Introduction
Dr. Lawrence N. Curcio, President of NiPERA, introduced the Workshop.
Session I
Mechanism of Dermal Sensitization
Moderator: Dr. Ernst Gleichman
Medizinesches Institut für Umwelthygiene, Germany
This session served as a basis for understanding some of the mechanisms involved in the induction and the elicitation of nickel (Ni)-related contact dermatitis in both animals and humans. Although nickel is a common allergen in humans, it is surprisingly difficult to use Ni to elicit contact dermatitis (CD) in animals. Therefore, the understanding of Ni-related sensitization mechanisms needs to incorporate both what is known about dermal reactions in humans and subsequently link it to experimental models in animals.
One of the most important research areas currently under active study is the role nickel plays in Ni-specific T-cell reactions. Nickel ion by itself is not antigenic. Antigen formation may occur through the formation of a Ni-histidine or Ni-complexed protein, or by uncovering of a cryptic peptide. Normally, only certain peptides (dominant peptides) of a protein are exposed; therefore, the immune system develops tolerance only to these peptides. If a protein is denatured by a metal ion such as nickel, other peptides (cryptic peptides) can suddenly be presented to T cells. The immune system does not recognize these cryptic peptides as "self," resulting in an immune response. It is theoretically possible to create an autoimmune response, which has been demonstrated for gold and mercury, but has yet to be proven for nickel.
CD4+ T-cell hybridomas can be generated that are specific to one of the epitopes, i.e., peptides of the protein antigen presented by MHC molecules, that are present in an antigen. Only one hybridoma specific for Ni was obtained when immunizing with Ni(II). By contrast, many hybridomas occur when using Ni IV-0(OH)2 (generated with hypochloric acid). This may signify the more reactive capacity of Ni (IV) in interacting with proteins.
Within mammalian systems, T-lymphocytes (T-cells) play a central role in immunoregulation as well as in identifying exogenous antigens in the skin. Certain T-cells, CD4+ T-cells, have receptors that can identify an antigen if this antigen is presented together with molecules from the major histocompatibility complex (MHC II). The response can trigger signal 1 alone (immunotolerance) or both signal 1 and signal 2 (allergic reaction).
In one study T-cells specific to Ni in mice (Ni bound to albumin in vivo) were created and then challenged T-cells in vitro with Ni in antigen-presenting cells, without albumin. Albumin was used as a vehicle to get Ni to the immune system. More experiments need to be done. Ni-specific clones from patients (human and animal) may be used as detection probes.
As mentioned above, the immune response can be modulated by signals 1 and 2. Normally in the skin there are resting Langerhans cells, which are activated by contact with the antigen to migrate to the lymph nodes where they meet T-cells. It is possible that if signal 2 does not occur, the Langerhans cells would remain in the skin and not migrate to the lymph nodes, thereby avoiding an allergic response.
The oxidation state of heavy metals is also important in eliciting a response. In the case of gold, Au(I) is oxidized to Au(III), which is more reactive. An analogous reaction could occur with nickel, which may result in the generation of NI(III) and hydroxyl radicals. NI(III) can react with proteins and, in addition, together with the OH radical may provide the signal (signal 2) needed to cause the migration of the Langerhan cells.
Discussion, Questions, Responses Possible areas of research were discussed, including:
Signal 1 Related Topics:
- Antigen presentation and processing
- Identification of Ni-binding proteins
- Metabolism of Ni in skin
Signal 2 Related Topics:
- Conditions favoring signal 2 responses - Role of oral intake of nickel in preventing signal 2
Other Areas:
- Possible animal models for sensitization and desensitization
- Identification of genetic predisposition (biomarkers of sensitivity)
- Tests designed to evaluate the sensitizing ability of alloys
Other concerns and questions focused on several broad issues, including:
Cross reactivity to nickel
Q How do you explain cross reactivity of T-cells to metals?
A It could be explained because both gold(Au) and Ni show the same cryptic peptide and the allergic response is, therefore, to the peptide rather than to the metal.
Q Do Au and Ni affect proteins in the same way?
A Clinical Au allergy is extremely rare even though patch tests are positive. If ear-piercing takes place with both metals at the same time, that could also explain cross reactivity. Au is not a problem for the general public due to lack of exposure to Au salts.
Q Is there any data on whether Ni sulfide or oxide could cause skin sensitization?
A None is known.
Variations in allergic reactions to different nickel compound
- Most patients react to NiCl2 and NiSO4; some people react to only one. NiCl2 may penetrate better. Dermatologists use a 5% solution of either NiCl2 or NiSO4, of which there are more molecules in NiCl2 than NiSO4.
- Can there be an explanation for the different reactions to NiCl2 and NiSO4?
- Is the difference a simple reflection of Ni2+ absorption through the skin? One would expect that nickel ions dissociate from NiCl2 or NiSO4 they are Ni ions, and should all be the same and react the same.
- This may be due to the different oxidative stages of Ni, which will change as it goes through the skin. Each compartment changes the oxidation state. The anion may affect the type of complex that is formed and, therefore, the type of antigen that is presented. It must be considered that the allergic reaction to Ni2+ can be dependent on the number, type, and accessibility of ligands. Ni may change ligands as it moves through the different layers of the skin. This may exert changes on the oxidation state and the geometry of the Ni complexes. All this can affect the immunogenicity of Ni.
Fenton-type reaction
- A presentation of Dr. Gleichman's results in using the PLN (Popliteal Lymph Node) Assay to explore the role of Fenton-type reactions follows. The PLN Assay involves a subcutaneous injection of Ni(II) plus or minus H2O2 (allowing for a Fenton-type reaction) into right foot pad of mice on day 0 and measurement of right and left rear lymph nodes (PLN) by counting cells on day 6. Results were compared using index of size: treated side PLN/untreated side PLN. The results demonstrated that 10 mM Ni(II)Cl2 alone was not significantly different and Ni with 80 mM H2O2 was significantly different than the untreated side.
Q H2O2 is a vasoconstrictor and potent irritant that interferes with wound healing. Controls are needed since H2O2 may act as a contact irritant. What was the response to H2O2 alone?
A H2O2 alone gave a reduced response when compared to H2O2 plus nickel. A control with Ni(II) and a different irritant could be used to better understand the effect of H2O2.
Q What is relevance of Fenton-type reactions in vivo when H2O2 inside cells are 10-8M?
A It is not the average cytoplasmic H2O2 concentration that is relevant here, but that in phagolysosomes of phagocytic cells and that occurring extra cellularly in inflamed tissue where phagocytes undergo an oxidative burst and release huge amounts of H2O2.
Research Goals
Method to test sensitizing potential of alloys by incubating them with macrophages (to process antigen) and then use the PLN Assay.
- The test should be clinically relevant; for example, the sweat test has been shown to be clinically relevant. Keep in mind the exposure source to Ni, and in what form Ni is presented.
- The focus should not be only on piercing since sensitization existed prior to that (suspenders, watchbands, etc.). Other sources of exposure should also be investigated.
