1 Introduction

Some causes of contact allergy have proven to be both common and persistent. Of these, there are contact allergies where regulation of the health problem is largely not possible, for example, poison ivy dermatitis in North America or parthenium dermatitis in India. Allergies from other causes, however, are susceptible to improvements through risk assessment and/or risk management. For example, fragrance allergy has been the subject of both of these strategies, with improvements to risk assessment being demanded, as well as risk management measures involving better communication of allergen content, and even the prohibition of certain allergens (e.g. [1, 2]). In this chapter, two common and persistent causes of allergic contact dermatitis, nickel and chromium, will be considered, specifically in relation to the impact that the imposition of specific regulations (i.e. risk management measures) has had on the burden of skin disease. Of course, it is important to note that the regulations applied to these metals are very different in nature, two being rather general restrictions applying to metal objects in prolonged contact with skin (nickel) [3] and leather products (chromium) [4] and the third applying to a quite specific problematic product used in the construction industry (chromium in cement) [5]. Nevertheless, there are both positive outcomes on which to reflect, as well as lessons to be learned concerning the value of communication and the need to fill important data gaps which continue to hinder more effective management of the risks to human health.

2 Nickel

2.1 Background

Nickel is considered to be a weak sensitiser [6,7,8], with the amount of exposure needed to cause nickel allergy or nickel allergic contact dermatitis (Ni ACD) being relatively high compared to other dermal allergens. The historical and current prevalence of nickel allergy has been due to frequency and type of nickel exposure, not to the high strength (or potency) of nickel as an allergen. Nickel allergy was first noticed in occupational scenarios where nickel salts were being produced or used [9]. As a form of nickel that is readily solubilised in water or sweat, nickel salts were the primary source of nickel allergy and Ni ACD in occupations where there was significant skin exposure to these salts. Awareness of the source of the problem resulted in workplace changes to decrease skin exposure and associated nickel-allergic reactions. Occupational causes of nickel allergy and Ni ACD from exposure to nickel salts are uncommon these days.

Paradoxically, increases in non-occupational sources of nickel allergy followed the decline in occupational causes, though the non-occupational sources were due entirely to materials containing nickel metal (i.e. alloys, nickel-plated items, etc.). Ni ACD was initially observed in individuals who had prolonged skin contact with clothing items releasing nickel, such as nickel-coated suspenders, buckles, zippers, and clasps [9]. The incidence of Ni ACD increased with the growing use of nickel-plated jewellery. The most common cause of nickel allergy and subsequent Ni ACD is body piercing. Inserting nickel-releasing studs into the piercing wound to prevent closure during healing provides an even more direct route of nickel exposure than contact with intact skin. In addition, the conditions within a piercing wound are conducive to corrosion which facilitates release of solubilised nickel ions into the surrounding area. Once healed, with the piercing stud removed, Ni ACD may occur through additional contact with high nickel-releasing jewellery items in the pierced holes.

Ni ACD has also been more recently (since 2000) associated with individual cases of direct and prolonged contact with portable computers, mobile phones, and other handheld electronic devices (e.g. [10, 11]). Surfaces of these devices were coated with nickel, which was used to provide an appealing surface finish or for electromagnetic shielding. Recognition of these items as sources of Ni ACD is leading to modification of many of these products to the use of materials that do not release significant amounts of nickel for those parts that come in direct contact with the skin.

