UKPID MONOGRAPH
NICKEL SULPHATE
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
NICKEL SULPHATE
Toxbase summary
Type of product
Soluble nickel salt used in nickel plating, as a catalyst component
and in the dye and printing industry.
Toxicity
An important cause of contact dermatitis. May precipitate occupational
asthma. Gastrointestinal irritation has occurred following ingestion
but severe poisoning is rare. A two year-old child has died after
ingesting 15 g (Daldrup et al, 1983).
Features
Topical
- Primary skin irritant and an important cause of contact
dermatitis.
Ingestion
Mild/moderate ingestions:
- Small ingestions of dilute solutions may produce no
symptoms. Nausea, vomiting, abdominal pain and diarrhoea
occur within two hours in more substantial ingestions,
possibly associated with headache, giddiness and myalgia.
Substantial ingestions:
- Severe gastrointestinal irritation and haemorrhage may
ensue. Fatalities have occurred.
- Investigations may reveal transient hyperbilirubinaemia,
albuminuria or a reticulocytosis. Transient first degree
heart block has been described.
Inhalation
- A potential cause of occupational asthma. Chronic inhalation
may cause rhinitis, sinusitis, anosmia and perforation of
the nasal septum.
Management
Topical
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Chelation therapy in nickel contact dermatitis cannot be
advocated routinely but is an area of research interest. Discuss
with NPIS.
Ingestion
1. In mild cases symptomatic and supportive measures will suffice.
2. Gastric lavage is best avoided in view of potential oesophageal
irritation.
3. In symptomatic patients obtain blood and urine for nickel
concentration estimation.
4. Ensure a good urine output in those with suspected or confirmed
nickel toxicity.
Inhalation
1. Remove from exposure.
2. Symptomatic and supportive measures as required.
3. Occupational asthma should be managed conventionally.
References
Daldrup T, Haarhoff K, Szathmary SC.
Tödliche nickelsulfatintoxikation.
Beitr Gerichtl Med 1983; 41: 141-4.
Novey HS, Habib M, Wells ID.
Asthma and IgE antibodies induced by chromium and nickel salts.
J Allergy Clin Immunol 1983; 72: 407-12.
Sunderman Jr FW, Dingle B, Hopfer SM, Swift T.
Acute nickel toxicity in electroplating workers who accidentally
ingested a solution of nickel sulfate and nickel chloride.
Am J Ind Med 1988; 14: 257-66.
Substance name
Nickel sulphate
Origin of substance
Nickel sulphate occurs naturally as the mineral morenosite.
(DOSE, 1994)
Nickel sulphate may be produced by dissolving nickel oxide in
sulphuric acid and concentrating the solution to precipitate
nickel sulphate heptahydrate, which on heating forms the
commercial crystalline nickel sulphate hexahydrate.
(HSDB, 1996)
Synonyms
Nickel (II) sulphate
Nickel monosulphate
Nickelous sulphate (DOSE, 1994)
Chemical group
A compound of nickel, a transition metal (d block) element.
Reference numbers
CAS 7786-81-4 (DOSE, 1994)
RTECS QR935000 (RTECS, 1996)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
Nickel sulphate, NiSO4 (DOSE, 1994)
Molecular weight
154.77 (DOSE, 1994)
Physical state at room temperature
Solid
Colour
Alpha form: blue to blue-green crystals; Beta form: green
transparent crystals. (MERCK, 1989)
Odour
Odourless (HSDB, 1996)
Viscosity
NA
pH
The aqueous solution is acid, approximately pH 4.5
(MERCK, 1989)
Solubility
Soluble in water : 293 g/L at 0°C. (HSDB, 1996)
Soluble in methanol. (DOSE, 1994)
Autoignition temperature
NA
Chemical interactions
NIF
Major products of combustion
Toxic gases and vapours including nickel carbonyl may be released
in a fire involving nickel. (HSDB, 1996)
Explosive limits
NIF
Flammability
Non-flammable (HSDB, 1996)
Boiling point
NIF
Density
3.86 at 20°C (DOSE, 1994)
Vapour pressure
NIF
Relative vapour density
NIF
Flash Point
NA
Reactivity
Nickel sulphate is incompatible with strong acids.
(HSDB, 1996)
Uses
Nickel sulphate is used widely in nickel plating; as a raw
material for the production of catalysts; as a mordant in dyeing
and printing fabrics; for blackening zinc and brass and in
jewellery manufacture.
