Nickel Compounds Toxicity
- Chemical and Physical
- Nickel (atomic number, 28; atomic weight, 58.7; boiling point, 2,732 C; specific gravity, 8.9 at 25 C), from natural sources, is a mixture of 5 stable isotopes.
- 9 unstable nickel isotopes have also
- Major deposits of nickel ores are
located in Australia, Canada, Cuba, Indonesia, New Caledonia, and
- Nickel exists in 5 major forms :
- - elemental nickel and its
- - inorganic, water-soluble
- - inorganic, water-insoluble
- - organic, water-insoluble
- - nickel carbonyl Ni(CO)4
- Nickel is a silver-white, lustrous,
hard, malleable, ductile, ferromagnetic metal that is relatively
resistant to corrosion and is a fair conductor of heat and
- Black NiO is chemically reactive and
readily yields nickel salts on contact with mineral acids; green
NiO is relatively inert and refractory to solubilization in dilute
- The volatility and lipid solubility of
nickel carbonyl Ni(CO)4 enable it to cross cell membranes, and the
redox reactivity of Ni(CO)4 contributes to its high
- Exposure sources
- I-Occupational Exposures :
- Exposure to nickel is possible
- - the production of nickel. The annual
world production is estimated at 900,000 tons;
- - the fabrication of alloys with copper,
- - the preparation of corrosion and heat
resistant special steels;
- - nickel plating by electrolysis (use of
nickel sulphate, chloride and nitrate);
- - arc welding,
- - plasma spraying and flame
- - producing and processing nickel
- - fabricating Ni-Cd batteries;
- - producing molds for the hollow-glass
- - chemical reactors (as a catalyst);
- - the manufacture of coins, jewelry;
- - the manufacture of kitchen wares;
- - the manufacture of medical and dental
- - applying nickel glazes to
- - painting with nickel pigments;
- - manufacturing electrical resistors,
magnetic tapes, and computer components;
- - the metallization with nickel.
- - incinerating or reprocessing
- - combusting fossil fuels;
- - etc.
- Many cements contain small amounts of
nickel (< 1000 ppm)
- II-Environmental Exposures
- A-Water Sources :
- Nickel enters groundwater and surface
waters from dissolution of rocks and soils, biological cycles,
atmospheric fallout, industrial processes, and waste
- Nickel leached from dump sites can
contribute to nickel contamination of the aquifer, with potential
- Acid rain has a tendency to mobilize
nickel from soil and increase the nickel concentration in
groundwater, leading eventually to increased uptake and possible
toxicity in microorganisms, plants, and animals.
- Drinking water usually contains less
than 20 µg of nickel per L.; much higher concentrations may
occur due to pollution of the water supply or leaching from
nickel-containing pipes and nickel-plated faucets.
- B-Air Sources :
- Nickel enters the atmosphere from
natural sources such as volcanic emissions and windblown dusts
produced by weathering of rocks and soils, combustion of fossil
fuels, emissions of mining and refining operations, metal
consumption in industrial processes, and incineration of
- Substantial atmospheric concentrations
of nickel are derived from fly-ash released from coal-fired power
plants, nickel derived from petroleum is released into the
environment in automotive exhaust fumes.
- Cigarette smoking can increase the
amount of inhaled nickel by as much as 4 µg per pack of
- C-Other sources :
- The dietary intake of nickel by adult
persons averages approximately 165µg per day but may reach
900 µg in diets rich in oatmeal, cocoa, chocolate, nuts, and
- Wearing or handling of jewelry, coins,
and ustensils that are fabricated from nickel alloys or that have
nickel-plated coatings can induce allergic dermatitis.
- Implantation of nickel-containing
prostheses or iatrogenic administration of nickel-contaminated
medications or media leads to parenteral exposures, which can
cause acute toxicity and immunologic disturbances.
- I-Absorption, Metabolism, and
- A-Absorption :
- Contrary to insoluble compounds, such as
NiO, soluble salts are readily absorbed by the pulmonary and
digestive tracts, and less by the skin.
- The alimentary absorption of nickel is
greatly influenced by dietary constituents, fasting individuals
- The respiratory, oral, and parenteral
exposure routes are important for acute nickel toxicity (e.g
inhalation of nickel carbonyl; ingestion of nickel-contaminated
beverages and foods; implantation of nickel-containing devices;
administration of nickel-contaminated medications).
- Inhaled nickel carbonyl Ni(CO)4 is
rapidly absorbed by the lungs and enters red blood cells where the
compound undergoes conversion to Ni2+ and CO.
- Respiratory exposure is of paramount
importance in nickel carcinogenesis.