2.2 The Regulations

The first regulatory action taken to reduce nickel allergy and Ni ACD came into force in Denmark in July 1989 under Statutory Order no. 472 (Ministry of the Environment (Denmark)) [12]. Items produced before the enforcement date were allowed to be sold until January 1991, thus making this the date when all of the nickel-releasing items on the market in Denmark would have to be in compliance. This regulation restricted nickel release for specific consumer items to no more than 0.5 μg Ni/cm2/week if the surface coating contained nickel [13]. Items included (1) ear ornaments or ear stickers; (2) necklaces, bracelets and chains, anklets, finger rings, and nail clips; (3) back of wristwatch cases, watch straps, and tighteners; (4) spectacle frames; and (5) garments equipped with buttons, tighteners, rivets, zippers, and metal marks which will by normal use come into close and prolonged contact with the skin. Compliance was determined by the dimethylglyoxime (DMG) test, which uses a cotton swab with liquid chemicals that react with available nickel ions. If a sufficient amount of available nickel is present, then a pink to red colour is evident on the swab to indicate failure of the DMG test. Failure of the DMG test by the items listed above meant they were not allowed for sale by manufacturers or importers in Denmark. The basis for this release rate was a study investigating a number of nickel-containing materials which were tested for nickel release comparing the release rate to patch test reactivity of those materials in nickel-allergic individuals [14]. Nickel release testing was measured using a basic synthetic sweat test as well as the DMG test. The nickel release rate limit of the materials that cause significant Ni ACD in patch testing was similar to the detection limit for the DMG test [14, 15]. The DMG test is much easier and less expensive to use than the synthetic sweat test, which explains the decision to use the DMG test as the measure of compliance. The Danish regulation was expected to reduce the number of cases of Ni ACD but would not necessarily protect every individual from Ni ACD [13]. “This regulation will not prevent all cases of nickel sensitization in the future, as some people might still develop nickel allergy from objects negative to the dimethylglyoxime test and releasing less than 0.5 μg nickel/cm2/week”.

Sweden enacted legislation in 1990 restricting ear piercing with nickel-containing piercers or rings made of alloys containing more than 0.05% nickel or having a nickel coating of more than 0.1 μm thick [16]. These values were based on the detection limits for nickel by atomic absorption at that time. The focus on piercing materials was due to the strong association of nickel allergy and ear piercing [16,17,18,19,20,22].

In 1992, the German Ministry of Health declared labelling mandatory (“Contains nickel”), if a product remaining in prolonged contact with the skin (e.g. jewellery, tools, and textile accessories) released more than 0.5 μg/cm2/week [23].

Due to the difficulties posed by differing and/or lack of regulation among European countries, a European initiative combining the existing Danish and Swedish nickel regulations was adopted in 1994 as the Council Directive 94/27/EC (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:1994:188:0001:0002:EN:PDF). This was the 12th amendment of Directive 76/769/EEC on restriction of the marketing and use of certain dangerous substances and preparations. To briefly summarise, the European regulation (known as the EU Nickel Directive) specified that:

  1. 1.

    Post assemblies inserted into pierced skin were limited to less than 0.05% nickel;

  2. 2.

    Nickel release was limited to less than 0.5 μg Ni/cm2/week for parts of products intended to come into direct and prolonged contact with the skin, such as those items specified in the Danish nickel regulation.

  3. 3.

    Products intended for direct and prolonged contact with the skin that have a non-nickel coating should meet the nickel release limit of 0.5 μg Ni/cm2/week for at least 2 years of normal use.

The nickel content limit was based on the Swedish regulation. The nickel release limit of 0.5 μg Ni/cm2/week was adopted based on the research that supported the Danish regulation, primarily the information from Menné et al. [14]. The intent of the EU and Danish regulation was to protect most of the population, but not necessarily every single individual. Standardised test methodologies were developed for compliance testing, but not until 1998, thus delaying the implementation of the EU Nickel Directive. The EN 1810:1998 standard [24] was used for body piercing assemblies as the reference test method for determination of nickel content by flame absorption spectrometry. The reference test method for the release of nickel from products intended to come into direct and prolonged contact with the skin was EN 1811:1998 [25], a standardised synthetic sweat test. Although the DMG test was researched for use as a reference test method (CR 12471 [26]), it was decided that it was not sufficiently accurate for compliance since it did not detect all high nickel-releasing items that caused positive patch tests in nickel-allergic individuals [15]. For simulation of wear and corrosion of coated items, EN 12472:1998 was developed (European Committee for Standardization (CEN), 1998c) [27]. This method was updated in 2005 and again in 2009 to make it more realistic for normal handling and use over a 2-year period [28, 29].

