UKPID MONOGRAPH
NICKEL (II) CHLORIDE
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
NICKEL CHLORIDE
Toxbase summary
Type of product
Nickel chloride is a soluble nickel salt used in nickel plating, in
the dye and printing industry, and as an adsorbent of ammonia in gas
masks.
Toxicity
An important cause of contact dermatitis. May precipitate
occupational asthma. Gastrointestinal irritation has occurred
following ingestion but severe poisoning is rare.
Features
Topical
- Primary skin and eye irritant and an important cause of
contact dermatitis.
Ingestion
Mild/moderate ingestions:
- Small ingestions of dilute solutions may produce no
symptoms. Nausea, vomiting, abdominal pain and diarrhoea
occur within two hours in more significant ingestions,
possibly associated with headache, giddiness and myalgia.
Substantial ingestions:
- Severe gastrointestinal irritation and haemorrhage may
ensue.
- Transient hyperbilirubinaemia, albuminuria or a
reticulocytosis have been reported and first degree heart
block has been described.
Inhalation
- A potential cause of occupational asthma. Chronic
inhalation may cause rhinitis, sinusitis, anosmia and
perforation of the nasal septum.
Management
Topical
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Chelation therapy in nickel contact dermatitis cannot be
advocated routinely but is an area of research interest. Discuss
with an NPIS physician.
Ingestion
1. In mild cases symptomatic and supportive measures will suffice.
2. Gastric lavage is best avoided in view of potential oesophageal
irritation.
3. In symptomatic patients measure blood and urine nickel
concentrations.
4. Ensure a good urine output in those with suspected or confirmed
nickel toxicity.
Inhalation
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Occupational asthma should be managed conventionally.
References
Sunderman Jr FW, Dingle B, Hopfer SM, Swift T.
Acute nickel toxicity in electroplating workers who accidentally
ingested a solution of nickel sulfate and nickel chloride.
Am J Ind Med 1988; 14: 257-66.
Wall LM, Calnan CD.
Occupational nickel dermatitis in the electroforming industry.
Contact Dermatitis 1980; 6: 414-20.
Substance Name
Nickel (II) chloride
Origin of substance
Nickel chloride may be prepared from nickel oxide by
chlorination, or by reaction with hydrogen chloride.
(HSDB, 1997)
Synonyms
Nickel chloride
Nickel dichloride
Nickelous chloride (DOSE, 1994)
Chemical group
A compound of nickel, a transition metal (d block) element.
Reference numbers
CAS 7718-54-9 (DOSE, 1994)
RTECS QR6470000 (RTECS, 1997)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
NiCl2 (DOSE, 1994)
Molecular weight
129.62 (DOSE, 1994)
Physical state at room temperature
Solid
Colour
Green (hexahydrate)
Golden-yellow (anhydrous salt) (MERCK, 1996)
Odour
Odourless (HSDB, 1997)
Viscosity
NA
pH
The aqueous solution is acidic. (MERCK, 1996)
Solubility
Soluble in water: 642 g/L at 20°C. Soluble in ethanol, ethylene
glycol and hydrazine. (DOSE, 1994)
Autoignition temperature
NIF
Chemical interactions
Nickel chloride may explode on impact when mixed with potassium.
(NFPA, 1986)
Nickel chloride reacts readily with strong acids.
(HSDB, 1997)
Major products of combustion
When heated to decomposition very toxic fumes of hydrogen
chloride may be emitted. (HSDB, 1997)
Explosive limits
NIF
Flammability
Non-flammable (HSDB, 1997)
Boiling point
987°C (sublimes) (DOSE, 1994)
Density
3.55 at 20°C (DOSE, 1994)
Vapour pressure
133.3 Pa at 671°C (HSDB, 1997)
Relative vapour density
NIF
Flash Point
NIF
Reactivity
NIF
Uses
Nickel chloride is used in the nickel-plating of cast zinc, and
in ink manufacture. The anhydrous salt is used as an adsorbant
for ammonia in gas masks. (MERCK, 1996)
Hazard/risk classification
NIF
INTRODUCTION AND EPIDEMIOLOGY
Nickel chloride is a soluble nickel salt. Poisoning by ingestion is
rare although occupational cases have been described (Sunderman et al,
1988). Nickel chloride inhalation may cause occupational asthma in
metal platers (McConnell et al, 1973). Nickel chloride is used in
nickel patch testing.
