacitracin on the list of top allergens.

According to NACDG data, bacitracin was the ninth most common allergen between 1998 and 2000, with 9.2% of 5,812 patients testing positive on patch testing.¹¹⁶ This was a significant increase from the 1.5% of positive reactions in patients tested from 1989 to 1990.¹¹³ Because of this significant increase in sensitization rates, the ACDS designated bacitracin as the 2003 Allergen of the Year. In the recent NACDG allergen frequency data, bacitracin ranked fourth, with 8.3% positive reactions noted, with 47% of these having definite, probable and possible clinical relevance.¹⁶

Bacitracin eventually also became known as an occupational allergen, affecting wound care nurses. It has been reported that nurses have the highest incidence to ACD to bacitracin.¹¹⁵ ACD to bacitracin may present as acute vesicular dermatitis or worsening chronic dermatitis. Topical bacitracin has also been linked to anaphylaxis in several cases.^117,118 In 1996, Smack et al¹¹⁹ conducted a double-blind, randomized, controlled trial looking at white petrolatum versus bacitracin for 1,249 surgical wounds in 922 patients. During the study, 4 patients developed ACD to bacitracin, yet no patients developed ACD to white petrolatum. In addition, there was no statistically significant difference in infection between the 2 treatment groups. Therefore, white petrolatum has been recommended over bacitracin for use in clean surgical wounds.

In 2014, Fraser et al⁵⁸ reported a 27-year-old woman with recurrent lip dermatitis to a number of clinically relevant allergens, one of which was bacitracin. When antibiotics, such as bacitracin (and steroids for that matter), are used to treat an underlying dermatitis (eg, atopic, irritant, allergic dermatitis), the patient can become sensitized to an increasing number of unrelated, yet relevant, allergens.

Thimerosal (2002)

Thimerosal is a mercury-containing compound that has been used as an antiseptic and preservative in a number of vaccines, cosmetic products, tattoo inks and ophthalmic solutions.¹²⁰ In the 1980s, the FDA banned the sale of topical thimerosal antibiotics due to potential adverse skin reactions. In July 1999, the US Department of Health and Human Services required that the amount of thimerosal be reduced in pediatric vaccines; and in 2004, California and Iowa banned the use of mercury in all vaccinations.¹²¹ The main concern behind thimerosal was that exposure to its metabolite, ethyl mercury, could potentially result in significant neurological, psychological and renal impairment. Examples of neurologic and psychologic adverse events include peripheral neuropathy, tremor, muscle weakness, dysgeusia, depression, anxiety and psychosis.¹²⁰ Ethyl mercury is also toxic to the skin and mucous membranes and may cause contact dermatitis, grayish or blue-black facial discoloration, flushing, erythroderma, purpura and gingivostomatitis.¹²²

Thimerosal may be found in vaccines, cosmetic products (eg, makeup removers, mascaras, eye moisturizers and bleaching creams), ear and ophthalmic drops, topical medications, antifungals, antiseptic sprays, contact lens solutions, tattoo inks, hormone injections and antimicrobial cleaners.^120-124 Tosti et al¹²⁵ reported several cases in which patients developed follicular allergic contact conjunctivitis secondary to thimerosal-containing eye drops. Also, there is a reported increased incidence of thimerosal contact allergy in women and healthcare workers due to a higher use of cosmetic products and vaccinations, respectively.¹²⁰ In 2002, thimerosal was named the Allergen of the Year to highlight its high frequency, but low clinical relevance. Notably, thimerosal is not currently tested by the NACDG.

As a side note, the use of mercury is prohibited for use in cosmetics in the United States. However, cosmetic products containing mercury may be illegally imported, especially for use in skin bleaching products. Mercury inhibits melanin synthesis by competing with copper necessary for tyrosinase activity.¹²⁶ In Mexico, mercury is prohibited for use in cosmetic products; yet, phenyl mercury and thimerosal are allowed as preservatives in eye makeup.¹²⁷ In addition, Zhao et al¹⁰⁹reported in 2014 that thimerosal was the number 1 cosmetic allergen in their Beijing study. Therefore, it is important to be aware of possible mercury exposure from imported cosmetic products.

