UKPID MONOGRAPH
NICKEL OXIDE
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
NICKEL OXIDE
Toxbase summary
Type of product
Insoluble nickel salt used in nickel refining, stainless steel
manufacture and electroplating. Also a component of alloys, ceramics
and glass.
Toxicity
Most exposures are via chronic occupational inhalation. Acute severe
toxicity is rare.
Features
Topical
- May cause contact dermatitis.
Ingestion
- There are no case reports of nickel oxide ingestion.
Inhalation
- A potential cause of occupational asthma. Chronic
inhalation may cause rhinitis, sinusitis, anosmia,
perforation of the nasal septum and/or pneumoconiosis.
Management
Topical
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Chelation therapy in nickel contact dermatitis cannot be
advocated routinely but is an area of research interest. Discuss
with NPIS.
Inhalation
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Occupational asthma and pneumoconiosis should be investigated and
managed conventionally.
References
Mastromatteo E.
Nickel.
Am Ind Hyg Assoc J 1986; 47: 589-601.
Muir DCF, Julian J, Jadon N, Roberts R, Roos J, Chan J, Maehle W,
Morgan WKC.
Prevalence of small opacities in chest radiographs of nickel sinter
plant workers.
Br J Ind Med 1993; 50: 428-31.
Substance name
Nickel oxide
Origin of substance
Nickel oxide is manufactured by heating nickel to above 400°C in
the presence of oxygen. (HSDB, 1996)
Synonyms
Black nickel oxide
Green nickel oxide
Bunsenite
Mononickel oxide
Nickel monoxide
Nickelous oxide
Nickel protoxide
Nickel oxide sinter 75 (RTECS, 1996)
Chemical group
A compound of nickel, a transition metal (d block) element.
Reference numbers
CAS 1313-99-1 (RTECS, 1996)
RTECS QR8400000 (RTECS, 1996)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
Nickel oxide, NiO (PATTY, 1994)
Molecular weight
74.71 (PATTY, 1994)
Physical state at room temperature
Solid
Colour
Exists in a green or black form (PATTY, 1994)
Odour
NIF
Viscosity
NA
pH
NIF
Solubility
The green form is insoluble in water but soluble in acids; the
black form is insoluble in both water and acids.
(PATTY, 1994)
Autoignition temperature
NIF
Chemical interactions
Nickel oxide is incandescent in fluorine gas.
Nickel oxide mixed with barium oxide will react vigorously with
hydrogen sulphide in air, and vivid incandescence or explosion
may result. (NFPA, 1986)
Nickel oxide mixed with calcium oxide in air may cause vivid
incandescence or explosion. (HSDB, 1996)
Major products of combustion
NIF
Explosive limits
NIF
Flammability
NIF
Boiling point
NIF
Density
6.67 at 20°C (PATTY, 1994)
Vapour pressure
NIF
Relative vapour density
NIF
Flash Point
NIF
Reactivity
The black form of nickel oxide is chemically reactive and will
form simple salts in the presence of acids. Green nickel oxide
is inert. (IPCS, 1991)
Uses
Nickel oxide is used in the production of alloys, in enamel frits
and ceramic glazes, for painting on porcelain and in glass
manufacture. (MERCK, 1989; PATTY, 1994)
It is also widely used in the manufacture of ferrites and nickel
salts, in the production of active nickel catalysts and in
electroplating. (HSDB, 1996)
Hazard/risk classification
Index no. 028-003-00-2
Risk phrases
Carc. Cat. 1; R49, R43. May cause cancer by inhalation. May
cause sensitization by skin contact.
Safety phrases
T; S53-45. Toxic; Avoid exposure - obtain special instruction
before use. In case of accident or if you feel unwell, seek
medical advice immediately (show label where possible).
EEC no. 215-215-7 (CHIP2, 1994)
INTRODUCTION AND EPIDEMIOLOGY
Nickel oxide exists in green or black forms which differ in
stoichiometry giving rise to different physicochemical properties (see
above).
Nickel oxide is an insoluble nickel salt. Exposure is predominantly
via chronic occupational inhalation in the nickel refining and
stainless steel manufacturing industries (Koponen et al, 1981; Draper
et al, 1994; Warner, 1984; Langard, 1994).
In the melting and casting processes of stainless steel manufacture
nickel occurs chiefly as the element in iron oxide fume (the total
dust contains 0.02-0.7 per cent nickel), with only small amounts of
nickel oxide produced.
Particulate nickel oxide is present in stainless steel welding fumes
(Koponen et al, 1981).