- In nickel refinery workers, inhaled
nickel dust is retained in the nasal sinuses and lungs for many
years after cessation of exposure; some of the nickel is slowly
absorbed, as evidenced by sustained hypernickelemia among these
- During hemodialysis, traces of Ni2+ in
hemodialysis fluid may be absorbed into the plasma, owing to the
chelating action of plasma albumin.
- Dermal exposure is primarely responsible
for nickel dermatitis, although oral or parenteral exposures to
nickel can potentiate hand ecxema in nickel-sensitive
- B-Metabolism :
- The metabolism and distribution of Ni2+
in humans have been fitted by a two-compartment toxicokinetic
- In human plasma, Ni2+ is bound to
ultrafilterable constituents :
- -nickeloplasmin, an
- The mean nickel concentrations of human
tissues may be ranked in order of highest to lowest concentration
as follows :
- -adrenal gland,
- In adult humans, the body burden of
nickel is estimated to average approximately 0.5 mg per 70 kg , or
approximately 7.3 µg per kg of body weight.
- In tissue cytosol, nickel is bound to
several proteins and peptides.
- C-Elimination :
- Nickel is not a cumulative toxicant. The
majority of the absorbed amount is excreted rapidly.
- Urine is the major route for elimination
of absorbed nickel with a half-life varying from 17 to 39 hours.
Therefore, urine and plasma nickel concentrations constitute
valuable indicators of recent exposure to soluble nickel
- Most nickel in food remains unabsorbed
in the alimentary tract and passes through into the feces.
- However, biliary excretion of nickel may
be quantitatively significant.
- Minor routes of elimination are :
- -gastric and intestinal
- -dermal detritus,
- -mother's milk,
- II-Acute Toxicity :
- A-Acute Nickel Carbonyl Poisoning
- Accidental inhalation of nickel carbonyl
Ni(CO)4 generally causes acute toxic effects in 2 stages:
- 1-Immediate symptoms :
- which usually last a few hours, followed
by an asymptomatic interval of 12 hours to 5 days before the onset
- 2-Delayed symptoms :
- -tightness of the chest,
- -nonproductive cough,
- -visual disturbances,
- -weakness , lassitude.
- The delayed symptoms often mimic viral
- In cases of severe Ni(CO)4 poisonning,
deaths have occurred 4-13 days after exposure.
- Autopsies have revealed the following
pulmonary lesions :
- -proteinaceous alveolar exudate,
- -interstitial pneumonitis,
- -damage to alveolar lining cells,
- -denudation of bronchial
- Autopsies have also revealed pathologic
- -parenchymal degeneration,
- -punctate hemorrhages,
- in other organs :
- -adrenal glands,
- In survivors, the recovery period tends
to be protracted, with lassitude and dyspnea persisting up to 6
- It is estimated that exposure to 30 ppm.
nickel carbonyl for 30 minutes may be lethal to humans.
- B-Acute Nickel Pneumonitis :
- Accidental inhalation of metallic nickel
particles can cause pneumonitis. For example, a welder died from
acute respiratory distress syndrome after inhalation of a finely
particulate nickel fume that was produced by a metal arc-welding
- C-Acute Toxicity from Divalent Nickel
- Acute Ni2+ toxicity occurred when 32
electroplating workers accidently drank water contaminated with
NiSO4 and NiCl2. Twenty of the workers promptly developed symptoms
- -abdominal discomfort,
- -shortness of breath,
- that generally ceased within a few
hours, but symptoms persisted for 1-2 days in seven cases.
- In the workers with symptoms, the
estimated nickel doses ranged from approximately 0.5-2.5 g.
- All subjects recovered rapidly, without
evident sequellae, and returned to work by the 8th day after
- III-Chronic Toxicity :
- A-Allergic and Immunologic Effects
- One of the most common causes of contact
dermatitis throughout the world is allergy to nickel alloys and
nickel compounds; positive dermal patch tests to nickel occur in
7-10% of women and 1-3% of men in the general population. Dermal
sensitization frequently occurs from exposures to :
- -nickel-containing coins,
- -watch cases,
- -clothing fasteners.
- Nickel dermatitis (nickel itch)
typically begins as papulovesicular erythema of hands, forearms,
earlobes, or other areas of skin that contact nickel alloys, and
spreads secondarily to areas (usually symmetric) that are distant
from the contact sites.
- The erythematous lesions become
eczematous and eventually undergo lichenification. Pompholyx (
i.e., dyshidrotic eczema) is the predominant type of
nickel-induced dermatitis, characteristically affecting the sides
of the fingers, the palms, and sometimes the soles.
