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

    Insoluble nickel salt used in nickel refining, stainless steel
    manufacture and electroplating.  Also a component of alloys, ceramics
    and glass.


    Most exposures are via chronic occupational inhalation.  Acute severe
    toxicity is rare.



         -    May cause contact dermatitis.


         -    There are no case reports of nickel oxide ingestion.


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



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


    Mastromatteo E.
    Am Ind Hyg Assoc J 1986; 47: 589-601.

    Muir DCF, Julian J, Jadon N, Roberts R, Roos J, Chan J, Maehle W,
    Morgan WKC.
    Prevalence of small opacities in chest radiographs of nickel sinter
    plant workers.
    Br J Ind Med 1993; 50: 428-31.

    Substance name

         Nickel oxide

    Origin of substance

         Nickel oxide is manufactured by heating nickel to above 400°C in
         the presence of oxygen.            (HSDB, 1996)


         Black nickel oxide
         Green nickel oxide
         Mononickel oxide
         Nickel monoxide
         Nickelous oxide
         Nickel protoxide
         Nickel oxide sinter 75             (RTECS, 1996)

    Chemical group

         A compound of nickel, a transition metal (d block) element.

    Reference numbers

         CAS            1313-99-1           (RTECS, 1996)
         RTECS          QR8400000           (RTECS, 1996)
         UN             NIF

    Physicochemical properties

    Chemical structure
         Nickel oxide, NiO                  (PATTY, 1994)

    Molecular weight
         74.71                              (PATTY, 1994)

    Physical state at room temperature

         Exists in a green or black form    (PATTY, 1994)




         The green form is insoluble in water but soluble in acids; the
         black form is insoluble in both water and acids.
                                            (PATTY, 1994)

    Autoignition temperature

    Chemical interactions
         Nickel oxide is incandescent in fluorine gas.
         Nickel oxide mixed with barium oxide will react vigorously with
         hydrogen sulphide in air, and vivid incandescence or explosion
         may result.                        (NFPA, 1986)

         Nickel oxide mixed with calcium oxide in air may cause vivid
         incandescence or explosion.        (HSDB, 1996)

    Major products of combustion

    Explosive limits


    Boiling point

         6.67 at 20°C                       (PATTY, 1994)

    Vapour pressure

    Relative vapour density

    Flash Point

         The black form of nickel oxide is chemically reactive and will
         form simple salts in the presence of acids.  Green nickel oxide
         is inert.                          (IPCS, 1991)


         Nickel oxide is used in the production of alloys, in enamel frits
         and ceramic glazes, for painting on porcelain and in glass
         manufacture.                       (MERCK, 1989; PATTY, 1994)

         It is also widely used in the manufacture of ferrites and nickel
         salts, in the production of active nickel catalysts and in
         electroplating.                    (HSDB, 1996)

    Hazard/risk classification

    Index no.     028-003-00-2

    Risk phrases
         Carc. Cat. 1; R49, R43.  May cause cancer by inhalation.  May
         cause sensitization by skin contact.

    Safety phrases
         T; S53-45.  Toxic; Avoid exposure - obtain special instruction
         before use.  In case of accident or if you feel unwell, seek
         medical advice immediately (show label where possible).

    EEC no.      215-215-7                  (CHIP2, 1994)


    Nickel oxide exists in green or black forms which differ in
    stoichiometry giving rise to different physicochemical properties (see

    Nickel oxide is an insoluble nickel salt.  Exposure is predominantly
    via chronic occupational inhalation in the nickel refining and
    stainless steel manufacturing industries (Koponen et al, 1981; Draper
    et al, 1994; Warner, 1984; Langard, 1994).

    In the melting and casting processes of stainless steel manufacture
    nickel occurs chiefly as the element in iron oxide fume (the total
    dust contains 0.02-0.7 per cent nickel), with only small amounts of
    nickel oxide produced.

    Particulate nickel oxide is present in stainless steel welding fumes 
    (Koponen et al, 1981).

    In the nickel refining industry, workers employed in the roasting and
    smelting processes are exposed mainly to nickel dust containing nickel
    oxide and subsulphide (average atmospheric concentration 0.5 mg
    Ni/m3).  Non-process workers may be exposed to numerous nickel
    composites including nickel oxide (average atmospheric concentration
    0.1 mg Ni/m3) (Torjussen and Andersen, 1979).