In the nickel refining industry, workers employed in the roasting and
smelting processes are exposed mainly to nickel dust containing nickel
oxide and subsulphide (average atmospheric concentration 0.5 mg
Ni/m3). Non-process workers may be exposed to numerous nickel
composites including nickel oxide (average atmospheric concentration
0.1 mg Ni/m3) (Torjussen and Andersen, 1979).
Historically, inefficient nickel refining processes (with poor nickel
recovery) necessitated recycling of nickel residues so workers were
frequently exposed to large amounts of nickel (and copper) oxide dusts
and some forms of arsenic. Increased refining efficiency avoids
recycling (Draper et al, 1994). Some modern nickel refining procedures
avoid nickel oxide production completely (Warner, 1984).
MECHANISM OF TOXICITY
In vitro studies demonstrate that nickel causes crosslinking of
amino acids to DNA, alters gene expression, induces gene mutations and
the formation of reactive oxygen species (Costa et al, 1994a and b;
Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994). Nickel also
suppresses natural killer cell activity and interferon production
(Shen and Zhang, 1994). Beyersmann (1994) has suggested nickel (and
other genotoxic metals) enhance the damaging effects of genotoxins
such as ultraviolet radiation and alkylating substances via impairing
DNA repair mechanisms.
TOXICOKINETICS
Absorption
Nickel oxide can be absorbed by inhalation and ingestion, the former
being more important occupationally. Significant percutaneous
absorption does not occur.
It has been estimated that 75 per cent of inspired particulate metals
(including nickel oxide) are retained in the respiratory tree
(Schroeder, 1970) and two thirds of this is eventually swallowed after
clearance from the airways by the mucociliary mechanism. Systemic
absorption from pulmonary tissue is slow (Roels et al, 1993).
Nickel oxide is less well absorbed following ingestion than are
soluble nickel salts.
Distribution and excretion
Once absorbed, nickel is transported in the blood bound principally to
albumin, concentrated in the kidneys, liver and lungs and is excreted
primarily in the urine. However, the concentration of nickel in
faeces will be much higher than in urine since most ingested nickel is
not absorbed and most inhaled nickel also appears in the gut.
The half-life of nickel in urine following nickel oxide inhalation has
been estimated around 50 hours (Sunderman, 1992) although some inhaled
nickel is retained significantly longer than this. Among a sample of
retired nickel refinery workers, the nickel half-life in the nasal
mucosa was estimated to be three and a half years.
Nickel crosses the placenta and is passed to the child in maternal
milk (Fairhurst and Illing, 1987; IPCS, 1991).
CLINICAL FEATURES: ACUTE EXPOSURE
Although nickel oxide is a pulmonary irritant, acute exposure is
unlikely to result in significant poisoning. Documented clinical
cases invariably involve chronic occupational inhalation.
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Nickel is a common precipitant of allergic contact dermatitis (Zhang
et al, 1991) although nickel oxide is less likely to initiate this
hypersensitivity response than are soluble nickel salts. However,
workers occupationally exposed to nickel oxide at nickel refining
plants are invariably also exposed to nickel sulphate and nickel
chloride. Even so, nickel dermatitis is not a significant
occupational hazard at these establishments, possibly due to
development of immunological tolerance following chronic nickel
inhalation (Menné, 1992). Non-occupational skin contact with nickel
plated objects or nickel alloys remains the primary cause of nickel
sensitization and is more common in women (Peltonen, 1979).
Chronic urticaria, a type 1 hypersensitivity cutaneous reaction, has
also been described (Abeck et al, 1993).
Nickel sensitivity has been implicated in the aetiology of pompholyx,
a vesicular eruption of the palmoplantar regions (Lodi et al, 1992).
Once an individual is sensitized, further exposure to only a very
small quantity of nickel initiates a reaction at the site of contact.
Nickel may penetrate rubber gloves (Wall, 1980).
In susceptible individuals nickel allergy may result in "secondary"
nickel dermatitis with dissemination to skin sites distant from that
of primary sensitization (typically the hands, flexures and eyelids
(Valsecchi et al, 1992). It is not clear whether the latter is an
endogenous phenomenon or simply reflects exogenous nickel
contamination, for example via perspiring fingers (Fisher, 1986).
Inhalation
Pulmonary Toxicity
Following chronic nickel oxide inhalation large amounts of nickel are
retained in pulmonary tissue (Roels et al, 1993).
