UKPID MONOGRAPH NICKEL (II) CHLORIDE 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 CHLORIDE Toxbase summary Type of product Nickel chloride is a soluble nickel salt used in nickel plating, in the dye and printing industry, and as an adsorbent of ammonia in gas masks. Toxicity An important cause of contact dermatitis. May precipitate occupational asthma. Gastrointestinal irritation has occurred following ingestion but severe poisoning is rare. Features Topical - Primary skin and eye irritant and an important cause of contact dermatitis. Ingestion Mild/moderate ingestions: - Small ingestions of dilute solutions may produce no symptoms. Nausea, vomiting, abdominal pain and diarrhoea occur within two hours in more significant ingestions, possibly associated with headache, giddiness and myalgia. Substantial ingestions: - Severe gastrointestinal irritation and haemorrhage may ensue. - Transient hyperbilirubinaemia, albuminuria or a reticulocytosis have been reported and first degree heart block has been described. Inhalation - A potential cause of occupational asthma. Chronic inhalation may cause rhinitis, sinusitis, anosmia and perforation of the nasal septum. 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 an NPIS physician. Ingestion 1. In mild cases symptomatic and supportive measures will suffice. 2. Gastric lavage is best avoided in view of potential oesophageal irritation. 3. In symptomatic patients measure blood and urine nickel concentrations. 4. Ensure a good urine output in those with suspected or confirmed nickel toxicity. Inhalation 1. Remove from exposure. 2. Symptomatic and supportive measures as required. 3. Occupational asthma should be managed conventionally. References Sunderman Jr FW, Dingle B, Hopfer SM, Swift T. Acute nickel toxicity in electroplating workers who accidentally ingested a solution of nickel sulfate and nickel chloride. Am J Ind Med 1988; 14: 257-66. Wall LM, Calnan CD. Occupational nickel dermatitis in the electroforming industry. Contact Dermatitis 1980; 6: 414-20. Substance Name Nickel (II) chloride Origin of substance Nickel chloride may be prepared from nickel oxide by chlorination, or by reaction with hydrogen chloride. (HSDB, 1997) Synonyms Nickel chloride Nickel dichloride Nickelous chloride (DOSE, 1994) Chemical group A compound of nickel, a transition metal (d block) element. Reference numbers CAS 7718-54-9 (DOSE, 1994) RTECS QR6470000 (RTECS, 1997) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure NiCl2 (DOSE, 1994) Molecular weight 129.62 (DOSE, 1994) Physical state at room temperature Solid Colour Green (hexahydrate) Golden-yellow (anhydrous salt) (MERCK, 1996) Odour Odourless (HSDB, 1997) Viscosity NA pH The aqueous solution is acidic. (MERCK, 1996) Solubility Soluble in water: 642 g/L at 20°C. Soluble in ethanol, ethylene glycol and hydrazine. (DOSE, 1994) Autoignition temperature NIF Chemical interactions Nickel chloride may explode on impact when mixed with potassium. (NFPA, 1986) Nickel chloride reacts readily with strong acids. (HSDB, 1997) Major products of combustion When heated to decomposition very toxic fumes of hydrogen chloride may be emitted. (HSDB, 1997) Explosive limits NIF Flammability Non-flammable (HSDB, 1997) Boiling point 987°C (sublimes) (DOSE, 1994) Density 3.55 at 20°C (DOSE, 1994) Vapour pressure 133.3 Pa at 671°C (HSDB, 1997) Relative vapour density NIF Flash Point NIF Reactivity NIF Uses Nickel chloride is used in the nickel-plating of cast zinc, and in ink manufacture. The anhydrous salt is used as an adsorbant for ammonia in gas masks. (MERCK, 1996) Hazard/risk classification NIF INTRODUCTION AND EPIDEMIOLOGY Nickel chloride is a soluble nickel salt. Poisoning by ingestion is rare although occupational cases have been described (Sunderman et al, 1988). Nickel chloride inhalation may cause occupational asthma in metal platers (McConnell et al, 1973). Nickel chloride is used in nickel patch testing. 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 that nickel enhances the damaging effects of genotoxins such as ultraviolet radiation and alkylating substances by impairing DNA repair mechanisms. TOXICOKINETICS Absorption Nickel chloride can be absorbed by inhalation and ingestion. Percutaneous uptake can occur, and is an important source of nickel contact sensitivity, but does not make a substantial contribution to the body nickel burden. It has been estimated that 75 per cent of inspired nickel is retained in the respiratory tree (Schroeder, 1970) and two thirds of this is eventually swallowed after clearance from the airways by the mucociliary mechanism. Distribution and excretion Once absorbed, nickel is transported in the blood bound principally to albumin (Lucassen and Sarkar, 1979). It is concentrated in the kidneys, liver and lungs and is excreted primarily in the urine. However, following ingestion, the concentration of nickel in faeces will be much higher than in urine since most is not absorbed. A substantial