    Historically, inefficient nickel refining processes (with poor nickel
    recovery) necessitated recycling of nickel residues so workers were
    frequently exposed to large amounts of nickel (and copper) oxide dusts
    and some forms of arsenic.   Increased refining efficiency avoids
    recycling (Draper et al, 1994). Some modern nickel refining procedures
    avoid nickel oxide production completely (Warner, 1984).


     In vitro studies demonstrate that nickel causes crosslinking of
    amino acids to DNA, alters gene expression, induces gene mutations and
    the formation of reactive oxygen species (Costa et al, 1994a and b;
    Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994).  Nickel also
    suppresses natural killer cell activity and interferon production
    (Shen and Zhang, 1994).  Beyersmann (1994) has suggested nickel (and
    other genotoxic metals) enhance the damaging effects of genotoxins
    such as ultraviolet radiation and alkylating substances via impairing
    DNA repair mechanisms.



    Nickel oxide can be absorbed by inhalation and ingestion, the former
    being more important occupationally.  Significant percutaneous
    absorption does not occur.

    It has been estimated that 75 per cent of inspired particulate metals
    (including nickel oxide) are retained in the respiratory tree
    (Schroeder, 1970) and two thirds of this is eventually swallowed after
    clearance from the airways by the mucociliary mechanism.   Systemic
    absorption from pulmonary tissue is slow (Roels et al, 1993).

    Nickel oxide is less well absorbed following ingestion than are
    soluble nickel salts.

    Distribution and excretion

    Once absorbed, nickel is transported in the blood bound principally to
    albumin, concentrated in the kidneys, liver and lungs and is excreted
    primarily in the urine.  However, the concentration of nickel in
    faeces will be much higher than in urine since most ingested nickel is
    not absorbed and most inhaled nickel also appears in the gut.

    The half-life of nickel in urine following nickel oxide inhalation has
    been estimated around 50 hours (Sunderman, 1992) although some inhaled
    nickel is retained significantly longer than this.  Among a sample of
    retired nickel refinery workers, the nickel half-life in the nasal
    mucosa was estimated to be three and a half years.

    Nickel crosses the placenta and is passed to the child in maternal
    milk (Fairhurst and Illing, 1987; IPCS, 1991).


    Although nickel oxide is a pulmonary irritant, acute exposure is
    unlikely to result in significant poisoning.  Documented clinical
    cases invariably involve chronic occupational inhalation.


    Dermal exposure

    Nickel is a common precipitant of allergic contact dermatitis (Zhang
    et al, 1991) although nickel oxide is less likely to initiate this
    hypersensitivity response than are soluble nickel salts.  However,
    workers occupationally exposed to nickel oxide at nickel refining
    plants are invariably also exposed to nickel sulphate and nickel
    chloride.  Even so, nickel dermatitis is not a significant
    occupational hazard at these establishments, possibly due to
    development of immunological tolerance following chronic nickel
    inhalation (Menné, 1992).  Non-occupational skin contact with nickel
    plated objects or nickel alloys remains the primary cause of nickel
    sensitization and is more common in women (Peltonen, 1979).

    Chronic urticaria, a type 1 hypersensitivity cutaneous reaction, has
    also been described (Abeck et al, 1993).

    Nickel sensitivity has been implicated in the aetiology of pompholyx,
    a vesicular eruption of the palmoplantar regions (Lodi et al, 1992).

    Once an individual is sensitized, further exposure to only a very
    small quantity of nickel initiates a reaction at the site of contact. 
    Nickel may penetrate rubber gloves (Wall, 1980).

    In susceptible individuals nickel allergy may result in "secondary"
    nickel dermatitis with dissemination  to skin sites distant from that
    of primary sensitization (typically the hands, flexures and eyelids
    (Valsecchi et al, 1992).  It is not clear whether the latter is an
    endogenous phenomenon or simply reflects exogenous nickel
    contamination, for example via perspiring fingers (Fisher, 1986).


    Pulmonary Toxicity

    Following chronic nickel oxide inhalation large amounts of nickel are
    retained in pulmonary tissue (Roels et al, 1993).

