1 Introduction

Nickel is the most common skin sensitizer, affecting large proportions of women, men and children. Nickel allergy is considerably more prevalent among girls and women than boys and men, owing to differences in exposure patterns. Skin exposure to nickel in various consumer articles results in nickel allergy and allergic contact dermatitis on exposed body parts, including the hands. Occupational exposure to nickel is an important cause of occupational skin disease, particularly hand eczema.

Nickel is used in numerous products and materials, many of which come in contact with the skin of consumers and workers. The use of nickel in steels and plating started around 1870, and nickel production has increased considerably since 1940 [1,2,3]. Today, approximately 65% of the nickel produced is used in stainless steels, 20% in other steels and alloys, and 15% in plating and also in chemical compounds (Nickel Institute https://www.nickelinstitute.org/).

Many of the products and materials intended for consumer and occupational use release nickel ions upon skin contact and contaminate the skin. It is thus difficult to avoid skin exposure to nickel in daily life and in the workplace.

2 Prevalence of Nickel Allergy

Results from some of the pioneering, largest and most recent studies on the prevalence of nickel allergy among dermatitis patients and the general population in Europe and North America are shown in Tables 32.1 and 32.2. Occupational groups affected by nickel allergy are shown in Table 32.3. There are large differences in the prevalence of nickel allergy between women and men and between age groups, countries and occupations, over time (Fig. 32.1). Most alarming is the persistent and high prevalence of nickel allergy and particularly the much higher prevalence among women compared with men.

Table 32.1 Prevalence of nickel allergy among dermatitis patients in European countries and North America. Examples to illustrate differences over time, between countries and genders
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Table 32.2 Prevalence of nickel allergy in the general population in European countries. Examples to illustrate differences over time, between countries and genders
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Table 32.3 Examples of occupations with work-related nickel allergy and nickel dermatitis and sources of occupational exposure to nickel [2, 20,21,22]
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Fig. 32.1
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Prevalence of nickel allergy among patch-tested dermatitis patients (a–c) and the general population (d–f) in Europe. Examples to display differences between countries, genders and age groups, over time. See also Tables 32.1 and 32.2. References: (a) [6]; (b) [7]; (c) [4]; (d) [15]; (e) [13, 14]; (f) [15,16,17, 19]. Country codes: CH Switzerland, DE Germany, DK Denmark, ES Spain, IT Italy, NL The Netherlands, PL Poland, PT Portugal, SE Sweden, SI Slovenia, UK United Kingdom. Colour codes: red/dots—women or girls, blue/stripes—men or boys, violet—all, pale red or blue—youngest, medium red or blue—middle, dark red or blue—oldest age group

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2.1 Dermatitis Patients

Table 32.1 shows that nickel allergy is extremely common among patch-tested adult dermatitis patients (range 12–25%) and three to six times more frequent among women than men. The prevalence of nickel allergy in children is also very high; to what extent stricter selectivity in patch testing children as compared to adults affects the results is not known.

2.2 General Population

There are few large patch test studies among the general population, compared with dermatitis patients. Table 32.2 shows that nickel allergy is extremely common among the general population, adults (range 5–19%) as well as children including adolescents (range 8–10%). Nickel allergy is four to ten times more frequent among women than men among the general population, and the prevalence differs largely also between girls and boys.

2.3 Geographical Differences

Healthcare and social security systems, access to dermatology and selection for patch testing, patch test routines, etc., vary between countries, which contribute to difficulties in comparing the prevalence of nickel allergy between countries. The highest prevalence rates among dermatitis patients in 12 European countries (Table 32.1, Fig. 32.1) were reported for Italy, Poland and Spain (25–26%) and the lowest for Denmark and Germany (12–13%). In North America, the generally used patch test concentration of nickel is 2.5%, half the concentration of that used in the European baseline series. It is likely that this has resulted in some underestimation of nickel allergy among patch-tested patients in North America (Table 32.1).

Likewise, there are large differences between countries in the prevalence of nickel allergy among the general population (Table 32.2 and Fig. 32.1).