There followed further discussion of the role of ear-piercing on sensitization to nickel.
Q Are there differences in sensitization for men compared to women or do prevalence rates reflect the degree of piercing?
A There is no differences between sexes, the difference is related to the degree of piercing.
Q What is the importance of the lesion when ear-piercing on causing sensitization? Is that why you don't see it in occupational settings?
A Data on irritated skin is inconsistent and inconclusive - could use reexamination of this area. However, ear-piercing is not necessary to induce sensitization. Buttons can sensitize too.
Q Why does eczema show up on hands vs. other parts of the body?
A It is not known, but is being looked at.
A It is important to study the experimental conditions for costimulation.
Session II
Immunotolerance to Nickel
Moderator: Dr. Desmond Burrows
The Royal Hospitals, Ireland
This session provided a background of immunosuppression and immunotolerance and their relevance to dermal sensitization. Immunosuppression involves getting rid of an existing allergy permanently. This has been shown by giving a large endovenous dose (LD50) of a chemical to a sensitized guinea pig, followed by patch testing 24-hours later with the same chemical. Using this method, no response is observed, but half of the test animals do not survive the experiment. Examples of chemicals that have demonstrated human immunosuppression include: cyclosporin, azathioprine, methotrexate, corticoid, and anti-cytokine antibody.
Immunotolerance in animals can be achieved by intravenous or oral pretreatment. Within 24-hours of a sensitizing treatment, it is possible to treat an animal with an intravenous dose of the same chemical and prevent sensitization. In this manner, tolerance to sensitization is developed. It is not known how long this effect lasts. An experiment was conducted with mice in glass vs. metal cages to test the ability to sensitize animals from each group to nickel. The results demonstrated that it was more difficult to sensitize animals from metal cages due to tolerance developed by the animals from licking the metal cages containing Ni. An experiment in which suppressor CD8+ T-cells were transferred from Ni-tolerant mice (who ate nickel) to other mice demonstrated that tolerance could be carried by CD8+ T-cells.
Human immunotolerance was demonstrated in a study of girls in Finland who wore dental braces prior to ear-piercing. Dental braces are made of alloys with higher Ni content than stainless steel, and appear to have caused immunotolerance to nickel by oral ingestion of nickel from the braces. The results showed 0% and 35% dermal nickel sensitization in girls who had braces before ear-piercing and those that did not, respectively. A similar study showed comparable results in Czechoslovakia. A study investigating nickel content and release levels in dental braces may explain the development of immunotolerance to nickel in Finland vs. other countries. As evident from both the animal and human studies, immunotolerance is most efficient through the mouth, possibly as a result of suppressor T-cells being generated in lymph nodes in the neck.
Proposed Experiment: Take people before ear-piercing and expose them to Ni sulfate orally or by inhalation to see if it prevents sensitization. This could not be done in humans due to ethical problems, but may be conducted in animals.
Proposed Industry Study: Hand eczema in the nickel refining industry does not seem to be a problem and it is unknown why workers do not have a high level of dermal nickel sensitization. It could be due to selection bias of workers. Therefore, a study was suggested to follow an individual worker using the lymphocyte transformation test (LTT) to see if stimulation of suppressor T-cells are seen as weeks go by at work. Additionally, cytokines could also be looked at to determine any changes. This may help in understanding if different tolerance is developed with exposure to different compounds, taking into account the combination with other metals that could cause synergy or antagonism, i.e., CD. This experiment would involve quantitating nickel in the skin and air, followed by an oral dose to workers and controls in order to see what kind of cytokine response they have. Controls in this study would be nickel-sensitized patients. Although food is a source of everyday exposure to nickel, this effect can be minimized by giving the study subjects general guidelines as to what to eat and measuring nickel in urine to see if there are similar levels before and after diet restrictions.
Discussion, Questions, Responses
Discussion focused on the following broad issues:
Potential Immunotolerance to Nickel in the Workplace
- Allergy is quite rare in the workplace. Any allergy should be investigated as to how many contacted nickel through jewelry vs. work.
- There is much less handling of nickel in industry these days.
- Few nickel allergies are seen at Kristiansand. Rashes were found early in employment, but not dermal sensitization occurred at later times. This could be due to tolerance by inhalation exposure within the working environment or selection bias. An example of worker selection bias may be that summer employees may not come back if they experienced work-related health problems.
- It is also important to look at coexposures to determine the source of any health problems that may exist.
Replacement of High-Nickel Alloys
Q Do we need to keep high nickel-releasing stainless steels in the market or can they be replaced?
A The high sulfur-containing nickel stainless steels (which release more nickel) used for machinery cannot be replaced with other stainless steels due to their unique properties. There are non-nickel-releasing stainless steels that could be used for cooking pots, but do not need to be used for appliances since this exposure is not a risk for dermatitis.
A Industry could do much to decrease nickel exposure from materials that can lead to prolonged exposure. Producers should recommend customers to abstain from using high nickel-releasing materials in making products that will be in prolonged contact with skin.
A Much of the nickel-plated material is imported from countries where nickel in jewelry is not going to be regulated.
Q Is it possible for industry to restrict use of its products by internal regulatory action? Maybe there should be a data sheet to inform users (manufacturers) of what the product (alloy) should and should not be used for.
A Producers have a Status Report(from NiDI) that warns consumers of products that releases too much Ni. It is more important to look at nickel release rather than just nickel content.
Research Goals
Acquiring Immunotolerance - The studies conducted in Finland and Czechoslovakia on dental braces inducing immunotolerance to nickel need to be compared. - It may be that dental braces are made of different material in Finland. - Nickel exposure from dental braces needs to be quantified by repeating the previous study. The study should look at different kinds of dental braces and conduct salivary enzyme tests on those braces.
Q Are there clinical steps to desensitize already sensitized people using high does of nickel?
A This would be a good area for further research.
Q Can a vaccine be produced against allergic reactions in people sensitized? It would have to be administered by oral route.
A This would be a very laborious process since the precise antigen is not known. If one clone is responsible, then it may be able to be done. If numerous clones were involved, as is currently suspected, vaccine development would be very difficult. It has been tried for autoimmune disease, but the antigens are partially known for these; the results have shown no deterioration and slight success.
A Allergy prophylaxis is not of interest like bacterial prevention is. Allergy to poison ivy is more prevalent than nickel allergy, and there is little interest in preventing that. For example, one study gave poison ivy antigen to newborns and it was relatively effective in preventing allergy. However, the study results did not develop into a vaccine due to lack of interest.
The following open discussion pursued on what kind of testing should be done.
Q Workers are seen prior to employment and annually after start of employment. We assume workers lack nickel sensitivity because of the lack of clinical symptoms, but how do we test for worker sensitivity?
A An in vitro test can be used, but not patch testing since it may increase the risk of sensitization.
A In vitro testing is not as reliable as patch testing, but for workers you can not risk sensitization when there will be future exposure.
