Nickel is widely used in a broad range of products, primarily made of alloys, used by humans on a daily basis. Previous assessments have shown that skin contact with some such products may cause nickel allergic contact dermatitis, induced by the release of nickel. However, data on nickel release from small nickel particles in artificial sweat for assessment of potential risks of workers in nickel-producing and nickel-using facilities are not available. The objective of this study was to fill this knowledge gap by determining nickel release from fine nickel powder ( approximately 4 microm diameter) of different loadings varying from 0.1 to 5 mg/cm(2), when immersed in artificial sweat. The amount of nickel released increased with increasing particle loading, whereas the highest release rate per surface area of particles was observed for the medium particle loading, 1 mg/cm(2), at current experimental conditions. All particle loadings showed time-dependent release rates, reaching a relative steady-state level of less than 0.1 microg/cm(2)/hr after 12 hr of immersion, whereby less than 0.5% of the nickel particle loading was released. Nickel release from particles was influenced by the surface composition, the active surface area for corrosion, particle size, and loading.

Levels of nickel and other potentially allergenic metals in Ni-tested commercial body creams.J Pharm Biomed Anal. 2007 May 3;

It is extensively well-known that Ni and other metals occurring as impurities in cosmetic products might give rise to contact dermatitis in subjects with pre-existing allergy. The present study on the content of 13 metals (Cd, Co, Cr, Cu, Hg, Ir, Mn, Ni, Pb, Pd, Pt, Rh, and V) in moisturizing creams, labelled as "Ni-tested" (i.e., Ni content <100ngg(-1)) and available on the Italian market, provides a basis for assessing their safety for consumers. Quantification of metals was performed by sector field inductively coupled plasma mass spectrometry after microwave-assisted acid digestion of products. The developed method had limits of quantification less than 0.8ngg(-1) for all the elements; recovery was in the interval 88% (Cd, Co) to 110% (Hg), and precision was always under 7%. Nickel was present in all the products with levels between 17.5 and 153ngg(-1); three skin creams were slightly above the concentration reported on the label. The other elements were at levels below 1mugg(-1). The highest concentrations, in ngg(-1), of Co, Cr, Cu, and Mn were 222, 303, 51.2, and 59.9, respectively. Mean Cd, Pb, and V were below 5ngg(-1), while Hg was absent in all the samples. Among the new emergent allergens, Ir and Rh were in traces or even undetectable, while Pt had levels of 2.65 and 6.28ngg(-1) in two creams and Pd was equal to 1.07ngg(-1) in one product. The overall results are below the sensitizing limit proposed for consumer products and, thus, probably have no significant toxicological effects. Nevertheless, some creams presented amounts of Co and Cr comparable to those of Ni and therefore they have to be monitored in consideration of their cross-reactivity as well.

Sensitization to nickel: etiology, epidemiology, immune reactions, prevention, and therapy.Rev Environ Health. 2006 Oct-Dec;21(4):253-80.

Nickel is a contact allergen causing Type I and Type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressing in a wide range of cutaneous eruptions following dermal or systemic exposure. As such, nickel is the most frequent cause of hypersensitivity, occupational as well as among the general population. In synoptic form, the many effects that nickel has on the organism are presented to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity, the types of exposure and resulting immune responses, the rate of diffusion through the skin, and immunotoxicity. Alternatives toward prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity are discussed. The merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating nickel allergic hypersensitivity.

The safety of nickel containing dental alloys.Dent Mater. 2006 Dec;22(12):1163-8. Epub 2006 Jan 6.

