Systemic contact dermatitis after oral exposure to nickel: a review with a modified meta-analysis

Systemic contact dermatitis can be elicited experimentally in nickel-sensitive individuals by oral nickel exposure. A crucial point interpreting such experiments has been the relevance of nickel exposure from drinking water and diet. The aim of this meta-analysis study on former nickel-exposure investigations was to provide the best possible estimation of threshold values of nickel doses that may cause systemic contact dermatitis in nickel-sensitive patients. 17 relevant investigations were identified, and statistical analyses were performed in a stepwise procedure. 9 studies were included in the final dose-response analysis, which divided the studies into a homogenous middle group of 5 studies and 2 groups of 2 studies with a higher and lower response frequency, respectively, described by logistic dose-response curves shifted in parallel. On the basis of these curves, calculations were made of the doses that, theoretically, would cause systemic contact dermatitis in exposed nickel-sensitive patients. The results from the 2 most sensitive groups show that 1% of these individuals may react with systemic contact dermatitis at normal daily nickel exposure from drinking water and diet, i.e. 0.22-0.35 mg nickel.     

Oral prednisone suppresses allergic but not irritant patch test reactions in individuals hypersensitive to nickel

A multicentre, randomized, double-blind, crossover study was designed to investigate the effects of prednisone on allergic and irritant patch test reactions. 24 subjects with known allergy to nickel were recruited and patch tested with a nickel sulfate dilution series in aqueous solution, 5% nickel sulfate in petrolatum and 2 dilution series of the irritants nonanoic acid and sodium lauryl sulfate. The subjects were tested x2, both during treatment with prednisone 20 mg oral daily and during placebo treatment. The total number of positive nickel patch test reactions decreased significantly in patients during prednisone treatment. The threshold concentration to elicit a patch test reaction increased and the overall degree of reactivity to nickel sulfate shifted towards weaker reactions. The effect of prednisone treatment on the response to irritants was divergent with both increased and decreased numbers of reactions, although there were no statistically significant differences compared with placebo. It is concluded that oral treatment with prednisone suppresses patch test reactivity to nickel, but not to the irritants tested.     

Nickel concentrations in fingernails as a measure of occupational exposure to nickel

The nickel concentration in fingernails from 2 groups of people occupationally exposed to nickel was determined. In one group, comprising 83 persons moderately exposed to nickel, the mean +/- standard deviation (SD) was 29.2 micrograms/g +/- 56.7 micrograms/g and the median 13.8 micrograms/g (range 0.926-396 micrograms/g). In the other group, comprising 51 persons heavily exposed to nickel, the mean +/- SD was 123 micrograms/g +/- 289 micrograms/g and the median 29.9 micrograms/g (range 1.95-1770 micrograms/g). Both levels were significantly different from the normal nickel concentration in nails (p less than 0.001). The difference between the 2 levels was also significant (p less than 0.001). No correlation between the nickel concentration in fingernails and the duration of exposure could be demonstrated. It was concluded that the higher the nickel level in the fingernails, the greater is the possibility that the person is occupationally exposed to nickel. Nail analysis is suggested as a measure of occupational exposure to nickel.     

A new method for intraoral patch testing

Intraoral patch testing was performed in 3 subjects, 2 of whom were contact sensitive to nickel. Maxillary acrylic plates carrying test pieces containing 66% nickel were applied for 48 h, and readings were performed 24 h after removal. Few if any clinical signs were detected, but biopsies from the mucosal contact sites showed lichenoid reactions. Biopsies from control sites showed no or slight non-specific inflammatory reactions.     

Assessment of skin exposure to nickel, chromium and cobalt by acid wipe sampling and ICP-MS

There is a great need to accurately assess skin exposure to contact allergens. We have developed a technique for assessment of skin exposure to nickel, chromium and cobalt using acid wipe sampling by cellulose wipes with 1% nitric acid. Chemical analysis was performed by inductively coupled plasma mass spectrometry (ICP-MS). The recovery of nickel, chromium and cobalt from arms and palms was 93%. The analytical result is expressed in terms of mass per unit area (microg/cm(2)). The developed acid wipe sampling technique is suitable for determination of nickel, chromium and cobalt deposited on the skin. The technique may be used in workplace studies, in studies of individuals in the general population, in dermatitis patients, in identification of risk groups, as well as in developing preventive strategies and in follow-up after intervention.     

Experimental nickel elicitation thresholds--a review focusing on occluded nickel exposure

Nickel (Ni) is the most frequent cause of contact allergy among the female population. This makes it interesting to examine thresholds for elicitation under different conditions. Even though Ni exposure may be open, occluded, penetrating or oral, most dose-response studies in the literature concern single occluded application. The aims of this study were to assess thresholds of response by making a statistical analysis of available dose-response studies with single occluded exposure and comparing the results to thresholds from other modes of exposure. 8 occluded Ni dose-response studies were selected based on statistical considerations. The statistical analysis showed that 5% of a sensitized population react to 0.44 microg Ni/cm2 and 10% react to 1.04 microg Ni/cm2. In another study with a single open application, 7.8% of sensitized persons responded to a dose x6 higher than the dose to which 10% reacted in occluded exposure. When combining the exposure to Ni with an irritant, divagating results were found, although the literature shows evidence of an augmented response when combining exposure to an allergen and an irritant. The thresholds of penetrating exposure were found to be lower than the thresholds of single occluded exposure. Comparisons of different kind of exposures across studies are difficult, because of differences in the studies, although a comparison could be made by a study that compares the different exposures within the same individuals at the same time.     