2.4 Time Trends

Studies where nickel allergy has been monitored over several years, or reevaluated under similar conditions, show convincingly that nickel allergy has started to decline in some countries. For dermatitis patients in Europe (Table 32.1), a significant decrease in nickel allergy has been noted among younger women (below age 30 or 40) in Denmark, Germany, Italy, Sweden and the UK, and an increase has been noted among women and men above this age in some of the countries (Fig. 32.1) [4, 5]. The reduced prevalence of nickel allergy in the younger age groups has been interpreted to be a result of the EU restriction of nickel and the increase in a cohort effect (see Chap. 5).

Only few studies allowing for trend analysis have been performed among the general population (Table 32.2, Fig. 32.1). A decrease in nickel allergy among the younger women was noted in Denmark between 1990/1991 and 2006; Denmark introduced a nickel restriction in 1991, 10 years before the EU [14].

For dermatitis patients in North America (Table 32.1), a significantly higher prevalence of nickel allergy has been recorded for the period 2013–2014 compared with 2001–2012 [8]. In a systematic review of peer-reviewed publications from the USA in 1961–2015, more than 18,000 adult nickel dermatitis cases were identified [29]. The number of published cases and articles had increased exponentially; suggested explanations for this were previous underdiagnosis and underreporting and increasing nickel exposure and sensitization. There is no nickel regulation in North America, and the North American Contact Dermatitis Group (NACDG) has suggested that regulations restricting release of nickel should be introduced also in North America.

Time trends in nickel exposure are discussed below.

3 Occupational Groups

Occupational nickel exposure is still an important risk factor for nickel allergy and related hand eczema, and certain occupational groups are affected more often than the general population [2, 3, 20]. Examples of occupational groups with a high frequency of nickel allergy are listed in Table 32.3.

More than a hundred years ago, nickel dermatitis was identified as an occupational skin disease among nickel platers. Until the 1930s nickel allergy was predominantly a male occupational disease. Improved industrial hygiene and technical development have decreased the risk, but safety standards vary significantly between workplaces, industries and countries. Outbreaks of nickel allergy are still reported in industrial settings involving platers, metalworkers and electronics industry workers. In such industries, the use of nickel or nickel chemicals is generally obvious and unavoidable (Table 32.3).

Many occupations in the construction industry or involving repair and maintenance work are associated with high exposure to nickel, resulting in occupational nickel allergy and nickel dermatitis (Table 32.3). Car mechanics, electricians, locksmiths, plumbers and other groups are exposed to nickel from intense contact with work materials, tools and other equipment, sometimes in conjunction with exposure to skin irritants.

The prevalence of nickel allergy and hand eczema is high in many occupations in the service and healthcare sectors (Table 32.3). Exposure to nickel in these occupations is often not as obvious as in the other groups. Exposure may be caused by repeated contact of short duration with various commonly occurring items, including coins, handles, keys and utensils (Table 32.4). Exposure to wet work and other irritant factors in many of these occupations impairs the skin barrier function, which facilitates penetration of nickel, sensitization and dermatitis. It has, however, sometimes been questioned whether or not the high rate of nickel allergy in female-dominated occupations such as hairdressing, cleaning and nursing is work related.

Table 32.4 Types of metallic items, including those listed in the nickel restriction by REACH, known to release nickel and to cause nickel allergy and dermatitis. Examples, beyond those listed in the restriction, mainly from reviews [2, 23, 24], market surveys [25,26,27,28] and patient-based studies [29, 30] are provided
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Two large studies in the UK in the 1990s assessed occupational contact dermatitis and nickel exposure. In 23% of 368 nickel-allergic patients, nickel was considered to be an occupational or possibly occupational allergen. The main workers were hairdressers, retail clerks, caterers, cleaners and metalworkers. Hand eczema was more prevalent in the occupational than nonoccupational group [21]. National occupational surveillance data was examined, and it was estimated that up to 12% of occupational contact dermatitis cases were associated with nickel exposure. Hairdressers, bar staff and chefs or cooks had the highest incidence rates [22].

Exposure assessments of the work environment are generally required to identify and validate the relevance of occupational nickel exposure (see Chap. 6).

