Nickel-Induced Allergic Dermatitis: A Call for U.S. Policy Aimed at “Goblin’s Copper”

Sharon E. Jacob, MD; Alina Goldenberg, MAS; Nanette Silverberg, MD; Luz Fonacier, MD; Bruce Brod, MD; Richard Usatine, MD; Robert Sidbury, MD, MPH; James Young, DO; Anthony Fransway, MD; Jonathan Silverberg, MD, PhD, MPH; Albert Yan, MD; and Janice L. Pelletier, MD

ABSTRACT: The incidence of nickel-induced allergic contact dermatitis is increasing in the United States, presenting a particular health danger to children and a diagnostic and treatment challenge to health care providers. In the 1990s, the European Union passed the Nickel Directive, which limits the weekly allowable release of nickel from consumer products such as jewelry and toys. However, similar legislation has yet to be adopted in the United States. This article reviews the burden of nickel sensitivity, and the initiatives that are in place and what more is needed to combat this growing problem.

As early as the 1600s, a dark red ore with a distinctive green coating became a notable source of irritation for copper miners in Saxony, in present-day Germany.1 Believing that the dark red substance was an ore of copper, they continued mining it. Because the ore was causing ailments, the miners turned to folklore and adopted a belief that it was protected by goblins. This ultimately led to the naming of the ore as kupfernickel, or “goblin’s copper.”1 It was not until the mid-1750s that Swedish chemist Axel Cronstedt discovered the true nature of kupfernickel ore (nickel arsenide) and, through experiments on magnetism, realized that is was a new element.1 Since then, because of its relatively low cost and unique properties such as its malleability and anticorrosive nature, nickel has been used in a large variety of fields and products.

After World War II, nickel was commonly included in costume jewelry, which became a major source of nickel exposure and hence nickel sensitization in the general population. Meteorites are one of the principal sources of nickel in the world. Metal-bead artifact jewelry made from meteorites has been found in Egyptian graves dating to as early as 5000 bce, and wedding rings made from the Gibeon meteorite, which fell in Namibia in prehistoric times, reportedly have caused nickel allergic contact dermatitis (ACD).2 The common practice among cultural groups around the world of girls and women wearing jewelry has resulted in a much higher rate of nickel sensitization among the female population than the male population.3

In 1981, Peltonen wrote a commentary about the problem of nickel sensitivity4 in which she described the importance of nickel over the previous 20 to 30 years; now 34 years later, nickel still ranks first on the list of allergens.5 Peltonen noted that nickel sensitivity was surprisingly common among the U.S. population according to epidemiologic studies.4 In 1978, 1,158 volunteers were tested with 2.5% nickel sulfate in order to determine the prevalence of underlying nickel sensitivity.6 The study found that 9% of participants had been sensitized; more recent research had found that this percentage has almost tripled since then.7 

Additionally, Peltonen reported the significant association between atopy, nickel sensitivity, and hand eczema. Some patients with underlying nickel sensitivity do not present in a clinically obvious fashion, but rather with eczema of the hands or other types of eczema.4 In fact, nickel sensitivity is a much wider problem, as Peltonen noted more than 30 years ago: “Half of the subjects sensitized to nickel have never consulted a doctor because of their nickel dermatitis; still fewer have visited a dermatologist.”4

The Hidden Nickel Dermatitis

While nickel dermatitis commonly is associated with a localized reaction, as many as 50% of children with nickel-induced ACD can present with more diffuse reactions, known as idiopathic nickel dermatitis. Idiopathic nickel dermatitis appears as pruritic papules in nonexposed sites such as the extremities and upper trunk.8 Areas that may not have directly contacted nickel can generate a response secondary to autosensitization from circulating immune cells.9 This reaction can be misdiagnosed as a form of eczema such as atopic dermatitis (AD) due to its diffuse nature and its common involvement of the upper arms, thighs, knees, and elbows.10

Furthermore, children with AD also may experience an exacerbation of atopic pruritus as a result of comorbid nickel ACD.8 Recent evidence indicates that persons with AD have a genetic mutation that allows nickel to more easily penetrate the upper epidermis, thus allowing easier exposure to the immune system.11 It is not known how many children with nickel dermatitis are placed on systemic immunosuppressive therapy for what is thought to be atopic disease rather than having nickel dermatitis accurately identified and being treated for ACD with allergen avoidance. As Peltonen wrote in 1981, large population-based studies including the cases that never are seen at dermatologic clinics, are needed.4

International Initiatives

Although products are available to test various materials for nickel content, the source of nickel ACD often is obvious (Table)—for example, neck or earlobe dermatitis from costume jewelry, dermatitis of the periumbilical area from a belt buckle or pants snap, or unilateral facial dermatitis from a cellular phone.8,12