MECHANISM OF TOXICITY
In vitro studies demonstrate that nickel causes crosslinking of
amino acids to DNA, alters gene expression, induces gene mutations and
the formation of reactive oxygen species (Costa et al, 1994a and b;
Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994). Nickel also
suppresses natural killer cell activity and interferon production
(Shen and Zhang, 1994). Beyersmann (1994) has suggested that nickel
enhances the damaging effects of genotoxins such as ultraviolet
radiation and alkylating substances by impairing DNA repair
mechanisms.
TOXICOKINETICS
Absorption
Nickel chloride can be absorbed by inhalation and ingestion.
Percutaneous uptake can occur, and is an important source of nickel
contact sensitivity, but does not make a substantial contribution to
the body nickel burden. It has been estimated that 75 per cent of
inspired nickel is retained in the respiratory tree (Schroeder, 1970)
and two thirds of this is eventually swallowed after clearance from
the airways by the mucociliary mechanism.
Distribution and excretion
Once absorbed, nickel is transported in the blood bound principally to
albumin (Lucassen and Sarkar, 1979). It is concentrated in the
kidneys, liver and lungs and is excreted primarily in the urine.
However, following ingestion, the concentration of nickel in faeces
will be much higher than in urine since most is not absorbed. A
substantial proportion of inhaled nickel chloride will eventually also
appear in the gut.
Animal and human volunteer studies suggest that the distribution and
elimination of nickel follows a two compartment model with an initial
rapid plasma elimination phase followed by a slower clearance phase
(IPCS, 1991).
In ten human volunteers the plasma elimination half-life of ingested
nickel was 28 ± (SD) 9 hours (Sunderman et al, 1989). Among ten
workers who accidentally drank 0.5 - 1.5 litres nickel chloride and
nickel sulphate-contaminated water, and who received intravenous
fluid (150 mL/hour) for three days the serum nickel half-life was
27 ± (SD) 7 hours. Among 11 individuals in whom a diuresis was not
induced the mean serum nickel half-life was 60 ± (SD) 11 hours.
Nickel crosses the placenta and is passed to the child in maternal
milk (Fairhurst and Illing, 1987; IPCS, 1991).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
There is relatively little information on the acute dermal toxicity of
nickel chloride in humans, though at high concentrations it is likely
to be a primary skin irritant as is nickel sulphate (Frosch and
Kligman, 1976).
Dermal exposure to nickel chloride is associated mainly with the
development of nickel contact sensitivity (see Chronic exposure).
Ocular exposure
Nickel chloride (0.5 per cent) produced no adverse effects when
directly applied to rabbit eyes. There are no human data (Grant and
Schuman, 1993).
Ingestion
Gastrointestinal toxicity
Sunderman et al (1988) reported an industrial accident involving 32
workers at an electroplating plant who accidentally drank water
contaminated with nickel chloride, nickel sulphate (total nickel
concentration 1.63 g/L) and boron (68 mg/L). Symptoms occurred
primarily in those who had ingested more than 500 mL and began within
two hours of ingestion. Gastrointestinal effects including nausea,
vomiting, abdominal pain and diarrhoea were the most common. Ten of
these 32 patients required hospital admission, though all were
asymptomatic within three days. The mean urine nickel concentration
the day following the incident among 15 of those exposed was 5.8 mg/L
(range 0.23 - 37.1 mg/L) , with a mean serum nickel concentration of
286 µg/L (range 12.8 - 1340 µg/L). Among 11 nickel platers who did
not drink the contaminated water the mean urine nickel concentration
was 50 ± (SD) 13 µg/L with a mean serum nickel concentration of 4.0 ±
(SD) 1.2 µg/L (Sunderman et al, 1988).
Fatalities have occurred from gastrointestinal haemorrhage following
soluble nickel salt ingestion though there are no case reports
involving nickel chloride.
Hepatotoxicity
Two of the ten patients admitted following ingestion of 0.5 - 1.5
litres nickel chloride/sulphate contaminated water (see above)
developed mild transient hyperbilirubinaemia (30 µmol/L and 43 µmol/L
respectively) but this resolved within six weeks (Sunderman et al,
1988).
Neurotoxicity
Of 20 workers who accidentally ingested water contaminated with nickel
chloride and sulphate (see above) seven complained of giddiness, six
of lassitude, five of headache and one of myalgia. Symptoms resolved
within hours in most cases and within two days in all (Sunderman et
al, 1988). In the same accident it was noted that the mean body
temperature of the ten most substantially exposed patients was
slightly diminished (mean 36.7 ± (SD) 0.3°C on day 2). The authors
proposed nickel-induced impaired thermoregulation (which has been
described in animals) as the mechanism, but there are insufficient
clinical data to substantiate this.