Andersen and Svenes (1989) analysed lung specimens obtained at autopsy
from 39 nickel refinery workers. Workers employed in the roasting and
smelting department (n=15) exposed chiefly to nickel oxide and
sulphide had significantly higher (p<0.01) lung nickel concentrations
(mean 330 ± (SD) 380 µg/g dry weight) than employees from the
electrolysis department (n=24) exposed primarily to soluble nickel
sulphate and nickel chloride (mean lung nickel concentrations 34 ±
(SD) 48 µg/g). These values compare to a mean lung nickel
concentration of 0.76 ± (SD) 0.39 µg/g among 16 autopsies of
non-exposed people.
Nickel pneumoconiosis and interstitial fibrosis with a mild
restrictive lung function defect have been described in steel workers
exposed to mixtures of nickel oxide, iron oxide and chromium oxide
fumes for at least 14 years (Graham Jones and Warner, 1972). It is
impossible to determine the precise aetiological role of nickel oxide
in these cases.
Muir et al (1993) reviewed chest X-rays of 745 nickel sinter plant
workers exposed to nickel oxide and subsulphide while employed between
1948 and 1963. One hundred and forty nine individuals had been
employed at the plant for at least five years. In every case the most
recent chest X-ray available was reviewed. Employees were exposed to
nickel concentrations up to 100 mg/m3 which had previously been
associated with an increased lung cancer incidence. However their
chest X-rays showed only minimal evidence of small (round or
irregular) opacities, similar to those described in smokers or workers
exposed to low-fibrogenic dusts. These authors concluded that
occupational exposure to nickel dust did not elicit an inflammatory
or fibrogenic lung response (Muir et al, 1993).
In summary, limited evidence suggests chronic nickel oxide inhalation
may cause pneumoconiosis but concomitant exposure to other pulmonary
irritants precludes a definitive conclusion.
While electroplaters are exposed to mists of soluble nickel salts from
plating baths, workers involved in the buffing and polishing processes
are exposed to metallic nickel and nickel oxide. Employees in all
stages of nickel plating may develop chronic rhinitis, nasal
sinusitis, anosmia and perforation of the nasal septum (Mastromatteo,
1986). There are also reports of asthma attributed to nickel allergy
in this industry (McConnell et al, 1973).
It is likely nickel allergy is involved in the aetiology of
'hard-metal' asthma (typically associated with cobalt exposure) with
evidence of cross reactivity between cobalt and nickel (Shirakawa et
al, 1990; Shirakawa et al, 1992).
Nephrotoxicity
A study of renal function in 26 nickel refinery workers found no
significant elevation of urinary total protein or ß2 microglobin
(Sanford and Nieboer, 1992).
Ingestion
There are no reported cases of chronic nickel oxide ingestion although
ingested nickel in any form may exacerbate nickel dermatitis (see
below).
Dermal toxicity
Although primary nickel sensitization occurs only following skin
contact, nickel dermatitis may be reactivated subsequently by ingested
nickel (Gawkrodger et al, 1986; Nielsen et al, 1990). This is unusual
because most antigens induce a state of immunological tolerance when
administered orally, an effect that has also been described in nickel
sensitive subjects (Sjövall et al, 1987; Panzani et al, 1995).
An exacerbation of nickel dermatitis following ingestion is localized
often to the initial sensitization site. This suggests that the
antigen-presenting cells responsible for initiating the allergic
reaction are relatively immobile (Nicklin and Nielsen, 1992). This
may have important implications for the prevention and treatment of
nickel dermatitis since if the body burden of nickel can be reduced
(for example by chelating agents), the likelihood of nickel activation
of the antigen presenting cells may be diminished. This is discussed
further below (Management). Paradoxically the suggested mechanism of
oral hyposensitization in nickel sensitive subjects is stimulation of
suppressor T-cell production by antigen excess (Sjövall et al, 1987).
Chronic urticaria, a type 1 hypersensitivity response, has been
attributed to dietary nickel (Abeck et al, 1993), but this is unusual.
MANAGEMENT
Dermal exposure
Avoidance of exposure and symptomatic treatment of dermatitis
exacerbations with topical or systemic steroids remain the mainstay of
treatment of nickel allergy although dietary nickel restriction
(Kaaber et al, 1978) or oral (Panzani et al, 1995) or topical (Allenby
and Basketter, 1994) hyposensitization have been advocated. Oral
cyclosporin does not appear to be effective (De Rie et al, 1991). The
role of chelation therapy is discussed below.
Inhalation
Removal from exposure and symptomatic and supportive treatment are all
that are likely to be required following acute nickel oxide
inhalation. Respiratory symptoms in nickel refinery workers should be
investigated conventionally remembering that respiratory tract
malignancy occurs more frequently in those chronically exposed to high
concentrations of nickel oxide and subsulphide (see below,
Carcinogenicity).