In light of the rising rate of nickel sensitization and ACD, the Danish Ministry of the Environment passed legislation in 1992 to limit the amount of nickel released from products with prolonged skin contact to less than 0.5 µg/cm2 per week in an effort to decrease the rates of sensitization to nickel.13 This limitation helped decrease the rates of nickel sensitization among Danish children aged 18 years and younger from 24.8% in 1985 to 9.2% in 1998.14

In 1994, the European Union (EU) recognized this dramatic decrease in morbidity and enacted the Nickel Directive. This regulation limited the weekly allowable release of nickel to less than 0.5 µg/cm2. A 2004 amendment further reduced the weekly allowable release of nickel from jewelry posts inserted into pierced ears and other pierced parts of the body to 0.02 µg/cm2.

These initiatives in Europe not only have decreased nickel sensitization rates, but also have greatly reduced the indirect and direct societal costs of nickel dermatitis, saving a reported U.S. $2 billion over 20 years.15-17 Nevertheless, nickel ACD continues to be problematic, even in the EU, as the reported number of recognized cases in younger children without a history of piercing continues to increase.18 Thus, other sources of nickel exposure need to be investigated, and reductions of exposure on a broader scope ultimately may be necessary. Moreover, analyses of the mechanisms for and timing of nickel release from products may provide more information about safer materials or practices for nickel-containing items.

U.S. Nickel Regulation

Despite regulations in Europe with proven clinical outcome success, similar legislation has yet to be adopted in the United States, even in the face of similar nickel sensitization rates to those seen in Europe in the mid-1980s.3 For example, the most recent 2005-2012 data from the North American Contact Dermatitis Group (NACDG) demonstrate that 25.6% of 883 children who underwent patch testing had a clinically relevant response to nickel.3

In order to prevent early exposure to nickel and decrease the nickel contact allergy rate, U.S. initiatives are needed to limit the quantity of nickel released from products with prolonged skin contact. To that end, more than 10 years ago, representatives of the Nickel Development Institute and the Nickel Producers Environmental Research Association met with the U.S. Consumer Product Safety Commission (CPSC) to urge adoption of legislation similar to the EU’s 1994 Nickel Directive, which now is a part of the broader Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulations.18 Even though the CPSC shared concerns about the need to set limits on nickel release from items with direct and prolonged contact with the skin, the commission could not commit to action.18 Thus, the United States lacks legislation regulating not only products such as piercing equipment and jewelry posts, but also children’s merchandise and clothing.19

Jensen and colleagues recently found that more than a third of toys containing metal in the United States contain nickel.18 Furthermore, the number of potential sources of nickel is increasing with the number of cell phones, laptop and tablet computers, and other electronic devices, including the rapidly expanding market of wearable fitness-tracking devices.20-22

One group of authors in 2009 described the need for an EU-like Nickel Directive in the United States to limit the maximum allowable release of nickel from products with prolonged skin contact, consistent with the concentrations mandated in Europe.23 Given that approximately 36% of North American patch-tested female patients under the age of 18 were reported to have nickel contact allergy,7 the authors suggest that a U.S. Nickel Directive could dramatically lower the burden of ACD from nickel through national legislation and public health education.23 Nevertheless, because nickel ACD cases are widely underreported and potentially undiagnosed, a better understanding of the epidemiology of nickel sensitivity is needed in order to accurately assess the before-and-after impact of any legislation.

Monitoring Nickel Sensitivity

In 1939, Bonnevie proposed the first standard series of 21 epicutaneous patch test antigens in the United States showing nickel to be a prominent allergen.24 Even 76 years later, nickel remains at the top of the sensitizer chart.7 A literature review by researchers at Loma Linda University (LLU) resulted in the identification of 611 confirmed cases of U.S. children with clinically relevant nickel dermatitis published between 1986 and 2014 from more than 200 providers and/or centers (ranging from large groups such as the Mayo Clinic and the NACDG to case series and single case reports).

Moreover, the literature review revealed that despite the previous perception that contact dermatitis was less prevalent in children than in adults (which we now know to be a false assumption due to representational underreporting), pediatric patch testing is being performed by a wide range of practitioners from allergists, dentists, and general dermatologists to pediatric dermatologists, family physicians, and occupational medicine providers. Nevertheless, the peer-reviewed literature is incomplete, with some states with only 1 reported case of pediatric nickel ACD, and other states with reporting data completely missing (Figure).

As part of the recruitment effort for the LLU Pediatric Contact Dermatitis Registry project, investigators contacted medical practices in states with less than 2 reported pediatric cases of nickel ACD in the peer-reviewed literature to offer information on the study. This process canvassed private individual practitioners, group practices, and academic institutions, and it included physicians, physician assistants (PAs), and nurse practitioners (NPs). The findings confirmed that although a significant percentage of nickel dermatitis cases in children are being clinically seen and identified, the majority of the providers stated that these cases have remained unpublished. Practitioners also noted that confirmatory patch testing is not always performed because the “nickel source was obvious.”