(IPCS, 1991; DOSE, 1994)
Hazard/risk classification
Index no 028-009-00-5
Risk phrases
Carc. Cat 3; R40. Xn; R22, R42/43.
Possible risk of irreversible effects. Harmful if swallowed. May
cause sensitization by inhalation and skin contact.
Safety phrases
S(2-) 22 - 36/37.
Keep out of reach of children. Do not breathe dust. Wear suitable
protective clothing and gloves.
EEC no 232-104-9 (CHIP2, 1994)
INTRODUCTION AND EPIDEMIOLOGY
Nickel sulphate is a soluble nickel salt used widely in nickel patch
testing. Poisoning by ingestion is rare although occupational
(Sunderman et al, 1988) and domestic (Daldrup et al, 1983) cases have
been described. Nickel sulphate inhalation may cause occupational
asthma in metal platers (Novey et al, 1983) and polishers (Block and
Yeung, 1982).
MECHANISM OF TOXICITY
In vitro studies demonstrate that nickel causes crosslinking of
amino acids to DNA, alters gene expression, induces gene mutations and
the formation of reactive oxygen species (Costa et al, 1994a and b;
Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994). Nickel also
suppresses natural killer cell activity and interferon production
(Shen and Zhang, 1994).
TOXICOKINETICS
Absorption
Nickel sulphate can be absorbed by inhalation, ingestion and following
percutaneous exposure, the latter not being quantitatively significant
though an important source of contact sensitivity (IPCS, 1991).
Significant mucociliary clearance of inhaled particles occurs.
Gastrointestinal absorption is affected by co-ingestion of other
substances; in a volunteer study the absorption of nickel sulphate was
27 per cent from water and less than one per cent from food (Sunderman
et al, 1989).
Distribution and excretion
Once absorbed, nickel is transported in the blood bound principally to
albumin, it is concentrated in the kidneys, liver and lungs and is
excreted primarily in the urine. However, following ingestion the
concentration of nickel in faeces will be much higher than in urine
since most is not absorbed. Some 50 per cent of inhaled nickel
sulphate may eventually also appear in the gut.
Animal and human volunteer studies suggest that the distribution and
elimination of soluble nickel salts follows a two compartment model
with an initial rapid plasma elimination phase (over two days)
followed by a slower clearance phase (IPCS, 1991).
In ten human volunteers the plasma elimination half-life of ingested
nickel was 28 ± (SD) 9 hours (Sunderman et al, 1989). Among ten
workers who accidentally drank 0.5-1.5 L nickel sulphate and nickel
chloride-contaminated water the serum nickel half-life was 27 ± (SD) 7
hours (Sunderman et al, 1988). These individuals received intravenous
fluid (150 mL/hour) for three days following the accident. Among 11
individuals in whom a diuresis was not induced the mean serum nickel
half-life was 60 ± (SD) 11 hours.
Nickel crosses the placenta and is passed to the child in maternal
milk (Fairhurst and Illing, 1987; IPCS, 1991).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
There is relatively little information on the acute dermal toxicity of
soluble nickel salts in humans, though at high concentrations they are
primary skin irritants (Frosch and Kligman, 1976). Dermal nickel
sulphate exposure is associated mainly with the development of nickel
contact sensitivity (see Chronic exposure).
Ingestion
Gastrointestinal toxicity
Sunderman et al (1988) reported an industrial accident involving 32
workers at an electroplating plant who accidentally drank water
contaminated with nickel sulphate, nickel chloride (total nickel
concentration 1.63 g/L) and boron (68 mg/L). Symptoms occurred
primarily in those who had ingested more than 500 mL and began within
two hours of ingestion. Gastrointestinal effects were the most common
with nausea, vomiting, abdominal pain and diarrhoea.
Ten of 32 patients required hospital admission with symptoms
persisting for two days though all were asymptomatic within three
days. The mean urine nickel concentration among 15 of those exposed
was 5.8 mg/L (range 0.23 - 37.1 mg/L) the day following the incident,
with a mean serum nickel concentration of 286 µg/L (range 12.8 - 1340
µg/L). Among 11 nickel platers who did not drink the contaminated
water the mean urine nickel concentration was 50 ± (SD) 13 µg/L with a
mean serum nickel concentration of 4.0 ± (SD) 1.2 µg/L (Sunderman et
al, 1988).