    Andersen and Svenes (1989) analysed lung specimens obtained at autopsy
    from 39 nickel refinery workers.  Workers employed in the roasting and
    smelting department (n=15) exposed chiefly to nickel oxide and
    sulphide had significantly higher (p<0.01) lung nickel concentrations
    (mean 330 ± (SD) 380 µg/g dry weight) than employees from the
    electrolysis department (n=24) exposed  primarily to soluble nickel

    sulphate and nickel chloride (mean lung nickel concentrations  34 ±
    (SD) 48 µg/g).  These values compare to a mean lung nickel
    concentration of  0.76 ± (SD) 0.39 µg/g among 16 autopsies of
    non-exposed people.

    Nickel pneumoconiosis and interstitial fibrosis with a mild
    restrictive lung function defect have been described in steel workers
    exposed to mixtures of nickel oxide, iron oxide and chromium oxide
    fumes for at least 14 years (Graham Jones and Warner, 1972).  It is
    impossible to determine the precise aetiological role of nickel oxide
    in these cases.

    Muir et al (1993) reviewed chest X-rays of 745 nickel sinter plant
    workers exposed to nickel oxide and subsulphide while employed between
    1948 and 1963.   One hundred and forty nine individuals had been
    employed at the plant for at least five years.  In every case the most
    recent chest X-ray available was reviewed.  Employees were exposed to
    nickel concentrations up to 100 mg/m3  which had previously been
    associated with an increased lung cancer incidence.  However their
    chest X-rays showed only minimal evidence of small (round or
    irregular) opacities, similar to those described in smokers or workers
    exposed to low-fibrogenic dusts.  These authors concluded that
    occupational exposure to nickel dust  did not elicit an inflammatory
    or fibrogenic lung response (Muir et al, 1993).

    In summary, limited evidence suggests chronic nickel oxide inhalation
    may cause pneumoconiosis but concomitant exposure to other pulmonary
    irritants precludes a definitive conclusion.

    While electroplaters are exposed to mists of soluble nickel salts from
    plating baths, workers involved in the buffing and polishing processes
    are exposed to metallic nickel and nickel oxide.  Employees in all
    stages of nickel plating may develop chronic rhinitis, nasal
    sinusitis, anosmia and perforation of the nasal septum (Mastromatteo,
    1986).  There are also reports of asthma attributed to nickel allergy
    in this industry (McConnell et al, 1973).

    It is likely nickel allergy is involved in the aetiology of
    'hard-metal' asthma (typically associated with cobalt exposure)  with
    evidence of cross reactivity between cobalt and nickel (Shirakawa et
    al, 1990; Shirakawa et al, 1992).


    A study of renal function in 26 nickel refinery workers found no
    significant elevation of urinary total protein or ß2 microglobin
    (Sanford and Nieboer, 1992).


    There are no reported cases of chronic nickel oxide ingestion although
    ingested nickel in any form may exacerbate nickel dermatitis (see

    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 dermatitis
    exacerbations with topical or systemic steroids remain the mainstay of
    treatment of nickel allergy although dietary nickel restriction
    (Kaaber et al, 1978) or oral (Panzani et al, 1995) or topical (Allenby
    and Basketter, 1994) hyposensitization have been advocated.  Oral
    cyclosporin does not appear to be effective (De Rie et al, 1991).  The
    role of chelation therapy is discussed below.


    Removal from exposure and symptomatic and supportive treatment are all
    that are likely to be required following acute nickel oxide
    inhalation.  Respiratory symptoms in nickel refinery workers should be
    investigated conventionally remembering that respiratory tract
    malignancy occurs more frequently in those chronically exposed to high
    concentrations of nickel oxide and subsulphide (see below,


    Nickel oxide ingestion has not been reported.  Symptomatic and
    supportive measures are likely to be all that are required should this
    occur, with measurement of nickel concentrations in blood and urine
    only in symptomatic patients. Since nickel is eliminated mainly in the
    urine, maintenance of a high urine output is important in those with a

    confirmed or suspected increased body nickel burden.  The role of
    chelation therapy in nickel poisoning is discussed below (Antidotes).


    The role of chelation therapy in nickel oxide poisoning is limited
    since toxicity is due primarily to pulmonary nickel deposits following
    chronic inhalation. Most animal studies involve parenteral
    administration of soluble nickel salts. Available clinical data
    involve the management of nickel dermatitis.