In 2004, the directive was amended (Directive 2004/96/EC [30]) to modify the requirement for post assemblies, so that this restriction would also be based on nickel release rather than nickel content. This release rate was lower, being 0.2 μg Ni/cm2/week, compared to items intended for use in direct and prolonged contact with skin surface (0.5 μg Ni/cm2/week) to address the fact that the epidermal layer was compromised during piercing exposure, providing less of a barrier for nickel to cross the skin barrier. This change from a regulation on nickel content to nickel release for piercing items was based on targeted RA study performed on LGC report “Risks of sensitisation of Humans to Nickel by piercing post-assemblies” [31]. There was recognition that piercing materials made of high-grade stainless steels used in surgical implants (ISO 5823) would not meet the content limit of 0.05% nickel but would release a very low amount (if any) of nickel [14, 30,31,34] and had low patch test reactivity [14, 35]. The release rate of 0.2 μg Ni/cm2/week was ratified by the European Commission’s Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) in their opinion of November 2003 (http://ec.europa.eu/health/ph_risk/committees/sct/documents/out211_en.pdf). Recital 3 of the amended directive also recognised an “adjustment factor” of 0.1 to be applied to the release rate result measured according to EN 1811:1998 to compensate for inter-laboratory variation and difficulty with measuring surface area of items. The European Committee for Standardization (CEN) was invited to review this standard so as to reduce this adjustment factor appropriately.

The original EN1811:1998 methodology and corresponding adjustment factor of 0.1 were updated in 2011 [36]. This version of the standard (EN1811:2011) introduced an uncertainty interval in place of the previous adjustment factor for:

  • Post assemblies: non-compliant = 0.35 μg Ni/cm2/week, compliant = 0.11 μg Ni/cm2/week, and no clear decision = >0.11 and <0.35 μg Ni/cm2/week

  • Items intended for direct and prolonged contact: non-compliant = 0.88 μg Ni/cm2/week, compliant = 0.28 μg Ni/cm2/week, and no clear decision = >0.28 and <0.88 μg Ni/cm2/week

Due to a number of concerns with the EN1811:2011 methodology, including failure of materials that were generally considered to not cause Ni ACD and the uncertainty resulting from the “no decision” category, EN1811 was amended in 2015 [37]. This updated version, which is the current one, resulted in an uncertainty adjustment of the acceptable release rate: <0.35 μg/cm2/week for post assemblies and <0.88 μg/cm2/week for items intended for direct and prolonged skin contact. Also in 2011, a separate reference test method was provided for spectacle frames [38]. This method was to specifically evaluate the release of nickel from parts of spectacle frames and sunglasses intended to come into close and prolonged contact with the skin.

With the implementation of the European Regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), many of the previous individual directives, including the EU Nickel Directive, were subsumed under REACH. The nickel restriction was included as entry 27 in Annex XVII, which came into force in June 2009 [39]. The only change compared to the previous independent directive was the use of the term “articles” instead of “products” for consistency with the REACH terminology.

Two official clarifications have been made to the EU nickel regulation. One is that coinage is not covered under the EU nickel regulation [40, 41]. This is at least in part due to the targeted risk assessment done by the Danish authorities in the context of the EU Existing Substances Risk Assessment of Nickel [38,39,43] which concluded that there was a lack of evidence of any effect of coinage in causing Ni ACD in consumers and that additional studies were not considered necessary. The second clarification is that mobile phones are covered by the restriction and should comply with the release limit, as their use involves “direct and prolonged contact with the skin” [41, 44]. This is now included in the question and answers section on restrictions on the ECHA website [44].

Of outstanding concern was the definition of “prolonged contact” in order to determine what articles should be considered covered by the scope of the restriction. In 2011 the European Chemicals Agency (ECHA) was asked to assess the issue, and a definition paper was presented to Competent Authorities for REACH and CLP (CARACAL) in late 2013. This paper was endorsed by CARACAL in April 2014 and was included as a Q&A to clarify the existing regulation [45]. The agreed definition was:

“Prolonged contact with the skin is defined as contact with the skin to articles containing nickel of potentially more than

  • 10 minutes on three or more occasions within two weeks, or

  • 30 minutes on one or more occasions within two weeks.