A two year-old child reported in the German literature died within
hours of ingesting about 15 g nickel sulphate crystals from a
chemistry set. Haemorrhagic gastritis was described at autopsy
(Daldrup et al, 1983).
Hepatotoxicity
Two of the ten patients admitted following ingestion of 0.5 - 1.5 L
nickel sulphate/chloride contaminated water (see above) developed
transient hyperbilirubinaemia (30 µmol/L and 43 µmol/L respectively)
but this resolved within six weeks (Sunderman et al, 1988).
Neurotoxicity
Of 20 workers who accidentally ingested water contaminated with nickel
sulphate and nickel chloride (see above) seven complained of
giddiness, six of lassitude, five of headache and one of myalgia.
Symptoms resolved within hours in most cases and within two days in
all (Sunderman et al, 1988).
In the same accident it was noted that the mean body temperature of
the ten most substantially exposed patients was slightly diminished
(mean 36.7 ± (SD) 0.3°C on day 2). The authors proposed nickel-induced
impaired thermoregulation (which has been described in animals) but
there are insufficient clinical data to substantiate this.
Pulmonary toxicity
Of the 21 workers who drank nickel contaminated water (nickel
concentration 1.63 g/L), abnormal physical signs were reported only in
two; expiratory wheeze in a patient with known bronchial asthma and
dyspnoea and mild cyanosis in another with chronic obstructive airways
disease (Sunderman et al, 1988).
Nephrotoxicity
Two of the subjects described by Sunderman et al (1988) developed
transient albuminuria in the two days following ingestion of nickel
sulphate/chloride contaminated water (see above). In both cases this
resolved by day five.
Haemotoxicity
Sunderman et al (1988) reported a modest erythropoietic effect among
ten workers who accidentally drank nickel
sulphate/chloride-contaminated water (see above) with an increase
(p<0.01) in the mean blood haemoglobin concentration between days
three and eight post exposure. There was a similar statistically
significant increase in the blood reticulocyte count.
Cardiovascular toxicity
Ingestion of 0.5 - 1.5 L nickel sulphate/chloride contaminated water
(nickel content 1.63 g/L) was associated in one patient with transient
first degree heart block (Sunderman et al, 1988).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Nickel sulphate is a common precipitant of allergic contact dermatitis
(Zhang et al, 1991) which is a cell-mediated (type IV)
hypersensitivity response.
Chronic urticaria, a type 1 hypersensitivity cutaneous reaction has
also been described (Abeck et al, 1993).
Nickel sensitivity has been implicated in the aetiology of pompholyx,
a vesicular eruption of the palmoplantar regions (Lodi et al, 1992).
Primary nickel sensitization is more common in women (Peltonen, 1979)
and usually follows prolonged non-occupational skin contact with
nickel-plated objects or nickel alloys. Common sources include
jewellery, buttons, zips and coins. The amount of nickel released from
these items depends on their resistance to corrosion and the presence
of sweat which acts to release the metal ion. Nickel valve prostheses
and nickel-containing pacemakers have also been suggested as triggers
of nickel allergy (Lyell and Bain, 1974; Landwehr and van Ketel,
1983).
Once an individual is sensitized, further exposure to only a very
small quantity of nickel initiates a reaction at the site of contact.
Nickel may penetrate rubber gloves (Wall, 1980).
In susceptible individuals nickel allergy may result in "secondary"
nickel dermatitis with dissemination to skin sites distant from that
of primary sensitization (typically the hands, flexures and eyelids
(Valsecchi et al, 1992)). It is not clear whether the latter is an
endogenous phenomenon or simply reflects exogenous nickel
contamination, for example via perspiring fingers (Fisher, 1986).
Nickel sulphate is widely used as the allergen in nickel patch testing
and as the stimulus of lymphocyte blast transformation in the in
vitro confirmation of nickel sensitivity (Al-Tawil et al, 1981;
Silvennoinen-Kassinen, 1981; Everness et al, 1990; Grimsdottir et al,
1994).
Inhalation
Pulmonary toxicity
Nickel sulphate inhalation is a cause of occupational asthma with
circulating IgE nickel antibodies (Nieboer et al, 1984) and resolution
of symptoms when away from work (Block and Yeung, 1982). Cases have
been reported among metal platers (McConnell et al, 1973; Novey et al,
1983) and polishers (Block and Yeung, 1982).