Ingestion
Nickel oxide ingestion has not been reported. Symptomatic and
supportive measures are likely to be all that are required should this
occur, with measurement of nickel concentrations in blood and urine
only in symptomatic patients. Since nickel is eliminated mainly in the
urine, maintenance of a high urine output is important in those with a
confirmed or suspected increased body nickel burden. The role of
chelation therapy in nickel poisoning is discussed below (Antidotes).
Antidotes
The role of chelation therapy in nickel oxide poisoning is limited
since toxicity is due primarily to pulmonary nickel deposits following
chronic inhalation. Most animal studies involve parenteral
administration of soluble nickel salts. Available clinical data
involve the management of nickel dermatitis.
Animal studies
The effect of chelating agents on nickel distribution is dependent on
their lipid solubility. Lipophilic agents (such as
diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride
(TETA)) are more able to penetrate cell membranes with potential
nickel redistribution to lipid rich tissues such as the liver and
brain (Misra et al, 1987). By contrast, hydrophilic chelating agents
(e.g. sodium calcium ethylenediamine tetraacetic acid (EDTA)) are more
likely to enhance renal nickel clearance without cellular nickel
accumulation (Misra et al, 1987).
Misra et al (1987) observed a significant reduction (p<0.05) in renal
nickel content in rodents following treatment with both lipophilic
(1,4,8,11-tetra-azacyclotetradecane and TETA) and hydrophilic (sodium
calcium edetate, 1,2,cyclohexylenediamine tetraacetic acid,
diethylenetriamine pentaacetic acid) chelating agents 500 µmol/kg
subcutaneously 60 minutes post nickel poisoning (as subcutaneous
nickel chloride 250 µmol/kg). By contrast the hepatic nickel content
was increased following treatment with lipophilic agents, but reduced
after hydrophilic antidote administration (Misra et al, 1987).
Oskarsson and Tjälve (1980) investigated the effect on nickel
distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine
3.4 mmol/kg in mice administered a chelating agent ten minutes before
an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg). DDC
caused increased tissue nickel retention compared to control mice
(injected with nickel chloride alone), with the highest radioactivity
in adipose tissue followed by the liver, kidneys, brain and spinal
cord. The brain nickel content of DDC treated mice was 57 times
higher than control mice. Following d-penicillamine the tissue nickel
content was lower than in control mice. For example, the "kidney
contained about 1% and the lung about 4%" of the radioactivity
observed in mice given 63nickel chloride only.
Sodium calcium edetate 400 µmol/kg subcutaneously reduced the nickel
content of the liver, heart, kidney and lung by 20-40 per cent in
rodents poisoned with nickel (as subcutaneous nickel chloride 200
µmol/kg) 30 minutes previously (Dwivedi et al, 1986).
In rats (n=20-25 in each group) the two week mortality following
intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95 0.29
mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg, (0.3
times its LD50) was given one minute prior to nickel dosing (Horak et
al, 1976). Under the same experimental conditions TETA 1.36 mmol/kg
(0.6 times its LD50) reduced (p<0.001) the two week mortality to 25
per cent but DDC was ineffective. Sodium calcium edetate 0.68 mmol/kg
reduced the two week mortality to 32 per cent (p<0.001) when the
nickel chloride dose was 0.136 mmol/kg (greater than its LD50).
Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium calcium
edetate (administered intraperitoneally at a molar ratio of 10:1
chelating agent: nickel) increased survival in rodents systemically
poisoned with nickel (as intraperitoneal nickel acetate, 62 mg/kg).
The results are summarized in Table 1 (Basinger et al, 1980).
Table 1. Survival rates in nickel intoxicated mice following chelation
therapy (see text)
n= Chelating agent Survival %
5 None 0
10 DMPS 80
10 d-penicillamine 100
10 Sodium calcium edetate 100
(after Basinger et al, 1980)
Shen et al (1979) studied the effect of several chelating agents
(administered subcutaneously) on renal nickel clearance in rats
administered a continuous nickel chloride infusion. Each chelating
agent was administered to a different group of six rats with eight
controls. d-Penicillamine 1 µmol/h increased mean renal nickel
clearance by 53 per cent (p<0.001) and TETA 1 µmol/h by 26 per cent
(p< 0.025) but DDC 2 µmol/h did not affect renal nickel clearance.
DMPS 0.5 mmol/kg significantly enhanced urine nickel excretion
(0.001< p < 0.05) when administered subcutaneously to rats poisoned
with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant
decreases in nickel-induced hyperglycaemia and aminoaciduria were
noted following chelation therapy. Faecal nickel excretion was
unaffected and DMPS was ineffective in mobilizing nickel from the
brain (Sharma et al, 1987).