Nickel is a constituent of many dental alloys. This paper reviews mainly papers published after 1985 with regards to biological reactions to nickel in dentistry. Nickel is an allergen, but there is no evidence that individual patients are at a significant risk of developing sensitivity solely due to contact with nickel-containing dental appliances and restorations. Hypersensitivity reactions to nickel are only likely to occur with prior sensitization from non-dental contacts and even these are rare. Clinical evidence has been presented to show that small doses of nickel, e.g. from dental appliances, may induce tolerance to this allergen. The papers reviewed report low rates of release of nickel from dental alloys. Some nickel compounds, which are mildly cytotoxic, have been implicated as carcinogens by inhalation in industrial settings, but these compounds are not present in dentistry-related operations, including dental technology procedures. Nickel-containing alloys and compounds have not been associated with increased cancer risk by oral or dermal routes of exposure. It is concluded that, subject to use according to established techniques, nickel-containing dental alloys do not pose a risk to patients or members of the dental team.

Persisting risk of nickel related lung cancer and nasal cancer among Clydach refiners. Occup Environ Med. 2006 May;63(5):365-6.

OBJECTIVE: To evaluate the risk of lung cancer and nasal cancer among workers employed at the Clydach nickel refinery, South Wales since 1930 by combining data from the two most recently published papers on this cohort. METHODS: Observed and expected numbers of cancer deaths were extracted for workers who had a minimum of five years service and were employed for the first time between 1902 and 1992. Standardised mortality ratios (SMR) were calculated for subgroups according to year of employment, time since first employment, and process work. RESULTS: A persisting excess of respiratory cancer was found for workers employed in the period 1930-92, with a lung cancer SMR of 133 (95% CI 103 to 172) and a SMR for nasal cancer of 870 (95% CI 105 to 3141). The lung cancer excess was most clearly seen 20 years or more after first employment and seemed to be confined to process workers. There was no indication of a further reduction in risk since 1930. CONCLUSION: The extreme nickel related cancer hazard at the refinery before 1920 was greatly reduced during subsequent years. Some of the carcinogenic exposures seem to have remained after 1930, producing an elevated risk of nasal cancer and a 30% excess of lung cancer in the workforce. There was evidence of a persisting risk among process workers first employed since 1953.

Carcinogenic effect of nickel compounds. Mol Cell Biochem. 2005 Nov;279(1-2):45-67.

Nickel is a widely distributed metal that is industrially applied in many forms. Accumulated epidemiological evidence confirms that exposures to nickel compounds are associated with increased nasal and lung cancer incidence, both in mostly occupational exposures. Although the molecular mechanisms by which nickel compounds cause cancer are still under intense investigation, the carcinogenic actions of nickel compounds are thought to involve oxidative stress, genomic DNA damage, epigenetic effects, and the regulation of gene expression by activation of certain transcription factors related to corresponding signal transduction pathways. The present review summarizes our current knowledge on the molecular mechanisms of nickel carcinogenesis, with special emphasis on the role of nickel induced reactive oxygen species (ROS) and signal transduction pathways.

Soluble nickel interferes with cellular iron homeostasis. Mol Cell Biochem. 2005 Nov;279 (1-2):157-62.

Soluble nickel compounds are likely human carcinogens. The mechanism by which soluble nickel may contribute to carcinogenesis is unclear, though several hypotheses have been proposed. Here we verify the ability of nickel to enter the cell via the divalent metal ion transporter 1 (DMT1) and disturb cellular iron homeostasis. Nickel may interfere with iron at both an extracellular level, by preventing iron from being transported into the cell, and at an intracellular level, by competing for iron sites on enzymes like the prolyl hydroxylases that modify hypoxia inducible factor-1alpha (HIF-1alpha). Nickel was able to decrease the binding of the Von Hippel-Lindau (VHL) protein to HIF-1alpha, indicating a decrease in prolyl hydroxylase activity. The ability of nickel to affect various iron dependent processes may be an important step in nickel dependent carcinogenesis. In addition, understanding the mechanisms by which nickel activates the HIF-1alpha pathway may lead to new molecular targets in fighting cancer.

Ascorbate depletion: a critical step in nickel carcinogenesis?Environ Health Perspect. 2005 May;113(5):577-84.