proportion of inhaled nickel chloride will eventually also appear in the gut. Animal and human volunteer studies suggest that the distribution and elimination of nickel follows a two compartment model with an initial rapid plasma elimination phase followed by a slower clearance phase (IPCS, 1991). In ten human volunteers the plasma elimination half-life of ingested nickel was 28 ± (SD) 9 hours (Sunderman et al, 1989). Among ten workers who accidentally drank 0.5 - 1.5 litres nickel chloride and nickel sulphate-contaminated water, and who received intravenous fluid (150 mL/hour) for three days the serum nickel half-life was 27 ± (SD) 7 hours. Among 11 individuals in whom a diuresis was not induced the mean serum nickel half-life was 60 ± (SD) 11 hours. Nickel crosses the placenta and is passed to the child in maternal milk (Fairhurst and Illing, 1987; IPCS, 1991). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure There is relatively little information on the acute dermal toxicity of nickel chloride in humans, though at high concentrations it is likely to be a primary skin irritant as is nickel sulphate (Frosch and Kligman, 1976). Dermal exposure to nickel chloride is associated mainly with the development of nickel contact sensitivity (see Chronic exposure). Ocular exposure Nickel chloride (0.5 per cent) produced no adverse effects when directly applied to rabbit eyes. There are no human data (Grant and Schuman, 1993). Ingestion Gastrointestinal toxicity Sunderman et al (1988) reported an industrial accident involving 32 workers at an electroplating plant who accidentally drank water contaminated with nickel chloride, nickel sulphate (total nickel concentration 1.63 g/L) and boron (68 mg/L). Symptoms occurred primarily in those who had ingested more than 500 mL and began within two hours of ingestion. Gastrointestinal effects including nausea, vomiting, abdominal pain and diarrhoea were the most common. Ten of these 32 patients required hospital admission, though all were asymptomatic within three days. The mean urine nickel concentration the day following the incident among 15 of those exposed was 5.8 mg/L (range 0.23 - 37.1 mg/L) , with a mean serum nickel concentration of 286 µg/L (range 12.8 - 1340 µg/L). Among 11 nickel platers who did not drink the contaminated water the mean urine nickel concentration was 50 ± (SD) 13 µg/L with a mean serum nickel concentration of 4.0 ± (SD) 1.2 µg/L (Sunderman et al, 1988). Fatalities have occurred from gastrointestinal haemorrhage following soluble nickel salt ingestion though there are no case reports involving nickel chloride. Hepatotoxicity Two of the ten patients admitted following ingestion of 0.5 - 1.5 litres nickel chloride/sulphate contaminated water (see above) developed mild transient hyperbilirubinaemia (30 µmol/L and 43 µmol/L respectively) but this resolved within six weeks (Sunderman et al, 1988). Neurotoxicity Of 20 workers who accidentally ingested water contaminated with nickel chloride and sulphate (see above) seven complained of giddiness, six of lassitude, five of headache and one of myalgia. Symptoms resolved within hours in most cases and within two days in all (Sunderman et al, 1988). In the same accident it was noted that the mean body temperature of the ten most substantially exposed patients was slightly diminished (mean 36.7 ± (SD) 0.3°C on day 2). The authors proposed nickel-induced impaired thermoregulation (which has been described in animals) as the mechanism, but there are insufficient clinical data to substantiate this. Pulmonary toxicity Of 21 workers who drank nickel contaminated water (nickel concentration 1.63 g/L), one patient with known bronchial asthma developed an expiratory wheeze and another patient with chronic obstructive airways disease developed cyanosis. Whether these respiratory symptoms were nickel-induced is unknown (Sunderman et al, 1988). Nephrotoxicity Two of the subjects described by Sunderman et al (1988) developed transient albuminuria in the two days following ingestion of nickel chloride/sulphate contaminated water (see above). In both cases this resolved within five days. Haemotoxicity Sunderman et al (1988) reported a modest erythropoietic effect among ten workers who accidentally drank nickel chloride/sulphate- contaminated water (see above) with an increase in the mean blood haemoglobin concentration from 15.1 ± (SD) 0.7 g/dL on day three post exposure to 16.0 ± (SD) 0.6 g/L on day eight (p<0.01). There was a similar statistically significant increase in the blood reticulocyte count. Cardiovascular toxicity Ingestion of 0.5 - 1.5 L nickel chloride/sulphate contaminated water (nickel content 1.63 g/L) was associated in one patient with transient first degree heart block (Sunderman et al, 1988). CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Nickel chloride is a common precipitant of allergic contact dermatitis (Kalimo and Lammintausta, 1984; Christensen and Wall, 1987; Serup and Staberg 1987 a and