UKPID MONOGRAPH NICKEL OXIDE SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. NICKEL OXIDE Toxbase summary Type of product Insoluble nickel salt used in nickel refining, stainless steel manufacture and electroplating. Also a component of alloys, ceramics and glass. Toxicity Most exposures are via chronic occupational inhalation. Acute severe toxicity is rare. Features Topical - May cause contact dermatitis. Ingestion - There are no case reports of nickel oxide ingestion. Inhalation - A potential cause of occupational asthma. Chronic inhalation may cause rhinitis, sinusitis, anosmia, perforation of the nasal septum and/or pneumoconiosis. Management Topical 1. Remove from exposure. 2. Symptomatic and supportive measures as required. 3. Chelation therapy in nickel contact dermatitis cannot be advocated routinely but is an area of research interest. Discuss with NPIS. Inhalation 1. Remove from exposure. 2. Symptomatic and supportive measures as required. 3. Occupational asthma and pneumoconiosis should be investigated and managed conventionally. References Mastromatteo E. Nickel. Am Ind Hyg Assoc J 1986; 47: 589-601. Muir DCF, Julian J, Jadon N, Roberts R, Roos J, Chan J, Maehle W, Morgan WKC. Prevalence of small opacities in chest radiographs of nickel sinter plant workers. Br J Ind Med 1993; 50: 428-31. Substance name Nickel oxide Origin of substance Nickel oxide is manufactured by heating nickel to above 400°C in the presence of oxygen. (HSDB, 1996) Synonyms Black nickel oxide Green nickel oxide Bunsenite Mononickel oxide Nickel monoxide Nickelous oxide Nickel protoxide Nickel oxide sinter 75 (RTECS, 1996) Chemical group A compound of nickel, a transition metal (d block) element. Reference numbers CAS 1313-99-1 (RTECS, 1996) RTECS QR8400000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure Nickel oxide, NiO (PATTY, 1994) Molecular weight 74.71 (PATTY, 1994) Physical state at room temperature Solid Colour Exists in a green or black form (PATTY, 1994) Odour NIF Viscosity NA pH NIF Solubility The green form is insoluble in water but soluble in acids; the black form is insoluble in both water and acids. (PATTY, 1994) Autoignition temperature NIF Chemical interactions Nickel oxide is incandescent in fluorine gas. Nickel oxide mixed with barium oxide will react vigorously with hydrogen sulphide in air, and vivid incandescence or explosion may result. (NFPA, 1986) Nickel oxide mixed with calcium oxide in air may cause vivid incandescence or explosion. (HSDB, 1996) Major products of combustion NIF Explosive limits NIF Flammability NIF Boiling point NIF Density 6.67 at 20°C (PATTY, 1994) Vapour pressure NIF Relative vapour density NIF Flash Point NIF Reactivity The black form of nickel oxide is chemically reactive and will form simple salts in the presence of acids. Green nickel oxide is inert. (IPCS, 1991) Uses Nickel oxide is used in the production of alloys, in enamel frits and ceramic glazes, for painting on porcelain and in glass manufacture. (MERCK, 1989; PATTY, 1994) It is also widely used in the manufacture of ferrites and nickel salts, in the production of active nickel catalysts and in electroplating. (HSDB, 1996) Hazard/risk classification Index no. 028-003-00-2 Risk phrases Carc. Cat. 1; R49, R43. May cause cancer by inhalation. May cause sensitization by skin contact. Safety phrases T; S53-45. Toxic; Avoid exposure - obtain special instruction before use. In case of accident or if you feel unwell, seek medical advice immediately (show label where possible). EEC no. 215-215-7 (CHIP2, 1994) INTRODUCTION AND EPIDEMIOLOGY Nickel oxide exists in green or black forms which differ in stoichiometry giving rise to different physicochemical properties (see above). Nickel oxide is an insoluble nickel salt. Exposure is predominantly via chronic occupational inhalation in the nickel refining and stainless steel manufacturing industries (Koponen et al, 1981; Draper et al, 1994; Warner, 1984; Langard, 1994). In the melting and casting processes of stainless steel manufacture nickel occurs chiefly as the element in iron oxide fume (the total dust contains 0.02-0.7 per cent nickel), with only small amounts of nickel oxide produced. Particulate nickel oxide is present in stainless steel welding fumes (Koponen et al, 1981). In the nickel refining industry, workers employed in the roasting and smelting processes are exposed mainly to nickel dust containing nickel oxide and subsulphide (average atmospheric concentration 0.5 mg Ni/m3). Non-process workers may be exposed to numerous nickel composites including nickel oxide (average atmospheric concentration 0.1 mg Ni/m3) (Torjussen and Andersen, 1979). Historically, inefficient nickel refining processes (with poor nickel recovery) necessitated recycling of nickel residues so workers were frequently exposed to large amounts of nickel (and copper) oxide dusts and some forms of arsenic. Increased refining efficiency avoids recycling (Draper et al, 1994). Some modern nickel refining procedures avoid nickel oxide production completely (Warner, 1984). MECHANISM OF TOXICITY In vitro studies demonstrate that nickel causes crosslinking of amino acids to DNA, alters gene expression, induces gene mutations and the formation of reactive oxygen species (Costa et al, 1994a and b; Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994). Nickel also suppresses natural killer cell activity and interferon production (Shen and Zhang, 1994). Beyersmann (1994) has suggested nickel (and other genotoxic metals) enhance the damaging effects of genotoxins such as ultraviolet radiation and alkylating substances via impairing DNA repair mechanisms. TOXICOKINETICS Absorption Nickel oxide can be absorbed by inhalation and ingestion, the former being more important occupationally. Significant percutaneous absorption does not occur. It has been estimated that 75 per cent of inspired particulate metals (including nickel oxide) are retained in the respiratory tree (Schroeder, 1970) and two thirds of this is eventually swallowed after clearance from the airways by the mucociliary mechanism. Systemic absorption from pulmonary tissue is slow (Roels et al, 1993). Nickel oxide is less well absorbed following ingestion than are soluble nickel salts. Distribution and excretion Once absorbed, nickel is transported in the blood bound principally to albumin, concentrated in the kidneys, liver and lungs and is excreted primarily in the urine. However, the concentration of nickel in faeces will be much higher than in urine since most ingested nickel is not absorbed and most inhaled nickel also appears in the gut. The half-life of nickel in urine following nickel oxide inhalation has been estimated around 50 hours (Sunderman, 1992) although some inhaled nickel is retained significantly longer than this. Among a sample of retired nickel refinery workers, the nickel half-life in the nasal mucosa was estimated to be three and a half years. Nickel crosses the placenta and is passed to the child in maternal milk (Fairhurst and Illing, 1987; IPCS, 1991). CLINICAL FEATURES: ACUTE EXPOSURE Although nickel oxide is a pulmonary irritant, acute exposure is unlikely to result in significant poisoning. Documented clinical cases invariably involve chronic occupational inhalation. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Nickel is a common precipitant of allergic contact dermatitis (Zhang et al, 1991) although nickel oxide is less likely to initiate this hypersensitivity response than are soluble nickel salts. However, workers occupationally exposed to nickel oxide at nickel refining plants are invariably also exposed to nickel sulphate and nickel chloride. Even so, nickel dermatitis is not a significant occupational hazard at these establishments, possibly due to development of immunological tolerance following chronic nickel inhalation (Menné, 1992). Non-occupational skin contact with nickel plated objects or nickel alloys remains the primary cause of nickel sensitization and is more common in women (Peltonen, 1979). Chronic urticaria, a type 1 hypersensitivity cutaneous reaction, has also been described (Abeck et al, 1993). Nickel sensitivity has been implicated in the aetiology of pompholyx, a vesicular eruption of the palmoplantar regions (Lodi et al, 1992). Once an individual is sensitized, further exposure to only a very small quantity of nickel initiates a reaction at the site of contact. Nickel may penetrate rubber gloves (Wall, 1980). In susceptible individuals nickel allergy may result in "secondary" nickel dermatitis with dissemination to skin sites distant from that of primary sensitization (typically the hands, flexures and eyelids (Valsecchi et al, 1992). It is not clear whether the latter is an endogenous phenomenon or simply reflects exogenous nickel contamination, for example via perspiring fingers (Fisher, 1986). Inhalation Pulmonary Toxicity Following chronic nickel oxide inhalation large amounts of nickel are retained in pulmonary tissue (Roels et al, 1993). Andersen and Svenes (1989) analysed lung specimens obtained at autopsy from 39 nickel refinery workers. Workers employed in the roasting and smelting department (n=15) exposed chiefly to nickel oxide and sulphide had significantly higher (p<0.01) lung nickel concentrations (mean 330 ± (SD) 380 µg/g dry weight) than employees from the electrolysis department (n=24) exposed primarily to soluble nickel sulphate and nickel chloride (mean lung nickel concentrations 34 ± (SD) 48 µg/g). These values compare to a mean lung nickel concentration of 0.76 ± (SD) 0.39 µg/g among 16 autopsies of non-exposed people. Nickel pneumoconiosis and interstitial fibrosis with a mild restrictive lung function defect have been described in steel workers exposed to mixtures of nickel oxide, iron oxide and chromium oxide fumes for at least 14 years (Graham Jones and Warner, 1972). It is impossible to determine the precise aetiological role of nickel oxide in these cases. Muir et al (1993) reviewed chest X-rays of 745 nickel sinter plant workers exposed to nickel oxide and subsulphide while employed between 1948 and 1963. One hundred and forty nine individuals had been employed at the plant for at least five years. In every case the most recent chest X-ray available was reviewed. Employees were exposed to nickel concentrations up to 100 mg/m3 which had previously been associated with an increased lung cancer incidence. However their chest X-rays showed only minimal evidence of small (round or irregular) opacities, similar to those described in smokers or workers exposed to low-fibrogenic dusts. These authors concluded that occupational exposure to nickel dust did not elicit an inflammatory or fibrogenic lung response (Muir et al, 1993). In summary, limited evidence suggests chronic nickel oxide inhalation may cause pneumoconiosis but concomitant exposure to other pulmonary irritants precludes a definitive conclusion. While electroplaters are exposed to mists of soluble nickel salts from plating baths, workers involved in the buffing and polishing processes are exposed to metallic nickel and nickel oxide. Employees in all stages of nickel plating may develop chronic rhinitis, nasal sinusitis, anosmia and perforation of the nasal septum (Mastromatteo, 1986). There are also reports of asthma attributed to nickel allergy in this industry (McConnell et al, 1973). It is likely nickel allergy is involved in the aetiology of 'hard-metal' asthma (typically associated with cobalt exposure) with evidence of cross reactivity between cobalt and nickel (Shirakawa et al, 1990; Shirakawa et al, 1992). Nephrotoxicity A study of renal function in 26 nickel refinery workers found no significant elevation of urinary total protein or ß2 microglobin (Sanford and Nieboer, 1992). Ingestion There are no reported cases of chronic nickel oxide ingestion although ingested nickel in any form may exacerbate nickel dermatitis (see below). Dermal toxicity Although primary nickel sensitization occurs only following skin contact, nickel dermatitis may be reactivated subsequently by ingested nickel (Gawkrodger et al, 1986; Nielsen et al, 1990). This is unusual because most antigens induce a state of immunological tolerance when administered orally, an effect that has also been described in nickel sensitive subjects (Sjövall et al, 1987; Panzani et al, 1995). An exacerbation of nickel dermatitis following ingestion is localized often to the initial sensitization site. This suggests that the antigen-presenting cells responsible for initiating the allergic reaction are relatively immobile (Nicklin and Nielsen, 1992). This may have important implications for the prevention and treatment of nickel dermatitis since if the body burden of nickel can be reduced (for example by chelating agents), the likelihood of nickel activation of the antigen presenting cells may be diminished. This is discussed further below (Management). Paradoxically the suggested mechanism of oral hyposensitization in nickel sensitive subjects is stimulation of suppressor T-cell production by antigen excess (Sjövall et al, 1987). Chronic urticaria, a type 1 hypersensitivity response, has been attributed to dietary nickel (Abeck et al, 1993), but this is unusual. MANAGEMENT Dermal exposure Avoidance of exposure and symptomatic treatment of dermatitis exacerbations with topical or systemic steroids remain the mainstay of treatment of nickel allergy although dietary nickel restriction (Kaaber et al, 1978) or oral (Panzani et al, 1995) or topical (Allenby and Basketter, 1994) hyposensitization have been advocated. Oral cyclosporin does not appear to be effective (De Rie et al, 1991). The role of chelation therapy is discussed below. Inhalation Removal from exposure and symptomatic and supportive treatment are all that are likely to be required following acute nickel oxide inhalation. Respiratory symptoms in nickel refinery workers should be investigated conventionally remembering that respiratory tract malignancy occurs more frequently in those chronically exposed to high concentrations of nickel oxide and subsulphide (see below, Carcinogenicity). Ingestion Nickel oxide