The skin contact time of 10 minutes applies when there are three or more occasions of skin contacts within a two-week time period. The skin contact time of 30 minutes applies when there is at least one occasion within a two-week time period”.

In addition to the definition of “prolonged contact”, the CARACAL members requested further guidance and clarification in the form of a list of articles to be considered falling into the scope of this new definition. ECHA was formally asked to derive this list of articles, with input from various stakeholders. The ECHA draft list of articles is expected to be available for public consultation in late 2016 or early 2017.

In North America, ASTM International has developed standards for children’s jewellery [46] and adult jewellery [47] which also mimic the EU nickel restriction, including reference to the standardised test methodology. However, ASTM standards are not required, so no regulation currently exists in North America.

ASTM F2923 – 14 for children’s jewellery states:

Section 10.1—“Migration of nickel in any post assemblies of children’s jewelry which are inserted into pierced ears and other pierced parts of the human body shall not exceed 0.2 μg/cm 2 /week (migration limit)”.

Section 10.2—“Migration of nickel in metal components of jewelry intended to come into direct and prolonged contact with the skin shall not exceed 0.5 μg/cm 2 /week. Items covered include: (1) components of earrings (other than post assemblies), (2) necklaces, bracelets, chains, anklets, finger rings, (3) wrist-watch cases, watch straps and tighteners”.

Section 10.3—“Where the components used in items listed in 10.2 have a non-nickel coating such coating shall be sufficient to ensure that the rate of nickel release from those parts of such articles coming into direct and prolonged contact with the skin will not exceed 0.5 μg/cm 2 /week for a period of at least two years of normal use of the article”.

Section 10.4—“Precious metals listed in Table 2, and stainless or surgical steel grades 304, 316 and 430, are expected to comply with the requirements of 10.1 through 10.3 and do not require further testing for nickel migration”.

Section 10.5—“Reference: EN 1811: 2011; CR 12741: 2002; EN 12472: 2009”.

ASTM F2999 – 14 for adult jewellery states:

Section 6.1—“Body-piercing jewelry shall be made exclusively of the materials listed in Table 5.1”

Table 5.1 Approved materials for adult body-piercing jewelry. With kind permission from ASTM [47]
Full size table

.

Section 10.1—“Representations regarding the safety of adult jewelry for adults sensitive to nickel or the limited potential for nickel to be released from metal components of adult jewelry shall be based on reasonable and representative tests, analyses or compositional assessments suitable for the application. Reasonable and appropriate test methods include, but are not limited to, those identified in 14.6. Precious metals listed in Table 2, and stainless or surgical steel grades 304, 316 or 430, are expected to meet these requirements and do not require testing”.

Section 10.2—“Reference—EN 1811: 2011; CR 12741: 2002; EN 12472: 2009”.

2.3 Evidence of Effectiveness

Numerous studies have investigated the changes in the prevalence of nickel allergy using patch test data (using nickel sulphate hexahydrate) to evaluate the effectiveness of the early regulations in Denmark, Sweden, and Germany in the early 1990s, followed by the later EU Nickel Directive (Table 5.2) [45,46,47,48,49,50,51,52,53,54,58]. However, as others have done (personal communication), the authors of this chapter also would suggest that the regulation itself is a major, but not sole, part of the reason for the observed decrease in nickel allergy. Education and communication about nickel allergy and Ni ACD associated with the implementation of the regulation likely also played a role in raising awareness and avoidance of exposure to items causing nickel allergy and Ni ACD.

Table 5.2 Overview of changes in the prevalence of nickel allergy in young people of various European countries before and after nickel regulation
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Since nickel allergy is a life-long condition (once you are allergic to nickel, you will always be allergic to nickel), the analysis of patch test results is only an indication of the number of people allergic to nickel, not the number of people having Ni ACD reactions. In order to understand the effectiveness of the regulations in Europe, the number of newly sensitised individuals should be evaluated. Assessment of the prevalence of nickel allergy in young people who would (theoretically) only have been exposed to low-nickel releasing items since the implementation of the regulations provides the best indication of the effectiveness of preventing nickel allergy. A number of studies have investigated patch test reactivity in children in Europe. As shown in Table 5.2, rates of nickel allergy have decreased significantly in almost every study. In addition to the observed significant decreases in prevalence of nickel allergy, a study in Denmark demonstrated a significant decrease in the strength of the patch test reactivity in nickel-allergic individuals [59].