b; Goebeler et al, 1993) which is a cell-mediated (type IV) hypersensitivity response. Chronic urticaria, a type 1 hypersensitivity cutaneous reaction to nickel, 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). Primary nickel contact sensitization is more common in women (Peltonen, 1979) and usually follows prolonged non-occupational skin contact with nickel-plated objects or nickel alloys. Common sources include jewellery, buttons, zips and coins (Lacroix et al, 1979; Gollhausen and Ring, 1991). The amount of nickel released from these items depends on their resistance to corrosion and the presence of sweat which acts to release the metal ion as soluble nickel salts including nickel chloride. Nickel ions may penetrate rubber gloves (Wall, 1980). Once an individual is sensitized, further exposure to only a very small quantity of nickel initiates a reaction at the site of contact. Nickel valve prostheses and nickel-containing pacemakers have been suggested as triggers of nickel allergy (Lyell and Bain, 1974; Landwehr and van Ketel, 1983). 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). It is not clear whether the latter is an endogenous phenomenon or simply reflects exogenous nickel contamination, for example via perspiring fingers (Fisher, 1986). Interpretation of patch test responses may be difficult. Measurement of transepidermal water loss (Serup and Staberg, 1987a) and assessment of skin oedema by ultrasound (Serup and Staberg, 1987b) have been suggested to differentiate between true allergic and irritant nickel patch test responses. Simultaneous contact sensitivity to nickel and cobalt is common probably via a shared effect on inflammatory-cell recruitment (Goebeler et al, 1993). Investigations by Wall and Calnan (1980) following an outbreak of occupational dermatitis in an electroforming plant found nickel chloride to be a more reliable patch test allergen than nickel sulphate. Patch testing with nickel sulphate alone would have failed to detect seven of 13 nickel allergic patients. There is evidence that the skin permeation rate is some 15 times faster for nickel chloride than nickel sulphate (Fullerton et al, 1986). This partly explains why a nickel chloride patch test (48 h occlusion) gives a "more positive and allergic toxic reaction" than nickel sulphate (Kalimo and Lammintausta, 1984). A further advantage of nickel chloride is its greater solubility in alcohol (Christensen and Wall, 1987). Nickel chloride may be used as the stimulus of lymphocyte blast transformation in the in vitro confirmation of nickel sensitivity as is nickel sulphate (Everness et al, 1990; Grimsdottir et al, 1994). Inhalation Pulmonary toxicity Chronic exposure to aerosols of nickel chloride, emitted as mists from electroplating baths may lead to chronic rhinitis, nasal sinusitis, anosmia and perforation of the nasal septum (Mastromatteo, 1986). Nickel chloride inhalation may cause occupational asthma with circulating IgE nickel antibodies as has been reported with nickel sulphate (Nieboer et al, 1984); resolution of symptoms occurs when the individual is away from work (Block and Yeung, 1982). Occupational asthma has been reported among metal platers (McConnell et al, 1973). It is likely that 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 There is some evidence that chronic inhalation of high concentrations of soluble nickel compounds causes increased urinary protein and renal tubular enzyme excretion but the significance of these findings is unknown (Vyskocil et al, 1994). Ingestion Dermal toxicity Although primary nickel sensitization occurs only following skin contact, nickel dermatitis may be reactivated subsequently by ingested nickel (Gawkrodger et al, 1986). 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. 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 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 Symptomatic and supportive treatment is all that is likely to be required in those with symptoms of respiratory tract irritation following acute exposure to nickel chloride. Occupational asthma should be managed conventionally, and further exposure avoided. Ingestion There is no evidence that gastric lavage reduces nickel chloride absorption. General symptomatic and supportive measures are likely to be all that are required in most cases. Measurement of nickel concentrations in blood and urine need only be undertaken 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 nickel burden. Following inadvertent ingestion of 0.5 - 1.5 litres nickel chloride/sulphate-contaminated water (nickel concentration 1.63 g/L), Sunderman et al (1988) demonstrated a mean serum nickel half life of 27 hours (n=10) in those treated with intravenous fluids compared to a half-life of 60 hours (n=11) in those not receiving intravenous fluids. The role of chelation therapy in nickel chloride poisoning is discussed below. Antidotes 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 redistribution of nickel 