ingestion has not been reported. Symptomatic and supportive measures are likely to be all that are required should this occur, with measurement of nickel concentrations in blood and urine only in symptomatic patients. Since nickel is eliminated mainly in the urine, maintenance of a high urine output is important in those with a confirmed or suspected increased body nickel burden. The role of chelation therapy in nickel poisoning is discussed below (Antidotes). Antidotes The role of chelation therapy in nickel oxide poisoning is limited since toxicity is due primarily to pulmonary nickel deposits following chronic inhalation. Most animal studies involve parenteral administration of soluble nickel salts. Available clinical data involve the management of nickel dermatitis. Animal studies The effect of chelating agents on nickel distribution is dependent on their lipid solubility. Lipophilic agents (such as diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride (TETA)) are more able to penetrate cell membranes with potential nickel redistribution to lipid rich tissues such as the liver and brain (Misra et al, 1987). By contrast, hydrophilic chelating agents (e.g. sodium calcium ethylenediamine tetraacetic acid (EDTA)) are more likely to enhance renal nickel clearance without cellular nickel accumulation (Misra et al, 1987). Misra et al (1987) observed a significant reduction (p<0.05) in renal nickel content in rodents following treatment with both lipophilic (1,4,8,11-tetra-azacyclotetradecane and TETA) and hydrophilic (sodium calcium edetate, 1,2,cyclohexylenediamine tetraacetic acid, diethylenetriamine pentaacetic acid) chelating agents 500 µmol/kg subcutaneously 60 minutes post nickel poisoning (as subcutaneous nickel chloride 250 µmol/kg). By contrast the hepatic nickel content was increased following treatment with lipophilic agents, but reduced after hydrophilic antidote administration (Misra et al, 1987). Oskarsson and Tjälve (1980) investigated the effect on nickel distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine 3.4 mmol/kg in mice administered a chelating agent ten minutes before an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg). DDC caused increased tissue nickel retention compared to control mice (injected with nickel chloride alone), with the highest radioactivity in adipose tissue followed by the liver, kidneys, brain and spinal cord. The brain nickel content of DDC treated mice was 57 times higher than control mice. Following d-penicillamine the tissue nickel content was lower than in control mice. For example, the "kidney contained about 1% and the lung about 4%" of the radioactivity observed in mice given 63nickel chloride only. Sodium calcium edetate 400 µmol/kg subcutaneously reduced the nickel content of the liver, heart, kidney and lung by 20-40 per cent in rodents poisoned with nickel (as subcutaneous nickel chloride 200 µmol/kg) 30 minutes previously (Dwivedi et al, 1986). In rats (n=20-25 in each group) the two week mortality following intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95 0.29 mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg, (0.3 times its LD50) was given one minute prior to nickel dosing (Horak et al, 1976). Under the same experimental conditions TETA 1.36 mmol/kg (0.6 times its LD50) reduced (p<0.001) the two week mortality to 25 per cent but DDC was ineffective. Sodium calcium edetate 0.68 mmol/kg reduced the two week mortality to 32 per cent (p<0.001) when the nickel chloride dose was 0.136 mmol/kg (greater than its LD50). Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium calcium edetate (administered intraperitoneally at a molar ratio of 10:1 chelating agent: nickel) increased survival in rodents systemically poisoned with nickel (as intraperitoneal nickel acetate, 62 mg/kg). The results are summarized in Table 1 (Basinger et al, 1980). Table 1. Survival rates in nickel intoxicated mice following chelation therapy (see text) n= Chelating agent Survival % 5 None 0 10 DMPS 80 10 d-penicillamine 100 10 Sodium calcium edetate 100 (after Basinger et al, 1980) Shen et al (1979) studied the effect of several chelating agents (administered subcutaneously) on renal nickel clearance in rats administered a continuous nickel chloride infusion. Each chelating agent was administered to a different group of six rats with eight controls. d-Penicillamine 1 µmol/h increased mean renal nickel clearance by 53 per cent (p<0.001) and TETA 1 µmol/h by 26 per cent (p< 0.025) but DDC 2 µmol/h did not affect renal nickel clearance. DMPS 0.5 mmol/kg significantly enhanced urine nickel excretion (0.001< p < 0.05) when administered subcutaneously to rats poisoned