- Nickel itch may be prevented by the use
of a ointment containing 10% sodium diethyl-
- Nickel hypersensitivity can cause
- -pulmonary asthma,
- -eosinophilic pneumonitis,
- -inflammatory reactions around
nickel-containing implants (e.g., orthopedic prostheses, dental
inlays or bridges, cardiac valve prostheses, pacemaker
- -anaphylactoid reactions after
parenteral injection of nickel-contaminated medications.
- B-Respiratory Effects :
- Chronic respiratory insufficiency may
develop as a consequence of acute Ni(CO)4 poisonning.
- In workers in nickel refineries, plating
shops, or welding shops, inhalation of irritant nickel-containing
dusts and aerosols may contribute to chronic respiratory diseases,
- The workers may develop :
- -hypertrophic rhinitis,
- -nasal polyposis,
- -nasal septal perforation,
- Incidences of such non-neoplastic
respiratory diseases in nickel-exposed workers have not been
thoroughly studied, and the etiologic role of nickel is often
unclear, as the affected workers generally are exposed to " sundry
" dusts and vapors in addition to nickel compounds
- C-Renal Effects :
- Workers who are exposed to soluble
nickel compounds may develop mild renal tubular dysfunction, as
evidenced by increased urinary excretion of ß2-microglobulin
- D-Reproductive effects :
- 1-In animals :
- In experimental animals, a range of
reproductive effects can be induced by nickel.
- In male rats, exposure to nickel salts
results in degenerative changes in the testes and epididymis and
in effects on spermatogenesis.
- Exposure of pregnant animals has been
associated with delayed embryonic development, increased
resorptions, and an increase in structural malformations. It has
been noted, however, that doses used are high and may not relate
at all to human exposures.
- 2-In man :
- Increased incidences of congenital
defects and spontaneous or threatened abortion were observed in a
study of 758 Russian women who were employed in a nickel
hydrometallurgy refining plant.
- A sixfold increase in the relative risk
of cardiovascular defects was noted in the infants of
- In light of these findings and those
found in rodents and other animals, further investigations are
needed of the adverse reproductive effects in nickel-exposed
- D-Carcinogenesis :
- Epidemiologic studies have demonstrated
increased mortality from carcinomas of the lung and nasal cavities
in nickel refinery workers who were chronically exposed to
inhalation of nickel-containing dusts and fumes from roasting,
smelting, and electrolysis processes.
- The respiratory tract cancers in nickel
refinery workers have been associated with inhalation exposures to
nickel compounds with low aqueous solubility such as Ni3S2, NiO;
as well as soluble nickel compounds like NiSO4.
- A review of the whole of epidemiologic
studies has demonstrated that the risk for cancer of the
respiratory tract is increased when the atmospheric concentration
of soluble nickel exceeds 1 mg Ni/m3 and that of insoluble
derivatives exceeds 10 mg Ni/m3.
- Nickel cumulates in the nasal mucosa of
exposed workers, its concentration is in proportion with the
lenght of exposure; since its biologic half-life is 3½ years
its concentration remains high even after cessation of
- An investigation of respiratory tract
cancers in former workers at a Canadian nickel sinter plant
demonstrated that the excess risk of death from cancers of the
lung or nasal cavities continued for as long as 30-40 years after
leaving the sinter plant; this reflects long-term persistence of
carcinogenic nickel compounds in the respiratory tract
- The interaction between smoking and
nickel exposure appears to be additive rather than
- The mechanism by which nickel exerts its
carcinogenic action is not known because its derivatives are
usually of low mutagenic activitry. It is possible that divalent
salts interfere with DNA reparation mechanisms.
- In 1990 the IARC (International Agency
for Research on Cancer) classified nickel compounds as
carcinogenic to humans (Group I); and metallic nickel as possibly
carcinogenic to humans (Group 2B)
- Clinical management
- I-Acute Nickel Carbonyl Poisoning
- After acute exposure to Ni(CO)4, the
victim should be quickly transported to a hospital; after removal
of contaminated clothing, life support measures and administration
of oxygen should be instituted .
- Hyperglycemia and glycosuria typically
develop after exposure to Ni(CO)4.
- An acute exposure to Ni(CO)4 may be
classified as :
- A-Mild :
- if the initial 8-hour urine collection
reveals a nickel concentration of less than 100 µg/L.
- B-Moderate :
- if the nickel concentration in the
initial 8-hour urine collection is between 100 µg/L.and 500
- C-Severe :
- if the nickel concentration in the
initial 8-hour urine collection is greater than 500
- Patients in the moderate and severe
categories of acute Ni(CO)4 poisonning should be treated
immediately with a chelating drug, sodium diethyldithiocarbamate
- The beneficial effect of DDC in acute
Ni(CO)4 poisonning has been attributed to diminution of the
pulmonary nickel burden.