An asthmatic reaction to nickel sulphate inhalation has also been
reported in a patient without demonstrable nickel IgE (Malo et al,
1985).
It is likely nickel allergy is involved in the aetiology of
'hard-metal' asthma (typically associated with cobalt exposure) with
evidence of cross reactivity between cobalt and nickel (Shirakawa et
al, 1990; Shirakawa et al, 1992).
Chronic exposure to aerosols of soluble nickel salts, including nickel
sulphate, may lead to chronic rhinitis, nasal sinusitis, anosmia and
perforation of the nasal septum (Mastromatteo, 1986).
Nephrotoxicity
There is some evidence that chronic inhalation of high concentrations
of soluble nickel compounds causes increased urinary protein and renal
tubular enzyme excretion but the significance of these findings is not
known (Vyskocil et al, 1994).
Ingestion
Dermal toxicity
Although primary nickel sensitization occurs only following skin
contact, nickel dermatitis may be reactivated subsequently by ingested
nickel (Gawkrodger et al, 1986; Nielsen et al, 1990). This is unusual
because most antigens induce a state of immunological tolerance when
administered orally, an effect that has also been described in nickel
sensitive subjects (Sjövall et al, 1987; Panzani et al, 1995).
An exacerbation of nickel dermatitis following ingestion is localized
often to the initial sensitization site. This suggests that the
antigen-presenting cells responsible for initiating the allergic
reaction are relatively immobile (Nicklin and Nielsen, 1992). This may
have important implications for the prevention and treatment of nickel
dermatitis since if the body burden of nickel can be reduced (for
example by chelating agents), the likelihood of nickel activation of
the antigen presenting cells may be diminished. This is discussed
further below (Management). Paradoxically the suggested mechanism of
oral hyposensitization in nickel sensitive subjects is stimulation of
suppressor T-cell production by antigen excess (Sjövall et al, 1987).
Chronic urticaria, a type 1 hypersensitivity response, has been
attributed to dietary nickel (Abeck et al, 1993), but this is unusual.
MANAGEMENT
Dermal exposure
Avoidance of exposure and symptomatic treatment of exacerbations with
topical or systemic steroids remain the mainstay of treatment of
nickel allergy although dietary nickel restriction (Kaaber et al,
1978) or oral (Panzani et al, 1995) or topical (Allenby and Basketter,
1994) hyposensitization have been advocated. Oral cyclosporin does not
appear to be effective (De Rie et al, 1991). The role of chelation
therapy is discussed below.
Inhalation
Symptomatic and supportive treatment is all that is likely to be
required in those with symptoms of respiratory tract irritation
following acute exposure to nickel sulphate. Occupational asthma
should be managed conventionally, and further exposure avoided.
Ingestion
Spontaneous vomiting is likely in patients who have ingested a
substantial quantity of nickel sulphate and if this does not occur
gastric lavage should be avoided in view of potential oesophageal
inflammation. General symptomatic and supportive measures are likely
to be all that are required in most cases. Measurement of nickel
concentrations in blood and urine should be considered only in
symptomatic patients.
Since nickel is eliminated mainly in the urine, maintenance of a high
urine output is important in those with a confirmed or suspected
increased nickel burden. Following inadvertent ingestion of 0.5-1.5 L
nickel sulphate/ chloride-contaminated water (nickel concentration
1.63 g/L), Sunderman et al (1988) demonstrated a mean serum nickel
half life of 27 hours (n=10) in those treated with intravenous fluids
compared to a half-life of 60 hours (n=11) in those not admitted to
hospital.
The role of chelation therapy in nickel sulphate poisoning is
discussed below (Antidotes).
Antidotes
Animal studies
Most experimental studies of nickel chelation therapy have utilized
nickel chloride rather than nickel sulphate but the results are
relevant to all soluble nickel salts.
The effect of chelating agents on nickel distribution is dependent on
their lipid solubility. Lipophilic agents (such as
diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride
(TETA)) are more able to penetrate cell membranes with potential
redistribution of nickel to lipid rich tissues such as the liver and
brain (Misra et al, 1987). By contrast hydrophilic chelating agents
(e.g. sodium calcium ethylenediamine tetraacetic acid (EDTA)) are more
likely to enhance renal nickel clearance without cellular nickel
accumulation (Misra et al, 1987).