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) 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 triethylenetetramine) and hydrophilic (sodium calciumedetate, 1,2,cyclohexylenediamine tetraacetic acid, diethylenetriamine pentaacetic acid) chelating agents given subcutaneously (500 µmol/kg) 60 minutes post dosing with nickel chloride (250 µmol/kg subcutaneously). By contrast the hepatic nickel content was increased following treatment with lipophilic agents, but reduced after hydrophilic drug 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 calciumedetate 400 µmol/kg subcutaneously reduced the nickel content of the liver, heart, kidney and lung by 20 - 40 per cent in rodents administered nickel chloride (200 µmol/kg subcutaneously) 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 triethylenetetramine 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 calciumedetate 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 calciumedetate (administered intraperitoneally at a molar ratio of 10:1 chelating agent: nickel) increased survival in rodents systemically poisoned 20 minutes previously 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 calciumedetate 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 triethylenetetramine 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 a more recent controlled study, Tandon et al (1996) investigated the effects of chelating agents on nickel toxicity. Groups (n=6) of nickel poisoned rats (1.5 mg/kg nickel sulphate intraperitoneally, 6 days a week for 30 days) were intraperitoneally administered a chelating agent 0.3 mmol/kg once a day for five days. DMSA and DMPS significantly (p<0.001, p<0.01 respectively) enhanced faecal but not urinary nickel excretion. DDC did not enhance elimination by either route. DMSA, DMPS and DDC significantly (p<0.01) reduced blood, liver, kidney and heart (but not brain) nickel concentrations compared to controls. The DDC homologue (N-benzyl-D-glucamine dithiocarbamate) was the most effective of all antidotes studied, significantly enhancing both urinary and faecal excretion (p<0.01) and reducing (p<0.001) the nickel concentrations in all tissues examined. 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). Intraperitoneal DMSA 400 µmol/kg, 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 or triethylenetetramine. Evidence regarding the effect of DMPS and DMSA on renal nickel elimination is conflicting. DDC does not enhance nickel excretion. Clinical studies There are no human data involving chelation therapy in nickel chloride toxicity save that relating to the management of nickel dermatitis. Diethyldithiocarbamate 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 metabolized 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 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 Mean ± SD Pretreatment challenge 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) Systemic 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. Although disulfiram increases urine nickel excretion in patients with nickel dermatitis (Table 4), there was no overall significant difference between treatments in a double-blind study involving 24 patients treated with disulfiram 200 mg daily or placebo for six weeks (Kaaber et al, 1983). Adverse effects of DDC and disulfiram There is concern that DDC and disulfiram may promote nickel accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al, 1987; Nielsen and Andersen, 1994). 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 include abnormal liver 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 calciumedetate Seventeen nickel allergic patients pretreated with a cream containing 10 per cent sodium calciumedetate showed a significant reduction in positive patch tests to nickel sulphate (1 per cent 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 calciumedetate barrier creams in nickel sensitive subjects but this requires further study. Clioquinol A recent clinical study reported that topical administration of the chelating agent clioquinol (3 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. 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 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 calciumedetate 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 chloride 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 potential exposure to nickel special consideration should be given to those with a history of contact dermatitis or respiratory disease. 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. 