Nickel compounds are known to cause respiratory cancer in humans and induce tumors in experimental animals. The underlying molecular mechanisms may involve genotoxic effects; however, the data from different research groups are not easy to reconcile. Here, we challenge the common premise that direct genotoxic effects are central to nickel carcinogenesis and probably to that of other metals. Instead, we propose that it is formation of metal complexes with proteins and other molecules that changes cellular homeostasis and provides conditions for selection of cells with transformed phenotype. This is concordant with the major requirement for nickel carcinogenicity, which is prolonged action on the target tissue. If DNA is not the main nickel target, is there another unique molecule that can be attacked with carcinogenic consequences? Our recent observations indicate that ascorbate may be such a molecule. Nickel depletes intracellular ascorbate, which leads to the inhibition of cellular hydroxylases, manifested by the loss of hypoxia-inducible factor (HIF)-1alpha and -2alpha hydroxylation and hypoxia-like stress. Proline hydroxylation is crucial for collagen and extracellular matrix assembly as well as for assembly of other protein molecules that have collagen-like domains, including surfactants and complement. Thus, the depletion of ascorbate by chronic exposure to nickel could be deleterious for lung cells and may lead to lung cancer.

Industrial aerosols are a risk factor of oncologic diseases in underground miners.Vestn Ross Akad Med Nauk. 2005;(3):30-2.

The paper contains new data on the carcinogenicity of industrial aerosol to miners engaged to underground extraction of sulphide copper and nickel ores. Earlier appearance of oncologic diseases (lung and stomach cancer) is typical of this category of workers, exposed to higher aerogenic concentration of nickel in mine atmosphere. This fact demonstrates that the leading role in the ethiology of these diseases is played by multicomponent industrial aerosol containing nickel in the form of complex sulphides.

Nickel contact dermatitis. A ring signal in actual pathology.Rev Med Chir Soc Med Nat Iasi. 2004 Jul-Sep;108(3):497-502.

Contact dermatitis produced by nickel is extremely common in women by earrings or other items of jewelry which contain nickel. Areas of involvement are under rings, bracelets, watches, spectacle frames, coins in pockets, jeans studs and other sites of direct contact with the metal. The frequency of nickel dermatitis is increasing in the male population and this may be due of body-piercing or professional contact in the field of metallic constructions. The treatment is difficult because of the presence of nickel in so many substances, things or even food. The management of contact dermatitis include the reduction or elimination of the allergen, the use of topical or systemic steroids, oral desensitisation and use of nickel in selected cases.

Assessment of respiratory carcinogenicity associated with exposure to metallic nickel: a review.Regul Toxicol Pharmacol. 2005 Nov;43(2):117-33. Epub 2005 Aug 29.

Human studies prior to 1990 have shown an association between respiratory cancer and exposure to some nickel compounds, but not to metallic nickel. Numerous reviews have examined the nature of the association between nickel compounds and respiratory cancer, but little has been published on metallic nickel. This paper reviews the animal and human cancer-related data on metallic nickel to determine whether the conclusions regarding metallic nickel reached a decade ago still apply. Based upon past and current human studies, metallic nickel appears to show little evidence of carcinogenicity when present at the same or higher concentrations than those seen in current workplace environments. By comparison, animal studies currently available have shown mixed results. A number of studies have shown evidence of carcinogenicity in animals exposed to nickel powders via injection, but other studies have shown no or inconsistent results in animals exposed via inhalation or intratracheal instillation. Further studies in animals via inhalation and humans would be helpful in elucidating the respiratory carcinogenic potential of metallic nickel.

Provocative use test of nickel coins in nickel-sensitized subjects and controls.Br J Dermatol. 2003 Aug;149(2):311-7.