It is interesting to compare the results in Europe following the regulation with the prevalence studies for similar years and age groups in North America, where no nickel regulation exists (adapted from Zug et al. [60]); see Table 5.3. Note that this high incidence approximately doubles in the data collations of the North American Contact Dermatitis Group (for the full age range) from the 1970s [61] through to the most recent data [62].

Table 5.3 The prevalence of nickel allergy in North America in the twenty-first century
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Reduction of the incidence of Ni ACD in already nickel-allergic individuals requires information on the number of Ni ACD reactions that are seen in patch test clinics, either in the form of case reports or number of relevant positive patch tests. Unfortunately, this data is not always recorded or easily accessible. A study by Smith et al. [55] provided information on patch test positive reactions and their relevance to the concurrent dermatitis for two different time periods. For 1995–2004, 44 out of 500 tested children (8.8%) had positive patch tests for nickel sulphate, but only three of these reactions were relevant to their existing dermatitis for which they were seeking treatment. The 2005–2012 data showed that 24 of the 500 tested children (4.8%) had positive patch tests for nickel sulphate, with only 7 of these 24 reactions being relevant to their existing dermatitis. The patch test prevalence to nickel significantly decreased, but given the low numbers of relevant reactions (and lack of presented statistics for relevance), the amount of change is not clear to assess a decrease in Ni ACD reactions.

Conflicting evidence exists on whether there has been a change in the association of nickel allergy and piercings following the EU nickel regulations. Mortz et al. [63] found a remaining significant association, while Jensen et al. [64] encountered a significant decrease in the association between piercing and nickel sensitisation. In countries where no regulation has been implemented, piercing is still a major risk factor for nickel allergy [65, 66].

2.4 Scope for Improvement

Although there is clearly a significant decrease in the prevalence of nickel allergy in Europe in the young population, the values still remain non-negligible. The sources of this continued induction of nickel allergy are not clear. Certainly there is evidence that enforcement of the nickel restriction is of concern given the market surveys and case reports where high nickel-releasing items are documented to still be on the market [63,64,65,70]. In addition, a recent questionnaire-based study highlighted that Ni ACD reactions were primarily reported as associated with articles, such as ear piercings, specifically listed in the current EU nickel regulation [71]. These findings would suggest that these items may not be compliant with the regulation. For instance, according to the same report from the Danish EPA [71], several investigations show that up to 20% of articles are still positive to the nickel DMG test. Given the lack of available funding and human resources in many countries, along with the lack of requirement for enforcing this regulation under REACH, it is quite likely that products that are not compliant with the regulation remain on the market in Europe.

A less likely possibility is that the existing nickel release rate limits are not sufficiently low to prevent nickel allergy or Ni ACD reactions. However, this seems improbable given the type and amount of scientific data that has gone into the derivation of the current nickel release limits. Furthermore, nickel is known to be a weak allergen [6,7,8], with an elicitation threshold of 0.44 μg Ni/cm2 (skin surface area) [72]. In addition, much work has been done to refine the protocols for measuring the nickel release rate by the CEN committees and related EN standards. Nevertheless, there remains the consideration of particularly susceptible subpopulations of individuals; this is an entire chapter in its own right and one where there remains an absence of consensus. Factors that should be kept in mind though include the need to consider the role of frequent low-dose exposure compared to less frequent but prolonged higher doses and the potential for filaggrin deficiency to elevate the risk of susceptibility to sensitisation (but not elicitation) [73, 74]. Indeed, although some factors such as psoriasis and atopic dermatitis appear unrelated to the acquisition of Ni ACD (where the presence of this allergic disease remains elevated), it is always necessary to keep an open mind regarding “current wisdom”, potential causation, and the role of any regulatory or other actions which have the aim of reducing the morbidity.