with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant decreases in nickel-induced hyperglycaemia and aminoaciduria were noted following chelation therapy. Faecal nickel excretion was unaffected and DMPS was ineffective in mobilizing nickel from the brain (Sharma et al, 1987). In mice systemically poisoned with nickel chloride (5 mg/kg), intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the brain (Xie et al, 1994). DMSA 400 µmol/kg intraperitoneally, significantly enhanced (p<0.05) the faecal and urinary excretion of the metal and there was no redistribution to the brain (Xie et al, 1994). The same group recently found parenteral DMSA and N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the testicular nickel concentration and so protecting against nickel-induced testicular toxicity in mice administered intraperitoneal nickel chloride (Xie et al, 1995). In summary, in rodents systemically poisoned with soluble nickel salts, renal nickel clearance is increased and mortality reduced by the parenteral administration of d-penicillamine, TETA or DMPS. DMSA also increases renal nickel elimination. DDC is not an effective antidote in experimental systemic soluble nickel salt poisoning. Clinical studies There are no data specifically involving nickel oxide exposure. Diethlydithiocarbamate and disulfiram in nickel dermatitis Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that: 2(DDC) + Ni2+ ---- Nickel bis(DDC) which is renally excreted. DDC is not available as a pharmaceutical preparation in many countries although disulfiram (Antabuse), which is metabolised to DDC (two molecules of DDC from each of disulfiram), has been employed. The rationale for the use of DDC and disulfiram in nickel dermatitis is that both agents reduce the body nickel burden and so minimise the amount of nickel available for the endogenous activation of immunocompetent cells. Topical DDC van Ketel and Bruynzeel (1982) investigated the role of topical DDC in the prevention of nickel sensitivity in 17 patients with known nickel allergy. Prior to nickel challenge seven patients were pretreated for 24 hours with 10 per cent DDC under an occlusive dressing. They were challenged with nickel (as nickel sulphate 0.01, 0.1, 1.0 and 5.0 per cent solutions) and a nickel coin (99.7 per cent nickel). Ten patients applied 10 per cent DDC six hourly for 24 hours prior to nickel sulphate challenge. There were no differences in mean patch test scores between DDC-treated and non DDC-treated skin in all groups (Table 2). Table 2. Topical DDC in nickel dermatitis n= 24 h Nickel challenge Mean ± SD Pretreatment patch-test score Control DDC 7 10% DDC Nickel sulphate 3.9 ± 2.1 4.0 ± 3.2 under occlusion (0.01, 0.1, 1.0 and 5.0%) 7 10% DDC Coin 0.9 ± 0.7 1.8 ± 1.1 under occlusion (99.7% nickel) 10 10% DDC Nickel sulphate 2.9 ± 2.7 2.5 ± 3.1 qds (0.01, 0.1, 1.0 and 5.0%) (van Ketel and Bruynzeel, 1982) Oral DDC and disulfiram Several uncontrolled studies report the successful resolution of nickel dermatitis following oral DDC or disulfiram. Uncontrolled studies of disulfiram therapy in nickel dermatitis are summarized in Table 3. Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg daily for 20 days led to an improvement in dermatitis although the condition recurred when treatment was discontinued. In another patient (Spruit et al, 1978) oral DDC for two months failed to produce a negative nickel patch test, although less local treatment was required. Disulfiram certainly increases urine nickel excretion in patients with nickel dermatitis (Table 4) but in a double-blind study involving 24 such patients treated with disulfiram 200 mg daily or placebo for six weeks, there was no overall significant difference between treatments (Kaaber et al, 1983). Adverse effects of DDC and disulfiram There is concern that disulfiram and DDC may promote nickel accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al, 1987). DDC is lipophilic and in in vitro studies can enhance cellular Ni2+ uptake (Nieboer et al, 1984; Menon and Nieboer, 1986). Disulfiram is also associated frequently with a 'flare-up' of nickel dermatitis soon after commencing treatment (Kaaber et al, 1979; Menné et al, 1980; Christensen and Kristensen, 1982; Christensen, 1982 (Table 3); Klein and Fowler, 1992; Gamboa et al, 1993). Other reported adverse effects of disulfiram therapy include abnormal liver Table 3. Uncontrolled studies of disulfiram in nickel dermatitis n= Disulfiram Effect on dermatitis Study Dose Duration & Early % % % (mg/day) (wks) flare "Healed" "Improved" Rebound1 1 300 8 - - 100 100 Menné & Kaaber, 1978 11 200-400 "4-10" 82 64 18 55 Kaaber et al, 1979 11 200-400 ? 