Gold (2001)

The love for gold can be seen as early as the Stone Age, when the earliest humans found gold along streams and used it to make jewelry. In Greek mythology, gold has been a symbol for man’s desire for power. In the story of King Midas, the Greek god Dionysus offers to grant Midas any wish, and Midas’ wish was for the ability to turn anything he touched into gold. However, he then realized that he was no longer able to eat, as his bread and wine were also turned into gold. The 1849 California Gold Rush is considered by some as the world’s greatest gold frenzy — a period when over a quarter million “forty-niners” migrated west in hopes of finding gold and becoming rich.

Besides being a valuable commodity, gold is utilized as a medicinal in treatment for various ailments such as rheumatic arthritis and bronchial asthma. In 1953, a case of severe pulmonary allergy to gold was reported, and there were several reports of lichenoid dermatitis after gold therapy.^128,129 The NACDG determined that gold was the sixth most frequent allergen from 1996 to 1998.¹³⁰

Recognition of gold as a significant cause of ACD led it to be designated as the 2001 Allergen of the Year. Contact dermatitis to gold is seen in areas of skin where eye makeup, foundation or sunscreens containing harder metals (eg, titanium, zinc) are applied (Figure 4). Black dermographism is the phenomenon when cosmetics contain hard metals that abrade softer jewelry metals and leave black deposits on the skin.¹³¹ The dark color seen is due to their small size, which prevents the reflection of light. This can be seen with gold-containing jewelry. In other words, harder metals may cause gold-containing items, such as jewelry and watches, to release sensitizing antigens.

While ACD to gold is well-recognized, pseudolymphoma reactions (known as cutaneous lymphoid hyperplasia) are reportedly rare. Laftah et al¹³² described this reaction to gold in 2014.

Disperse Blue Dyes (2000)

The earliest written record of the use of dyes dates back to ancient China around 2600 bc. These records illustrate techniques for dyeing silk using plant-derived dyes. In 1856, the first synthetic dye was born when William H. Perkin, a chemistry major at England’s Royal College of Chemistry, accidentally synthesized the first aniline dye while attempting to create synthetic quinine for the treatment of malaria.¹³³

Today, more than 1,200 dyes are used in the textile industry. Dyes are classified using either their chemical structure or by their application (procedure for applying dyes to fabric). Chemical classifications for dyes include the following dyes: azo, anthraquinone, azine, indigoide, nitro, quinoline and triarylmethane. An example of a dye categorized by application is disperse blue dye. Disperse blue 106 is both a disperse dye (application categorization) and an azo dye (chemical categorization).

Disperse dyes are the most common dye sensitizers because they are partially water soluble and tend to leach out of fabrics and rub onto the skin.¹³⁴ The most frequently positive dye sensitizers are disperse blue 124 and disperse blue 106. In 2000, 2 studies reported that 18%¹³⁵ and 40%¹³⁶ of patients with suspected textile ACD had positive patch tests to textile dyes, with disperse blue dyes being the most common.¹³⁴ This finding led to the designation of disperse blue dyes as the ACDS Allergen of the Year for 2000. Dye dermatitis presents in the distribution of contact with the responsible fabric, and areas with increased friction and sweating tend to be more affected.

In 2014, Evans et al¹³⁷ researched the utilization of disperse dyes in disposable diapers. None of the diapers studied that are currently available on the market used disperse dyes. Instead, they were found to contain safe non-sensitizing pigments.

Figure 4. Contact dermatitis to gold is seen in areas of skin where eye makeup, foundation or sunscreens containing harder metals (eg, titanium, zinc) are applied.

Conclusion

The Allergen of the Year is an annual “award” of dubious distinction voted upon by members of the ACDS. When Ponciano Cruz, MD, created the section, the original intent was to call attention to individual allergens and specifically draw attention to allergens that are very common, underrecognized, merit more attention (because they are causing significant ACD) and are no longer causing significant relevant disease (as in thimerosal in the United States). The core intent is academic in nature — to highlight societal and public awareness. Nominations for the Allergen of the Year are solicited from the ACDS, and final determination is made through a committee, chaired by Donald Belsito, MD. Afterwards, an expert on the allergen is selected to review and author a manuscript on the allergen for publication in Dermatitis. n

Dr. Jacob, the Section Editor of Allergen Focus, is associate professor, dermatology, director of the Contact Dermatitis Clinic at Loma Linda University in Loma Linda, CA.

Mr. Vazirnia is a UC San Diego School of Medicine student.

Disclosure: Mr. Vazirnia reports no relevant financial relationships.

Dr. Jacob has served as an investigator of Smartchoice USA the PREA-1 and PREA-2 trials.

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