Misra et al (1987) observed a significant reduction (p<0.05) in renal
nickel content in rodents following treatment with both lipophilic
(1,4,8,11-tetra-azacyclotetradecane and TETA) and hydrophilic (sodium
calcium edetate, 1,2,cyclohexylenediamine tetraacetic acid,
diethylenetriamine pentaacetic acid) chelating agents 500 µmol/kg
subcutaneously 60 minutes post poisoning with nickel (as subcutaneous
nickel chloride 250 µmol/kg). By contrast the hepatic nickel content
was increased following treatment with lipophilic agents, but reduced
after hydrophilic drug administration (Misra et al, 1987).
Oskarsson and Tjälve (1980) investigated the effect on nickel
distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine
3.4 mmol/kg in mice administered a chelating agent ten minutes before
an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg). DDC
caused increased tissue nickel retention compared to control mice
(injected with nickel chloride alone), with the highest radioactivity
in adipose tissue followed by the liver, kidneys, brain and spinal
cord. The brain nickel content of DDC treated mice was 57 times higher
than control mice. Following d-penicillamine the tissue nickel content
was lower than in control mice. For example, the "kidney contained
about 1 % and the lung about 4 %" of the radioactivity observed in
mice given 63nickel chloride only.
Sodium calcium edetate 400 µmol/kg subcutaneously reduced the nickel
content of the liver, heart, kidney and lung by 20-40 per cent in
rodents poisoned with nickel (as subcutaneous nickel chloride 200
µmol/kg) 30 minutes previously (Dwivedi et al, 1986).
In rats (n=20-25 in each group) the two week mortality following
intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95 0.29
mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg (0.3
times its LD50) was given one minute prior to nickel dosing (Horak
et al ,1976). Under the same experimental conditions TETA 1.36 mmol/kg
(0.6 times its LD50 ) reduced (p<0.001) the two week mortality to
25 per cent but DDC was ineffective. Sodium calcium edetate 0.68
mmol/kg reduced the two week mortality to 32 per cent (p<0.001) when
the nickel chloride dose was 0.136 mmol/kg (greater than its LD50).
Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium calcium
edetate (administered intraperitoneally at a molar ratio of 10:1
chelating agent: nickel) increased survival in rodents systemically
poisoned with nickel (as intraperitoneal nickel acetate, 62 mg/kg).
The results are summarized in Table 1 (Basinger et al, 1980).
Table 1. Survival rates in nickel intoxicated mice following chelation
therapy (see text)
n= Chelating agent Survival %
5 None 0
10 DMPS 80
10 d-penicillamine 100
10 Sodium calcium edetate 100
(after Basinger et al, 1980)
Shen et al (1979) studied the effect of several chelating agents
(administered subcutaneously) on renal nickel clearance in rats
administered a continuous nickel chloride infusion. Each chelating
agent was administered to a different group of six rats with eight
controls. d-Penicillamine 1 µmol/h increased mean renal nickel
clearance by 53 per cent (p< 0.001) and TETA 1 µmol/h by 26 per cent
(p<0.025) but DDC 2 µmol/h did not affect renal nickel clearance.
DMPS 0.5 mmol/kg significantly enhanced urine nickel excretion
(0.001< p< 0.05) when administered subcutaneously to rats poisoned
with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant
decreases in nickel-induced hyperglycaemia and aminoaciduria were
noted following chelation therapy. Faecal nickel excretion was
unaffected and DMPS was ineffective in mobilizing nickel from the
brain (Sharma et al, 1987).
In mice systemically poisoned with nickel chloride (5 mg/kg),
intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the
brain (Xie et al, 1994). Intraperitoneal DMSA 400 µmol/kg,
significantly enhanced (p<0.05) the faecal and urinary excretion of
the metal and there was no redistribution to the brain (Xie et al,
1994). The same group recently found parenteral DMSA and
N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the
testicular nickel concentration and so protecting against
nickel-induced testicular toxicity in mice administered
intraperitoneal nickel chloride (Xie et al, 1995).
In summary, in rodents systemically poisoned with soluble nickel
salts, renal nickel clearance is increased and mortality reduced by
the parenteral administration of d-penicillamine, TETA or DMPS. DMSA
also increases renal nickel elimination. DDC is not an effective
antidote in systemic soluble nickel salt poisoning.
Clinical studies
There are no human data involving chelation therapy in nickel sulphate
toxicity save that relating to the management of nickel dermatitis.