Pulmonary toxicity
Of 21 workers who drank nickel contaminated water (nickel
concentration 1.63 g/L), one patient with known bronchial asthma
developed an expiratory wheeze and another patient with chronic
obstructive airways disease developed cyanosis. Whether these
respiratory symptoms were nickel-induced is unknown (Sunderman et al,
1988).
Nephrotoxicity
Two of the subjects described by Sunderman et al (1988) developed
transient albuminuria in the two days following ingestion of nickel
chloride/sulphate contaminated water (see above). In both cases this
resolved within five days.
Haemotoxicity
Sunderman et al (1988) reported a modest erythropoietic effect among
ten workers who accidentally drank nickel chloride/sulphate-
contaminated water (see above) with an increase in the mean blood
haemoglobin concentration from 15.1 ± (SD) 0.7 g/dL on day three post
exposure to 16.0 ± (SD) 0.6 g/L on day eight (p<0.01). There was a
similar statistically significant increase in the blood reticulocyte
count.
Cardiovascular toxicity
Ingestion of 0.5 - 1.5 L nickel chloride/sulphate contaminated water
(nickel content 1.63 g/L) was associated in one patient with
transient first degree heart block (Sunderman et al, 1988).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Nickel chloride is a common precipitant of allergic contact dermatitis
(Kalimo and Lammintausta, 1984; Christensen and Wall, 1987; Serup and
Staberg 1987 a and b; Goebeler et al, 1993) which is a cell-mediated
(type IV) hypersensitivity response. Chronic urticaria, a type 1
hypersensitivity cutaneous reaction to nickel, has also been described
(Abeck et al, 1993).
Nickel sensitivity has been implicated in the aetiology of pompholyx,
a vesicular eruption of the palmoplantar regions (Lodi et al, 1992).
Primary nickel contact sensitization is more common in women
(Peltonen, 1979) and usually follows prolonged non-occupational skin
contact with nickel-plated objects or nickel alloys. Common sources
include jewellery, buttons, zips and coins (Lacroix et al, 1979;
Gollhausen and Ring, 1991). The amount of nickel released from these
items depends on their resistance to corrosion and the presence of
sweat which acts to release the metal ion as soluble nickel salts
including nickel chloride. Nickel ions may penetrate rubber gloves
(Wall, 1980).
Once an individual is sensitized, further exposure to only a very
small quantity of nickel initiates a reaction at the site of contact.
Nickel valve prostheses and nickel-containing pacemakers have been
suggested as triggers of nickel allergy (Lyell and Bain, 1974;
Landwehr and van Ketel, 1983).
In susceptible individuals nickel allergy may result in "secondary"
nickel dermatitis with dissemination to skin sites distant from that
of primary sensitization (typically the hands, flexures and eyelids).
It is not clear whether the latter is an endogenous phenomenon or
simply reflects exogenous nickel contamination, for example via
perspiring fingers (Fisher, 1986).
Interpretation of patch test responses may be difficult. Measurement
of transepidermal water loss (Serup and Staberg, 1987a) and assessment
of skin oedema by ultrasound (Serup and Staberg, 1987b) have been
suggested to differentiate between true allergic and irritant nickel
patch test responses.
Simultaneous contact sensitivity to nickel and cobalt is common
probably via a shared effect on inflammatory-cell recruitment
(Goebeler et al, 1993).
Investigations by Wall and Calnan (1980) following an outbreak of
occupational dermatitis in an electroforming plant found nickel
chloride to be a more reliable patch test allergen than nickel
sulphate. Patch testing with nickel sulphate alone would have failed
to detect seven of 13 nickel allergic patients.
There is evidence that the skin permeation rate is some 15 times
faster for nickel chloride than nickel sulphate (Fullerton et al,
1986). This partly explains why a nickel chloride patch test (48 h
occlusion) gives a "more positive and allergic toxic reaction" than
nickel sulphate (Kalimo and Lammintausta, 1984). A further advantage
of nickel chloride is its greater solubility in alcohol (Christensen
and Wall, 1987).
Nickel chloride may be used as the stimulus of lymphocyte blast
transformation in the in vitro confirmation of nickel sensitivity as
is nickel sulphate (Everness et al, 1990; Grimsdottir et al, 1994).
Inhalation
Pulmonary toxicity
Chronic exposure to aerosols of nickel chloride, emitted as mists from
electroplating baths may lead to chronic rhinitis, nasal sinusitis,
anosmia and perforation of the nasal septum (Mastromatteo, 1986).