    Animal studies

    The effect of chelating agents on nickel distribution is dependent on
    their lipid solubility.  Lipophilic agents (such as
    diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride
    (TETA)) are more able to penetrate cell membranes with potential
    nickel redistribution to lipid rich tissues such as the liver and
    brain (Misra et al, 1987).  By contrast, hydrophilic chelating agents
    (e.g. sodium calcium ethylenediamine tetraacetic acid (EDTA)) are more
    likely to enhance renal nickel clearance without cellular nickel
    accumulation (Misra et al, 1987).

    Misra et al (1987) observed a significant reduction (p<0.05) in renal
    nickel content in rodents following treatment with both lipophilic
    (1,4,8,11-tetra-azacyclotetradecane and TETA) and hydrophilic (sodium
    calcium edetate, 1,2,cyclohexylenediamine tetraacetic acid,
    diethylenetriamine pentaacetic acid) chelating agents 500 µmol/kg
    subcutaneously 60 minutes post nickel poisoning (as subcutaneous
    nickel chloride 250 µmol/kg).  By contrast the hepatic nickel content
    was increased following treatment with lipophilic agents, but reduced
    after hydrophilic antidote administration (Misra et al, 1987).

    Oskarsson and Tjälve (1980) investigated the effect on nickel
    distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine
    3.4 mmol/kg in mice administered a chelating agent ten minutes before
    an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg).  DDC
    caused increased tissue nickel retention compared to control mice
    (injected with nickel chloride alone), with the highest radioactivity
    in adipose tissue followed by the liver, kidneys, brain and spinal
    cord.  The brain nickel content of DDC treated mice was 57 times
    higher than control mice.  Following d-penicillamine the tissue nickel
    content was lower than in control mice.  For example,  the "kidney
    contained about 1% and the lung about 4%" of the radioactivity
    observed in mice given 63nickel chloride only.

    Sodium calcium edetate 400 µmol/kg subcutaneously reduced the nickel
    content of the liver, heart, kidney and lung by 20-40 per cent in
    rodents poisoned with nickel (as subcutaneous nickel chloride 200
    µmol/kg) 30 minutes previously (Dwivedi et al, 1986).

    In rats (n=20-25 in each group) the two week mortality following
    intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95 0.29
    mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg, (0.3
    times its LD50) was given one minute prior to nickel dosing (Horak et
    al, 1976).  Under the same experimental conditions TETA 1.36 mmol/kg
    (0.6 times its LD50) reduced (p<0.001) the two week mortality to 25
    per cent but DDC was ineffective.  Sodium calcium edetate 0.68 mmol/kg
    reduced the two week mortality to 32 per cent (p<0.001) when the
    nickel chloride dose was 0.136 mmol/kg (greater than its LD50).

    Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium calcium
    edetate (administered intraperitoneally at a molar ratio of 10:1
    chelating agent: nickel) increased survival in rodents systemically
    poisoned with nickel (as intraperitoneal nickel acetate, 62 mg/kg). 
    The results are summarized in Table 1 (Basinger et al, 1980).

    Table 1. Survival rates in nickel intoxicated mice following chelation
    therapy (see text)


    n=        Chelating agent              Survival %

     5        None                             0
    10        DMPS                            80
    10        d-penicillamine                100
    10        Sodium calcium edetate         100

                                     (after Basinger et al, 1980)

    Shen et al (1979) studied the effect of several chelating agents
    (administered subcutaneously) on renal nickel clearance in rats
    administered a continuous nickel chloride infusion.  Each chelating
    agent was administered to a different group of six rats with eight
    controls.  d-Penicillamine 1 µmol/h increased mean renal nickel
    clearance by 53 per cent (p<0.001) and TETA 1 µmol/h by 26 per cent
    (p< 0.025) but DDC 2 µmol/h did not affect renal nickel clearance.

    DMPS 0.5 mmol/kg significantly  enhanced urine nickel excretion
    (0.001< p < 0.05) when administered subcutaneously to rats poisoned
    with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant
    decreases in nickel-induced hyperglycaemia and aminoaciduria were
    noted following chelation therapy.  Faecal nickel excretion was
    unaffected and DMPS was ineffective in mobilizing nickel from the
    brain (Sharma et al, 1987).

    In mice systemically poisoned with nickel chloride (5 mg/kg),
    intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the
    brain (Xie et al, 1994).  DMSA 400 µmol/kg intraperitoneally,
    significantly enhanced (p<0.05) the faecal and urinary excretion of
    the metal and there was no redistribution to the brain (Xie et al,

    1994). The same group recently found parenteral DMSA and
    N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the
    testicular nickel concentration and so protecting against
    nickel-induced testicular toxicity in mice administered
    intraperitoneal nickel chloride (Xie et al, 1995).

