SM Bradberry BSc MB MRCP
    ST Beer BSc

    National Poisons Information Service
    (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    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


    Toxbase summary

    Type of product

    Soluble nickel salt used in nickel plating, as a catalyst component
    and in the dye and printing industry.


    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).



         -    Primary skin irritant and an important cause of contact


    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.


         -    A potential cause of occupational asthma. Chronic inhalation
              may cause rhinitis, sinusitis, anosmia and perforation of
              the nasal septum.



    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.


    1.   In mild cases symptomatic and supportive measures will suffice.
    2.   Gastric lavage is best avoided in view of potential oesophageal
    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.


    1.   Remove from exposure.
    2.   Symptomatic and supportive measures as required.
    3.   Occupational asthma should be managed conventionally.


    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)


         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

    Physicochemical properties

    Chemical structure
         Nickel sulphate, NiSO4                  (DOSE, 1994)

    Molecular weight
         154.77                                  (DOSE, 1994)

    Physical state at room temperature

         Alpha form: blue to blue-green crystals; Beta form: green
         transparent crystals.                   (MERCK, 1989)

         Odourless                               (HSDB, 1996)


         The aqueous solution is acid, approximately pH 4.5
                                                 (MERCK, 1989)

         Soluble in water : 293 g/L at 0°C.      (HSDB, 1996)
         Soluble in methanol.                    (DOSE, 1994)

    Autoignition temperature

    Chemical interactions

    Major products of combustion
         Toxic gases and vapours including nickel carbonyl may be released
         in a fire involving nickel.             (HSDB, 1996)

    Explosive limits

         Non-flammable                           (HSDB, 1996)

    Boiling point

         3.86 at 20°C                            (DOSE, 1994)

    Vapour pressure

    Relative vapour density

    Flash Point

         Nickel sulphate is incompatible with strong acids.
                                                 (HSDB, 1996)


         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)


    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).


     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).



    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).


    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).


    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).


    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).


    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).


    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.


    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).


    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,

    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,


    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,

    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).


    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).


    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.


    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.


    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.


    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

    The role of chelation therapy in nickel sulphate poisoning is
    discussed below (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.


    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

    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.


    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.


    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).



    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).


    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,

    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.


     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,

    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

    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).


    SM Bradberry BSc MB MRCP
    ST Beer BSc

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    B18 7QH

    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


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    See Also:
       Toxicological Abbreviations