Effects of repeated skin exposure to low nickel concentrations: a model for allergic contact dermatitis to nickel on the hands

We studied the effects of repeated daily exposure to low nickel concentrations on the hands of patients with hand eczema and nickel allergy. The concentrations used were chosen to represent the range of trace to moderate occupational nickel exposure. The study was double-blinded and placebo controlled. Patients immersed a finger for 10 min daily into a 10-p.p.m. nickel concentration in water for the first week, and during the second week into a 100-p.p.m. nickel concentration. This regimen significantly increased (P = 0.05) local vesicle formation and blood flow (P = 0.03) as compared with a group of patients who immersed a finger into water. The nickel concentrations used also provoked significant inflammatory skin changes on sodium lauryl sulphate (SLS)-treated forearm skin of the patients, whereas inflammatory skin changes were not observed in healthy volunteers without hand eczema and nickel allergy, either on normal or on SLS-treated forearm skin. The present study strongly suggests that the changes observed were specific to nickel exposure. Standardized methods to assess trace to moderate nickel exposure on the hands, and the associated effects in nickel-sensitized subjects, are needed.     

Coin exposure may cause allergic nickel dermatitis: a review

Nickel is used in coins because the metal has beneficial properties, including price, colour, weight, and corrosion resistance, and also because it is easy to stamp. It has often been claimed that the duration of skin contact with coins is too short to cause nickel release and dermatitis. However, it is well known by dermatologists specialized in occupational skin diseases, and by their nickel‐allergic patients, that hand eczema in cashiers and other professionals who handle coins may be caused or aggravated by nickel release from coins. In this review, we present evidence from past studies showing that nickel‐containing coins can indeed pose a risk for those who handle them. For protection of the health of consumers, cashiers, and other workers who handle coins, it is suggested that coins without nickel release should be used as a substitute for the high nickel‐releasing coins currently in widespread use. The key risk factor in this situation is the ability of metal alloys in coins to release nickel and contaminate the skin after repeated contact from coin handling.     

An anatomo-clinical study of delayed skin allergic reactions to nickel following intradermal injections of lidocaïne with a Dermo-Jet

10 women allergic in nickel developed skin reactions al injection sites with a Dermo-Jet (Krantz® model) of (a) 2% lidocaïne solution and (b)0.9% Saline solution. 10 women (age-matched) not allergic to nickel were selected as controls and submitted to the same injections; they had no positive reactions. Various controls (including injections with a needle and patch tests) were made in both groups. Nickel was leached into fluids from the metallic internal parts of the Dermo-Jet. The positive reactions were allergic and due to nickel. Histology showed changes of an allergic contact dermatitis with particular features, probably due to the intradermal injection of nickel. Some practical implications regarding the quality of medical instruments are discussed.     

Sensitivity caused by internal exposure to nickel,chrome and cobalt *

Five cases of sensitivity arising from metals within the body are described. The different ways in which these presented and the time taken to develop sensitivity are emphasized.     

Occupational hand eczema caused by nickel and evaluated by quantitative exposure assessment

Background. EU legislation has reduced the epidemic of nickel contact allergy affecting the consumer, and shifted the focus towards occupational exposure. The acid wipe sampling technique was developed to quantitatively determine skin exposure to metals. Objectives. To assess the clinical usefulness of the acid wipe sampling technique as part of the diagnostic investigation for occupational nickel allergy‐associated hand dermatitis. Patients and methods. Six patients with vesicular dermatitis on the hands were included. Acid wipe sampling of skin and patch testing with a nickel sulfate dilution series were performed. Results. Nickel was detected in all samples from the hands. In all patients, the nickel content on the hands was higher than on the non‐exposed control area. Conclusions. Occupational exposure to nickel‐releasing items raised the nickel content on exposed skin as compared with a non‐exposed control site. Nickel‐reducing measures led to complete symptom relief in all cases. In cases of a positive nickel patch test reaction and hand eczema, patients should perform the dimethylglyoxime (DMG) test on metallic items at home and at work. The acid wipe sampling technique is useful for the diagnosis of occupational hand eczema following screening with the inexpensive DMG test.     

Contact allergies to nickel sulfate, gold sodium thiosulfate and palladium chloride in patients claiming side-effects from dental alloy components

397 patients claiming various subjective symptoms related to dental restoration materials have been tested for the presence of metal allergy. The resultant data have been com pared with the corresponding allergies of eczematous patients. The frequency difference of metal allergy in the dental group is statistically significant or close to significance for nickel sulfate, potassium dichromate, cobalt chloride, palladium chloride and gold sodium thiosulfate. The findings suggest that the dental patient group represents a subgroup with a high frequency of metal allergy.     