Q Is the specificity of the patch test known? The platinum skin prick test is very accurate; in that, if you have never been exposed to platinum, you will not have a positive reaction.
A In vitro studies of nickel allergy with comparison to patch test results could be done. Patch testing may not always be accurate. Currently, positive patch test responses are observed in people that have never had symptoms and negative patch test results are seen when classic nickel-sensitization symptoms are present.
A You can have a positive patch test without a positive lymphocyte reaction. In vitro quantitation of T-cells and antigens is necessary to determine sensitization.
Q Would a questionnaire be helpful in monitoring workers?
A No, they need to be seen.
A The questionnaire would not work since the responses obtained from workers may differ from that of occupational physicians or other doctors.
A The effects of systemic exposure of nickel on sensitization also need to be studied. It is not known whether sensitized people are more sensitive to nickel exposure or if the prognosis is worse for sensitized people. As mentioned earlier, this can be done by looking at industry workers and sensitized individuals and measuring samples for differences in cytokines, lymphocytes, etc.
A The method of T-cell activation is preferable for this type of study since there are some suppressors of T-cell activation.
Further discussion ensued to consider what factors need to be taken into account for these studies.
Studies should look at workers under different exposure conditions.
Studies should have good exposure and urine data for workers.
Keep in mind, however, that not all industry is as carefully monitored as Williams' refinery. Smaller shops are less careful in monitoring workers.
In designing these kinds of studies, it must be kept in mind that currently there are diet restrictions for humans participating in experiments to limit unanticipated sources of nickel intake. Increasing nickel-testing concentrations to minimize the effect of other sources of nickel could solve this problem.
The determination if nickel is an essential element needs to be made. If nickel is essential, then investigation into whether the cutaneous route of exposure is able to fulfill the biological requirement necessary. It may be that nickel is only toxic via the skin, leading to looking at the importance of persistence of nickel in the skin.
Session III
Elicitation of Nickel-Related Dermal Reaction
Moderator: Dr. Howard Maibach
University of California, USA
This session summarizes the factors that affect nickel contact dermatitis reactions and how to test for them. In 1925 the first diagnostic patch test for nickel was performed. Years later, in 1960, the lymphocyte transformation test (LTT) was developed as another tool to test for nickel sensitization. Remarkable differences exist between sensitization induced experimentally in man vs. natural sensitization.
Numerous factors may affect experimental or clinical contact dermatitis:
Concentration: It is the concentration of the material that is crucial, measured as mass/unit area. Poison ivy is a common sensitizing agent (50% of Americans are sensitized) but there is no effect below the threshold mass/unit dose.
Age: The data are incomplete.
Gender: There is evidence of a gender effect in guinea pigs, but not in humans; in humans it appears to be exposure-dependent; marked differences are seen with clonidine, but probably not with nickel.
Anatomic Site: The upper back on humans is twice as reactive as the lower back; the palms of the hand and forearm are the least reactive areas.
Salt: The results are confounded since molarity should be used instead of percent to express concentration; therefore, the data are inconclusive.
Vehicle: Petrolatum.
Occlusion: Sensitization to watchbands and jewelry is dependent on the amount of nickel released and the degree of occlusion; occlusion changes the number and function of antigen-presenting cells.
Irritation: Exposures in amounts approximating the irritating dose are used with patch testing. With a more moderate dose a minimal allergic response could be generated without causing irritant dermatitis. With current patch testing we do not have tools to distinguish between moderate irritation and allergic reaction, resulting in a lot of false positive responses.
Multiple Dosing: A person on the street has a single dose during ear-piercing compared to repeated dosing of workers.
Race: The data is incomplete and irrelevant to nickel; this requires human experiments.
General Health: There is no information for nickel.
Skin Health: There is no information for nickel.
Using sensitizing experiments, it is possible to rank the sensitizing potential of different materials. In animal experiments, local lymph nodes of guinea pigs or mice can be sensitized by altering their biochemistry with vitamin A.
Some examples of diagnostic patch testing studies include the following:
Occlusion patch testing (TRUE TEST) was conducted on the back of test subjects and left for 48-hours; the reaction was evaluated after 96-hours. Results showed that 38 of the 72 subjects responded to 3-0.3 µg Ni/cm2 (threshold). This is a 300-fold range in response; even though it was a homogenous group of people (Andersen, K. E.; Lidén, C.; Hansen, J.; Volund, A. (1993): Dose-response testing with nickel sulfate using the TRUE test in nickel-sensitive individuals). Multiple nickel sulphate patch-test reactions do not cause an "angry back." (Br. J. Dermatol. 129:50-56).
A single open (no occlusion) application was conducted on the forearm. 0 of 51 subjects reacted to 100 ppm; therefore, the threshold for the reaction is >100ppm. (Menné and Calvin (1993): Concentration threshold of non-occluded nickel exposure in nickel sensitive…(Contact Dermatitis 29:180)).
Nickel disks were applied in a patch test manner. The release of Ni2+ from the disks was measured. Release at a rate of 0.5 µg Ni/cm2 per week per disk was found to be the threshold (weak reactions) (Menné et al., (1987): Patch test reactivity to nickel alloys (Contact Dermatitis 16:255)).
The provocative use test (PUT) involves application of SDS and nickel to hands; 1ppm for 23-days gave no reaction (Allenby, C. F. and Basketter, D. A. (1994): The effect of repeated open exposure to low levels of nickel on compromised hand skin of nickel-allergic subjects (Contact Dermatitis 30(3): 135-138)).
Experiment conducted by Dr. Howard Maibach:
A solution of Ni (35.3 mg Ni/cm2) was applied to the skin. The actual concentration of Ni on the skin was analyzed by ICP-AES (Inductively Coupled Plasma Atomic Emission Spectrometry). The dimethylglioxime method and AAS (Atomic Absorption Spectrometry) did not have enough sensitivity to quantify Ni on the skin. The ICP-AES detection limit is 7 ppb (µg/L) with analytical precision at 1 ppm of 0.6% and at 20 ppm of 2%. After 30 minutes only 68.1% of the 35.3 mg Ni/cm2 applied to the forearm as 0.1% NiCl2 (1000 ppm) was recovered. Recovery of nickel was conducted by scotch tape stripping of the area where NiCl2 was applied. The experiment was repeated at 3 dose levels: 353 (1%), 35.3 (0.1%), and 3.5 mg Ni/cm2 (0.01%). For the lower dose, 83% of the nickel was recovered. With increased time there is less nickel on the tape stripped from the skin. The remaining undetected dose of nickel could have penetrated through skin or exfoliated. This experiment needs to be repeated with less time between application and measurement. It may be possible to use this technique to measure exposure in workers. A certain density of MHC-embedded epitopes per antigen-presenting cell is needed to get a response. It is not known how many epitopes generated by nickel are needed.