Nickel chloride inhalation may cause occupational asthma with
circulating IgE nickel antibodies as has been reported with nickel
sulphate (Nieboer et al, 1984); resolution of symptoms occurs when the
individual is away from work (Block and Yeung, 1982). Occupational
asthma has been reported among metal platers (McConnell et al, 1973).
It is likely that nickel allergy is involved in the aetiology of
'hard-metal' asthma (typically associated with cobalt exposure) with
evidence of cross reactivity between cobalt and nickel (Shirakawa et
al, 1990; Shirakawa et al, 1992).
Nephrotoxicity
There is some evidence that chronic inhalation of high concentrations
of soluble nickel compounds causes increased urinary protein and renal
tubular enzyme excretion but the significance of these findings is
unknown (Vyskocil et al, 1994).
Ingestion
Dermal toxicity
Although primary nickel sensitization occurs only following skin
contact, nickel dermatitis may be reactivated subsequently by ingested
nickel (Gawkrodger et al, 1986). This is unusual because most
antigens induce a state of immunological tolerance when administered
orally, an effect that has also been described in nickel sensitive
subjects (Sjövall et al, 1987; Panzani et al, 1995).
An exacerbation of nickel dermatitis following ingestion is localized
often to the initial sensitization site. This suggests that the
antigen-presenting cells responsible for initiating the allergic
reaction are relatively immobile (Nicklin and Nielsen, 1992). This
may have important implications for the prevention and treatment of
nickel dermatitis since if the body burden of nickel can be reduced
(for example by chelating agents), the likelihood of nickel activation
of the antigen presenting cells may be diminished. Paradoxically the
suggested mechanism of oral hyposensitization in nickel sensitive
subjects is stimulation of suppressor T-cell production by antigen
excess (Sjövall et al, 1987).
Chronic urticaria, a type 1 hypersensitivity response has been
attributed to dietary nickel (Abeck et al, 1993), but this is unusual.
MANAGEMENT
Dermal exposure
Avoidance of exposure and symptomatic treatment of exacerbations with
topical or systemic steroids remain the mainstay of treatment of
nickel allergy although dietary nickel restriction (Kaaber et al,
1978) or oral (Panzani et al, 1995) or topical (Allenby and Basketter,
1994) hyposensitization have been advocated. Oral cyclosporin does
not appear to be effective (De Rie et al, 1991). The role of
chelation therapy is discussed below.
Inhalation
Symptomatic and supportive treatment is all that is likely to be
required in those with symptoms of respiratory tract irritation
following acute exposure to nickel chloride. Occupational asthma
should be managed conventionally, and further exposure avoided.
Ingestion
There is no evidence that gastric lavage reduces nickel chloride
absorption. General symptomatic and supportive measures are likely to
be all that are required in most cases. Measurement of nickel
concentrations in blood and urine need only be undertaken in
symptomatic patients.
Since nickel is eliminated mainly in the urine, maintenance of a high
urine output is important in those with a confirmed or suspected
increased nickel burden. Following inadvertent ingestion of 0.5 - 1.5
litres nickel chloride/sulphate-contaminated water (nickel
concentration 1.63 g/L), Sunderman et al (1988) demonstrated a mean
serum nickel half life of 27 hours (n=10) in those treated with
intravenous fluids compared to a half-life of 60 hours (n=11) in those
not receiving intravenous fluids.
The role of chelation therapy in nickel chloride poisoning is
discussed below.
Antidotes
Animal studies
The effect of chelating agents on nickel distribution is dependent on
their lipid solubility. Lipophilic agents (such as
diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride
(TETA)) are more able to penetrate cell membranes with potential
redistribution of nickel to lipid rich tissues such as the liver and
brain (Misra et al, 1987). By contrast hydrophilic chelating agents
(e.g. sodium calcium ethylenediamine tetraacetic acid) are more likely
to enhance renal nickel clearance without cellular nickel accumulation
(Misra et al, 1987).
Misra et al (1987) observed a significant reduction (p<0.05) in renal
nickel content in rodents following treatment with both lipophilic
(1,4,8,11-tetra-azacyclotetradecane and triethylenetetramine) and
hydrophilic (sodium calciumedetate, 1,2,cyclohexylenediamine
tetraacetic acid, diethylenetriamine pentaacetic acid) chelating
agents given subcutaneously (500 µmol/kg) 60 minutes post dosing with
nickel chloride (250 µmol/kg subcutaneously). By contrast the hepatic
nickel content was increased following treatment with lipophilic
agents, but reduced after hydrophilic drug administration (Misra et
al, 1987).