Gene expression changes in peripheral blood mononuclear cells in occupational exposure to nickel

Allergic contact dermatitis is preceded by a clinically silent phase of sensitisation. In this study, we investigated whether the expression levels of six genes were related to nickel exposure and/or nickel sensitisation, and whether they could predict allergic manifestations to nickel. The mRNA expression level of six genes involved in cell growth (PIM1 and ETS2), metabolism/synthesis (HSD11B1 and PRDX4), apoptosis (CASP8) and signal transduction (CISH) was investigated by means of quantitative real-time RT-PCR in a cohort of 110 subjects, including healthy controls (n=51), nickel-exposed workers (n=23) and patients allergic to nickel (n=36). Our findings show that the expression levels of the analysed genes did not differ between allergic patients and healthy controls, while higher expression levels of ETS2 and CASP8 were detected in the nickel-exposed workers. Changes in ETS2 and CASP8 expression are likely to be related to nickel exposure rather than to allergy.     

Serum and urine nickel in nickel-sensitized women: effects of oral challenge with the metal

15 women with a positive patch test only to nickel (Ni) and without atopy and 10 control women were selected for the study. Blood and urine specimens were collected with a standard procedure either before (at 8 a.m.) or 4 and 24 h after the ingestion of 10 mg of Ni (as Ni sulfate). 7 of the Ni-sensitized patients showed a flare-up of eczema and/or urticaria during the test, while the other women were non-symptomatic. Serum and urine Ni of controls and Ni-sensitized women did not significantly differ. Serum and urine Ni levels determined before the oral Ni challenge were in the range of reference values recently reported by other authors (0.2–2.0 μg/l of serum or urine). Ni was greatly augmented in urine and serum 4 h after the challenge (25th–75th percentiles: 43–264 μg/l urine Ni and 15–52 μg/l serum Ni). 24 h after Ni ingestion, urine Ni was 41–153 μg/l and serum Ni 4–17 μg/l. Our study confirms a previous investigation showing similar levels of serum and urine Ni following ingestion of the metal in control and Ni-sensitized women without atopy.     

Dermal nickel exposure associated with coin handling and in various occupational settings: assessment using a newly developed finger immersion method

BACKGROUND: The role of nickel in causing hand dermatitis in some occupations has been difficult to assess due to problems with reliable measurement of the exposure to nickel in the workplace and lack of a definitive threshold for nickel allergic contact dermatitis. It is not uncommon to find nickel allergy on patch testing but it is difficult to determine whether this is of relevance to occupational nickel exposure or simply a reflection of past exposure to nickel-plated jewellery or other nonoccupational nickel exposure. OBJECTIVES: To devise a simple and reproducible method to quantify the amount of nickel on the skin and to apply the technique to measure dermal nickel exposure in various occupational settings. METHODS: A rapid and simple sampling procedure was developed for determination of nickel on the skin of workers potentially exposed to nickel by exposing individuals to nickel-releasing coins and measuring exposure by immersing the exposed thumbs and index fingers directly into graduated sample tubes containing ultrapure water and aqueous nickel extracts. The solutions were analysed by inductively coupled plasma-optical emission spectrometry after stabilization with nitric acid. The method shows advantages over alternatives such as wipe testing and tape stripping in terms of extraction efficiency, speed and ease of operation in the field. A pilot survey of dermal nickel exposure for workers in several occupational settings was conducted. RESULTS: The study suggested that a 'normal' level of nickel on the skin is <10 ng cm(-2). Coin handling induced an appreciable increase in the amount of nickel on the skin within 2 min. Experiments indicated a linear relationship between coin handling (exposure time) and measured dermal nickel levels following standardized coin handling. A pilot survey, conducted among cashiers, shop assistants, bar staff, hairdressers and workers in the nickel industry revealed dermal nickel concentrations ranging from <0.9 to 7160 ng cm(-2). The levels of nickel on the skin of cashiers, shop assistants, bar staff and hairdressers were below the threshold level for water-soluble ionic nickel for occluded exposure at which 10% of nickel-allergic subjects react (0.01% or 100 parts per million, equivalent to 530 ng cm(-2)) and the five-times higher threshold for unoccluded exposure (500 parts per million). The levels in some nickel platers and nickel refinery workers approached or exceeded these levels. However, few cases of nickel dermatitis are observed in plating and refinery facilities, perhaps due to immune tolerance, self-selection or, for refinery workers, exposure to water-insoluble rather than water-soluble nickel compounds. The elicitation threshold for water-soluble nickel compounds cannot be compared directly with dermal exposure to water-insoluble nickel compounds as the latter release a significantly lesser amount of nickel ions. CONCLUSIONS: We describe a reproducible, simple and rapid procedure for the assessment of nickel levels in occupationally exposed individuals.