82 73 - - Menné et al, 1980 11 200 8 100 18 73 100 Christensen & Kristensen, 1982 3 50-200 18 (mean) 100 33 66 33 Christensen, 1982 61 50-400 12 (mean) ?2 46 30 85 (n=27)3 Kaaber et al, 1987 98 - 47 32 66 (n=64) 1 Rebound dermatitis when disulfiram discontinued 2 Flares of dermatitis "frequently seen" but number not stated 3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases Table 4. Disulfiram in nickel dermatitis: urine nickel excretion n= Disulfiram Mean ± SD urine Study dose nickel excretion (mg/day) (µg/24 h) Before Maximum during treatment treatment 3 200-400 1.2 ± 0.3 53 ± 15.5 Kaaber et al, 1979 6 200-400 1.7 ± 0.5 60 ± 23.8 Menné et al, 1980 function (Kaaber et al, 1983; Kaaber et al, 1987), an acne-like rash (Kaaber et al, 1983), headache (Kaaber et al, 1979; Kaaber et al, 1983), fatigue and dizziness (Kaaber et al, 1979) and an adverse reaction with alcohol. Reactivation of nickel sensitivity often occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber et al, 1987; Table 3). Sodium calcium edetate Seventeen nickel allergic patients pretreated with a cream containing 10 per cent sodium calcium edetate showed a significant reduction in positive patch tests to nickel (as a one per cent nickel sulphate solution) compared to results on untreated skin (three positive reactions compared to 14 respectively, p<0.01) (van Ketel and Bruynzeel, 1982). The authors suggested use of 10 per cent sodium calcium edetate barrier creams in nickel sensitive subjects but this requires further study. Clioquinol A recent study reported that topical administration of the chelating agent clioquinol (three per cent) "completely abolished" reactivity to nickel in 29 nickel-sensitive subjects and the authors advocated its use as a barrier ointment in nickel allergic patients (Memon et al, 1994) but this requires confirmation. Antidotes: Conclusions and recommendations Nickel contact sensitivity 1. Nickel contact sensitivity is managed most effectively by avoiding exposure and treating acute exacerbations with topical and/or systemic steroids. 2. Topical DDC has no role. There is some evidence that barrier creams containing sodium calcium edetate or clioquinol may be useful. 3. While there are two case reports claiming benefit from oral DDC in the treatment of nickel dermatitis, this has not been confirmed in a controlled clinical study. 4. In the only published controlled clinical study using disulfiram in the management of nickel dermatitis there was no overall benefit from treatment. 5. Uncontrolled studies with oral disulfiram suggest improvement in secondary nickel dermatitis but the incidence of significant side-effects is high. 6. Chelation therapy in nickel dermatitis cannot be advocated routinely but remains an area of research interest. Systemic nickel poisoning 1. There are no human data available regarding chelation therapy in systemic nickel oxide toxicity. 2. Animal studies suggest d-penicillamine is probably the most effective nickel antidote although there are promising results and less adverse effects with the newer thiol chelating agents, particularly DMPS. MEDICAL SURVEILLANCE Prior to employment involving nickel exposure special consideration should be given to those with a history of contact dermatitis or respiratory disease. The maximum long-term exposure limit in air in the UK for insoluble nickel is 0.5 mg/m3 (Health and Safety Executive, 1995). Monitoring of nickel concentrations in blood and urine are not indicated routinely because while they provide evidence of recent exposure to soluble nickel compounds and nickel metal powder, they do not reflect the total body nickel burden and are of limited use for monitoring workers exposed primarily to nickel oxide and other insoluble salts. Moreover, urine nickel concentrations vary considerably and should be interpreted as groups of 24 hour samples rather than individual urine specimens (Nickel Producers Environmental Research Association and the Nickel Development Institute, 1994). Serum nickel concentrations are used in some industries since they avoid contamination from work-place dust and provide fairly consistent values within a given work environment; mean serum nickel concentrations ranging from 0.9 µg/L for grinders and polishers to 11.9 µg/L in electrolytic refining workers have been cited (Nickel Producers Environmental Research Association and the Nickel Development Institute, 1994). In a controlled study Torjussen and Andersen (1979) determined nasal mucosal, plasma and urine nickel concentrations in 318 present and 15 retired workers all employed for at least eight years in a nickel refining plant. Mean nickel concentrations in all samples were significantly lower in the control group (n=57) than the corresponding values for the active (p<0.01) and