    In summary, in rodents systemically poisoned with soluble nickel
    salts, renal nickel clearance is increased and mortality reduced by
    the parenteral administration of d-penicillamine, TETA or DMPS.  DMSA
    also increases renal nickel elimination.  DDC is not an effective
    antidote in experimental systemic soluble nickel salt poisoning.

    Clinical studies

    There are no data specifically involving nickel oxide exposure.

    Diethlydithiocarbamate and disulfiram in nickel dermatitis

    Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that:

    2(DDC) + Ni2+  ----  Nickel bis(DDC)  which is renally excreted.

    DDC is not available as a pharmaceutical preparation in many countries
    although disulfiram (Antabuse), which is metabolised to DDC (two
    molecules of DDC from each of disulfiram), has been employed.

    The rationale for the use of DDC and disulfiram in nickel dermatitis
    is that both agents reduce the body nickel burden and so minimise the
    amount of nickel available for the endogenous activation of
    immunocompetent cells.

    Topical DDC

    van Ketel and Bruynzeel (1982) investigated the role of topical DDC in
    the prevention of nickel sensitivity in 17 patients with known nickel
    allergy.  Prior to nickel challenge seven patients were pretreated for
    24 hours with 10 per cent DDC under an occlusive dressing.  They were
    challenged with nickel (as nickel sulphate 0.01, 0.1, 1.0 and 5.0 per
    cent solutions) and a nickel coin (99.7 per cent nickel).  Ten
    patients applied 10 per cent DDC six hourly for 24 hours prior to
    nickel sulphate challenge.  There were no differences in mean patch
    test scores between DDC-treated and non DDC-treated skin in all groups
    (Table 2).

    Table 2.  Topical DDC in nickel dermatitis


    n=   24 h               Nickel challenge                    Mean ± SD
         Pretreatment                                        patch-test score
                                                         Control       DDC

    7    10% DDC            Nickel sulphate              3.9 ± 2.1     4.0 ± 3.2
         under occlusion    (0.01, 0.1, 1.0 and 5.0%) 

    7    10% DDC            Coin                         0.9 ± 0.7     1.8 ± 1.1
         under occlusion    (99.7% nickel)

    10   10% DDC            Nickel sulphate              2.9 ± 2.7     2.5 ± 3.1
         qds                (0.01, 0.1, 1.0 and 5.0%)
                                                   (van Ketel and Bruynzeel, 1982)

    Oral DDC and disulfiram

    Several uncontrolled studies report the successful resolution of
    nickel dermatitis following oral DDC or disulfiram.  Uncontrolled
    studies of disulfiram therapy in nickel dermatitis are summarized in
    Table 3.

    Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg
    daily for 20 days led to an improvement in dermatitis although the
    condition recurred when treatment was discontinued.

    In another patient (Spruit et al, 1978) oral DDC for two months failed
    to produce a negative nickel patch test, although less local treatment
    was required.

    Disulfiram certainly increases urine nickel excretion in patients with
    nickel dermatitis (Table 4) but  in a double-blind study involving 24
    such patients treated with disulfiram 200 mg daily or placebo for six
    weeks, there was no overall significant difference between treatments
    (Kaaber et al, 1983).

    Adverse effects of DDC and disulfiram

    There is concern that disulfiram and DDC may promote nickel
    accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al,
    1987). DDC is lipophilic and in  in vitro studies can enhance
    cellular Ni2+ uptake  (Nieboer et al, 1984; Menon and Nieboer, 1986).
    Disulfiram is also associated frequently with a 'flare-up' of nickel
    dermatitis soon after commencing treatment (Kaaber et al, 1979; Menné
    et al, 1980; Christensen and Kristensen, 1982; Christensen, 1982
    (Table 3); Klein and Fowler, 1992; Gamboa et al, 1993).  Other
    reported adverse effects of disulfiram therapy include abnormal liver

        Table 3.  Uncontrolled studies of disulfiram in nickel dermatitis


    n=            Disulfiram                      Effect on dermatitis                       Study
            Dose        Duration    & Early       %            %               % 
            (mg/day)    (wks)       flare         "Healed"     "Improved"      Rebound1

