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Nickel Allergic Contact Dermatitis

The Basic Science Papers: ENV-1

"The following is a technical paper on Nickel Allergic Contact Dermatitis. For the nickel industry position on Nickel Allergic Contact Dermatitis and how its incidence can be reduced, click here."

This is one of a series of papers on the basic science issues associated with the production, use and final disposal of nickel and nickel-containing materials. Other papers in the series deal with carcinogenicity and ecotoxicity. These papers reflect the current understanding of the science associated with health and environmental issues. The essential contributions of B.R. Conard, Ph.D., and of the Nickel Producers Environmental Research Association (NiPERA) are gratefully acknowledged.

1. EXECUTIVE SUMMARY
2. SUPPORTING DOCUMENTATION
2.1 What is Allergic Contact Dermatitis (ACD)?
2.2 What are the Conditions Necessary for Inducing Nickel ACD?
2.3 What Portion of the Population May Be at Risk?
2.4 What Regulatory Controls are Currently in Place?
2.5 What are the Nickel Industry's Beliefs Concerning Nickel ACD?
2.6. What Scientific Information is Needed?
2.6.1 Present State of Knowledge
2.6.2 Research Needed
3. REFERENCES

1. Executive Summary

  • Many chemical agents, including nickel, can cause allergic contact dermatitis (ACD) which results in inflammation of areas of the skin in sensitized individuals.

  • Elemental nickel and sweat-soluble nickel salts both cause ACD by sweat solubilization (corrosion) of nickel and the formation of nickel ions, during intimate and prolonged contact with the skin. The rate of nickel ion release to the skin is dependent primarily on the specific substance having contact with the skin. Non-occupational contact with nickel in Europe, primarily through nickel-plated clothing fasteners and jewellery in pierced ears, has reportedly sensitized about 5-15% of females and about 0.5-1% of males.

  • The nickel industry supports the intent of legislation such as the European Union's Nickel Directive, which prohibits the use of nickel in products where intimate and prolonged skin contact will result in solubilization of nickel at a rate exceeding 0.5 micrograms per square centimetre per week. Furthermore, the nickel industry accepts the expert opinion of dermatologists who state that such a prohibition will by itself reduce the incidence of nickel ACD in the general population to very low levels.

  • There is no justification for banning nickel from uses in general consumer products unless there is clear evidence, resulting from a detailed risk assessment, that such a use poses a health risk. The use of nickel in, for example, coinage and tools does not pose a health risk for the general population because such applications do not involve intimate and prolonged contact with the skin under normal handling and use. North American populations, having used nickel in coinage for many decades, show no evidence of coinage-induced nickel ACD.

  • The use of most stainless steel alloys in consumer products does not constitute a health risk from nickel ACD both because most stainless steels have been shown to be incapable of causing nickel sensitivity and/or because such items would not come into contact with the skin at the required intensity or for the required time.

  • The nickel industry is involved in and will continue to be proactive in supporting scientific research on the mechanism of nickel ACD, in improving tests for nickel sensitivity, and in conducting studies to ensure that specific uses of nickel do not pose health risks for the general population.

Refer to the attached Supporting Documentation for a more detailed explanation of these points.

 

While technical in nature, this is not a peer-reviewed science paper. It is intended to be an overview of a topic that has generated over time a very extensive and well-reported literature.

For those wanting to investigate the basic science, the few references given at the end of this paper are a good place to start. In addition, a reader may wish to contact the Nickel Producers Environmental Research Association (NiPERA) at e-mail: nipera@nipera.org or web site: www.nipera.org

2. Supporting Documentation

2.1 WHAT IS ALLERGIC CONTACT DERMATITIS (ACD)?

Many chemical agents such as poison ivy, rubber accelerators, epoxy resins, certain solvents, certain perfumes and some metals (nickel, chromate, gold and mercury are examples) are able to cause allergic contact dermatitis (ACD). This condition is characterized by a broad range of skin symptoms ranging from dryness, chapping and inflammation to eczema and blisters. Discomfort is caused by skin inflammation and itching. There are usually social stigmas present due to the discolourations and eruptions of local areas of the skin that are visible to others.