BACKGROUND: Consensus exists on levels of nickel release that are well tolerated in exposure to nickel-containing items in direct and continuous contact with skin (e.g. watches). The clinical relevance of nickel-containing coins eliciting nickel dermatitis associated with extensive occupational exposure (e.g. coins handled by cashiers) has not been determined. OBJECTIVES: To examine whether nickel-containing coins might be an elicitor of allergic contact dermatitis (ACD) in occupational settings with extensive exposure to coins (i.e. cashiers). METHODS: Eighteen subjects (10 nickel sensitized and eight non-nickel sensitized) completed this study after screening of history, physical examination and diagnostic patch testing (5% nickel sulphate). Each volunteer handled 10 coins (nickel-containing coins or non-nickel-containing coins) in a cross-over design at 5-min intervals (5 min handling followed by 5 min rest) for 8 h per day, for a total of 12 days excluding the weekend. One hand was gloved while the other was not during coin handling. Visual scoring and bioengineering measurements were recorded at each of four predetermined sites at baseline (day 1), end of day 5 and day 12 (last day of exposure). RESULTS: There were no statistical differences for either visual or bioengineering data comparing: (i) nickel-sensitized vs. non-nickel-sensitized subjects handling nickel-containing coins at day 1, day 5 and day 12; (ii) day 12 vs. day 1 (baseline) for nickel-sensitized subjects handling nickel-containing coins; (iii) handling of nickel-containing coins vs. non-nickel-containing coins by nickel-sensitized subjects at day 5 and day 12; (iv) gloved hand vs. ungloved hand of nickel-sensitized subjects handling nickel-containing coins at day 12. Limitations of the method and clinical extrapolation are detailed. CONCLUSIONS: Individuals handling these nickel-containing coins daily did not develop ACD, as judged by visual signs or bioengineering parameters.

Nickel release from coins. Contact Dermatitis. 2001 Mar;44(3):160-5.

Nickel allergy is the most frequent contact allergy and is also one of the major background factors for hand eczema. The clinical significance of nickel release from coins was discussed when the composition of euro coins was decided. Current European coinage is dominated by cupro-nickel coins (Cu 75; Ni 25); other nickel-containing and non-nickel alloys are also used. Nickel release from used coinage from the UK, Sweden and France was determined. It was shown that nickel ions are readily available on the surface of used coins. After 2 min in artificial sweat, approximately 2 microg of nickel per coin was extracted from cupro-nickel coins. Less nickel was extracted from non-nickel coins. Nickel on the surface was mainly present as chloride. After 1 week in artificial sweat approximately 30 microg/cm2 was released from cupro-nickel coins: less nickel was released from coins made of other nickel alloys. Theoretically, several microg of nickel salts may be transferred daily onto hands by intense handling of high-nickel-releasing coins.

Nickel release from metals, and a case of allergic contact dermatitis from stainless steel. Contact Dermatitis. 1994 Nov;31(5):299-303.

The prevalence of allergic contact dermatitis (ACD) caused by nickel is increasing. The probable cause is the increased use of nickel-containing metals in intimate contact with the skin. The critical factor is the amount of nickel released from these metals (bioavailable nickel) onto the skin. In the present study, we determined, with flame atomic absorbtion spectrometry, the amount of nickel released into synthetic sweat from metal samples. The results of this method were compared with the results of the dimethylglyoxime (DMG) test, which is considered to be a reliable means of identifying whether nickel-containing metals may cause allergy symptoms in sensitive individuals. Out of 10 samples studied, only small amounts (< 0.5 microgram/cm2/week) were released from 2 samples, and the DMG test was negative. From 5 samples, more than 0.5 microgram/cm2/week was released, and the DMG test was positive. For 3 samples, however, the DMG test was negative, though the flame atomic absorption spectrometry test showed considerable release of nickel. Therefore, although the DMG test can be used as a first line test for determining nickel release, some DMG-negative metal materials probably induce nickel sensitization, and should by no means be advertised as safe in this respect. We also report a nickel-allergic patient who developed ACD from stainless steel, indicating that some types of stainless steel release enough nickel to elicit allergic symptoms.