Past estimates of percutaneous penetration may have overestimated what goes through the skin. It is important to consider how to decontaminate skin and how do we measure what is left on the skin. With increased dose there is a greater difference between Ni levels in the upper and lower layers of stratum corneum. Not until 20, 30 or 40 hours after administration can the concentrations of nickel be measured internally, as a result of penetration. To study skin penetration the skin nickel levels can be measured by using tape, etc. With our current knowledge, many of the past experiments should be repeated since there are now fewer confounders.
Discussion, Questions, Responses
Discussion focused on the following major topics.
Potential Sources of Nickel Exposure other than Jewelry
QIf nickel is removed from jewelry, would you solve the nickel dermatitis problems?
A You would solve the induction of sensitization problem (as we understand it now), but not the reactions of already sensitized people.
Q Can handling coins induce sensitization?
A Sensitization does not appear to occur as a result of casual coin handling or ingestion of nickel. Coins are not a problem for the general public or are considered to be close and prolonged contact.
Q Can you quantitate the amount of Ni people are exposed to by handling coinage and quantitate how much they absorbed? If so, then you can test that amount to see if they elicit a response with patch testing.
A Tools that are handled regularly release a lot of metal. 27% of the tools in the Swedish market release nickel that can be detected with the DMG test. The composition of these tools is not known. The nickel release corresponds to the eczema seen in males. Locksmiths and car mechanics are exposed to nickel in using these tools. Could these be inducing sensitization, or are these elicitation reactions? Men also need to be looked at, not just women, and also elsewhere besides the traditionally investigated work areas. Irritation and primary sensitization as well as elicitation reactions need to be looked at.
Eczema vs. Nickel Dermatitis
- "The Hand Eczema Syndrome," a book by Menné and Maibach, explains that hand eczema is not one entity. There are many causes, exogenous and endogenous. It is not known how much nickel is required to induce hand eczema. Tools are not available to determine if nickel played a role in past cases of eczema seen in the clinic. These cases may be exposures that have not been traced carefully to the correct source, such as a reaction to knitting needles that may release nickel.
Q How much of general public's eczema is due to nickel and what are other consumer products that are putting the public at risk? How much risk are we willing to accept?
A Among those with nickel allergy, there is twice as much risk for hand eczema. The question becomes how can you relate the incidence of hand eczema to skin disease? A study in 1990-93 showed hand eczema in 20,000 people in the general public, with 10% of the population showing a reaction (including weak reactions):
| TYPE OF DERMATITIS |
MEN |
WOMEN |
| Allergic |
1% |
2% |
| Irritant |
1-2% |
3-4% |
Another study did random sampling of a population using patch tests. This study showed 20% of young females and 2-4% males have positive patch tests for nickel sensitization. However, as a result of the poor exposure assessments in the past, many of these areas require further research.
Research Goals
Investigating Quantitative Structure Activity Relationship (QSAR)
Q With divalent elements, why don't we see contact dermatitis with magnesium?
A Because we don't understand the interactions, we need to study QSAR.
Measurement of Nickel Concentration in the Skin
Q Could you place the exposure area in a chamber to determine loss of chemical to the air vs. absorption into the skin?
A Yes, that is possible.
Q Can nickel laterally diffuse through the dermis?
A Yes, that is why we use a piece of tape larger than the exposure area. Non-destructive sampling in industrial settings can be done as well. Workplace sampling is widely done, but on skin it is very inaccurate. The number of hours between workers spraying and their next entrance into the field is done by measuring the concentrations of chemicals on a piece of cotton worn by the workers in the field. This is more accurate than skin measurements. Another test that may eventually be used for worker evaluation is the lymphocyte transformation test (LTT), which is only now entering the clinical area.
A Risk can be reduced by using gloves or protective creams. Then the concentrations in the epidermis can be measured, as Dr. Maibach suggested (where antigen presentation takes place).
Q Is it possible to measure nickel in intracellular fluid?
A Using microdialysis, it may be possible to measure the concentration of nickel in the dermis. However, the concentration in the epidermis is more interesting since that is where the Langerhans cells are located. Fingernails may be used as a biomarker of nickel exposure. Urinary nickel as a biomarker is currently in experimental stages.
A It may not require long exposures to estimate the dose that is received by the body since within 30 minutes of contact, the stratum cornea is saturated with material, reflecting what may potentially enter the body.
Session IV - Part I
Implications of Regulations on Nickel:
Moderator: Dr. Torkil Menné
Gentofte Hospital, Denmark
This session describes the history of nickel dermatitis leading to nickel regulation and some studies that may be helpful in influencing nickel regulation. Allergic contact dermatitis was recognized as early as 1881 when the first case was described in the plating industry. From 1880-1935, most dermatitis was from plating. In 1924, nickel contact dermatitis was first described. Nickel dermatitis was recognized as a consumer problem primarily from jewelry and clasps with secondary spread to hands in 1935. The link of hand eczema to people with contact dermatitis was subsequently made. One major difference between occupational and consumer dermatitis is that secondary occupational dermatitis is rare. We have moved from a situation where, in the past, nickel contact dermatitis was most common in the occupational environment, to now where occupational dermatitis is secondary to consumer/user dermatitis. In light of the allergic capacity of nickel in consumers and occupational settings, it is important to note that nickel in nature is not an allergen. This may be due to the low sensitizing potentials of oxides or sulfides, although these are not yet known.
Three factors play a role in primary sensitization: genetic predisposition, potency and exposure. There is evidence of genetic predisposition, but that this is not the most important determinant for sensitization. With regards to potency, nickel is characterized as a moderate sensitizer. The most important element in sensitization is exposure (amount/cm2). As a result of varying exposures, some people are at increased risk for contact dermatitis.
Contact dermatitis is a "delayed" type of dermatitis; in that, first contact does not produce the allergic reaction. First there is induction where a high level of exposure (related to dose/area) with close and prolonged contact is required. This is referred to as the 'concentration of induction.' The second phase is elicitation, where the level of exposure can be much lower than what was needed to cause induction, referred to as the 'concentration of elicitation.'
It is important to determine the prevalence of nickel sensitivity to understand the extent of the problem. In a study (Nielson and Menné (1992)) of an unselected (random) Danish population, the following figures were obtained for nickel sensitivity:
| AGE |
MALE |
FEMALE |
| 15-24 |
2-4% |
19.6% |
| 35-49 |
1.1% |
7.9% |
| 50-69 |
3.0% |
11.1% |
Compared to older studies, this would seem that the figures are not trending upward. They are steady, albeit high.
It is important to note that not all nickel-containing compounds are equally reactive (likely to cause sensitization). There are "safe" alloys (stainless steel, white gold, nickel-tin) and 'sensitizing' alloys (nickel-silver, plated nickel, nickel-iron). Bioavailability of Ni2+ is the most important characteristic of the metal, not the actual amount of Ni present in the metal. This was demonstrated by a study in which 1 cm2 disks of different alloys were made. These disks were used for sweat tests and patch testing, with measurement of nickel release by AA (atomic absorption). These assays were able to differentiate between high and low nickel-releasing alloys. The results of such studies could be used to determine safe uses of different alloys.