Oskarsson and Tjälve (1980) investigated the effect on nickel
distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine
3.4 mmol/kg in mice administered a chelating agent ten minutes before
an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg). DDC
caused increased tissue nickel retention compared to control mice
(injected with nickel chloride alone), with the highest radioactivity
in adipose tissue followed by the liver, kidneys, brain and spinal
cord. The brain nickel content of DDC treated mice was 57 times
higher than control mice. Following d-penicillamine the tissue nickel
content was lower than in control mice. For example, the "kidney
contained about 1% and the lung about 4%" of the radioactivity
observed in mice given 63nickel chloride only.
Sodium calciumedetate 400 µmol/kg subcutaneously reduced the nickel
content of the liver, heart, kidney and lung by 20 - 40 per cent in
rodents administered nickel chloride (200 µmol/kg subcutaneously) 30
minutes previously (Dwivedi et al, 1986).
In rats (n = 20 - 25 in each group) the two week mortality following
intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95 0.29
mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg (0.3
times its LD50) was given one minute prior to nickel dosing (Horak
et al ,1976). Under the same experimental conditions
triethylenetetramine 1.36 mmol/kg (0.6 times its LD50) reduced
(p<0.001) the two week mortality to 25 per cent but DDC was
ineffective. Sodium calciumedetate 0.68 mmol/kg reduced the two week
mortality to 32 per cent (p<0.001) when the nickel chloride dose was
0.136 mmol/kg (greater than its LD50).
Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium
calciumedetate (administered intraperitoneally at a molar ratio of
10:1 chelating agent: nickel) increased survival in rodents
systemically poisoned 20 minutes previously with nickel (as
intraperitoneal nickel acetate, 62 mg/kg). The results are summarized
in Table 1 (Basinger et al, 1980).
Table 1. Survival rates in nickel intoxicated mice following chelation
therapy (see text)
n= Chelating agent Survival %
5 None 0
10 DMPS 80
10 d-Penicillamine 100
10 Sodium calciumedetate 100
(after Basinger et al, 1980)
Shen et al (1979) studied the effect of several chelating agents
(administered subcutaneously) on renal nickel clearance in rats
administered a continuous nickel chloride infusion. Each chelating
agent was administered to a different group of six rats with eight
controls. d-Penicillamine 1 µmol/h increased mean renal nickel
clearance by 53 per cent (p< 0.001) and triethylenetetramine 1 µmol/h
by 26 per cent (p<0.025) but DDC 2 µmol/h did not affect renal nickel
clearance.
DMPS 0.5 mmol/kg significantly enhanced urine nickel excretion
(0.001< p< 0.05) when administered subcutaneously to rats poisoned
with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant
decreases in nickel-induced hyperglycaemia and aminoaciduria were
noted following chelation therapy. Faecal nickel excretion was
unaffected and DMPS was ineffective in mobilizing nickel from the
brain (Sharma et al, 1987).
In a more recent controlled study, Tandon et al (1996) investigated
the effects of chelating agents on nickel toxicity. Groups (n=6) of
nickel poisoned rats (1.5 mg/kg nickel sulphate intraperitoneally, 6
days a week for 30 days) were intraperitoneally administered a
chelating agent 0.3 mmol/kg once a day for five days. DMSA and DMPS
significantly (p<0.001, p<0.01 respectively) enhanced faecal but not
urinary nickel excretion. DDC did not enhance elimination by either
route. DMSA, DMPS and DDC significantly (p<0.01) reduced blood,
liver, kidney and heart (but not brain) nickel concentrations compared
to controls. The DDC homologue (N-benzyl-D-glucamine dithiocarbamate)
was the most effective of all antidotes studied, significantly
enhancing both urinary and faecal excretion (p<0.01) and reducing
(p<0.001) the nickel concentrations in all tissues examined.
In mice systemically poisoned with nickel chloride (5 mg/kg),
intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the
brain (Xie et al, 1994). Intraperitoneal DMSA 400 µmol/kg,
significantly enhanced (p<0.05) the faecal and urinary excretion of
the metal and there was no redistribution to the brain (Xie et al,
1994). The same group recently found parenteral DMSA and
N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the
testicular nickel concentration and so protecting against
nickel-induced testicular toxicity in mice administered
intraperitoneal nickel chloride (Xie et al, 1995).
In summary, in rodents systemically poisoned with soluble nickel
salts, renal nickel clearance is increased and mortality reduced by
the parenteral administration of d-penicillamine or
triethylenetetramine. Evidence regarding the effect of DMPS and DMSA
on renal nickel elimination is conflicting. DDC does not enhance
nickel excretion.