- II-Acute poisoning from Divalent
- Presumptive diagnosis of acute Ni2+
poisonning is based on the clinical history and analysis of nickel
in the exposure medium.
- The immediate supportive treatment is
- A- to maintain body temperature, because
Ni2+ impairs thermoregulation;
- B- to induce diuresis by administration
of intravenous fluids, because Ni2+ is eliminated primarely via
- Confirmation of the diagnosis rests on
the quantative determinations of nickel in body fluids, usually
serum and urine.
- Hemodialysis would be the therapy of
choice for patients with acute Ni2+ poisonning, if renal function
fails, or if cardiotoxicity and neurotoxicity become
- Chelation with DDC is not recommended in
severe Ni2+ toxicity because DDC enhances the cerebral uptake of
Ni2+ in rodents.
- Biological and Medical
- I-Biological Monitoring :
- Urine is the most practical specimen for
biological monitoring of occupational, environmental, or
iatrogenic exposures to nickel compounds. Nickel can also be
measured in serum, plasma, and whole blood.
- Feces are the best specimen for
monitoring oral nickel intake.
- Nickel concentrations in saliva, hair,
fingernails, sweat, milk, and blood lymphocytes sometimes are
assayed in clinical investigations, but such tests seldom are
practical for routine biological monitoring.
- Analysis of expired breath may be useful
to detect Ni(CO)4 after its inhalation.
- In persons without occupational
exposure, and based on a critical evaluation of published data for
nickel determinations in body fluids, the upper limit for serum
nickel concentration is approximately 1 µg/L and the upper
limit for urinary nickel concentration is approximately 6
- A-Soluble compounds :
- Nickel concentrations in urine or serum
specimens from workers with inhalation exposures to soluble nickel
salts (e.g. NiCl2, NiSO4) are generally proportional to the
exposure levels and reflect the amount of nickel absorbed during
the 1 or 2 preceding days.
- B-Poorly soluble nickel compounds,
nickel powders, nickel alloys :
- In workers with inhalation exposures,
nickel concentrations in urine and serum specimens reflect the
combined influences of recent exposures and long-term
accumulation, as well as the bioavailability of the nickel
- Absence of increased values does not
necessarily indicate freedom from health risk (e.g. cancers of the
nasal cavities and lungs) that have been associated with chronic
exposure to such compounds.
- II-Biological Monitoring :
- A- Clinical Examination :
- A special attention should be paid to
the examination of the nasal mucosa, lungs, and skin.
- B- Diagnostic Tests :
- Certain diagnostic tests may assist in
detecting the pathologic sequelae of nickel exposures. These tests
- 1-To detect nickel allergy :
- - dermal patch test;
- - lymphocyte transformation
- 2-To detect nephrotoxicity :
- 3-To detect pneumonitis, sinusitis, and
- -radiographic imaging of the lungs,
mediastinum and nasal cavities
- 4-To detect respiratory tract dysplasia
and neoplasia :
- - biopsy and exfoliative
- 5- Pulmonary function tests.
- Occupational exposure
- I- In Quebec, the VEMPs (Valeur
d'Exposition Moyenne Pondérée) are as follows
- Insoluble compounds, as
- Soluble compounds, as
- Nickel carbonyl, as
- Nickel sulfide, roasted,
fumes and dust, as Ni
- C1 =Confirmed carcinogen to humans.
- RP =Substance whose recirculation is
prohibited in accordance with the law.
- EM =Substance that should be kept at the
lowest practicable level.
- II- In the USA, ACGIH proposed the
following in 2001 :
Nickel, as Ni
- Soluble compounds
- Insoluble compounds
- Nickel subsulfide
- A1=Confirmed Human Carcinogen
- A4=Not Classifiable as a Human
- A5=Not Suspected as a Human
- Good housekeeping of your studio is
important. Avoidance of processes generating unnecessary dust is
- Depending on the severity of exposure,
local ventilation should be used and the aspired air should be
vented outside to avoid producing dust from work tables and the
- The wearing of an approved dust mask
when the exposure seems hazardous is mandatory.
- It should be forbidden to drink, eat or
smoke in the workshop.
- References :
- 1-Occupational Medicine,Carl Zenz,
- 2-Clinical Environmental Health and
Toxic Exposures, Sullivan & Krieger; last edition.
- 3-Sax's Dangerous Properties of
Industrial Materials, Lewis C., last edition.
- 4-Toxicologie Industrielle et
Intoxications Professionnelles, Lauwerys R. last
- 5-Chemical Hazards of the Workplace,
Proctor & Hughes, 4th edition.
By Edouard Bastarache