Although the technical and aesthetic merits of nickel used as an interliner for gold finishes is appreciated, the ability of the gold overlay to protect against nickel release varies enormously and unreliably. In tests, a thin gold overlay of 0.5 mm/cm2 allowed release of nickel ions in human sweat in only 2-days. Experiments revealed that thin layers of gold are broken down within 2-days of manufacture, as evidenced by a negative DMG test immediately after manufacturing and a positive DMG test 2-days later.
The results of the reactivity to nickel alloys and coatings in Ni-sensitized individuals and the release of Ni2+ from the alloy is shown below. The percent of the population that reacts to nickel alloys and coatings in individuals sensitive to nickel varies with the rate of Ni released.
[z-axis: Ni release in µg/cm2/week;y-axis: % reactive. Straight line relationship]
Ni RELEASE (µg/cm
2/week)
Reactivity to nickel alloys and nickel coatings in nickel sensitive individuals is less than 10% when the release rate is 0.5 µg/cm2/week (Lidén, C.; Menné, T.; Burrows, D. (1996) Nickel-containing alloys and plating and their ability to cause dermatitis (Br. J. Dermatol. 134:193-198)).
The following information is relevant in preventing nickel dermatitis:
An allergy is a specific immunological event.
The primary causes of sensitization to nickel are known.
Nickel contact dermatitis/eczema is judged to be a significant health issue.
Quantitative methods for sensitization and elicitation are known, and control methods are available.
The EU Nickel Directive makes the following restrictions:
Ear-piercing devices should contain less than 0.05% nickel as total weight ("nickel free").
Items that are in direct and prolonged contact with the skin may release no more than 0.5 mg Ni/cm2/week.
Coatings on nickel should have a maximal release rate of 0.5 µg Ni/cm2/week for 2 years of normal use.
Government control of other substances has proven to be beneficial for decreasing the prevalence of sensitization. An example of successful control/prevention of sensitization can be found in the building of the English/France tunnel compared to the Danish tunnel connecting Sealand and Funen. The building of the England/France tunnel used European cement containing Cr(VI), resulting in hundreds of concrete workers developing chromate dermatitis. By contrast, the Danish tunnel used Scandinavian cement containing Cr(III), with none of the concrete workers developing dermatitis. This is due to the addition of iron sulphate to the cement to transform any Cr(VI) into Cr(III). Hopefully, the nickel directive in the EU will, over time, have a similar effect in reducing the percentage of the population that becomes sensitized to nickel or afflicted with nickel-induced dermatitis.
Generations can pass where a disease and the mechanism of the disease are known but the disease does not become a public issue. Lung cancer became an issue only in recent decades. Recalling the nickel dermatitis suffered by females because of suspenders, the cause was known but accepted for decades. Dermatitis caused by nickel was completely accepted in the 50s and 60s, i.e., women's garters, but only now is something being done about it. It is important to get society to question that acceptance. Once that is accomplished, decreasing the incidence can be much easier.
Listed below are some papers of interest in the context of measurement of exposure.
Allenby and Basketter (1994):
The thumb skin immersion test was conducted in 0.1-1 ppm nickel in detergent. Although there was no reaction in either controls or treated individuals, nickel-exposed people had more nickel in their fingernails, particularly the keratin. How can you control for confounding effects of systemic exposure? [It was suggested to use toenails as controls].
Peters et al. 1991: Nickel Exposure was Evaluated by Measuring the Nickel in Fingernails:
| EXPOSURE |
CONCENTRATION
(µg/g) |
OCCUPATIONAL
GROUP |
| Low |
1.19 - 1.61 |
Hospital
Administration |
Moderate
Heavy |
29.2 - 56.71
23.0 - 289.0 |
Electronics
Plating |
Fullerton et al. (1988): Recovery of nickel was done using skin strips after application of 5% NiCl2.
Clinically relevant experiences with nickel dermatitis:
Past occupational exposures were primarily associated with electroplating. With older plating operations, workers were exposed to nickel through splashing of the plating fluid. DMG tests were conducted in these shops and found to be positive inside as well as outside of the gloves worn to protect the workers from exposure to the liquid. Dermatitis was present over the hands, arms and body of workers. Current plating operations are often much cleaner.
A more current concern is exposure to nickel through handling of nickel-releasing objects in the workplace, which is an underestimated source of exposure. These exposures include: handles (for driving trains), keys (locksmiths, nurses, jailers, etc.), cold-scaled aluminum (building industry, engravers, etc.; reference: Lidén, C. (1994): Cold-Impregnated Aluminum-A New Source of Nickel Exposure. Contact Dermatitis 31:22-24), coin handling (cashiers), and various tools (many occupations). Examination of 565 tools revealed that 27% tested positive with the DMG test; some of them were analyzed for nickel release and composition of coating and base alloy. Manufacturers and retailers did not know or had only vague understandings of what was in the materials they were using. "Vanadium" was stamped on many tools, but no vanadium was detected. One manufacturer stated that this was more of a tradition and a marketing aspect than an indication of the actual presence of vanadium in the tool. In Sweden alone, there are millions of tools capable of nickel release and 500,000 workers occupationally exposed at and 'intense' level (short duration but repeated exposures under conditions of sweat, pressure and friction, by using tools; such as, saws, files, wrenches; keys and the like were used).
Several variables may affect Ni-induced sensitization by tools, including; the sensitivity of the individual, nickel-release characteristics of the tool alloy, repetition of the task and intensity of the task. With the generation of pressure and torque in the use of hand tools, there is generation of sweat, very intimate contact between skin and metal, and repetition during a work period. These could, together, produce a sensitization or elicitation potential similar to the 'direct and prolonged contact with the skin' scenario contained in the European Nickel Directive. A publication on this issue is in preparation. Tools could easily be made of other materials without affecting the nickel-producing industry. But it has not been addressed as a problem. Tools made in many countries; such as, Sweden, Germany and Argentina have been tested; some released a great deal of nickel (from Argentina) and others did not.
Research Goals
Definition of "Direct and Prolonged Contact"
- There is no definition of "prolonged" contact. It is not easy to define.
- This is a key statement, the relationship between time, exposure and reactivity. However, this would not be difficult to measure. The basic study would involve testing alloys used in tools and putting them on the skin for various time periods to help define what is prolonged contact and seeing how much needs to be released to cause a reaction.
Q It is possible to achieve induction of nickel sensitization from transitory use. Could it be possible to become sensitized from keys, for instance?
A It would be rare but may be possible.
Influence of the Danish Regulation on Nickel and the European Nickel Directive
- The Danish regulation on Ni was approved 5-years ago, but there had been a phase-in period to allow industry and the market to prepare. Under Danish regulation, articles may not release nickel when the article is sold. This, however, may not be very effective because, as is known, nickel release can begin within days of an article being worn or used.