Diethyldithiocarbamate and disulfiram in nickel dermatitis
Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that:
2(DDC) + Ni2+ ---> Nickel bis(DDC) which is renally excreted.
DDC is not available as a pharmaceutical preparation in many countries
although disulfiram (Antabuse), which is metabolized to DDC (two
molecules of DDC from each of disulfiram), has been employed.
The rationale for the use of DDC and disulfiram in nickel dermatitis
is that both agents reduce the body nickel burden and so minimise the
amount of nickel available for the endogenous activation of
immunocompetent cells.
Topical DDC
van Ketel and Bruynzeel (1982) investigated the role of topical DDC in
the prevention of nickel sensitivity in 17 patients with known nickel
allergy. Prior to nickel challenge seven patients were pretreated for
24 hours with 10 per cent DDC under an occlusive dressing. They were
challenged with nickel sulphate (0.01, 0.1, 1.0 and 5.0 per cent
solutions) and a nickel coin (99.7 per cent nickel). Ten patients
applied 10 per cent DDC six hourly for 24 hours prior to nickel
sulphate challenge. There were no differences in mean patch test
scores between DDC-treated and non DDC-treated skin in all groups.
(Table 2).
Table 2. Topical DDC in nickel dermatitis
n= 24 h Nickel Mean ± SD
Pretreatment challenge patch-test score
Control DDC
7 10% DDC Nickel sulphate 3.9 ± 2.1 4.0 ± 3.2
under occlusion (0.01, 0.1, 1.0 and 5.0%)
7 10% DDC Coin 0.9 ± 0.7 1.8 ± 1.1
under occlusion (99.7% nickel)
10 10% DDC Nickel sulphate 2.9 ± 2.7 2.5 ± 3.1
qds (0.01, 0.1, 1.0 and 5.0%)
(van Ketel and Bruynzeel, 1982)
Oral DDC and disulfiram
Several uncontrolled studies report the successful resolution of
nickel dermatitis following oral DDC or disulfiram. Uncontrolled
studies of disulfiram therapy in nickel dermatitis are summarized in
Table 3.
Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg
daily for 20 days led to an improvement in dermatitis although the
condition recurred when treatment was discontinued.
In another patient (Spruit et al, 1978) oral DDC for two months failed
to produce a negative nickel patch test, although less local treatment
was required.
Table 3. Uncontrolled studies of disulfiram in nickel dermatitis
n= Disulfiram Effect on dermatitis Study
Dose Duration & Early % % %
(mg/day) (wks) flare "Healed" "Improved" Rebound1
1 300 8 - - 100 100 Menné & Kaaber, 1978
11 200-400 "4-10" 82 64 18 55 Kaaber et al, 1979
11 200-400 ? 82 73 - - Menné et al, 1980
11 200 8 100 18 73 100 Christensen & Kristensen, 1982
3 50-200 18 (mean) 100 33 66 33 Christensen, 1982
61 50-400 12 (mean) ?2 46 30 85 (n=27)3 Kaaber et al, 1987
98 - 47 32 66 (n=64)
1 Rebound dermatitis when disulfiram discontinued
2 Flares of dermatitis "frequently seen" but number not stated
3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases
Table 4. Disulfiram in nickel dermatitis: urine nickel excretion
n= Disulfiram Mean ± SD urine Study
dose nickel excretion
(mg/day) (µg/24 h)
Before Maximum during
treatment treatment
3 200-400 1.2 ± 0.3 53 ± 15.5 Kaaber et al, 1979
6 200-400 1.7 ± 0.5 60 ± 23.8 Menné et al, 1980
Disulfiram certainly increases urine nickel excretion in patients with
nickel dermatitis (Table 4) but in a double-blind study involving 24
such patients treated with disulfiram 200 mg daily or placebo for six
weeks, there was no overall significant difference between treatments
(Kaaber et al, 1983).
Adverse effects of DDC and disulfiram
There is concern that DDC and disulfiram may promote nickel
accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al, 1987;
Nielsen and Andersen, 1994). Disulfiram is also associated frequently
with a 'flare-up' of nickel dermatitis soon after commencing treatment
(Kaaber et al, 1979; Menné et al, 1980; Christensen and Kristensen,
1982; Christensen, 1982 (Table 3); Klein and Fowler, 1992; Gamboa et
al, 1993). Other reported adverse effects of disulfiram include
abnormal liver function (Kaaber et al, 1983; Kaaber et al, 1987), an
acne-like rash (Kaaber et al, 1983), headache (Kaaber et al, 1979;
Kaaber et al, 1983), fatigue and dizziness (Kaaber et al, 1979) and an
adverse reaction with alcohol. Reactivation of nickel sensitivity
often occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber
et al, 1987; Table 3).