retired (p<0.05) workers (Torjussen and Andersen, 1979). In the same study (Torjussen and Andersen, 1979) smelting and roasting workers exposed to nickel oxide and subsulphide dust (average air nickel concentration 0.5 mg/m3) exhibited significantly higher (p<0.01) nasal mucosal nickel concentrations (467.2 ± (SD) 594.6 µg/100 g wet weight) than electrolytic workers exposed to soluble nickel sulphate and nickel chloride aerosols (178.1 ± (SD) 234.7 µg/100g wet weight). Plasma and urine nickel concentrations however were significantly higher (p<0.01) in electrolytic workers than in those exposed to nickel oxide (Torjussen and Andersen, 1979). In the roasting/smelting workers nasal mucosal nickel concentrations significantly correlated (p<0.01) with duration of exposure (to nickel oxide and subsulphide). Among the retired workers the authors estimated a nickel half-life in the nasal mucosa of three and a half years (Torjussen and Andersen, 1979). They suggested that nasal mucosal nickel concentrations were more reliable indicators of upper respiratory tract nickel accumulation then were plasma or urine nickel concentrations (Torjussen and Andersen, 1979). In another controlled study Roels et al (1993) measured the nickel concentration of total inhalable dust (mean 22.9 µg/m3), respirable dust (mean 3.5 µg/m3) and pre- and post-shift urine for five days in 20 workers exposed to nickel oxide during electrical resistance manufacture. In nineteen workers nickel urine concentrations did not differ between pre- (mean 1.2 µg/g creatinine) and post- (1.1 µg/g creatinine) shift samples (control mean 0.5 µg/g creatinine, n=17). In addition, urine nickel elimination was not affected by up to two weeks vacation. These results add further support to the view that urine nickel excretion is not a reliable indicator of occupational nickel exposure. The interpretation of urine nickel excretion data is further complicated by the fact that the particle size of inhaled nickel greatly affects its bioavailability. For example, one worker in the study by Roels et al (1993) had substantially higher post-shift urine nickel concentrations (range 21-101 µg/g creatinine) compared to pre-shift values (range 11-33 µg/g creatinine). His urine nickel excretion was also reduced (to 4.4 µg/g creatinine) following a two week vacation. The authors explained these results by noting that this individual handled smaller nickel oxide particles than his 19 colleagues (particle diameter 1-8 µm compared to 150-600 µm). He therefore had a substantially higher respirable nickel fraction (respirable nickel concentration 158 µg/m3 compared to 3 µg/m3). Gammelgaard et al (1992) suggested that a fingernail nickel content greater than 8 ppm indicates likely occupational (rather than domestic) nickel exposure in patients with nickel dermatitis but the reliability of this proposal has not been confirmed. OCCUPATIONAL DATA Maximum exposure limit Nickel, inorganic, insoluble compounds: Long-term maximum exposure limit (8 hour TWA reference period) 0.5 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity The carcinogenic status of nickel oxide has been disputed. Assessment is difficult since nickel workers are rarely occupationally exposed to nickel oxide alone. For example, Draper et al (1994) studied two historical dust samples (1920 and 1929) from a nickel refining plant in Wales and identified the presence of up to 10 per cent arsenic in addition to nickel oxide. The later sample had a lower arsenic content, correlating with a reduction in the number of respiratory cancers reported among 'nickel' workers at this time. The authors concluded that arsenic, probably in the form of nickel arsenide, was the likely aetiological agent responsible for the cancers observed (Draper et al, 1994). Smoking habits of employees further complicates the interpretation of cancer mortality data in the nickel industry. Cigarette smoking not only directly increases the risk of respiratory tract cancer but also indirectly increases risk via impaired mucociliary clearance of toxic particles from the bronchial mucosa (Langard, 1994). Cox et al (1981) considered the mortality of 1925 nickel alloy manufacturing workers employed for at least five years and exposed to metallic nickel and nickel oxide (nickel concentrations 0.5-0.9 mg/m3) but not nickel subsulphide. The standardized mortality ratio among these employees for lung cancer, cancer of other respiratory sites, respiratory disease or ischaemic heart disease was not increased significantly. That nickel oxide should not be considered carcinogenic was suggested also by Longstaff et al (1984) in a review of epidemiological data concerning the incidence of respiratory cancer