UKPID MONOGRAPH NICKEL SULPHATE 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 SULPHATE Toxbase summary Type of product Soluble nickel salt used in nickel plating, as a catalyst component and in the dye and printing industry. Toxicity An important cause of contact dermatitis. May precipitate occupational asthma. Gastrointestinal irritation has occurred following ingestion but severe poisoning is rare. A two year-old child has died after ingesting 15 g (Daldrup et al, 1983). Features Topical - Primary skin 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 substantial ingestions, possibly associated with headache, giddiness and myalgia. Substantial ingestions: - Severe gastrointestinal irritation and haemorrhage may ensue. Fatalities have occurred. - Investigations may reveal transient hyperbilirubinaemia, albuminuria or a reticulocytosis. Transient 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 NPIS. 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 obtain blood and urine for nickel concentration estimation. 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 Daldrup T, Haarhoff K, Szathmary SC. Tödliche nickelsulfatintoxikation. Beitr Gerichtl Med 1983; 41: 141-4. Novey HS, Habib M, Wells ID. Asthma and IgE antibodies induced by chromium and nickel salts. J Allergy Clin Immunol 1983; 72: 407-12. 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. Substance name Nickel sulphate Origin of substance Nickel sulphate occurs naturally as the mineral morenosite. (DOSE, 1994) Nickel sulphate may be produced by dissolving nickel oxide in sulphuric acid and concentrating the solution to precipitate nickel sulphate heptahydrate, which on heating forms the commercial crystalline nickel sulphate hexahydrate. (HSDB, 1996) Synonyms Nickel (II) sulphate Nickel monosulphate Nickelous sulphate (DOSE, 1994) Chemical group A compound of nickel, a transition metal (d block) element. Reference numbers CAS 7786-81-4 (DOSE, 1994) RTECS QR935000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure Nickel sulphate, NiSO4 (DOSE, 1994) Molecular weight 154.77 (DOSE, 1994) Physical state at room temperature Solid Colour Alpha form: blue to blue-green crystals; Beta form: green transparent crystals. (MERCK, 1989) Odour Odourless (HSDB, 1996) Viscosity NA pH The aqueous solution is acid, approximately pH 4.5 (MERCK, 1989) Solubility Soluble in water : 293 g/L at 0°C. (HSDB, 1996) Soluble in methanol. (DOSE, 1994) Autoignition temperature NA Chemical interactions NIF Major products of combustion Toxic gases and vapours including nickel carbonyl may be released in a fire involving nickel. (HSDB, 1996) Explosive limits NIF Flammability Non-flammable (HSDB, 1996) Boiling point NIF Density 3.86 at 20°C (DOSE, 1994) Vapour pressure NIF Relative vapour density NIF Flash Point NA Reactivity Nickel sulphate is incompatible with strong acids. (HSDB, 1996) Uses Nickel sulphate is used widely in nickel plating; as a raw material for the production of catalysts; as a mordant in dyeing and printing fabrics; for blackening zinc and brass and in jewellery manufacture. (IPCS, 1991; DOSE, 1994) Hazard/risk classification Index no 028-009-00-5 Risk phrases Carc. Cat 3; R40. Xn; R22, R42/43. Possible risk of irreversible effects. Harmful if swallowed. May cause sensitization by inhalation and skin contact. Safety phrases S(2-) 22 - 36/37. Keep out of reach of children. Do not breathe dust. Wear suitable protective clothing and gloves. EEC no 232-104-9 (CHIP2, 1994) INTRODUCTION AND EPIDEMIOLOGY Nickel sulphate is a soluble nickel salt used widely in nickel patch testing. Poisoning by ingestion is rare although occupational (Sunderman et al, 1988) and domestic (Daldrup et al, 1983) cases have been described. Nickel sulphate inhalation may cause occupational asthma in metal platers (Novey et al, 1983) and polishers (Block and Yeung, 1982). 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). TOXICOKINETICS Absorption Nickel sulphate can be absorbed by inhalation, ingestion and following percutaneous exposure, the latter not being quantitatively significant though an important source of contact sensitivity (IPCS, 1991). Significant mucociliary clearance of inhaled particles occurs. Gastrointestinal absorption is affected by co-ingestion of other substances; in a volunteer study the absorption of nickel sulphate was 27 per cent from water and less than one per cent from food (Sunderman et al, 1989). Distribution and excretion Once absorbed, nickel is transported in the blood bound principally to albumin, 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. Some 50 per cent of inhaled nickel sulphate may eventually also appear in the gut. Animal and human volunteer studies suggest that the distribution and elimination of soluble nickel salts follows a two compartment model with an initial rapid plasma elimination phase (over two days) 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 L nickel sulphate and nickel chloride-contaminated water the serum nickel half-life was 27 ± (SD) 7 hours (Sunderman et al, 1988). These individuals received intravenous fluid (150 mL/hour) for three days following the accident. 