While the release limit in the nickel restriction is not likely to be the cause of the remaining nickel allergy and Ni ACD reactions, the associated test method (EN1811) for measuring nickel release may play a role. The original EN1811 test method [25], included an adjustment factor of 0.1 that was applied to the results of the nickel-release test measurement to address difficulties in measuring surface area and intra-laboratory variability. Application of this adjustment factor meant that items could release as much as ten times the release limit and still be compliant with the nickel restriction. Improvements in the test methods were made, and the adjustment factor was replaced by an uncertainty adjustment in 2011, with the amendment in 2015 (EN1811:2011+A1 2015; [36], European Committee for Standardisation (CEN) 2015). This uncertainty adjustment resulted in nickel release rate limits (<0.35 μg/cm2/week for post assemblies and <0.88 μg/cm2/week for items intended for direct and prolonged skin contact) that much more closely approximate the nickel restriction limits (<0.2 μg/cm2/week for post assemblies and <0.5 μg/cm2/week for items intended for direct and prolonged skin contact).

It also may be possible that additional items should be included under the EU nickel regulation. In the recent study by the Ministry of Environment and Food of Denmark [71], keys were noted as being responsible for recent Ni ACD reactions. As they are not listed specifically in the EU regulation and they may not generally be considered as being in direct and prolonged contact by many people, this may be an example of an item that could be overlooked by the current EU nickel regulation.

2.5 Outstanding Questions

In addition to the question of why nickel allergy continues to be seen in the young population where a nickel regulation exists, the question of what the clinical definition of the duration of prolonged contact needed to cause nickel allergy or Ni ACD remains. The current definition of prolonged contact, as approved by CARACAL, was based on a number of conservative assumptions. In addition, the data used was not necessarily relevant to nickel allergy and Ni ACD reactions observed in humans and associated with articles on the market that are responsible for causing these allergic reactions. An ongoing study involves patch testing nickel-allergic individuals for varying amounts of time, including those specified in the current CARACAL definition [75]. This study uses nickel-plated discs to represent types of materials in articles used by consumers that are most likely to trigger Ni ACD reactions. The results are expected to either confirm the exposure times currently noted in the definition of prolonged contact or better define what exposure times are needed for Ni ACD reactions. A report for this study is expected in mid-2017.

Another significant question is what the primary sources of nickel allergy and Ni ACD in children are. While ear piercing is certainly an ongoing source and concern, even children without pierced ears can become allergic to nickel. A retrospective study looking at data from the Ni ACDRG database is being initiated at the end of 2016 to identify what sources are associated with nickel allergy in children. This study is expected to be completed by the end of 2017 [76].

Finally, the question of the presence on the EU market of articles which are non-compliant with the EU nickel regulation remains. Data from a study in two locations identified that this was a problem in about one in six earrings purchased in Warsaw and London [69]. A larger survey of nickel release (EN1811 and DMG testing) of items that are currently covered under the nickel regulation, from a variety of price ranges and types of retailers in different countries, would help address this question. As females continue to be affected more than males, with the explanation being more use of pierced items and other jewellery by females, these items will be a particular focus. Such a survey is planned for 2017 to better understand the contribution of enforcement issues to the ongoing nickel allergy prevalence and incidence of Ni ACD [77]. Furthermore, a coordinated enforcement project (REF-4) was launched in 2016 at the EU level, in cooperation with member states, to check compliance with a number of REACH restrictions, including the one on nickel release in articles in direct and prolonged skin contact. The results are expected to be available in 2017. Such efforts to further improve enforcement and compliance with the existing EU nickel restriction are welcome and can give an important contribution to reduce the prevalence of nickel allergy and incidence of Ni ACD.