Nickel ACD is not an inherited condition. It is related to intimate and prolonged skin contact (i.e., exposure) by nickel metal or nickel soluble salts. Nickel ACD was first noticed in occupational settings where soluble forms of nickel came into contact with workers' skin. Individuals working in electroplating shops, in battery manufacturing and with nickel catalysts were the most susceptible to exposure.

Non-occupational nickel dermal sensitization is also well known. It was first observed in individuals who had skin contact with clothing items having nickel-coated buckles, zippers and clasps. Increased incidence of nickel ACD occurred with increasing use of nickel-plated jewellery and, most significantly, with the increase in the practice of ear lobe piercing, which often involves inserting nickel-containing studs into the wound to prevent closure during healing. Once healed, with the stud removed, additional contact with nickel in the ear-pierced area routinely occurs by wearing earrings that have nickel-coated posts.

2.2 WHAT ARE THE CONDITIONS NECESSARY FOR INDUCING NICKEL ACD?

The development of nickel ACD requires that an individual become immunologically sensitized to nickel. This is termed the induction phase or sensitization phase and takes from 1 to 3 weeks of intimate skin contact with a form of nickel that can provide sufficient amount of soluble nickel ions to the skin primarily via sweat. The quantity of nickel ions that is sufficient to induce sensitivity varies with the individual. If the skin is already damaged, sensitization will be induced more quickly and by lower amounts of the solubilized nickel. Temperature, the presence of other allergic conditions, race, sex and age may also be determining factors on the susceptibility for and the speed of sensitization to nickel. Induction of ACD is more common if exposure is combined with skin irritants and/or moist skin.

A sensitized individual, when re-exposed to nickel ions on the skin in sufficient amounts, may have an allergic response within a matter of hours. This is termed the elicitation phase, which often occurs at a much lower concentration of nickel than required for inducing sensitization in the first place. The elicitation of nickel ACD can occur in skin remote from the site of contact with nickel.(1)

While systemic elicitation of ACD in sensitized individuals by direct skin contact is well documented, there exists some controversy(2) about the ability of nickel to elicit a systemic allergic response when taken orally, intravenously or inhaled. Only about 1-10% of dietary nickel is absorbed by the body. Average daily ingested intake of nickel is about 200 mg. A few studies have shown that nickel-sensitive individuals orally given >5000 micrograms nickel (as NiSO4) as a single dose had a dermal allergic response. While such exposures are far in excess of those encountered in normal diets, some researchers suggest that dietary control of nickel intake may help in the ongoing treatment of nickel ACD caused by other sources. Nickel at 1-3 mg by intravenous administration has shown severe ACD in sensitized patients.

A correlation between nickel ACD and asthma due to respiratory exposure to soluble nickel is not found. This is likely the result of different mechanisms: respiratory sensitization is known to be a type 1 mediated immuniological reaction, whereas the skin involves a type 4 reaction.

2.3 WHAT PORTION OF THE POPULATION MAY BE AT RISK?

Studies of the prevalence of nickel sensitivity generally show that 5-15% of women and 0.5-1% of men are nickel sensitive.(3)

Public health advocates are using these figures to project that over 10% of the world's population, that is, hundreds of millions of people, are at risk of being sensitized to nickel. This projection, however, fails to take into account the method of exposure that has likely caused the current prevalence. There is widespread unanimity among dermatologists that "the principal way in which sensitization can be induced in susceptible individuals appears to be by contact with a high concentration of sweat-soluble nickel from a localized area."(4)

Nickel-plated jewellery, nickel-releasing ear-piercing studs and nickel-plated clothing clasps are viewed as the items responsible for the current prevalence of nickel sensitivity. Body-piercing practices are increasing in North America and Europe. The significant differences in prevalence between females and males is correlated with the much higher prevalence of ear-piercing among women, particularly in European cultures, but other factors such as hormone differences may also play a role.(5)

One of the chief questions is: If the use of nickel-releasing materials in jewellery and ear-piercing studs were eliminated, what would be the resulting long-term risk of nickel ACD among the population? As such controls are now being imposed in certain countries, it will be several years before meaningful data can be collected to answer this question. However, dermatologists specializing in nickel ACD have stated that "regulations modelled after the EU [European Union] Nickel Directive will likely be successful and should be closely followed over several years to document the effectiveness of such approaches".(4)