- The wear test is being updated and revisions will be completed during the week of 25 March 1997. A few weeks or months later, the draft language will go to CEN members for a formal vote. Other aspects of the testing protocol will also be put to a final vote shortly.
- Enforcement of the Danish regulation began only 2-years ago and focussed only on the few large retailers. This did not take into account of the many small and informal makers and sellers of costume jewelry and such items. Consequently, there is probably still quite a lot of nickel in Denmark. The study conducted in 1990 to determine the prevalence of nickel sensitization in the Danish population will be repeated in 1997 to see if there has been a decline in this prevalence within stated guidelines of the Danish regulation on nickel. There is not expected to be any significant change from 1990 (2.2% of men, 11.1% of women); it is too soon to expect measurable changes. Self-selection bias was not a problem since 80% of the random population that was called came to the clinic to be tested. Follow-up is important, as has been done in the cases of cement and cosmetics. We intend to do the same with nickel. This is already done in the context of the approximately 150 patients with nickel contact dermatitis. In taking their history, they were questioned on their exposure to items covered by the Nickel Directive. This may provide information on impact of legislation. With regards to enforcement of the Danish regulation, Denmark had its first legal case against a company, which was filed for by the government, for repeatedly ignoring the Danish regulation. It was settled out of court and the company paid a fine. The purpose of the regulation was to reduce exposure which; in turn, would reduce incidence. The example of cement workers mentioned earlier was a good example of this. One experiment looked at 5,000 recent cases of contact dermatitis; only 1-case of Cr contact dermatitis was found with cement exposure. Regulations there had an impact. Now there is a problem with perfumes. There is no control on exposure. There have been virtual epidemics of dermatitis caused by changing the preservatives used in cosmetics in recent years. Through concerted action by regulators and industry, reductions in exposure were achieved and reductions in the cases of eczema. Perfumes represented an increasing concern and, in some countries, perfume allergies were more significant than nickel allergies.
- Black hair dye was another significant concern (paraphenylinediamine), which has since been regulated in some countries, and the prevalence of sensitivity has decreased. It has, however, been allowed in hair dyes again, and dermatologists expect an increase in sensitization.
- In designing these follow-up studies, it is important to have controls in a country; such as the USA, which has not attempted to regulate nickel exposure.
Q Could a follow-up on the incidence of sensitization be done after the Nickel Directive is in Force?
A Yes, an epidemiological follow-up on the European Nickel Directive should be conducted.
A As with the Danish regulation on nickel, it will take many years to see the results of the Nickel Directive.
Session IV - Part II
Implication of Regulations on Nickel: Industry
Perspective and Role in Regulation Development
Moderator: Dr. Hans Gross
Consultant to the Nickel Development Institute, Germany
This session outlined the industry perspective on nickel dermatitis with specific reference to the production of airplane engines. Workers (2,000-3,000) in the airplane engine-producing industry are exposed to nickel in the form of alloys, compounds, and ions but there does not appear to be any problems with Ni contact dermatitis. These alloys have a high chromium content and may resemble stainless steel in some ways. Some of the lack of nickel sensitization may be due to selection bias by not hiring workers who had their ears pierced.
Workers were exposed to water-based coolants containing nickel ion up to 6 ppm. Hand eczema was found in workers in the past, but was due to additives in the coolant (disinfectant or alkali). Upon removal of the additive, eczema was no longer present. A women who knew she was sensitized to nickel consulted a dermatologist to test if the coolant she would be working with would cause nickel dermatitis. This was tested by using the coolant in a patch test. A standard patch test to Ni was positive, but with the coolant was negative (suggesting low nickel ion concentration).
Another contributing factor to some cases of dermatitis may have been rags containing metal splinters that were used for drying hands. Cuts on hands from the rags allowed the coolant to enter the skin more easily to provoke a dermal reaction. Replacement of rags with paper towels helped relieve the problem. Oil as a coolant contains no nickel ion but does contain particles of alloy. Occasional contact dermatitis was found with this coolant, but patch testing revealed that it was not related to nickel.
In one case, a man with contact dermatitis on his neck and fingers, said he worked with nickel powder. His patch test was positive for nickel sensitization. The worker was packing turbine blades into metal boxes and unpacking them after heat treatment (chemical vapour deposition). The base of the turbine blades was covered with nickel-containing paste. The box, packed with turbine blades, was filled with ammonium fluoride. The box with its contents was submitted to heat treatment. Due to the heat treatment, the ammonium fluoride dissociates, forming ammonia and fluoric acid. Under the influence of heat and fluoric acid, the nickel paste reacts with the metal of the turbine blades, forming a firmly adhesive layer. The worker had skin contact with the fluoric acid when he opened the box and removed the blades. He called the ammonium fluoride powder 'nickel powder,' because he used it whenever turbine blades covered with nickel paste had to be treated. He spoke of ''nickel powder' and thus confused the dermatologist, who looked upon the fluoride dermatitis as nickel dermatitis. Understandably enough, because the nickel patch test was positive. Another case involved a patient who was a plater who developed dermal nickel dermatitis. His reaction was apparently due to his wristwatch and not occupational exposure. Current electroplating still cannot be fully automated, but it is a cleaner process with less skin exposure and no evidence of skin disease is present.
The enumeration of allergens does not refer to air engine manufacture alone. These allergens play a role in different occupations. They are mentioned here to show that there are other allergens that are far more potent than nickel, including:
- methylacrylate
- epoxydharz
- chromium VI
- formaldehyde
- p-phenylenediamine
- toluenediamine
- glycerylmonothioglycolate
In workers spraying nickel powder (20-30 people for 20 years) no cases of asthma or skin disease have been observed. However, turbine blade workers who drill holes have exposures to nickel ions, platinum and sulfuric acid. One of these workers had hand eczema and was removed from that job, but the source of the eczema is not clear due to the exposure to multiple chemicals.
Another study examined 2 workers that did the same type of work, where exposure to Ni occurred during alloy grinding. One had high urinary nickel excretion and the other was low. The worker with the higher urinary nickel level did not drink as much liquid as the other worker. If you correct for creatinine, you get identical curves. These curves showed peak concentrations mid-week for both workers, as well as for other workers studied; it is not known why. One possibility may be that there are peak absorption levels that trigger diminished absorption later on. Whatever the reason for this observation may be, the result is that sampling for biological monitoring should be done mid-week.
Conclusion:
- There does not appear to be a major skin problem with high nickel alloys in the occupational setting. However, it is not known whether the workers are nickel-sensitized and do not show dermatitis symptoms, whether they are not nickel sensitized, or if they are immunotolerant.
Discussion, Questions, Responses
There is a psychological element connected with occupational dermatitis. Workers get frightened and may give up their job.
Q What role do the psychological effects play in Ni contact dermatitis?
A It is not known, but there are close links between the immune system and the brain. One example is that stress can affect inflammatory reactions. The skin is also known to be susceptible to nervous system responses, such as sensitization and elicitation.
Q So health and state-of-mind could affect the response?