4 Exposure

4.1 Sources of Skin Exposure

It is necessary to identify sources of nickel exposure in the workplace, home and leisure environment for exposure reduction and prevention of dermatitis. The dimethylglyoxime (DMG) test indicates the presence of nickel ions by a pink colour. For decades, it has been the most valuable tool that has been used in dermatology in testing for nickel release. It is used in the clinic, market surveys and workplace studies, and it has been standardized and validated in relation to the limit value (0.5 μg/cm2/week) of the EU nickel restriction [31, 32] (see Chap. 6).

Examples of typical items known to release nickel and cause nickel allergy and dermatitis are given in Table 32.4. Numerous market surveys have been performed with the DMG test and only a few by nickel release in artificial sweat. Most studies have examined jewellery or earrings; others have assessed coins, clothes, electronic devices, tools, toys and other articles. See Chaps. 13, 14, 15, and 16.

4.2 Nickel Release in Artificial Sweat

Nickel release from materials and items is of large interest for risk assessment, and it can be quantified by immersion in artificial sweat according to EN 1811, the reference test method for nickel restriction [33]. The rate (speed) of release of nickel from materials is initially very high and declines rapidly, and samples should preferably be taken at several time points: after minutes, hours, days and a week. The release rate is important for understanding why contact with coins, handles, tools and other items can result in deposition of significant amounts of nickel on the skin [34,35,36].

4.3 Trends in Exposure

Fashion varies over time, and fashion items, including suspenders, ear clips, jeans buttons and piercing jewellery, have been important for widespread nickel sensitization. Technical development in material design and introduction of new types of consumer articles, including electronic devices such as mobile phones, laptops, play stations, activity bracelets and electronic cigarettes, have been highlighted as new sources of nickel exposure and dermatitis among children, consumers and workers (Table 32.4 and Chap. 13).

Three consecutive surveys in Sweden show significant adaptation to the requirements of the Nickel Directive that entered into full force in 2001 (Table 32.4) [37,38,39]. In 1999, 25% of 725 articles were DMG test-positive, in 2002 8%, and in 2010 9% were DMG test-positive. Only 4% of the earrings were DMG test-positive in 1999 and 2010, and 0% in 2002, considerably lower than recorded in other countries (15–31%) [40]. Sweden introduced a restriction on the nickel concentration (0.05%) in piercing posts used during epithelization in 1990, corresponding to former part 1 of the Nickel Directive, and a nationwide information campaign about the Nickel Directive was launched in Sweden in 1999.

Notwithstanding the relatively good compliance to the restriction in Sweden, the prevalence of nickel allergy was high among 16-year-old girls (9.8%) and boys (4.9%) born in 1994–1996 [19]. Sources of exposure other than piercing, jewellery, etc., likely contributed significantly to their sensitization.

4.4 Sharpening of the EU Nickel Restriction

Owing to the slow decrease of nickel allergy in the EU despite the restriction, the European Chemicals Agency (ECHA) was requested to define what should be interpreted as “prolonged contact” in the regulation. In 2014, ECHA published this definition (Table 32.4). ECHA has also been requested to prepare a list of examples of articles covered by the definition, as a guideline. Many of the items in Tables 32.3 and 32.4 should fit the definition.

The most pragmatic approach for manufacturers, retailers and employers, as well as for control of compliance with the regulation, would be that DMG test-positive items should not be used in contact with the skin.

4.5 Skin Exposure Assessment

It is now possible to quantify nickel and other metals deposited onto the skin. Acid wipe sampling, finger rinsing and tape stripping are methods that have been used in occupational, clinical and experimental studies [20, 41,42,43]. It is also possible to visualize nickel on the skin by the DMG test [44]. Skin exposure assessments of nickel and other metals will contribute important information for risk assessment, assessment of occupational dermatitis and prevention efforts (see Chaps. 6 and 28).

4.6 Systemic Exposure

The role of nickel in the diet, surgical implants and dental materials remains partly controversial and is reviewed in Chaps. 17, 19 and 22.