     1      300         8           -             -            100             100           Menné & Kaaber, 1978

    11      200-400     "4-10"      82            64           18              55            Kaaber et al, 1979

    11      200-400     ?           82            73           -               -             Menné et al, 1980

    11      200         8           100           18           73              100           Christensen & Kristensen, 1982

     3      50-200      18 (mean)   100           33           66              33            Christensen, 1982

    61      50-400      12 (mean)   ?2            46           30              85 (n=27)3    Kaaber et al, 1987
    98                              -             47           32              66 (n=64)

    1 Rebound dermatitis when disulfiram discontinued
    2 Flares of dermatitis "frequently seen" but number not stated
    3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases
    Table 4.  Disulfiram in nickel dermatitis: urine nickel excretion

    n=    Disulfiram         Mean ± SD urine        Study
          dose              nickel excretion
          (mg/day)              (µg/24 h)
                        Before      Maximum during
                        treatment   treatment

    3     200-400       1.2 ± 0.3   53 ± 15.5       Kaaber et al, 1979

    6     200-400       1.7 ± 0.5   60 ± 23.8       Menné et al, 1980

    function (Kaaber et al, 1983; Kaaber et al, 1987), an acne-like rash
    (Kaaber et al, 1983), headache (Kaaber  et al, 1979; Kaaber et al,
    1983), fatigue and dizziness (Kaaber et al, 1979) and an adverse
    reaction with alcohol.  Reactivation of nickel sensitivity often
    occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber et al,
    1987; Table 3).

    Sodium calcium edetate

    Seventeen nickel allergic patients pretreated with a cream containing
    10 per cent sodium calcium edetate showed a significant reduction in
    positive patch tests to nickel (as a one per cent nickel sulphate
    solution) compared to results on untreated skin (three positive
    reactions compared to 14 respectively, p<0.01) (van Ketel and
    Bruynzeel, 1982).  The authors suggested use of 10 per cent sodium
    calcium edetate barrier creams in nickel sensitive subjects but this
    requires further study.


    A recent study reported that topical administration of the chelating
    agent clioquinol (three per cent) "completely abolished" reactivity to
    nickel in 29 nickel-sensitive subjects and the authors advocated its
    use as a barrier ointment in nickel allergic patients (Memon et al,
    1994) but this requires confirmation.

    Antidotes: Conclusions and recommendations

    Nickel contact sensitivity

    1.   Nickel contact sensitivity is managed most effectively by
         avoiding exposure and treating acute exacerbations with topical
         and/or systemic steroids.
    2.   Topical DDC has no role.  There is some evidence that barrier
         creams containing sodium calcium edetate or clioquinol may be

    3.   While there are two case reports claiming benefit from oral DDC
         in the treatment of nickel dermatitis, this has not been
         confirmed in a controlled clinical study.
    4.   In the only published controlled clinical study using disulfiram
         in the management of nickel dermatitis there was no overall
         benefit from treatment.
    5.   Uncontrolled studies with oral disulfiram suggest improvement in
         secondary nickel dermatitis but the incidence of significant
         side-effects is high.
    6.   Chelation therapy in nickel dermatitis cannot be advocated
         routinely but remains an area of research interest.

    Systemic nickel poisoning

    1.   There are no human data available regarding chelation therapy in
         systemic nickel oxide toxicity.
    2.   Animal studies suggest d-penicillamine is probably the most
         effective nickel antidote although there are promising results
         and less adverse effects with the newer thiol chelating agents,
         particularly DMPS.


    Prior to employment involving nickel exposure special consideration
    should be given to those with a history of contact dermatitis or
    respiratory disease.  The maximum long-term exposure limit in air in
    the UK for insoluble nickel is 0.5 mg/m3 (Health and Safety
    Executive, 1995).

    Monitoring of nickel concentrations in blood and urine are not
    indicated routinely because while they provide evidence of recent
    exposure to soluble nickel compounds and nickel metal powder, they do
    not reflect the total body nickel burden and are of limited use for
    monitoring workers exposed primarily to nickel oxide and other
    insoluble salts.

    Moreover, urine nickel concentrations vary considerably and should be
    interpreted as groups of 24 hour samples rather than individual urine
    specimens (Nickel Producers Environmental Research Association and the
    Nickel Development Institute, 1994).