In mice systemically poisoned with nickel chloride (5 mg/kg),
intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the
brain (Xie et al, 1994). DMSA 400 µmol/kg intraperitoneally,
significantly enhanced (p<0.05) the faecal and urinary excretion of
the metal and there was no redistribution to the brain (Xie et al,
1994). The same group recently found parenteral DMSA and
N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the
testicular nickel concentration and so protecting against
nickel-induced testicular toxicity in mice administered
intraperitoneal nickel chloride (Xie et al, 1995).
In summary, in rodents systemically poisoned with soluble nickel
salts, renal nickel clearance is increased and mortality reduced by
the parenteral administration of d-penicillamine, TETA or DMPS. DMSA
also increases renal nickel elimination. DDC is not an effective
antidote in experimental systemic soluble nickel salt poisoning.
Clinical studies
There are no data specifically involving nickel oxide exposure.
Diethlydithiocarbamate and disulfiram in nickel dermatitis
Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that:
2(DDC) + Ni2+ ---- Nickel bis(DDC) which is renally excreted.
DDC is not available as a pharmaceutical preparation in many countries
although disulfiram (Antabuse), which is metabolised to DDC (two
molecules of DDC from each of disulfiram), has been employed.
The rationale for the use of DDC and disulfiram in nickel dermatitis
is that both agents reduce the body nickel burden and so minimise the
amount of nickel available for the endogenous activation of
immunocompetent cells.
Topical DDC
van Ketel and Bruynzeel (1982) investigated the role of topical DDC in
the prevention of nickel sensitivity in 17 patients with known nickel
allergy. Prior to nickel challenge seven patients were pretreated for
24 hours with 10 per cent DDC under an occlusive dressing. They were
challenged with nickel (as nickel sulphate 0.01, 0.1, 1.0 and 5.0 per
cent solutions) and a nickel coin (99.7 per cent nickel). Ten
patients applied 10 per cent DDC six hourly for 24 hours prior to
nickel sulphate challenge. There were no differences in mean patch
test scores between DDC-treated and non DDC-treated skin in all groups
(Table 2).
Table 2. Topical DDC in nickel dermatitis
n= 24 h Nickel challenge Mean ± SD
Pretreatment patch-test score
Control DDC
7 10% DDC Nickel sulphate 3.9 ± 2.1 4.0 ± 3.2
under occlusion (0.01, 0.1, 1.0 and 5.0%)
7 10% DDC Coin 0.9 ± 0.7 1.8 ± 1.1
under occlusion (99.7% nickel)
10 10% DDC Nickel sulphate 2.9 ± 2.7 2.5 ± 3.1
qds (0.01, 0.1, 1.0 and 5.0%)
(van Ketel and Bruynzeel, 1982)
Oral DDC and disulfiram
Several uncontrolled studies report the successful resolution of
nickel dermatitis following oral DDC or disulfiram. Uncontrolled
studies of disulfiram therapy in nickel dermatitis are summarized in
Table 3.
Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg
daily for 20 days led to an improvement in dermatitis although the
condition recurred when treatment was discontinued.
In another patient (Spruit et al, 1978) oral DDC for two months failed
to produce a negative nickel patch test, although less local treatment
was required.
Disulfiram certainly increases urine nickel excretion in patients with
nickel dermatitis (Table 4) but in a double-blind study involving 24
such patients treated with disulfiram 200 mg daily or placebo for six
weeks, there was no overall significant difference between treatments
(Kaaber et al, 1983).
Adverse effects of DDC and disulfiram
There is concern that disulfiram and DDC may promote nickel
accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al,
1987). DDC is lipophilic and in in vitro studies can enhance
cellular Ni2+ uptake (Nieboer et al, 1984; Menon and Nieboer, 1986).