5 Genetic Susceptibility

It is well known that skin exposure to nickel is the main risk factor for sensitization to nickel and nickel dermatitis. It is obvious that also endogenous factors are of importance for sensitization and allergic contact dermatitis. During recent years, efforts have been made to identify genetic factors associated with nickel allergy and nickel dermatitis. Most interest has concerned atopic dermatitis and filaggrin gene mutations.

Several studies have been performed to elucidate associations between genetic factors and nickel allergy or nickel dermatitis. A number of review articles have discussed recent developments [45,46,47,48,49]. Studies have been performed by various methodologies, including population-based studies among families, twins and the general population; studies in patients with atopic dermatitis, hand eczema or nickel allergy; and experimental studies in patients and animals and in vitro studies. To summarize some current positions that may be of particular relevance to clinicians:

  • The prevalence of nickel sensitization is increased in patients with atopic dermatitis.

  • Multiple factors affect the association between atopic dermatitis and skin sensitization.

  • Filaggrin gene mutations increase the risk of atopic dermatitis and likely the risk of sensitization to nickel due to compromised chelation of nickel in the stratum corneum.

  • Filaggrin null mutations have been associated with nickel allergy and self-reported jewellery dermatitis.

  • Some epidemiological filaggrin studies on nickel have been stratified for piercing.

  • Epigenetic regulation likely has a role in nickel dermatitis.

  • Results from epidemiological studies concerning genetic predisposition to nickel allergy have sometimes been conflicting.

  • More studies are needed to determine the role of genetics in the development of nickel allergy and nickel dermatitis.

Ongoing and future research is expected to contribute with further knowledge as to the role of genetic factors in nickel allergy. This may be of high relevance for diagnosis, treatment and prevention.

6 Potency, Cross-Reactivity and Concomitant Reactivity

It is sometimes assumed that nickel is a potent skin sensitizer, as it is a very frequent sensitizer. Based on results from predictive testing in animals by the guinea pig maximization test (GPMT) and the local lymph node assay (LLNA) in mice, however, it has been concluded that nickel is a moderate or weak sensitizer. Negative LLNA results are considered false negative, and mice have been sensitized to nickel by other test methods [50,51,52].

Although the sensitizing potency of nickel is moderate in animal experiments, the dose required for elicitation of nickel dermatitis in humans is very low (see “Dose-Response Studies”).

Concomitant reactivity to nickel and other metals is seen relatively often in dermatitis patients. It is generally difficult to tell if concomitant reactions to commonly occurring skin sensitizers are related to cross-reactivity, co-reactivity or increased susceptibility. Cross-challenge experiments in guinea pigs indicate cross-reactivity for nickel and palladium, but not nickel and cobalt or nickel and chromium [53,54,55].

Patch test results among dermatitis patients and adolescents in the general population have been analysed concerning concomitant and solitary reactivity to nickel, chromium and cobalt [19, 56, 57]. Of particular interest is that cobalt allergy without nickel allergy is relatively frequent, compared with the general assumption that cobalt allergy is coupled to nickel allergy owing to assumed concomitant exposure or cross-reactivity. It should also be noted that cobalt often is used in other forms and products than nickel (see Chap. 28).

7 Clinical Picture

Skin lesions in nickel-allergic persons may be transient or more persistent, localized to skin contact with certain items, to the hands, or more widespread. When localized to the skin under jewellery, buttons, a belt buckle, spectacle frames, a wristwatch and other personal items, it may be relatively easy to identify and avoid the causative exposure. It may, however, be difficult to identify the exposure(s) causing or contributing to hand eczema.

Historically, jewellery, suspenders, hooks, zippers and buttons in clothes and spectacle frames have often been reported to cause the first noted lesion (primary eruption). During recent decades, when ear and body piercing has been increasingly popular, dermatitis from jewellery for pierced holes has been common. The picture is dependent on fashion, which varies, and to the properties of the materials used, i.e. nickel release.

Nickel-allergic individuals run an increased risk of developing hand eczema [3]. Approximately 30–40% of nickel-allergic individuals report that they ever have experienced hand eczema, compared with 15–20% among non-nickel-allergic individuals [12, 58, 59]. Patients with hand eczema and nickel allergy often have recurrent vesicular hand eczema [60]. Occupational nickel exposure should be considered in nickel-allergic patients with hand eczema. In some countries, the association between nickel allergy and hand eczema in young women may have weakened (see “Severity and Prognosis”).