    Serum nickel concentrations are used in some industries since they
    avoid contamination from work-place dust and provide fairly consistent
    values within a given work environment; mean serum nickel
    concentrations ranging from 0.9 µg/L for grinders and polishers to
    11.9 µg/L in electrolytic refining workers have been cited (Nickel
    Producers Environmental Research Association and the Nickel
    Development Institute, 1994).

    In a controlled study Torjussen and Andersen (1979) determined nasal
    mucosal, plasma and urine nickel concentrations in 318 present and 15
    retired workers all employed for at least eight years in a nickel
    refining plant.  Mean nickel concentrations in all samples were
    significantly lower in the control group (n=57) than the corresponding
    values for the active (p<0.01) and retired (p<0.05) workers
    (Torjussen and Andersen, 1979).

    In the same study (Torjussen and Andersen, 1979) smelting and roasting
    workers exposed to nickel oxide and subsulphide dust (average air
    nickel concentration 0.5 mg/m3) exhibited significantly higher
    (p<0.01) nasal mucosal nickel concentrations (467.2 ± (SD) 594.6
    µg/100 g wet weight) than electrolytic workers exposed to soluble
    nickel sulphate and nickel chloride aerosols (178.1 ± (SD) 234.7
    µg/100g wet weight).  Plasma and urine nickel concentrations however
    were significantly higher (p<0.01) in electrolytic workers than in
    those exposed to nickel oxide (Torjussen and Andersen, 1979).

    In the roasting/smelting workers nasal mucosal nickel concentrations
    significantly correlated (p<0.01) with duration of exposure (to
    nickel oxide and subsulphide). Among the retired workers the authors
    estimated a nickel half-life in the nasal mucosa of three and a half
    years (Torjussen and Andersen, 1979). They suggested that nasal
    mucosal nickel concentrations were more reliable indicators of upper
    respiratory tract nickel accumulation then were plasma or urine nickel
    concentrations (Torjussen and Andersen, 1979).

    In another controlled study Roels et al (1993) measured the nickel
    concentration of total inhalable dust (mean 22.9 µg/m3), respirable
    dust (mean 3.5 µg/m3) and pre- and post-shift urine for five days in
    20 workers exposed to nickel oxide during electrical resistance
    manufacture.  In nineteen workers nickel urine concentrations did not
    differ between pre- (mean 1.2 µg/g creatinine) and post- (1.1 µg/g
    creatinine) shift samples (control mean 0.5 µg/g creatinine, n=17). 
    In addition, urine nickel elimination was not affected by up to two
    weeks vacation.  These results add further support to the view that
    urine nickel excretion is not a reliable indicator of occupational
    nickel exposure.

    The interpretation of urine nickel excretion data is further
    complicated by the fact that the particle size of inhaled nickel
    greatly affects its bioavailability.  For example, one worker in the
    study by Roels et al (1993) had substantially higher post-shift urine
    nickel concentrations (range 21-101 µg/g creatinine) compared to
    pre-shift values (range 11-33 µg/g creatinine).  His urine nickel
    excretion was also reduced (to 4.4 µg/g creatinine) following a two
    week vacation.  The authors explained these results by noting that
    this individual handled smaller nickel oxide particles than his 19
    colleagues (particle diameter 1-8 µm compared to 150-600 µm).  He
    therefore had a substantially higher respirable nickel fraction
    (respirable nickel concentration 158 µg/m3 compared to 3 µg/m3).

    Gammelgaard et al (1992) suggested that a fingernail nickel content
    greater than 8 ppm indicates likely occupational (rather than
    domestic) nickel exposure in patients with nickel dermatitis but the
    reliability of this proposal has not been confirmed.


    Maximum exposure limit

    Nickel, inorganic, insoluble compounds: Long-term maximum exposure
    limit (8 hour TWA reference period) 0.5 mg/m3 (Health and Safety
    Executive, 1995).



    The carcinogenic status of nickel oxide has been disputed.  Assessment
    is difficult since nickel workers are rarely occupationally exposed to
    nickel oxide alone.  For example, Draper et al (1994) studied two
    historical dust samples (1920 and 1929) from a nickel refining plant
    in Wales and identified the presence of up to 10 per cent arsenic in
    addition to nickel oxide.  The later sample had a lower arsenic
    content, correlating with a reduction in the number of respiratory
    cancers reported among 'nickel' workers at this time.  The authors
    concluded that arsenic, probably in the form of nickel arsenide, was
    the likely aetiological agent responsible for the cancers observed
    (Draper et al, 1994).