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 soluble nickel salts in humans, though at high concentrations they are primary skin irritants (Frosch and Kligman, 1976). Dermal nickel sulphate exposure is associated mainly with the development of nickel contact sensitivity (see Chronic exposure). 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 sulphate, nickel chloride (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 were the most common with nausea, vomiting, abdominal pain and diarrhoea. Ten of 32 patients required hospital admission with symptoms persisting for two days though all were asymptomatic within three days. The mean urine nickel concentration among 15 of those exposed was 5.8 mg/L (range 0.23 - 37.1 mg/L) the day following the incident, 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). A two year-old child reported in the German literature died within hours of ingesting about 15 g nickel sulphate crystals from a chemistry set. Haemorrhagic gastritis was described at autopsy (Daldrup et al, 1983). Hepatotoxicity Two of the ten patients admitted following ingestion of 0.5 - 1.5 L nickel sulphate/chloride contaminated water (see above) developed 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 sulphate and nickel chloride (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) but there are insufficient clinical data to substantiate this. Pulmonary toxicity Of the 21 workers who drank nickel contaminated water (nickel concentration 1.63 g/L), abnormal physical signs were reported only in two; expiratory wheeze in a patient with known bronchial asthma and dyspnoea and mild cyanosis in another with chronic obstructive airways disease (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 sulphate/chloride contaminated water (see above). In both cases this resolved by day five. Haemotoxicity Sunderman et al (1988) reported a modest erythropoietic effect among ten workers who accidentally drank nickel sulphate/chloride-contaminated water (see above) with an increase (p<0.01) in the mean blood haemoglobin concentration between days three and eight post exposure. There was a similar statistically significant increase in the blood reticulocyte count. Cardiovascular toxicity Ingestion of 0.5 - 1.5 L nickel sulphate/chloride 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 sulphate is a common precipitant of allergic contact dermatitis (Zhang et al, 1991) which is a cell-mediated (type IV) hypersensitivity response. 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). Primary nickel 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. 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. Nickel valve prostheses and nickel-containing pacemakers have also been suggested as triggers of nickel allergy (Lyell and Bain, 1974; Landwehr and van Ketel, 1983). 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). Nickel sulphate is widely used as the allergen in nickel patch testing and as the stimulus of lymphocyte blast transformation in the in vitro confirmation of nickel sensitivity (Al-Tawil et al, 1981; Silvennoinen-Kassinen, 1981; Everness et al, 1990; Grimsdottir et al, 1994). Inhalation Pulmonary toxicity Nickel sulphate inhalation is a cause of occupational asthma with circulating IgE nickel antibodies (Nieboer et al, 1984) and resolution of symptoms when away from work (Block and Yeung, 1982). Cases have been reported among metal platers (McConnell et al, 1973; Novey et al, 1983) and polishers (Block and Yeung, 1982). An asthmatic reaction to nickel sulphate inhalation has also been reported in a patient without demonstrable nickel IgE (Malo et al, 1985). 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). Chronic exposure to aerosols of soluble nickel salts, including nickel sulphate, may lead to chronic rhinitis, nasal sinusitis, anosmia and perforation of the nasal septum (Mastromatteo, 1986). 