Clinical studies
There are no human data involving chelation therapy in nickel chloride
toxicity save that relating to the management of nickel dermatitis.
Diethyldithiocarbamate and disulfiram in nickel dermatitis
Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that:
2(DDC) + Ni2+ ----- Nickel bis(DDC)
which is renally excreted.
DDC is not available as a pharmaceutical preparation in many countries
although disulfiram (Antabuse), which is metabolized to DDC (two
molecules of DDC from each of disulfiram), has been employed.
The rationale for the use of DDC and disulfiram in nickel dermatitis
is that both agents reduce the body nickel burden and so minimise the
amount of nickel available for the endogenous activation of
immunocompetent cells.
Topical DDC
van Ketel and Bruynzeel (1982) investigated the role of topical DDC in
the prevention of nickel sensitivity in 17 patients with known nickel
allergy. Prior to nickel challenge seven patients were pretreated for
24 hours with 10 per cent DDC under an occlusive dressing. They were
challenged with nickel sulphate (0.01, 0.1, 1.0 and 5.0 per cent
solutions) and a nickel coin (99.7 per cent nickel). Ten patients
applied 10 per cent DDC six hourly for 24 hours prior to nickel
sulphate challenge. There were no differences in mean patch test
scores between DDC-treated and non DDC-treated skin in all groups.
(Table 2).
Table 2. Topical DDC in nickel dermatitis
n= 24 h Nickel Mean ± SD
Pretreatment challenge patch-test score
Control DDC
7 10% DDC Nickel sulphate 3.9 ± 2.1 4.0 ± 3.2
under occlusion (0.01, 0.1, 1.0 and 5.0%)
7 10% DDC Coin 0.9 ± 0.7 1.8 ± 1.1
under occlusion (99.7% nickel)
10 10% DDC Nickel sulphate 2.9 ± 2.7 2.5 ± 3.1
qds (0.01, 0.1, 1.0 and 5.0%)
(van Ketel and Bruynzeel, 1982)
Systemic DDC and disulfiram
Several uncontrolled studies report the successful resolution of
nickel dermatitis following oral DDC or disulfiram. Uncontrolled
studies of disulfiram therapy in nickel dermatitis are summarized in
Table 3.
Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg
daily for 20 days led to an improvement in dermatitis although the
condition recurred when treatment was discontinued.
In another patient (Spruit et al, 1978) oral DDC for two months failed
to produce a negative nickel patch test, although less local treatment
was required.
Although disulfiram increases urine nickel excretion in patients with
nickel dermatitis (Table 4), there was no overall significant
difference between treatments in a double-blind study involving 24
patients treated with disulfiram 200 mg daily or placebo for six weeks
(Kaaber et al, 1983).
Adverse effects of DDC and disulfiram
There is concern that DDC and disulfiram may promote nickel
accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al, 1987;
Nielsen and Andersen, 1994). Disulfiram is also associated frequently
with a 'flare-up' of nickel dermatitis soon after commencing treatment
(Kaaber et al, 1979; Menné et al, 1980; Christensen and Kristensen,
1982; Christensen, 1982 (Table 3); Klein and Fowler, 1992; Gamboa et
al, 1993). Other reported adverse effects of disulfiram include
abnormal liver function (Kaaber et al, 1983; Kaaber et al, 1987), an
acne-like rash (Kaaber et al, 1983), headache (Kaaber et al, 1979;
Kaaber et al, 1983), fatigue and dizziness (Kaaber et al, 1979) and an
adverse reaction with alcohol. Reactivation of nickel sensitivity
often occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber
et al, 1987; Table 3).
Sodium calciumedetate
Seventeen nickel allergic patients pretreated with a cream containing
10 per cent sodium calciumedetate showed a significant reduction in
positive patch tests to nickel sulphate (1 per cent solution) compared
to results on untreated skin (three positive reactions compared to 14
respectively, p<0.01) (van Ketel and Bruynzeel, 1982). The authors
suggested use of 10 per cent sodium calciumedetate barrier creams in
nickel sensitive subjects but this requires further study.
Clioquinol
A recent clinical study reported that topical administration of the
chelating agent clioquinol (3 per cent) "completely abolished"
reactivity to nickel in 29 nickel-sensitive subjects and the authors
advocated its use as a barrier ointment in nickel allergic patients
(Memon et al, 1994) but this requires confirmation.