A Yes, as well as female cycles, i.e., before menstruation, the inflammatory response is higher. Animal breeding studies demonstrate that genetic factors are also important in determining the risk of sensitization. Some strains are more sensitive to certain chemicals. A family study was done by Dr. Maibach. When parents were easily sensitized, the children were too. Questionnaires were given to 1500 twin pairs and patch tests were conducted on those children where on twin gave positive response to the questionnaire. There was a correlation between the susceptibilities of the twins to nickel sensitization. With regard to the HLA (human leukocyte associated antigen) system, no significant correlation has been identified yet.
Research Goals
Evaluation of Occupational Nickel Sensitization
- Where workers used gloves working with nickel alloys, and during a 15-year period, no reported cases of dermatitis was made known.
- A study should be done to carefully evaluate those factories that have no nickel contact dermatitis and document that there is no problem. Additional factors that are needed to have a nickel effect may also be identified.
Q Is it important to know if workers are sensitized to nickel?
A Yes, but do not use patch testing, use the LTT, so you do not risk inducing sensitization. Patch testing should not be done on healthy skin, but if skin problems exist in the form of contact dermatitis symptoms, patch testing should be done to determine the cause of the problem.
Q Is there evidence that repeat or single patch testing can induce sensitization? Platinum patch testing has been done for years without inducing sensitization.
A You can sensitize with a single exposure dependent on the concentration; there is smaller risks with lower concentrations of nickel, but it is still not zero. You can exacerbate induction with further patch tests.
A With any patch testing, it should be conducted and evaluated by dermatologists to insure accurate application of the test and interpretation of the results.
Research Summary
The following summarizes the areas of research discussed throughout the workshop.
Possible Research Areas:
- Workplace Specification
- Roles of Cytokines
- Penetration Rates/Compartment Changes
- Quantification Exposure
- Nickel Desensitization
- Critical Literature Review
- Population Estimates
- Irritants vs. Sensitizers
- Method Development
- Worker Follow-Up
- Regulatory Follow-Up
- Exposure vs. Time Studies
Specific Products that May Warrant Research:
- Coins
- Orthodontia
- Alloys/Stainless Steel (content vs. release)
Possible Industry Roles:
- Support research relevant to business/regulatory needs
- Endorse measurement of release rather than percent composition (extraction/migration limits)
- Develop use-of-nickel recommendations for industry
- Develop a consensus agreement regarding nickel dermatitis
Discussion, Questions, Responses
Our first priority should be to ask questions and get answers by doing a critical literature review.
Orthodontics is not a critical area of research; as a result of the Finland study, it is critical to look at the material that is used for dental braces.
We need to look into braces.
We need to add barrier cream development to the list. Once you control sensitization, then barrier creams could be used to control elicitation.
We should look at the role of oral intake to prevent or elicit dermatitis.
Investigation into the relationship between patch test and LTT and the accuracy of the patch test should be done.
Hazard identification for compounds containing Ni using Ni-specific T-cell clones is also important research area as well as the possibility of developing sensitizing antigens.
The role of divalent ions needs to be evaluated. Nickel sulfate, orally, can improve contact dermatitis to nickel. It is worse in summer. Ni-amino acid is a better antigen. This may be related to the redox activity of nickel.
Specific questions on the sweat test included:
Q What is the variability in sweat composition?
A There are different concentrations of salts in sweat. This could be a study.
Q What about sweat test vs. sweat excretion of nickel, etc.?
A Nickel is excreted in sweat, which has more acid than serum does.
Q Do we need to look into developing other sweat tests? This could be important to implement in the Nickel Directive.
Summary of Scientific Discussions
The following summarizes what is thought to be the most important areas of research with respect to dermal nickel sensitization. Questions were addressed throughout this session to better define the studies
I. Nickel sensitization needs to be monitored in the workplace. People should be tested before they start employment and continue monitoring during employment using LTT. An addition to this study could be to give nickel sulfate tablets to some of these workers to see if they are less likely to be sensitized than their coworkers.
II. The correlation between the patch test (5% solution) and the LTT needs to be improved. The LTT could be improved by using existing T-cell cloning and different ways of presenting the antigen so that it could be as reliable as the patch test. The current problem with the LTT is that there is not good reproducibility from day-to-day. The cost would be $100-200K for optimization of the LTT.
III. Investigation into the Festoon-type redox reaction Ni2+/Ni3+ and enhancement of this reaction with amino acids (use with LTT) could be done.
IV. Hazard identification for different Ni compounds needs to be conducted. Ni-specific clones could be used after compounds have been bioactiviated with macrophages. This could also be done in vivo in mice by bioactivation, using cells to inject into the mice.
Q How many people are needed for study I?
A A pilot study should be done with 10 individuals. Then you can get an idea of the power of the study and how many people will be needed for a definitive study. Follow-up should be done for 1-year. Immunotolerance studies in mice were all done by the same group. They should be confirmed by a different group. The cost of the LTT minimum and LTT extended (w/cytokines I1-4, 13, interferon, etc., in culture supernatant) would be $100-!,000. Blood samples cannot be preserved so the studies should be done on-site.
A A large cohort of newly hired employees would be better for this study. However, there are only 10 new employees per year at best.
A Another possibility is a cross sectional study with different exposures, looking at the percent response to the LTT of exposed individuals compared to the control group. Two advantages to this study are that you do not need to follow-up on the workers or have them ingest nickel sulfate.
V. Should we look into nickel in water, establish the safety of it, and say that more nickel will protect from future nickel sensitization?
A This can not be said for water, but it could be studied in the workplace where more ingestion occurs; this study might answer the question of immunotolerance induction by ingestion.
VI. Various stainless steels should be studied to see how much Ni they release.
VII. Dental braces should be investigated to see how braces could reduce sensitization to zero, as stated in the Finland study. This may be done by measuring nickel release from braces in saliva.
VIII. Not much work is being done with immunosuppression. Animal studies could be done to find a simple way to suppress animals.
IX. The question of whether nickel sensitized individuals are more prone to develop hand eczema should be addressed.
Intracutaneous exposure has been shown to sensitize animals, even without using adjuvant. Work with antigen in animal studies will provide more answers to support human work.
X. Money should be given to clinical dermatitis societies and attend their meetings, etc.
XI. An updated review of the literature needs to be conducted.
XII. A newsletter and literature service regarding dermatology and nickel should be set-up and a letter sent to Contact Dermatitis regarding availability of the CAB on the Nickel page.
XIII. Relatively broad plans should be made to co-sponsor some ongoing research and identify groups who are doing the relevant research since many of the projects are already going on.
XIV. Specific areas of research that need to be investigated include:
Dose-response and time-response for nickel alloys in nickel sensitive individuals on healthy skin and damaged skin; it would take 2 months to develop the application and $5-10K to produce it; protocols can be developed in 1-2 months.
Exposure Assessment.
Epidemiology in factories with nickel exposure who do not have problems.
XV. Basic immunology should be researched by announcing the topics and receiving good proposals for:
Vaccination to induce tolerance in sensitized individuals.