2.4 WHAT REGULATORY CONTROLS ARE CURRENTLY IN PLACE?

In 1991, Denmark forbade the sale of nickel-releasing objects that contact the skin and which release >0.5 micrograms/cm2/ week as measured by a dimethylglyoxime test.(6)

Updated October 2004 [The European Union "Nickel Directive" (94/27/EC) was amended by the European Commission on 27 September 2004 and will take effect on 1 September 2005.  The essential change was to change a prohibition on nickel content in post assemblies to a prohibition based on nickel release.  The amended Nickel Directive prohibits the use of nickel:

  1. in post assemblies used during epithelialization (ear-piercing) if the release of nickel is greater than a limit to be determined by the European Committee for Standardisation in the near future.  It is expected that the release limit for post assemblies will be less than noted in b. and c. below.]
  2. in products intended to come into direct and prolonged contact with the skin (e.g., earrings, necklaces, watch straps, zippers) if the release of nickel is >0.5 µg/cm2/week.
  3. in coated products in (b), unless the coating is sufficient to ensure that nickel release will not exceed 0.5 µg/cm2/week for a period of two years of normal use of the product.

It should be noted that the 0.5 µg Ni/cm2/week release rate likely would not protect 100% of sensitized people from elicitation of ACD. However, clinical data indicates that the vast majority of sensitized individuals would not experience ACD at this level of nickel release and the vast majority of individuals not previously sensitized require substantially higher concentrations than 0.5 µg Ni/cm2/week to be released to the skin for sensitization to occur.(7)

 

2.5 WHAT ARE THE NICKEL INDUSTRY'S BELIEFS CONCERNING NICKEL ACD?

The nickel industry:

  • accepts that nickel ACD can be a significant health and social problem for individuals who have become sensitized.
  • accepts the opinion of experts in dermatology that induction of nickel dermal sensitivity is caused principally by prolonged and intimate contact by the skin with a sweat-soluble form of nickel.
  • accepts the opinion of experts that the use of nickel in ear-piercing studs, jewellery and clothing clasps and zippers is the prevailing method of inducing nickel ACD. We support regulations such as the EU Directive to restrict the contact that nickel-releasing jewellery has with skin.
  • supports the use of protective equipment and training for workers routinely handling nickel substances in industrial environments.
  • concurs with the Consensus Document from the 1997 Nickel Dermatitis Workshop that "transient, short-term contact with nickel-containing articles such as coinage, keys, handles, tools and other equipment does not appear to be a factor in the induction of an allergic contact dermatitis within the general population. If the contact is of short duration and infrequent, the risk of sensitization is negligible, and the risk of the elicitation of dermatitis is limited."(4)
  • concurs with the Workshop Consensus Document, which pointed out that in situations where a nickel product in dermal contact is expected to release in sweat > 0.5 µg Ni/cm2/week, "nickel producers or manufacturers should inform customers of this potential and work with them to manage or remove the risk to nickel-sensitive individuals."(4)
  • believes that adoption of regulations such as the Nickel Directive in the EU will result in a reduction in the prevalence of nickel ACD to an acceptable level.
  • is not aware of large numbers of cases of nickel ACD having been associated with nickel in coinage despite the more than a century of use in billions of coins handled by billions of people. In particular, we find no epidemiological report of adverse effects in the Canadian population from having pure nickel 5, 10 and 25 cent coins in circulation for decades. Nor are we aware of any adverse dermatological effects in the U.S. population from having a 25% Ni-Cu clad 25 cent coin.
  • believes that the provocation studies carried out in Sweden (by C. Lidén), where coins or tools are kept in intensive contact with the skin of sensitized individuals and which elicit an allergic response, are not relevant to coinage or tool use by the general population. In such cases where sensitized individuals are required, because of employment, to handle coinage virtually continuously throughout a working day, we believe that protective equipment (gloves) would be as much a benefit for hygienic purposes as for preventing nickel ACD elicitation. For the great majority of the general population, transient skin contact with nickel- containing coins or tools is unlikely to result in a dose sufficient to cause ACD.