3 Chromium

3.1 Background

Potassium dichromate was already a key allergen on the original diagnostic patch test list of the International Contact Dermatitis Research Group (ICDRG) in 1974, a clear indicator that clinical experience had previously demonstrated that allergic contact dermatitis to chromium was one of the 20 most important skin allergens of the twentieth century [78, 79]. The frequency of positive reactions varied according to location but commonly approached, or even exceeded, 10% of consecutive eczema patients with contact allergy to the material (e.g. [61, 79, 80]). The sources of chromium allergy were already well known at the time—leather, cement, and a host of other industrial uses [79]. Almost 40 years later, the most recent textbooks of contact dermatitis detail a very similar profile [81, 82]. However, the most important source of exposure detailed in these (and many other) publications was cement. Building workers who developed allergic contact dermatitis via this route were well known to have a poor prognosis [79, 83]. Consequently, this was the primary target for legislative action to regulate the exposure to hexavalent chromium. Subsequently, attention was turned to leather as a source of exposure, and legislation is also now in place for that material. All of this has been thoroughly reviewed relatively recently [84].

3.2 The Regulations

Within the European Union, a directive was introduced in 2003 which required that within 2 years, each member state would introduce legislation to limit the exposure to soluble hexavalent chromium (Cr VI) from cement to a maximum of 2 ppm [5]. It also required labelling to indicate the “shelf life” of product. That EU directive was itself superseded, but not changed, by the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) regulation a few years later [85]. The relevant industry responded with the necessary actions (e.g. see review of [86]). Subsequently, the EU regulation has been updated also to restrict the release of Cr VI from leather products [4]. The effect of this is to try to ensure that leather articles coming into contact with the skin are not placed on the market if they contain Cr VI in concentrations ≥3 mg/kg (0.0003% by weight) of the total dry weight of the leather. This action was no doubt prompted by the observation of the importance of leather as a source of chromium allergy, even to the extent that it was implicated as a reason for the increase that occurred in Denmark many years after the implementation of national cement legislation in that country ([56, 57]; Carøe et al., 2010).

3.3 Evidence of Effectiveness

A key indicator of the likelihood of the success of the EU legislation had already been foreshadowed by the marked differences in the experience of workers involved in the construction of the Channel Tunnel, between the UK and France. In the UK workforce, two-thirds of those with exposure and occupational dermatitis (largely grouters) were patch test positive to potassium dichromate [87]. However, anecdotally, workers on the French side were largely unaffected (Richard Rycroft, personal communication), and it was already well understood that the addition of a small dose of ferrous sulphate to the wet cement could lead to a dramatic reduction in the frequency of chromate allergy [88]. That experience from Denmark demonstrated that “there was a statistically significant decrease in the prevalence of chromate allergy and hand eczema following the addition of ferrous sulphate”. More recently, distinct evidence of a reduction in the frequency of chromium allergy in the German construction industry was reported [89]. However, it must be borne in mind that this last-mentioned publication reported a reduction in positive diagnostic patch tests from 43 to 29%, indicating, perhaps rather powerfully, that there is still distinct scope for improvement in the construction industry. The very latest and carefully conducted analysis from large occupational groups in the UK and France suggests that the impact of the Cr VI legislation in Europe has been to deliver an approximately 50% reduction in the incidence of disease [90]. Nevertheless, it is well worth noting that the legislation only has the chance to be effective if it is properly applied. The recent case of a 22-year-old Swedish concrete worker clearly demonstrated how important this is, as well as delivering a timely reminder of the risk of more chronic skin disease despite (apparent) removal from chromium exposure [91]. Finally, to counterbalance this relatively positive view of the effectiveness of the chromium legislation, it is of course quite possible that changes in the building industries, in the automation of process, and in the way materials are used have also made a significant contribution to the reduction in allergy.