To identify the clinicians are who are providing pediatric patch test services, LLU launched the Pediatric Contact Dermatitis Registry study (LLU Institutional Review Board approval No. 5140151) in November 2014. The first part of the study surveys for physicians, PAs, and NPs nationwide to identify those who offer patch test services to children. The second part of the study is a registry for practitioners to report their de-identified pediatric ACD cases in a centralized, confidential, and secure online system.

The registry project builds on the groundwork laid by the first 2 pivotal North American studies on pediatric ACD,25,26 which together documented the patch test results of 456 children, reported by 18 patch testers, over an average of 5.3 years. The 2 studies’ findings equaled to an average of 5 children being patch tested per year—a clear depiction of wide underreporting. However, of the 456 children screened, 124 (27%) had confirmed sensitization to nickel. Thus, despite the small sample size, these studies unequivocally point to significant nickel allergy rates in children tested in the United States and the rest of North America and to the need for preventive intervention.25,26

The use of unregulated jewelry, specifically in ear piercings in children, significantly increases the lifetime risk of nickel, cobalt, and likely potassium dichromate allergy. Thus, a legislative public health regulation limiting the maximum allowable release of nickel from products with prolonged skin contact at the concentrations mandated in Europe (0.5 µg/cm2/week, and body piercing post assemblies to 0.2 µg/cm2/week), in addition to a public awareness campaign about the risks of piercing practices, is needed.

The Nickel Allergy Alliance (NAA), a group of Pediatric Contact Dermatitis Registry clinicians and other interested parties, has been formed to track the growing number of confirmed nickel dermatitis cases and serve as a voice for those concerned with the increasing prevalence of nickel allergy in the United States. In February 2015, the American Contact Dermatitis Society (ACDS) and the NAA endorsed a resolution recommending that the American Academy of Dermatology’s Patient Safety and Quality Committee issue a health advisory about the high sensitization rates to nickel in the United States, and called for a mandatory national nickel directive to regulate the allowable release of nickel.

Nickel Dermatitis: Focusing on the Future

In 2001, in response to the rising rates of severe allergic reactions to paraphenylenediamine (PPD) or black henna, an antioxidant used in hair dye and temporary tattoos, the U.S. Food and Drug Administration launched a hotline to provide the public with an easy way of reporting such events (MedWatch, 800-332-1088 or http://www.fda.gov/Safety/MedWatch/).27 The number of cases continued to rise, and in 2006, ACDS named PPD as Allergen of the Year to heighten awareness in the professional and public sectors.28 In 2008, the ACDS and the American Academy of Dermatology jointly advised a ban on the practice of using PPD-enhanced henna tattoos. This collective effort has resulted in a visible reduction in reported pediatric cases of reactions to PPD-laced temporary tattoos.29

A similar consumer hotline for outbreaks of nickel ACD likewise could provide valuable evidence on the prevalence of nickel dermatitis in the United States. Correspondingly, the collaborative research under way through LLU’s pediatric registry hopes to address Peltonen’s 1981 conclusion: “Large population studies, including also those cases never seen at dermatologic clinics, are therefore needed to clarify the still controversial problems of relations between atopy and nickel sensitivity, as well as the frequency and clinical picture of hand eczema coexisting with nickel sensitivity.”4

In the last 3 decades, U.S. nickel dermatitis rates have risen dramatically, heightening its importance as a public health issue30 and signaling that, as in Europe in the 1990s, the time has come in the United States for legislation allowing nickel regulation. 

Manufacturers may act ahead of legislation by voluntarily mandating that their products adhere to EU guidelines (Levi Strauss31 and Apple32 are notable examples). Clinicians and consumers have the right to demand protective safety legislation and company compliance with directives, because as has been observed, “Regulation is a toothless tiger if compliance is not appropriately checked and enforced.”15 Primary prevention of nickel dermatitis stems from accurate surveillance and timely legislation. With an infrastructure in place that validates the burden of nickel allergy in children, clinicians will be able to shape sound health care policy. However, as in Denmark and the rest of the EU, this requires a collaborative effort from health professionals, consumers, manufacturers, and lawmakers.

Sharon E. Jacob, MD, is an associate professor of dermatology at Loma Linda University School of Medicine in Loma Linda, California.

Alina Goldenberg, MAS, is a medical student at the University of California, San Diego, School of Medicine in La Jolla, California.