    Smoking habits of employees further complicates the interpretation of
    cancer mortality data in the nickel industry. Cigarette smoking not
    only directly increases the risk of respiratory tract cancer but also
    indirectly increases risk via impaired mucociliary clearance of toxic
    particles from the bronchial mucosa (Langard, 1994).

    Cox et al (1981) considered the mortality of 1925 nickel alloy
    manufacturing workers employed for at least five years and exposed to
    metallic nickel and nickel oxide (nickel concentrations 0.5-0.9
    mg/m3) but not nickel subsulphide.  The standardized mortality ratio
    among these employees for lung cancer, cancer of other respiratory
    sites, respiratory disease or ischaemic heart disease was not
    increased significantly.  That nickel oxide should not be considered
    carcinogenic was suggested also by Longstaff et al (1984) in a review
    of epidemiological data concerning the incidence of respiratory cancer
    among nickel refining employees.

    In contrast more recent epidemiological studies have shown a
    significant increase in deaths from carcinoma of the lung and nasal
    sinuses among nickel refinery workers (Roberts et al, 1992; Andersen,
    1992).  The exact aetiological agent is unknown although nickel
    sulphate, oxide and subsulphide have been suspected. Nickel oxide and
    subsulphide are probably also responsible for the increased incidence
    of nasal mucosal dysplasia observed in nickel refiners (Torjussen et
    al, 1979).

    The most recent International Agency for Research on Cancer (IARC)
    monograph on nickel carcinogenicity (IARC, 1990) concluded "there is
    sufficient evidence in humans for the carcinogenicity of ...... the
    combinations of nickel sulfide and oxides encountered in the nickel
    refining industry".  The excess risk of death continues for several
    years after leaving employment (Muir et al, 1994).  An increased
    incidence of laryngeal cancer has not been confirmed (Roberts et al,

    Thirty-nine nickel refiners (Andersen and Svenes, 1989) diagnosed with
    lung cancer had lung nickel concentrations at autopsy equal to those
    who died of other causes, indicating that the pulmonary nickel
    concentration is not a reliable indicator of aetiology of death
    (Andersen and Svenes, 1989).

    Fortunately, measures to improve industrial hygiene have greatly
    reduced the occupational hazard of nickel oxide exposure but
    respiratory tract malignancies among nickel industry employees remain
    notifiable diseases in the UK (Seaton et al, 1994).

    Among stainless steel workers, it is unclear whether nickel or
    hexavalent chromium compounds present in the welding fume is the
    greater risk factor for lung cancer (Langard, 1994).


    There are no human data regarding the reprotoxicity of nickel oxide.

    Animal studies have shown reduced body weight following exposure of
    rat foetuses to nickel oxide (1.6 and 3.2 mg/m3).

    Following nickel oxide inhalation, nickel crossed the placenta in rats
    in a dose-dependent manner (Reprotext, 1996).


    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

    Nickel : LC50 (96 h) banded killfish, striped bass, pumpkin seed,
    white perch, American eel, carp 6.2-46.2 mg/L (salt unspecified).
    Rainbow trout exposed to nickel (salt unspecified) had a reduction in
    glucidic stores which is consistent with direct metal interactions
    with membranes and enzyme thiol groups of pancreas cells.
    Life-cycle study fathead minnow (pH 7.8, 18°C, 210 mg CaCO3 hardness)
    <0.38 mg/L (salt unspecified) did not adversely affect reproduction,
    survival or growth; 0.78 mg/L (salt unspecified) significantly
    affected the number and hatchability of eggs, growth survival of the
    first generation was not affected.

    LC50 (74 h) carp eggs 6.1 mg/L, larvae, 8.4 mg/L (salt unspecified);
    3 mg/L caused increased numbers of abnormal larvae and embryos which
    failed to hatch.

    LC50 (from fertilization to day 4 after hatching) channel catfish
    0.71 mg/L, goldfish 2.78 mg/L (salt unspecified) (DOSE, 1994).

    EC Directive on Drinking Water Quality 80/778/EEC

    Nickel : Maximum admissible concentration 50 µg/L (DOSE, 1994).

    WHO Guidelines for Drinking Water Quality

    Guideline value 0.02 mg/L, as nickel (WHO, 1993).


    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