Disulfiram is also associated frequently with a 'flare-up' of nickel
dermatitis soon after commencing treatment (Kaaber et al, 1979; Menné
et al, 1980; Christensen and Kristensen, 1982; Christensen, 1982
(Table 3); Klein and Fowler, 1992; Gamboa et al, 1993). Other
reported adverse effects of disulfiram therapy include abnormal liver
Table 3. Uncontrolled studies of disulfiram in nickel dermatitis
n= Disulfiram Effect on dermatitis Study
Dose Duration & Early % % %
(mg/day) (wks) flare "Healed" "Improved" Rebound1
1 300 8 - - 100 100 Menné & Kaaber, 1978
11 200-400 "4-10" 82 64 18 55 Kaaber et al, 1979
11 200-400 ? 82 73 - - Menné et al, 1980
11 200 8 100 18 73 100 Christensen & Kristensen, 1982
3 50-200 18 (mean) 100 33 66 33 Christensen, 1982
61 50-400 12 (mean) ?2 46 30 85 (n=27)3 Kaaber et al, 1987
98 - 47 32 66 (n=64)
1 Rebound dermatitis when disulfiram discontinued
2 Flares of dermatitis "frequently seen" but number not stated
3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases
Table 4. Disulfiram in nickel dermatitis: urine nickel excretion
n= Disulfiram Mean ± SD urine Study
dose nickel excretion
(mg/day) (µg/24 h)
Before Maximum during
treatment treatment
3 200-400 1.2 ± 0.3 53 ± 15.5 Kaaber et al, 1979
6 200-400 1.7 ± 0.5 60 ± 23.8 Menné et al, 1980
function (Kaaber et al, 1983; Kaaber et al, 1987), an acne-like rash
(Kaaber et al, 1983), headache (Kaaber et al, 1979; Kaaber et al,
1983), fatigue and dizziness (Kaaber et al, 1979) and an adverse
reaction with alcohol. Reactivation of nickel sensitivity often
occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber et al,
1987; Table 3).
Sodium calcium edetate
Seventeen nickel allergic patients pretreated with a cream containing
10 per cent sodium calcium edetate showed a significant reduction in
positive patch tests to nickel (as a one per cent nickel sulphate
solution) compared to results on untreated skin (three positive
reactions compared to 14 respectively, p<0.01) (van Ketel and
Bruynzeel, 1982). The authors suggested use of 10 per cent sodium
calcium edetate barrier creams in nickel sensitive subjects but this
requires further study.
Clioquinol
A recent study reported that topical administration of the chelating
agent clioquinol (three per cent) "completely abolished" reactivity to
nickel in 29 nickel-sensitive subjects and the authors advocated its
use as a barrier ointment in nickel allergic patients (Memon et al,
1994) but this requires confirmation.
Antidotes: Conclusions and recommendations
Nickel contact sensitivity
1. Nickel contact sensitivity is managed most effectively by
avoiding exposure and treating acute exacerbations with topical
and/or systemic steroids.
2. Topical DDC has no role. There is some evidence that barrier
creams containing sodium calcium edetate or clioquinol may be
useful.
3. While there are two case reports claiming benefit from oral DDC
in the treatment of nickel dermatitis, this has not been
confirmed in a controlled clinical study.
4. In the only published controlled clinical study using disulfiram
in the management of nickel dermatitis there was no overall
benefit from treatment.
5. Uncontrolled studies with oral disulfiram suggest improvement in
secondary nickel dermatitis but the incidence of significant
side-effects is high.
6. Chelation therapy in nickel dermatitis cannot be advocated
routinely but remains an area of research interest.
Systemic nickel poisoning
1. There are no human data available regarding chelation therapy in
systemic nickel oxide toxicity.
2. Animal studies suggest d-penicillamine is probably the most
effective nickel antidote although there are promising results
and less adverse effects with the newer thiol chelating agents,
particularly DMPS.
MEDICAL SURVEILLANCE
Prior to employment involving nickel exposure special consideration
should be given to those with a history of contact dermatitis or
respiratory disease. The maximum long-term exposure limit in air in
the UK for insoluble nickel is 0.5 mg/m3 (Health and Safety
Executive, 1995).
Monitoring of nickel concentrations in blood and urine are not
indicated routinely because while they provide evidence of recent
exposure to soluble nickel compounds and nickel metal powder, they do
not reflect the total body nickel burden and are of limited use for
monitoring workers exposed primarily to nickel oxide and other
insoluble salts.
Moreover, urine nickel concentrations vary considerably and should be
interpreted as groups of 24 hour samples rather than individual urine
specimens (Nickel Producers Environmental Research Association and the
Nickel Development Institute, 1994).
Serum nickel concentrations are used in some industries since they
avoid contamination from work-place dust and provide fairly consistent
values within a given work environment; mean serum nickel
concentrations ranging from 0.9 µg/L for grinders and polishers to
11.9 µg/L in electrolytic refining workers have been cited (Nickel
Producers Environmental Research Association and the Nickel
Development Institute, 1994).
In a controlled study Torjussen and Andersen (1979) determined nasal
mucosal, plasma and urine nickel concentrations in 318 present and 15
retired workers all employed for at least eight years in a nickel
refining plant. Mean nickel concentrations in all samples were
significantly lower in the control group (n=57) than the corresponding
values for the active (p<0.01) and retired (p<0.05) workers
(Torjussen and Andersen, 1979).