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 not known (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; 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 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 sulphate. Occupational asthma should be managed conventionally, and further exposure avoided. Ingestion Spontaneous vomiting is likely in patients who have ingested a substantial quantity of nickel sulphate and if this does not occur gastric lavage should be avoided in view of potential oesophageal inflammation. General symptomatic and supportive measures are likely to be all that are required in most cases. Measurement of nickel concentrations in blood and urine should be considered 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 nickel burden. Following inadvertent ingestion of 0.5-1.5 L nickel sulphate/ chloride-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 admitted to hospital. The role of chelation therapy in nickel sulphate poisoning is discussed below (Antidotes). Antidotes Animal studies Most experimental studies of nickel chelation therapy have utilized nickel chloride rather than nickel sulphate but the results are relevant to all soluble nickel salts. 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 (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 poisoning with nickel (as subcutaneous nickel chloride 250 µmol/kg). 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 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). 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, TETA or DMPS. DMSA also increases renal nickel elimination. DDC is not an effective antidote in systemic soluble nickel salt poisoning. Clinical studies There are no human data involving chelation therapy in nickel sulphate 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) 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. 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 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 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 calcium edetate Seventeen nickel allergic patients pretreated with a cream containing 10 per cent sodium calcium edetate (EDTA) 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 calcium edetate 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. 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 sulphate 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 long-term maximum exposure limit in air in the UK for soluble nickel is 0.1 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, such as nickel sulphate 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 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 soluble nickel sulphate and nickel chloride 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 maximum exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1995). 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 sulphate and its oxide and subsulphide 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). Fortunately, measures to improve industrial hygiene have greatly reduced the occupational hazard of nickel sulphate exposure but respiratory tract malignancies among nickel industry employees remain notifiable diseases in the UK (Seaton et al, 1994). Reprotoxicity Animal studies have shown reduced fertility and stunted fetal growth following the oral administration of nickel sulphate and testicular damage following oral or dermal nickel sulphate exposure (Reprotext, 1996). Human data specific to nickel sulphate are scarce. 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 sulphate aerosols (range 0.077-0.308 mg Ni/m3) compared to non-exposed controls. Unfortunately this data lacks adequate sampling and statistical details but suggests that the potential reprotoxic hazard of nickel sulphate requires further investigation. Genotoxicity Salmonella typhimurium TA98, TA100, TA1537 without metabolic activation negative. Escherichia coli WP2 without metabolic activation negative. Photobacterium fischeri bioluminescence test negative. Saccharomyces cerevisiae D7 gene conversion equivocal. In vitro Syrian hamster embryo cells, Chinese hamster ovary cells, P338D1 mouse macrophage line, human peripheral blood lymphocytes: Sister chromatid exchanges positive. In vitro Syrian hamster cells, human peripheral blood lymphocytes: Unscheduled DNA synthesis and chromosomal aberrations positive. In vivo rat bone marrow: Chromosomal aberrations negative (DOSE, 1994). 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 LC50 (duration unspecified) rainbow trout 0.36 mg/L. LC50 (14 day) coho salmon 11.2 mg/L. LC50 (1 day) giant gourami 96 mg/L (DOSE, 1994). EC Directive on Drinking Water Quality 80/778/EEC Nickel: Maximum admissible concentration 50 µg/L. Sulphates : Maximum admissible concentration 250 mg/L, guide level 25 mg/L (DOSE, 1994). WHO Guidelines for Drinking Water Quality Guideline value 0.02 mg/L, as nickel (WHO, 1993). 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See Also: Nickel(II) sulphate (ICSC)