Table 3. Uncontrolled studies of disulfiram in nickel dermatitis
n= Disulfiram Effect on dermatitis Study
Dose Duration & Early % % %
(mg/day) (wks) flare "Healed" "Improved" Rebound1
1 300 8 - - 100 100 Menné & Kaaber, 1978
11 200-400 "4-10" 82 64 18 55 Kaaber et al, 1979
11 200-400 ? 82 73 - - Menné et al, 1980
11 200 8 100 18 73 100 Christensen & Kristensen, 1982
3 50-200 18 (mean) 100 33 66 33 Christensen, 1982
61 50-400 12 (mean) ?2 46 30 85 (n=27)3 Kaaber et al, 1987
98 - 47 32 66 (n=64)
1 Rebound dermatitis when disulfiram discontinued
2 Flares of dermatitis "frequently seen" but number not stated
3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases
Table 4. Disulfiram in nickel dermatitis: urine nickel excretion
n= Disulfiram Mean ± SD urine Study
dose nickel excretion
(mg/day) (µg/24 h)
Before Maximum during
treatment treatment
3 200-400 1.2 ± 0.3 53 ± 15.5 Kaaber et al, 1979
6 200-400 1.7 ± 0.5 60 ± 23.8 Menné et al, 1980
Antidotes: Conclusions and recommendations
Nickel contact sensitivity
1. Nickel contact sensitivity is managed most effectively by
avoiding exposure and treating acute exacerbations with topical
and/or systemic steroids.
2. Topical DDC has no role. There is some evidence that barrier
creams containing sodium calciumedetate or clioquinol may be
useful.
3. While there are two case reports claiming benefit from oral DDC
in the treatment of nickel dermatitis, this has not been
confirmed in a controlled clinical study.
4. In the only published controlled clinical study using disulfiram
in the management of nickel dermatitis there was no overall
benefit from treatment.
5. Uncontrolled studies with oral disulfiram suggest improvement in
secondary nickel dermatitis but the incidence of significant
side-effects is high.
6. Chelation therapy in nickel dermatitis cannot be advocated
routinely but remains an area of research interest.
Systemic nickel poisoning
1. There are no human data available regarding chelation therapy in
systemic nickel chloride toxicity.
2. Animal studies suggest d-penicillamine is probably the most
effective nickel antidote although there are promising results
and less adverse effects with the newer thiol chelating agents,
particularly DMPS.
MEDICAL SURVEILLANCE
Prior to employment involving potential exposure to nickel special
consideration should be given to those with a history of contact
dermatitis or respiratory disease.
Monitoring of nickel concentrations in blood and urine are not
indicated routinely because while they provide evidence of recent
exposure to soluble nickel compounds (and nickel metal powder), they
do not reflect the total body nickel burden.
Urine nickel concentrations vary considerably and should be
interpreted as groups of 24 hour samples rather than individual urine
specimens (Nickel Producers Environmental Research Association and the
Nickel Development Institute, 1994).
Serum nickel concentrations are used in some nickel industries since
they avoid contamination from work-place dust and provide fairly
consistent values within a given work environment; mean serum nickel
concentrations ranging from 0.9 µg/L (reference range varies widely
but a typical value for an adult is less than 1.3 µg/L) for grinders
and polishers to 11.9 µg/L in electrolytic refining workers have been
cited (Nickel Producers Environmental Research Association and the
Nickel Development Institute, 1994).
In a controlled study Torjussen and Andersen (1979) determined nasal
mucosal, plasma and urine nickel concentrations in 318 present and 15
retired workers all employed for at least eight years in a nickel
refining plant. Mean nickel concentrations in all samples were
significantly lower in the control group (n=57) than the corresponding
values for the active (p<0.01) and retired (p<0.05) workers
(Torjussen and Andersen, 1979).
In the same study (Torjussen and Andersen, 1979) electrolytic workers
exposed to nickel chloride and sulphate exhibited significantly lower
(p<0.01) nasal mucosal nickel concentrations (178.1 ± (SD) 234.7
µg/100g wet weight) than smelting and roasting workers exposed to
insoluble nickel oxide and subsulphide dust (467.2 ± (SD) 594.6
µg/100 g wet weight). Plasma and urine nickel concentrations, however,
were significantly higher (p<0.01) in electrolytic workers than in
those exposed to nickel oxide (Torjussen and Andersen, 1979).
Gammelgaard et al (1992) have suggested that a nickel content of
fingernails greater than 8 ppm indicates likely occupational (rather
than domestic) nickel exposure in patients with nickel dermatitis but
the reliability of this proposal has not been confirmed.
OCCUPATIONAL DATA
Maximum exposure limit
Nickel, inorganic soluble compounds: Long-term exposure limit (8 hour
TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1997).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
Epidemiological studies have shown a significant increase in deaths
from carcinoma of the lung and nasal sinuses among nickel refinery
workers (Roberts et al, 1992; Andersen, 1992). The excess risk of
death continues for several years after leaving employment (Muir et
al, 1994).