Nanette Silverberg, MD, is a clinical professor of dermatology at Icahn School of Medicine at Mount Sinai, chief of pediatric dermatology at Mount Sinai Health System, and director of pediatric and adolescent dermatology in the Department of Dermatology at Mount Sinai St. Luke’s and Mount Sinai Roosevelt in New York, New York.

Luz Fonacier, MD, is a professor of clinical medicine at the State University of New York at Stony Brook and head of the Allergy Section of the division of Rheumatology, Allergy, and Immunology at Winthrop-University Hospital in Mineola, New York.

Bruce Brod, MD, is a clinical professor of dermatology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania.

Richard Usatine, MD, is a professor in the Department of Family and Community Medicine and in the Division of Dermatology and Cutaneous Surgery at the University of Texas Health Science Center at San Antonio, and the medical director of the University Health System Skin Clinic, in San Antonio, Texas.

Robert Sidbury, MD, MPH, is an associate professor in the Department of Pediatrics and chief of the Division of Dermatology at the University of Washington School of Medicine and Seattle Children’s Hospital in Seattle, Washington.

James Young, DO, is president of Yankton Medical Clinic in Yankton, South Dakota, and an associate clinical professor of dermatology at the University of South Dakota in Vermillion, South Dakota.

Anthony Fransway, MD, is a dermatologist at Associates in Dermatology in Fort Myers, Florida.

Jonathan Silverberg, MD, PhD, MPH, is an assistant professor in the departments of dermatology, preventive medicine, and medical social sciences at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Albert Yan, MD, is an associate professor of pediatrics and dermatology at the Perelman School of Medicine at the University of Pennsylvania and chief of the Division of Dermatology at the Children’s Hospital of Philadelphia in Philadelphia, Pennsylvania.

Janice L. Pelletier, MD, is a pediatric dermatologist at Pediatric Dermatology of Maine and head of pediatric dermatology at Eastern Maine Medical Center in Bangor, Maine.

References

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2. Quenan S, Pasche F, Piletta P. “ET” material allergic contact dermatitis. Dermatitis. 2014;25(5):275.

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6. Prystowsky SD, Allen AM, Smith RW, Nonomura JH, Odom RB, Akers WA. Contact sensitivity to nickel, neomycin, ethylenediamine, and benzocaine: relationships between age, sex, history of exposure, and reactivity to standard patch tests and use tests in a general population. Arch Dermatol. 1979;115(8):959-962.

7. Rietschel RL, Fowler JF, Warshaw EM, et al. Detection of nickel sensitivity has increased in North American patch-test patients. Dermatitis. 2008;19(1):16-19.

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18. Jensen P, Hamann D, Hamann CR, Jellesen MS, Jacob SE, Thyssen JP. Nickel and cobalt release from children’s toys purchased in Denmark and the United States. Dermatitis. 2014;25(6):356-365.

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20141019/new-fitbit-wearable-will-come-with-allergen-warnings.htm. Accessed May 4, 2015.

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24. Bonnevie P. Aetiologie und Pathogenese der Ekzemkrankheiten: Klinische Studien über die Ursachen der Ekzeme unter besonderer Berüksichtigung des diagnostischen Wertes der Ekzemproben. Copenhagen, Denmark: Nyt Nordisk Forlag Arnold Busck; 1939.

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26. Zug KA, McGinley-Smith D, Warshaw EM, et al. Contact allergy in children referred for patch testing: North American Contact Dermatitis Group data, 2001-2004. Arch Dermatol. 2008;144(10):1329-1336.

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Disclosures

Sharon E. Jacob reports receiving an American Contact Dermatitis Society Mid-Career Development Award for information technology and research design training for the development of the Pediatric Contact Dermatitis Registry Project. The Pediatric Contact Dermatitis Registry Project is funded in part by a Society for Pediatric Dermatology pilot project research grant. She reports serving as an independent investigator for the safety and efficacy trial of the SmartPractice Thin-layer Rapid Use Epicutaneous (TRUE) Test panels 1.1, 2.1, and 3.1 in children and adolescents. She reports serving as a consultant for Johnson & Johnson. Nanette Silverberg reports serving as a consultant for Johnson & Johnson. Luz Fonacier reports receiving research and educational grants administered via Winthrop-University Hospital from Genentech, Baxter, and Merck, and is in the speakers’ bureau of Baxter. She reports serving on the board of directors of the Advocacy Council of the American College of Allergy, Asthma, and Immunology (ACAAI) and serving as chair of the Work Group of the ACAAI/American Academy of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters. Anthony Fransway reports being an emeritus member of the North American Contact Dermatitis Group. Alina Goldenberg, Bruce Brod, Richard Usatine, Robert Sidbury, James Young, Jonathan Silverberg, Albert Yan, and Janice L. Pelletier report no financial interests.