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 nickel 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 (reference range varies widely but a typical value for an adult is less than 1.3 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) electrolytic workers exposed to nickel chloride and sulphate exhibited significantly lower (p<0.01) nasal mucosal nickel concentrations (178.1 ± (SD) 234.7 µg/100g wet weight) than smelting and roasting workers exposed to insoluble nickel oxide and subsulphide dust (467.2 ± (SD) 594.6 µg/100 g 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). Gammelgaard et al (1992) have suggested that a nickel content of fingernails 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 soluble compounds: Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1997). OTHER TOXICOLOGICAL DATA Carcinogenicity 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 excess risk of death continues for several years after leaving employment (Muir et al, 1994). The exact aetiological agent is unknown, although nickel chloride, nickel sulphate, nickel oxide and sub-sulphide have been suspected (IARC, 1990; Roberts et al, 1992; Andersen, 1992). An increased incidence of laryngeal cancer has not been confirmed (Roberts et al, 1992). Among employees at an aircraft engine factory lung cancer deaths (n = 42) between 1966 and 1976 were no more prevalent among nickel-exposed (exposed both to nickel alloys dust and aerosols of nickel sulphate and chloride) than non-exposed workmen (Bernacki et al, 1978). A study by Pang et al (1996) provided only weak evidence (observed 8.0, expected 2.49, SMR 322) of an increased risk of stomach cancer in a cohort of 284 nickel platers who handled nickel chloride and nickel sulphate, first employed for at least three months between 1945-75. Fortunately, measures to improve industrial hygiene have reduced greatly the occupational hazard of nickel chloride exposure but respiratory malignancies remain notifiable diseases among nickel industry employees in the UK (Seaton et al, 1994). Reprotoxicity Animal studies have shown reduced fertility and stunted fetal growth following the oral administration of nickel (as nickel sulphate) and testicular damage following oral or dermal nickel exposure (to nickel sulphate) (Reprotext, 1997). Smith et al (1993) provided evidence of increased perinatal mortality in rats fed nickel chloride for 11 weeks prior to mating then during two cycles of gestation and lactation. These are no human reprotoxicity data specific to nickel chloride. Chashschin et al (1994) reported an increased incidence of structural malformations and spontaneous and threatened abortions in pregnancies among 356 nickel refinery workers exposed to nickel aerosols (as nickel sulphate) (range 0.077 - 0.308 mg/m3) compared to non-exposed controls. Unfortunately their data lacked adequate sampling and statistical details but suggests that the potential reprotoxic hazard of soluble nickel salt exposure requires further investigation. Genotoxicity In vitro studies Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537, TA1538 with and without metabolic activation - negative. Escherichia coli WP2, WP67, CM871 with and without metabolic activation DNA-repair test - negative. Bacillus subtilis H17, M45 without metabolic activation - negative. Saccharomyces cerevisiae D7 without metabolic activation - positive. In vitro Chinese hamster ovary cells DNA strand breaks - positive. In vitro mouse FM3A mammary carcinoma cells, Chinese hamster ovary cells and human peripheral blood lymphocytes: chromosomal aberrations and sister chromatid exchanges - positive. In vitro Chinese hamster ovary cells, chromosomal aberrations - positive. In vivo studies Reduced sperm counts, sperm mobilities, induced sperm chromosomal aberrations, damaged testes ultrastructure, caused sperm head abnormalities and induced micronuclei in the polychromatic erythrocytes were found in mice. Intraperitoneal injection of 6-24 mg/kg nickel in mice induced bone marrow chromosomal aberrations (DOSE, 1994). Clinical studies In a controlled study Waksvik et al (1984) investigated chromosomal aberrations in the peripheral lymphocytes of retired nickel refinery workers (n=9) four to 15 years post retirement. The workers who had been exposed to either nickel chloride, nickel oxide, nickel sulphate or nickel subsulphide for greater than 25 years (nickel air concentrations >1 mg/m3) showed an increased incidence of chromosomal breaks (p<0.001) and gaps (p<0.05) but no difference in sister chromatid exchange compared with the non nickel-exposed controls (n=11). Fish toxicity LC50 (96 hr) fathead minnow, blue gill sunfish 4.9-5.3 mg/L in soft water (20 mg CaCO3/L) or 43.5-39.6 mg/L in hard water (300 mg CaCO3/L). LC50 (48 hr) rainbow trout 20, 80 mg/L in soft, hard water respectively. LC50 (96 hr) tidewater silver side larvae, adult spot fish 30, 70 mg/L respectively (DOSE, 1994). EC Directive on Drinking Water Quality 80/778/EEC Nickel: Maximum admissible concentration 50 µg/L. Chlorides guide level 25 mg/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. 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. Date of last revision 28/1/98 REFERENCES Abeck D, Traenckner I, Steinkraus V, Vieluf D, Ring J. Chronic urticaria due to nickel intake. Acta Derm Venereol 1993; 73: 438-9. Allenby CF, Basketter DA. 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