Sodium calcium edetate
Seventeen nickel allergic patients pretreated with a cream containing
10 per cent sodium calcium edetate (EDTA) showed a significant
reduction in positive patch tests to nickel sulphate (1 per cent
solution) compared to results on untreated skin (three positive
reactions compared to 14 respectively, p<0.01) (van Ketel and
Bruynzeel, 1982). The authors suggested use of 10 per cent sodium
calcium edetate barrier creams in nickel sensitive subjects but this
requires further study.
Clioquinol
A recent clinical study reported that topical administration of the
chelating agent clioquinol (3 per cent) "completely abolished"
reactivity to nickel in 29 nickel-sensitive subjects and the authors
advocated its use as a barrier ointment in nickel allergic patients
(Memon et al, 1994) but this requires confirmation.
Antidotes: Conclusions and recommendations
Nickel contact sensitivity
1. Nickel contact sensitivity is managed most effectively by
avoiding exposure and treating acute exacerbations with topical
and/or systemic steroids.
2. Topical DDC has no role. There is some evidence that barrier
creams containing sodium calcium edetate or clioquinol may be
useful.
3. While there are two case reports claiming benefit from oral DDC
in the treatment of nickel dermatitis, this has not been
confirmed in a controlled clinical study.
4. In the only published controlled clinical study using disulfiram
in the management of nickel dermatitis there was no overall
benefit from treatment.
5. Uncontrolled studies with oral disulfiram suggest improvement in
secondary nickel dermatitis but the incidence of significant
side-effects is high.
6. Chelation therapy in nickel dermatitis cannot be advocated
routinely but remains an area of research interest.
Systemic nickel poisoning
1. There are no human data available regarding chelation therapy in
systemic nickel sulphate toxicity.
2. Animal studies suggest d-penicillamine is probably the most
effective nickel antidote although there are promising results
and less adverse effects with the newer thiol chelating agents,
particularly DMPS.
MEDICAL SURVEILLANCE
Prior to employment involving nickel exposure special consideration
should be given to those with a history of contact dermatitis or
respiratory disease.
The long-term maximum exposure limit in air in the UK for soluble
nickel is 0.1 mg/m3 (Health and Safety Executive, 1995). Monitoring
of nickel concentrations in blood and urine are not indicated
routinely because while they provide evidence of recent exposure to
soluble nickel compounds, such as nickel sulphate and nickel metal
powder, they do not reflect the total body nickel burden.
Urine nickel concentrations vary considerably and should be
interpreted as groups of 24 hour samples rather than individual urine
specimens (Nickel Producers Environmental Research Association and the
Nickel Development Institute, 1994).
Serum nickel concentrations are used in some nickel industries since
they avoid contamination from work-place dust and provide fairly
consistent values within a given work environment; mean serum nickel
concentrations ranging from 0.9 µg/L for grinders and polishers to
11.9 µg/L in electrolytic refining workers have been cited (Nickel
Producers Environmental Research Association and the Nickel
Development Institute, 1994).
In a controlled study Torjussen and Andersen (1979) determined nasal
mucosal, plasma and urine nickel concentrations in 318 present and 15
retired workers all employed for at least eight years in a nickel
refining plant. Mean nickel concentrations in all samples were
significantly lower in the control group (n=57) than the corresponding
values for the active (p<0.01) and retired (p<0.05) workers
(Torjussen and Andersen, 1979).
In the same study (Torjussen and Andersen, 1979) electrolytic workers
exposed to soluble nickel sulphate and nickel chloride exhibited
significantly lower (p<0.01) nasal mucosal nickel concentrations
(178.1 ± (SD) 234.7 µg/100g wet weight) than smelting and roasting
workers exposed to insoluble nickel oxide and subsulphide dust (467.2
± (SD) 594.6 µg/100 g wet weight). Plasma and urine nickel
concentrations however were significantly higher (p<0.01) in
electrolytic workers than in those exposed to nickel oxide (Torjussen
and Andersen, 1979).