The exact aetiological agent is unknown, although nickel chloride,
nickel sulphate, nickel oxide and sub-sulphide have been suspected
(IARC, 1990; Roberts et al, 1992; Andersen, 1992). An increased
incidence of laryngeal cancer has not been confirmed (Roberts et al,
1992). Among employees at an aircraft engine factory lung cancer
deaths (n = 42) between 1966 and 1976 were no more prevalent among
nickel-exposed (exposed both to nickel alloys dust and aerosols of
nickel sulphate and chloride) than non-exposed workmen (Bernacki et
al, 1978).
A study by Pang et al (1996) provided only weak evidence (observed
8.0, expected 2.49, SMR 322) of an increased risk of stomach cancer in
a cohort of 284 nickel platers who handled nickel chloride and nickel
sulphate, first employed for at least three months between 1945-75.
Fortunately, measures to improve industrial hygiene have reduced
greatly the occupational hazard of nickel chloride exposure but
respiratory malignancies remain notifiable diseases among nickel
industry employees in the UK (Seaton et al, 1994).
Reprotoxicity
Animal studies have shown reduced fertility and stunted fetal growth
following the oral administration of nickel (as nickel sulphate) and
testicular damage following oral or dermal nickel exposure (to nickel
sulphate) (Reprotext, 1997). Smith et al (1993) provided evidence of
increased perinatal mortality in rats fed nickel chloride for 11 weeks
prior to mating then during two cycles of gestation and lactation.
These are no human reprotoxicity data specific to nickel chloride.
Chashschin et al (1994) reported an increased incidence of structural
malformations and spontaneous and threatened abortions in pregnancies
among 356 nickel refinery workers exposed to nickel aerosols (as
nickel sulphate) (range 0.077 - 0.308 mg/m3) compared to non-exposed
controls. Unfortunately their data lacked adequate sampling and
statistical details but suggests that the potential reprotoxic hazard
of soluble nickel salt exposure requires further investigation.
Genotoxicity
In vitro studies
Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537, TA1538
with and without metabolic activation - negative.
Escherichia coli WP2, WP67, CM871 with and without metabolic
activation DNA-repair test - negative.
Bacillus subtilis H17, M45 without metabolic activation - negative.
Saccharomyces cerevisiae D7 without metabolic activation - positive.
In vitro Chinese hamster ovary cells DNA strand breaks - positive.
In vitro mouse FM3A mammary carcinoma cells, Chinese hamster ovary
cells and human peripheral blood lymphocytes: chromosomal aberrations
and sister chromatid exchanges - positive.
In vitro Chinese hamster ovary cells, chromosomal aberrations -
positive.
In vivo studies
Reduced sperm counts, sperm mobilities, induced sperm chromosomal
aberrations, damaged testes ultrastructure, caused sperm head
abnormalities and induced micronuclei in the polychromatic
erythrocytes were found in mice. Intraperitoneal injection of 6-24
mg/kg nickel in mice induced bone marrow chromosomal aberrations
(DOSE, 1994).
Clinical studies
In a controlled study Waksvik et al (1984) investigated chromosomal
aberrations in the peripheral lymphocytes of retired nickel refinery
workers (n=9) four to 15 years post retirement. The workers who had
been exposed to either nickel chloride, nickel oxide, nickel sulphate
or nickel subsulphide for greater than 25 years (nickel air
concentrations >1 mg/m3) showed an increased incidence of
chromosomal breaks (p<0.001) and gaps (p<0.05) but no difference in
sister chromatid exchange compared with the non nickel-exposed
controls (n=11).
Fish toxicity
LC50 (96 hr) fathead minnow, blue gill sunfish 4.9-5.3 mg/L in soft
water (20 mg CaCO3/L) or 43.5-39.6 mg/L in hard water (300 mg
CaCO3/L).
LC50 (48 hr) rainbow trout 20, 80 mg/L in soft, hard water
respectively.
LC50 (96 hr) tidewater silver side larvae, adult spot fish 30, 70
mg/L respectively (DOSE, 1994).
EC Directive on Drinking Water Quality 80/778/EEC
Nickel: Maximum admissible concentration 50 µg/L.
Chlorides guide level 25 mg/L (DOSE, 1994).
WHO Guidelines for Drinking Water Quality
Guideline value 0.02 mg/L, as nickel (WHO, 1993).
AUTHORS
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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See Also:
Toxicological Abbreviations