In the same study (Torjussen and Andersen, 1979) smelting and roasting
workers exposed to nickel oxide and subsulphide dust (average air
nickel concentration 0.5 mg/m3) exhibited significantly higher
(p<0.01) nasal mucosal nickel concentrations (467.2 ± (SD) 594.6
µg/100 g wet weight) than electrolytic workers exposed to soluble
nickel sulphate and nickel chloride aerosols (178.1 ± (SD) 234.7
µg/100g wet weight). Plasma and urine nickel concentrations however
were significantly higher (p<0.01) in electrolytic workers than in
those exposed to nickel oxide (Torjussen and Andersen, 1979).
In the roasting/smelting workers nasal mucosal nickel concentrations
significantly correlated (p<0.01) with duration of exposure (to
nickel oxide and subsulphide). Among the retired workers the authors
estimated a nickel half-life in the nasal mucosa of three and a half
years (Torjussen and Andersen, 1979). They suggested that nasal
mucosal nickel concentrations were more reliable indicators of upper
respiratory tract nickel accumulation then were plasma or urine nickel
concentrations (Torjussen and Andersen, 1979).
In another controlled study Roels et al (1993) measured the nickel
concentration of total inhalable dust (mean 22.9 µg/m3), respirable
dust (mean 3.5 µg/m3) and pre- and post-shift urine for five days in
20 workers exposed to nickel oxide during electrical resistance
manufacture. In nineteen workers nickel urine concentrations did not
differ between pre- (mean 1.2 µg/g creatinine) and post- (1.1 µg/g
creatinine) shift samples (control mean 0.5 µg/g creatinine, n=17).
In addition, urine nickel elimination was not affected by up to two
weeks vacation. These results add further support to the view that
urine nickel excretion is not a reliable indicator of occupational
nickel exposure.
The interpretation of urine nickel excretion data is further
complicated by the fact that the particle size of inhaled nickel
greatly affects its bioavailability. For example, one worker in the
study by Roels et al (1993) had substantially higher post-shift urine
nickel concentrations (range 21-101 µg/g creatinine) compared to
pre-shift values (range 11-33 µg/g creatinine). His urine nickel
excretion was also reduced (to 4.4 µg/g creatinine) following a two
week vacation. The authors explained these results by noting that
this individual handled smaller nickel oxide particles than his 19
colleagues (particle diameter 1-8 µm compared to 150-600 µm). He
therefore had a substantially higher respirable nickel fraction
(respirable nickel concentration 158 µg/m3 compared to 3 µg/m3).
Gammelgaard et al (1992) suggested that a fingernail nickel content
greater than 8 ppm indicates likely occupational (rather than
domestic) nickel exposure in patients with nickel dermatitis but the
reliability of this proposal has not been confirmed.
OCCUPATIONAL DATA
Maximum exposure limit
Nickel, inorganic, insoluble compounds: Long-term maximum exposure
limit (8 hour TWA reference period) 0.5 mg/m3 (Health and Safety
Executive, 1995).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
The carcinogenic status of nickel oxide has been disputed. Assessment
is difficult since nickel workers are rarely occupationally exposed to
nickel oxide alone. For example, Draper et al (1994) studied two
historical dust samples (1920 and 1929) from a nickel refining plant
in Wales and identified the presence of up to 10 per cent arsenic in
addition to nickel oxide. The later sample had a lower arsenic
content, correlating with a reduction in the number of respiratory
cancers reported among 'nickel' workers at this time. The authors
concluded that arsenic, probably in the form of nickel arsenide, was
the likely aetiological agent responsible for the cancers observed
(Draper et al, 1994).
Smoking habits of employees further complicates the interpretation of
cancer mortality data in the nickel industry. Cigarette smoking not
only directly increases the risk of respiratory tract cancer but also
indirectly increases risk via impaired mucociliary clearance of toxic
particles from the bronchial mucosa (Langard, 1994).
Cox et al (1981) considered the mortality of 1925 nickel alloy
manufacturing workers employed for at least five years and exposed to
metallic nickel and nickel oxide (nickel concentrations 0.5-0.9
mg/m3) but not nickel subsulphide. The standardized mortality ratio
among these employees for lung cancer, cancer of other respiratory
sites, respiratory disease or ischaemic heart disease was not
increased significantly. That nickel oxide should not be considered
carcinogenic was suggested also by Longstaff et al (1984) in a review
of epidemiological data concerning the incidence of respiratory cancer
among nickel refining employees.