among nickel refining employees. In contrast more recent epidemiological studies have shown a significant increase in deaths from carcinoma of the lung and nasal sinuses among nickel refinery workers (Roberts et al, 1992; Andersen, 1992). The exact aetiological agent is unknown although nickel sulphate, oxide and subsulphide have been suspected. Nickel oxide and subsulphide are probably also responsible for the increased incidence of nasal mucosal dysplasia observed in nickel refiners (Torjussen et al, 1979). The most recent International Agency for Research on Cancer (IARC) monograph on nickel carcinogenicity (IARC, 1990) concluded "there is sufficient evidence in humans for the carcinogenicity of ...... the combinations of nickel sulfide and oxides encountered in the nickel refining industry". The excess risk of death continues for several years after leaving employment (Muir et al, 1994). An increased incidence of laryngeal cancer has not been confirmed (Roberts et al, 1992). Thirty-nine nickel refiners (Andersen and Svenes, 1989) diagnosed with lung cancer had lung nickel concentrations at autopsy equal to those who died of other causes, indicating that the pulmonary nickel concentration is not a reliable indicator of aetiology of death (Andersen and Svenes, 1989). Fortunately, measures to improve industrial hygiene have greatly reduced the occupational hazard of nickel oxide exposure but respiratory tract malignancies among nickel industry employees remain notifiable diseases in the UK (Seaton et al, 1994). Among stainless steel workers, it is unclear whether nickel or hexavalent chromium compounds present in the welding fume is the greater risk factor for lung cancer (Langard, 1994). Reprotoxicity There are no human data regarding the reprotoxicity of nickel oxide. Animal studies have shown reduced body weight following exposure of rat foetuses to nickel oxide (1.6 and 3.2 mg/m3). Following nickel oxide inhalation, nickel crossed the placenta in rats in a dose-dependent manner (Reprotext, 1996). Genotoxicity Cytogenetic analysis of chromosomal aberrations of peripheral lymphocytes was performed in a controlled study (Senft et al, 1992) of 21 workers exposed to either nickel oxide (n=6) or nickel sulphate (n=15). A statistically significant (p<0.001) increase in the mean percentage chromosome aberration value was observed in the exposed group (n=21) compared with the control group (19 non nickel-exposed employees at the same chemical plant) with more aberrations in the nickel oxide workers (9.5 ± (SD) 3.2 per cent) than in those producing nickel sulphate (5.2 ± (SD) 1.9 per cent). A significant increase (p<0.01) in the mean percentage chromosome aberration in the control group (4.05 ± (SD) 2.27 per cent) compared with the suggested normal value for the general population (up to 2 per cent) was attributed to the nickel polluted environment of the plant. The authors concluded that nickel exposure causes increased peripheral lymphocyte chromosomal aberrations and suggested a positive association between duration of employment and the frequency of these abnormalities. They also proposed that the higher frequency of aberrations following nickel oxide exposure was due to the longer biological half-life of insoluble nickel salts allowing more time to exert a genotoxic effect (Senft et al, 1992). Fish toxicity Nickel : LC50 (96 h) banded killfish, striped bass, pumpkin seed, white perch, American eel, carp 6.2-46.2 mg/L (salt unspecified). Rainbow trout exposed to nickel (salt unspecified) had a reduction in glucidic stores which is consistent with direct metal interactions with membranes and enzyme thiol groups of pancreas cells. Life-cycle study fathead minnow (pH 7.8, 18°C, 210 mg CaCO3 hardness) <0.38 mg/L (salt unspecified) did not adversely affect reproduction, survival or growth; 0.78 mg/L (salt unspecified) significantly affected the number and hatchability of eggs, growth survival of the first generation was not affected. LC50 (74 h) carp eggs 6.1 mg/L, larvae, 8.4 mg/L (salt unspecified); 3 mg/L caused increased numbers of abnormal larvae and embryos which failed to hatch. LC50 (from fertilization to day 4 after hatching) channel catfish 0.71 mg/L, goldfish 2.78 mg/L (salt unspecified) (DOSE, 1994). EC Directive on Drinking Water Quality 80/778/EEC Nickel : Maximum admissible concentration 50 µg/L (DOSE, 1994). WHO Guidelines for Drinking Water Quality Guideline value 0.02 mg/L, as nickel (WHO, 1993). AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH UK This monograph was produced by the staff of the Birmingham Centre of the National Poisons Information Service in the United Kingdom. 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