2.6 WHAT SCIENTIFIC INFORMATION IS NEEDED?

 

2.6.1 PRESENT STATE OF KNOWLEDGE

  • It is difficult to use animals to study nickel ACD because animals display different immune responses than do humans. For ethical reasons, it is difficult to expose human subjects to a substance that may compromise their health. Scientists therefore have a dilemma. They would like to understand the mechanisms involved in human nickel ACD, but they are not confident that the animals available for experimentation are good surrogates.
  • The current thinking is that Ni by itself is not antigenic, but rather that nickel complexes involving histidines or proteins are bound to Langerhans' cells. These cells, located in the basal layer of the epidermis, actively participate in cutaneous immune regulation and surveillance and are responsible for antigen processing and presenting the antigen to T-lymphocyte cells. The bound Langerhans' cells migrate to regional lymph nodes where further processing of the antigen occurs and ultimately a population of altered nickel-specific T-lymphocytes are created and recirculated where they may enter peripheral tissue (including the skin). At this point the individual is "sensitized".
  • In the sensitized individual, when antigen-specific T-lymphocytes encounter the antigen, they release lymphokines, which are proteins that cause a wide variety of actions on other cells including stimulation of macrophages and natural killer cells and other responses. This results in tissue inflammation and other allergic responses in an attempt to rid the body of the foreign entity. This integrated response is what causes the allergic dermatitis.
  • The condition of the skin is very important in nickel ACD response. Intact skin with normal barriers is less susceptible (i.e., less permeable to nickel ions) to developing an ACD than skin that is broken or otherwise abnormal. Heat, humidity and increased sweat promote the likelihood and speed with which nickel ions are presented to the skin.(8)
  • There is no known means of reversing immuno-activation (the sensitized condition). However, because the precise mechanism by which nickel ions and Langerhans' cells and T-lymphocytes interact is not understood, dermatologists are reluctant to conclude that such a reversal is biologically impossible. The feeling is that knowledge about the mechanism will result in awareness of how to "turn off" the immune system to nickel.
  • There is evidence that immunotolerance is possible. First, it is noteworthy that the nickel-producing and nickel-using industries very rarely have workers presenting symptoms of nickel ACD. It would be expected that a group of workers routinely coming into direct skin contact with various forms of nickel metal and salts would display ACD. The fact that it is not seen may be due to a tolerance that the workers acquire over time via an alternate route of exposure (inhalation or ingestion) that causes no allergic reaction by the immune system, even when higher nickel exposures are received later. Second, literature(9) indicates that dental braces made from a high-nickel alloys (e.g. Ni-Cr with 60-80% Ni) resulted in Ni-tolerance in girls subsequently having their ears pierced compared to a high nickel sensitivity in girls who had their ears pierced, but did not wear such dental braces prior to ear-piercing. This tolerance may be caused by a mechanism involving low nickel exposure orally over time. Third, immunotolerance in animals (mice) has been shown by nickel exposure either intravenously or orally, with T-lymphocytes in Ni-tolerant mice being transferable to other mice to make them Ni-tolerant.
  • Diagnosis of nickel-sensitivity is done via the patch test, which establishes contact of soluble nickel against a small portion of occluded skin. This is done under a specified procedure(10) to limit misinterpretation due to irritation rather than allergic response. An appropriate concentration of a solution of nickel sulphate is placed on a metallic or filter paper disc backed by aluminum foil (impermeable to water) and attached to the subject's upper back or upper arms by adhesive tape so that the skin area under test is completely covered. The patch is left in place for two days and then removed; the skin is graded for the severity of inflammation. There is some concern that unsensitized people can become sensitized by using this test. It is also capable of giving both false negative and false positive results. Nevertheless, it is by far the most routine diagnostic test for determining whether a person is nickel-sensitive.
  • In the 1960s another test, called the lymphocyte proliferation test (LPT), or the lymphocyte transformation test (LTT), was developed. Its advantage is that it uses a blood sample from a suspected nickel-sensitized individual and is performed in-vitro, thus avoiding the risk of having nickel in contact with the skin. The LPT (or LTT) is based on the fact that nickel-sensitized individuals have T-lymphocytes primed and ready for the nickel antigen being presented. The test pretreats the blood sample so as to concentrate the T-lymphocytes and then incubates them with a concentration of Ni . In the nickel-sensitive person, nickel's presence will cause the primed T-lymphocytes to "turn-on" and elicit an immune response. They "turn-on" by doing several things, one of which is to divide rapidly (proliferate). If a radioactively labelled DNA precursor iododeoxyuridine is also present in the culture, the new T-lymphocytes will use this to synthesize new DNA for their daughter cells. Following separation of the T-lymphocytes, an increase in radioactivity above a measured control (to account for normal cell division) is indicative of high cell proliferation, which means the original T-lymphocytes reacted to the nickel present. This test is only now becoming a clinical tool and more work is required to correlate it with patch test results and to make it reliable.