Beyond the investigation of specific occupational groups, it is of course also possible to monitor the frequency of chromium sensitivity in the general eczema population, i.e. in those that undergo diagnostic patch testing, not least since potassium dichromate is in the baseline series and thus tested on every patient. Some of the most extensive data could be derived from the North American Contact Dermatitis Group, but in the context of evidence of the effectiveness of legislation, this is of limited value, since there is no legislation in this region! However, it provides at least some background sufficient to advocate caution in the interpretation of other evidence—from 1970–1976 the frequency of positive reactions to potassium dichromate varied from 7.8 to 10.4% [61]. That rate was reduced to <2% in the 2011–2014 data (Warshaw et al., 2015; [92, 93]). This must be significant, but is it relevant? Probably not: the patch test concentration was lowered from 0.5 to 0.25% in the intervening period; industry practices, including the use of personal protection, may well have changed; referral practices that determine who is patch tested and with what are unlikely to have remained constant; sources of exposure will have changed. This is not to say that evidence of the effectiveness of legislation in the preceding paragraph is to be ignored, merely that care should be taken to ensure all variables are considered before drawing firm conclusions from routine patch test data. In this respect, it is valuable to examine the survey data recently published [84]. Apparent downward trends in the rates of positive reactions to potassium dichromate seen in an individual clinic (Gentofte), in Europe and in North America, are quite comparable, even though no legislation has been enacted in the last-mentioned location (see Fig. 5.1, which shows a 30-year period of screening with potassium dichromate sensitivity in the North American region compared to relevant European data). In reality, it is the upward trend in Asia, starting from an already higher base, that is truly worrisome [84, 94].

Fig. 5.1
figure 1

The prevalence of Cr VI-positive reactions in Europe versus North America

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3.4 Scope for Improvement

A first action to take must be to encourage introduction of the European type of legislation into other geographic locations. For example, a recent review from Israel demonstrates a clear need for such regulation in that country [95]. Similar calls from other countries are easily identified (e.g. [94, 91,92,98]). There is little doubt that all nations should adopt this good practice, although it might reasonably be argued that the cement industry itself should take the lead rather than wait to be compelled. Indeed, some nations have done precisely this.

Beyond the limitation of chromium exposure from cement, it is necessary further to limit exposure from other sources. Apparently to that end, the EU will introduce a ban on the use of hexavalent chromium salts for the plating of decorative objects during 2017 (see http://nomorehex.org/LEGISLATION/EU-MANDATE). However, this actually is an unintended consequence, since the legislation appears to be based on the carcinogenic properties of these salts, not on their potential for skin sensitisation. Chrome plating has not proven an important source of contact allergy in consumers but is relevant in the occupational environment. A similar logic applies to the restriction for packaging (not a frequent source of allergy), which limits the total content to a maximum of 100 ppm Cr VI [99], as well as for electrical/electronic equipment for which the substitution of safer alternatives to Cr VI (and several other toxic metals) has become a requirement (see http://ec.europa.eu/environment/waste/rohs_eee/index_en.htm). Thus, real improvement would necessarily only really come from the identification of important continuing sources of chromium allergy (as was done for leather), followed by appropriate action and monitoring.

3.5 Outstanding Questions

In a sense, the challenges faced for chromium allergy are similar to those found with many causes of allergic contact dermatitis: namely, to identify the key sources of exposure, particularly those that are relatively obscure (e.g. [84]). The second question is how to demonstrate the effectiveness of any particular legislative action, set against the background of changing work patterns, varying clinical referring and testing practices, and so on. Finally, whereas for nickel the DMG spot test (despite many limitations) provides a handy tool to detect the presence of the allergen, nothing truly similar exists for hexavalent chromium salts; recent development of a diphenylcarbazide (DPC) spot test has the potential to assist in reducing the morbidity of the disease and could be critical in helping to eliminate the chronic nature of chromium eczema [100]. However, the fact that the test needs to be kept frozen renders it somewhat less user-friendly, so only time will tell whether it functions to deliver similar benefits to the DMG test.

4 Concluding Remarks

Decreasing the prevalence of skin sensitisation to common allergens to a negligible or even to a socially acceptable level requires adequate and relevant scientific input into regulatory activities and communications with and between stakeholders. Through compliance with the resulting regulatory restrictions and sufficient stakeholder communication, significant and acceptable reduction in the prevalence of skin sensitisation to common allergens can be achieved. The complexity of monitoring the incidence/prevalence of the disease should not be underestimated but, as experience has shown, without appropriate monitoring, regulation alone may have little, if any, impact [78]. The experience with nickel and Cr VI provides an important learning opportunity that should help with the mitigation of other causes of allergic contact dermatitis, as well as with continuing efforts to manage other sources of exposure to these two allergenic metals.