Gammelgaard et al (1992) have suggested that a nickel content of
fingernails greater than 8 ppm indicates likely occupational (rather
than domestic) nickel exposure in patients with nickel dermatitis but
the reliability of this proposal has not been confirmed.
OCCUPATIONAL DATA
Maximum exposure limit
Nickel, inorganic soluble compounds: Long-term maximum exposure limit
(8 hour TWA reference period) 0.1 mg/m3 (Health and Safety
Executive, 1995).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
Epidemiological studies have shown a significant increase in deaths
from carcinoma of the lung and nasal sinuses among nickel refinery
workers (Roberts et al, 1992; Andersen, 1992). The excess risk of
death continues for several years after leaving employment (Muir et
al, 1994).
The exact aetiological agent is unknown, although nickel sulphate and
its oxide and subsulphide have been suspected (IARC, 1990; Roberts et
al, 1992; Andersen, 1992). An increased incidence of laryngeal cancer
has not been confirmed (Roberts et al, 1992).
Fortunately, measures to improve industrial hygiene have greatly
reduced the occupational hazard of nickel sulphate exposure but
respiratory tract malignancies among nickel industry employees remain
notifiable diseases in the UK (Seaton et al, 1994).
Reprotoxicity
Animal studies have shown reduced fertility and stunted fetal growth
following the oral administration of nickel sulphate and testicular
damage following oral or dermal nickel sulphate exposure (Reprotext,
1996).
Human data specific to nickel sulphate are scarce. Chashschin et al
(1994) reported an increased incidence of structural malformations and
spontaneous and threatened abortions in pregnancies among 356 nickel
refinery workers exposed to nickel sulphate aerosols (range
0.077-0.308 mg Ni/m3) compared to non-exposed controls.
Unfortunately this data lacks adequate sampling and statistical
details but suggests that the potential reprotoxic hazard of nickel
sulphate requires further investigation.
Genotoxicity
Salmonella typhimurium TA98, TA100, TA1537 without metabolic
activation negative.
Escherichia coli WP2 without metabolic activation negative.
Photobacterium fischeri bioluminescence test negative.
Saccharomyces cerevisiae D7 gene conversion equivocal.
In vitro Syrian hamster embryo cells, Chinese hamster ovary cells,
P338D1 mouse macrophage line, human peripheral blood lymphocytes:
Sister chromatid exchanges positive.
In vitro Syrian hamster cells, human peripheral blood lymphocytes:
Unscheduled DNA synthesis and chromosomal aberrations positive.
In vivo rat bone marrow: Chromosomal aberrations negative (DOSE,
1994).
Cytogenetic analysis of chromosomal aberrations of peripheral
lymphocytes was performed in a controlled study (Senft et al, 1992) of
21 workers exposed to either nickel oxide (n=6) or nickel sulphate
(n=15). A statistically significant (p<0.001) increase in the mean
percentage chromosome aberration value was observed in the exposed
group (n=21) compared with the control group (19 non nickel-exposed
employees at the same chemical plant) with more aberrations in the
nickel oxide workers (9.5 ± (SD) 3.2 per cent) than in those producing
nickel sulphate (5.2 ± (SD) 1.9 per cent).
A significant increase (p<0.01) in the mean percentage chromosome
aberration in the control group (4.05 ± (SD) 2.27 per cent) compared
with the suggested normal value for the general population (up to 2
per cent) was attributed to the nickel polluted environment of the
plant.
The authors concluded that nickel exposure causes increased peripheral
lymphocyte chromosomal aberrations and suggested a positive
association between duration of employment and the frequency of these
abnormalities. They also proposed that the higher frequency of
aberrations following nickel oxide exposure was due to the longer
biological half-life of insoluble nickel salts allowing more time to
exert a genotoxic effect (Senft et al, 1992).
Fish toxicity
LC50 (duration unspecified) rainbow trout 0.36 mg/L.
LC50 (14 day) coho salmon 11.2 mg/L.
LC50 (1 day) giant gourami 96 mg/L (DOSE, 1994).
EC Directive on Drinking Water Quality 80/778/EEC
Nickel: Maximum admissible concentration 50 µg/L.
Sulphates : Maximum admissible concentration 250 mg/L, guide level 25
mg/L (DOSE, 1994).
WHO Guidelines for Drinking Water Quality
Guideline value 0.02 mg/L, as nickel (WHO, 1993).
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
17/197
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