Barrier creams.
XVI. Epidemiology should be done to evaluate the effect of regulation on the incidence of nickel sensitization induction.
XVII. Collaboration should be offered to clinicians and dermatologists.
XVIII. The importance of doing bioavailability of nickel from consumer products and at the workplace should be stressed, including the studying of a wide range of alloys. This could involve dermatologists, chemists and/or producers.
XIX. Release tests need to be improved.
XX. Skin exposure to nickel needs to be quantified using the strip test and fingernails (~$20/sample) followed by washing hands and looking at nickel levels in the water.
Q Do doctors advise nickel-sensitive patients to avoid nickel in food?
A There are 2 publications on food ingestion.
A If you have nickel allergy already, you will not develop tolerance by oral ingestion of nickel, but you risk systemic contact dermatitis by inhalation or oral exposure.
A Dermatologists believe that the amount of nickel in food normally is not a problem, but intravenous nickel can have a big effect with even a few mg.
XXI. Material processing, both the way material is processed and the kind of material should be investigated.
XXII. Mechanism of excretion and deposition of nickel in the respiratory tract and in the lungs and its dependence on the alloy or compound inhaled.
End Notes
The Dermal Nickel Sensitization Workshop was sponsored by the Nickel Producers Environmental Research Association (NiPERA).
NiPERA's next step is to present these sensitization research projects to the SAC as possible areas of new research. The SAC will prioritize the research projects, NiPERA will solicit specific proposals, and the Board of Directors will approve the funding level.
NiDI wants the community to take the message that industry wants to deliver and act on this area. There is a role for us to play with consumers by taking the Nickel Directive into the world.
NiDI will prepare a Status Report on these issues. Recommend that communiqué be available through India's web site. The minutes of the workshop should have statements that researchers can agree on so industry can take appropriate action. Therefore, the minutes should be sent to participants for consensus.
ABBREVIATIONS
| AA |
Atomic Absorption |
| APC |
Antigen Presenting Cell |
| CD |
Contact Dermatitis |
| Cr |
Chromium |
| DMG |
Dimethylglioxime Test |
| HLA |
Human Leukocyte Associated Antigens |
| ICP-AES |
Inductively Coupled Plasma Atomic Emission Spectrometry |
| IS |
Immunosuppression |
| IT |
Immunotolerance |
| LTT |
Lymphocyte Transformation Assay |
| MHC |
Major Histocompatibility Complex |
| Ni |
Nickel |
| PLNA |
Popliteal Lymph Node Assay |
| QSAR |
Quantitative Structure-Activity Relationship |
| SAC |
Scientific Advisory Committee (NiPERA) |
| SS |
Stainless Steel |
| TCR |
T-Cell Receptor |
AGENDA FOR THE DERMAL NICKEL SENSITIZATION WORKSHOP
DAY 1
| 8:30 - 8:45 |
Introduction |
NiPERA Staff |
| 8:45 - 10:15 |
Session I |
Mechanisms of Dermal Nickel Sensitization
Dr. E. Gleichman (Medizinisches Institut für Umwelthygiene, Germany) |
| 10:15 - 10:30 |
Coffee Break |
|
| 10:30 - 12:00 |
Session II |
Immunotolerance to Nickel
Dr. D. Burrows (The Royal Hospitals, UK) |
| 12:00 - 1:00 |
Lunch |
|
| 1:00 - 2:30 |
Session III |
Elicitation of Nickel-related Dermal Reactions
Dr. H. Maibach (University of California, USA) |
| 2:30 - 2:45 |
Coffee Break |
|
| 2:45 - 4:30 |
Elicitation of Nickel-related Dermal Reactions (continued) |
|
DAY 2
|
| 9:00 - 10:45 |
Session IV |
Implications of Regulations on Nickel:
Part I - Scientific Perspective and Role in Regulation Development
Dr. T. Menné (Gentofte Hospital, Denmark) |
| 10:30 - 10:45 |
Coffee Break |
|
| 10:45 - 12:00 |
Session IV |
Implications of Regulations on Nickel
Part II - Industry Perspective and Role in Regulation Development
Dr. H. Gross (Consultant to: Nickel Development Institute) |
| 12:00 - 1:00 |
Lunch |
|
| 1:00 - 1:45 |
Summary of Scientific Discussions - Rapporteurs |
| 1:45 - 2:30 |
Discussion of Industry Concerns - NiPERA Staff |
| 2:30 - 3:00 |
Coffee Break |
|
| 3:00 - 4:00 |
Prioritized Research Activities - NiPERA Staff |
| 4:00 - 4:30 |
Next Steps - NiPERA Staff |
PARTICIPANTS IN THE WORKSHOP AND THE DRAFTING OF THIS DOCUMENT INCLUDE:
| NAME |
AFFILIATION |
COUNTRY |
| Dr. Steinar Berge |
Falconbridge, Ltd. |
Norway |
| Mr.Christian Bozec |
ERAMET |
France |
| Dr. Desmond Burrows |
The Royal Hospitals |
Ireland |
| Dr. Bruce Conard |
INCO, Ltd. |
Canada |
| Dr. Albert Cecutti |
Falconbridge, Ltd. |
Canada |
| Mr. Pierre-Jean Cunat |
Ugine, S.A. |
France |
| Dr. Bertrand Dautzenberg |
Group Hospitalier |
France |
| Dr. Robert Dowdeswell |
Rustenburg Platinum |
South Africa |
| Dr. Ernst Gleichman |
Med. Inst. für Umwelthygiene |
Germany |
| Dr. Hans Gross |
Arzt für Arbeitsmedizin |
Germany |
| Mr. Don Hall |
WMC Resources |
Australia |
| Mr. Toshiharu Kanai |
Sumitomo Metal Mining Co., Ltd. |
Japan |
| Dr. Kirsti Kalimo |
University of Turku |
Finland |
| Dr. Carola Lidén |
Karolinska Hospital |
Sweden |
| Dr. Howard Maibach |
University of California |
United States |
| Mr. Bruce McKean |
Nickel Development Institute |
Canada |
| Dr. Torkil Menné |
Gentofte Hospital |
Denmark |
| Mr. William Molloy |
Nickel Development Institute |
England |
| Dr. Lindsay Morgan |
NiPERA (Consultant) |
Wales |
| Mr. Michael Morley |
Nickel Development Institute |
England |
| Dr. Philippe Panier |
ERAMET |
France |
| Mr. Mal Price |
QNI, Ltd. |
Australia |
| Dr. Timo Rantanen |
Outokumpu Metals & Resources Oy |
Finland |
| Dr. Baldassare Santucci |
Inst. San Gallicano |
|
| Dr. Bert Swennen |
Union Minière |
Belgium |
| Dr. Lucas Van der Berg |
Impala Platinum |
South Africa |
| Dr. Sally Williams |
INCO, Ltd. |
England |
| NiPERA Staff |
NiPERA |
United States |