In contrast more recent epidemiological studies have shown a
significant increase in deaths from carcinoma of the lung and nasal
sinuses among nickel refinery workers (Roberts et al, 1992; Andersen,
1992). The exact aetiological agent is unknown although nickel
sulphate, oxide and subsulphide have been suspected. Nickel oxide and
subsulphide are probably also responsible for the increased incidence
of nasal mucosal dysplasia observed in nickel refiners (Torjussen et
al, 1979).
The most recent International Agency for Research on Cancer (IARC)
monograph on nickel carcinogenicity (IARC, 1990) concluded "there is
sufficient evidence in humans for the carcinogenicity of ...... the
combinations of nickel sulfide and oxides encountered in the nickel
refining industry". The excess risk of death continues for several
years after leaving employment (Muir et al, 1994). An increased
incidence of laryngeal cancer has not been confirmed (Roberts et al,
1992).
Thirty-nine nickel refiners (Andersen and Svenes, 1989) diagnosed with
lung cancer had lung nickel concentrations at autopsy equal to those
who died of other causes, indicating that the pulmonary nickel
concentration is not a reliable indicator of aetiology of death
(Andersen and Svenes, 1989).
Fortunately, measures to improve industrial hygiene have greatly
reduced the occupational hazard of nickel oxide exposure but
respiratory tract malignancies among nickel industry employees remain
notifiable diseases in the UK (Seaton et al, 1994).
Among stainless steel workers, it is unclear whether nickel or
hexavalent chromium compounds present in the welding fume is the
greater risk factor for lung cancer (Langard, 1994).
Reprotoxicity
There are no human data regarding the reprotoxicity of nickel oxide.
Animal studies have shown reduced body weight following exposure of
rat foetuses to nickel oxide (1.6 and 3.2 mg/m3).
Following nickel oxide inhalation, nickel crossed the placenta in rats
in a dose-dependent manner (Reprotext, 1996).
Genotoxicity
Cytogenetic analysis of chromosomal aberrations of peripheral
lymphocytes was performed in a controlled study (Senft et al, 1992) of
21 workers exposed to either nickel oxide (n=6) or nickel sulphate
(n=15). A statistically significant (p<0.001) increase in the mean
percentage chromosome aberration value was observed in the exposed
group (n=21) compared with the control group (19 non nickel-exposed
employees at the same chemical plant) with more aberrations in the
nickel oxide workers (9.5 ± (SD) 3.2 per cent) than in those producing
nickel sulphate (5.2 ± (SD) 1.9 per cent).
A significant increase (p<0.01) in the mean percentage chromosome
aberration in the control group (4.05 ± (SD) 2.27 per cent) compared
with the suggested normal value for the general population (up to 2
per cent) was attributed to the nickel polluted environment of the
plant.
The authors concluded that nickel exposure causes increased peripheral
lymphocyte chromosomal aberrations and suggested a positive
association between duration of employment and the frequency of these
abnormalities. They also proposed that the higher frequency of
aberrations following nickel oxide exposure was due to the longer
biological half-life of insoluble nickel salts allowing more time to
exert a genotoxic effect (Senft et al, 1992).
Fish toxicity
Nickel : LC50 (96 h) banded killfish, striped bass, pumpkin seed,
white perch, American eel, carp 6.2-46.2 mg/L (salt unspecified).
Rainbow trout exposed to nickel (salt unspecified) had a reduction in
glucidic stores which is consistent with direct metal interactions
with membranes and enzyme thiol groups of pancreas cells.
Life-cycle study fathead minnow (pH 7.8, 18°C, 210 mg CaCO3 hardness)
<0.38 mg/L (salt unspecified) did not adversely affect reproduction,
survival or growth; 0.78 mg/L (salt unspecified) significantly
affected the number and hatchability of eggs, growth survival of the
first generation was not affected.
LC50 (74 h) carp eggs 6.1 mg/L, larvae, 8.4 mg/L (salt unspecified);
3 mg/L caused increased numbers of abnormal larvae and embryos which
failed to hatch.
LC50 (from fertilization to day 4 after hatching) channel catfish
0.71 mg/L, goldfish 2.78 mg/L (salt unspecified) (DOSE, 1994).
EC Directive on Drinking Water Quality 80/778/EEC
Nickel : Maximum admissible concentration 50 µg/L (DOSE, 1994).
WHO Guidelines for Drinking Water Quality
Guideline value 0.02 mg/L, as nickel (WHO, 1993).
AUTHORS
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. 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
17/1/97
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