2.6.2 RESEARCH NEEDED

  2. A critical review of nickel ACD is needed. Such a review would focus on what populations are at risk by what means of exposure.
  3. Epidemiological studies are required on those European populations that have had controls on nickel release in jewellery. These surveys would be done as a function of time and age to determine the regulatory effectiveness in reducing nickel ACD incidence. Such studies can be done now in Denmark because of the regulations that were promulgated in 1991 and should follow Europe-wide in a number of years for a follow-up of the Nickel Directive.
  4. Work on immunotolerance should focus on determining which nickel alloys were used in the dental braces known to result in Ni-tolerance and studying the rate of nickel ion release under conditions present in the mouth. New work should also be started on populations using dental braces containing nickel to follow the status of the immune system as a function of time. By such studies it may be possible to determine how immunotolerance occurs.
  5. A better definition of "prolonged contact" is needed. It is believed that nickel sensitization occurs when a soluble form of nickel contacts the skin in a prolonged and intimate manner and nickel ions penetrate the skin. Quantitative measures of this are needed by measuring the nickel transported through the skin and by correlating such nickel concentrations and time with the onset of nickel sensitivity. Either patch tests or LTT tests can be used to determine when sensitization occurs.
  6. Methods for measuring the amount of nickel residing on the skin needs to be improved. Present methods using cellophane tape to strip the nickel off the skin are crude. Improvements will help in the assessment of nickel exposures required to induce or elicit ACD response.
  7. Immunotolerance to nickel should be researched. This is probably best done using a population of workers at a new industrial operation where species of nickel are present. By using air monitoring, urine monitoring and skin measurements, together with LTT blood (and cytokine analysis), it may be possible to determine what species of nickel and what route of exposure may be operating to make nickel workers tolerant.
  8. Fundamental work on the ability of different Ni-containing substances to provide soluble nickel in conditions present on the skin is required to rank the risk of ACD occurring for the substances. Of particular importance is determining how various stainless steels behave.
  9. Improved knowledge about the mechanism of nickel ACD is needed. With such knowledge it may be possible to clearly understand immunosuppression and immunotolerance to nickel and to create treatments so that nickel sensitization never occurs or is reversible in people already sensitized.

3. References

  1. Occupational Medicine, 3rd Edition, ed. by C. Zenz, Mosky: Toronto, p.99 (1994)
  2. Menne, T., Veien, N., Sjolin, K-E and Maibach, H.I., Amer. J. of Contact Dermatitis, 5 (1), pp. 1-12 (1994)
  3. Nickel and the Skin: Immunology and Toxicology, ed. by T. Menne and H.I. Maibach, CRC Press: Boca Raton, p. 118 (1989)
  4. Consensus Document from the NiPERA-sponsored Nickel Dermatitis Workshop, March 17-18, 1997, Brussels
  5. Kwangsukstith, C. and Maibach, H.I., "Effect of age and sex on the induction and elicitation of allergic contact dermatitis", Contact Dermatitis, 33, pp. 289-298 (1995)
  6. Kanerva, L. et al., Contact Dermatitis, 31, pp. 299-303 (1994)
  7. Gawkrodger, D.J., "Nickel dermatitis: how much nickel is safe?", Contact Dermatitis, 35, pp. 267-271 (1996)
  8. Hemingway, J.D. and Molokhia, M.M., "The dissolution of metallic nickel in artificial sweat", Contact Dermatitis, 16, pp. 99-105 (1987)
  9. von Hoojstraten, I.M.W. et al., "Reduced frequency of nickel allergy upon oral nickel contact at an early age", Clin. Exp. Immunol., 85, pp. 441-45 (1991)
  10. Cronin, E., Contact Dermatitis, Churchill-Livingstone: London, 12 (1980)

 

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