Systemic exposure to nickel by ingestion, implants and dental materials is reviewed in Chaps. 17, 19 and 22.

7.1 Severity and Prognosis

Many mild cases of nickel dermatitis will clear with avoidance of nickel exposure and with topical treatment. Hand eczema in nickel-sensitive patients has often been considered to have a poor prognosis and may in some cases be resistant to treatment and persist for years [2, 3, 61].

Severe hand eczema occurs in nickel-allergic patients, particularly in work-related cases when the exposure may be massive or difficult to avoid, and when combined with exposure to wet work and other skin irritants that impair the skin barrier function. Other well-known factors that contribute to severe symptoms or poor prognosis of nickel allergy are multiple sensitization and a history of atopic dermatitis [3, 47, 62].

Some studies among the general population indicate that the prognosis of nickel allergy has become more favourable. The association has weakened between nickel allergy and hand eczema among young women in Denmark, although not among older women, following the Danish nickel restriction of 1991 [63]. In a 20-year follow-up of patch-tested schoolgirls in Sweden, the prognosis of hand eczema in relation to nickel allergy was more favourable than previously reported [64]. The participants had, however, been patch tested with nickel and informed about any nickel allergy in the first study, and it is unknown if they had avoided nickel exposure since then.

8 Diagnosis and Prevention in the Clinic

8.1 Patch Test

Nickel sulphate 5% (2.0 mg/cm2) in petrolatum is used in the European baseline series, while 2.5% (1.0 mg/cm2) is used in the North American series [8, 65]. The ready-to-use patch test system TRUE Test® contains a nickel patch (0.20 mg/cm2). Active patch test sensitization from nickel sulphate 5% in petrolatum has not been reported. The proportion of irritant and doubtful patch test reactions to nickel is low, compared with that to cobalt, chromium and most other baseline patch test substances [57, 66, 67]. Poor reproducibility of patch test reactions to nickel among infants has been reported [68] (see Chap. 37).

Patch testing with serial dilutions of nickel is performed to assess an individual’s degree of sensitivity or to confirm that a reaction is allergic. Patch testing with metal discs of various nickel-containing materials gives information about the ability of materials to cause allergic contact dermatitis (Chap. 6) [69,70,71]. Such testing is sometimes used when patients are evaluated in relation to implants (see Chap. 24).

8.2 Dose-Response Studies

Compilations of dose-response results give important information on elicitation thresholds [72]. Dose-response studies have been performed with serial dilutions of nickel by patch testing and repeated open application testing (ROAT) [73]. The patch test dose to which 10% of nickel-allergic individuals reacted (ED10) was 0.78 μg nickel/cm2. The reactivity to the accumulated dose per unit area by ROAT was similar to that by patch test. Knowledge about elicitation thresholds is important for understanding that low doses of nickel are able to cause allergic contact dermatitis by prolonged contact and that nickel deposited onto the skin by short and repeated contact likewise is able to cause allergic contact dermatitis. See further Chap. 6 concerning measured levels of skin exposure to nickel in various occupations.

8.3 DMG Test

The DMG test presents a cheap, simple and powerful tool for prevention of nickel dermatitis by exposure reduction. All patients with nickel allergy and contact dermatitis should be encouraged to use the DMG test to minimize nickel exposure from personal items, in the workplace and during leisure. It may be necessary for the patient to get support by the occupational health service, safety representative or employer to reduce exposure in the workplace.

8.4 Exposure Assessment

In the case of suspected work-related nickel allergy, it may be of high importance to make a thorough assessment of the patient’s exposure to nickel, other skin sensitizers and skin irritants. This is essential for diagnosis, rehabilitation and medicolegal purposes [65]. The assessment should preferably include a systematic investigation with the DMG test to identify sources of nickel exposure in the workplace. Nickel on the skin should also be assessed qualitatively by the DMG test or quantitatively if chemical analysis is available (see “Exposure” and Chap. 6).